A Pilot Study Evaluating Photobiomodulation Therapy for Diabetic Macular Edema
Phase: NA
Conditions: Diabetic Macular Edema
Sponsor: Jaeb Center for Health Research

 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20  
 
 
 
DRCR Retina Network 
 
 
 
 
A Pilot Study Evaluating 
Photobiomodulation Therapy for Diabetic 
Macular Edema (Protocol AE) 
NCT03866473 
 
Sponsor: Jaeb Center for Health Research (JCHR) 
 
Version 4.0 
 
March 31, 2020 
 

 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20  
 
 
               i 
Signature Page 
A Pilot Study Evaluating Photobiomodulation Therapy for 
Diabetic Macular Edema  
Protocol Identifying Number: DRCR.net AE 
Sponsor: Jaeb Center for Health Research 
Version Number: 4.0 
31 March 2020 
 
 
Coordinating Center Director 
 
Name, degree 
Adam Glassman, MS 
Signature/Date 
 
 
JCHR Protocol Director 
 
Name, degree 
Cynthia Stockdale, MSPH 
Signature/Date 
 
 
 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20  
 
 
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KEY ROLES 
 
Protocol Chair 
 
Name, degree 
Judy E. Kim, MD 
Title 
Professor of Ophthalmology & Visual Sciences 
Institution Name 
Medical College of Wisconsin 
 
Coordinating Center Director 
 
Name, degree 
Adam Glassman, MS 
Title 
Director of DRCR Retina Network Coordinating Center 
Institution Name 
Jaeb Center for Health Research, Tampa, FL 
 
JCHR Protocol Director 
 
Name, degree 
Cynthia Stockdale, MSPH 
Title 
Assistant Director of DRCR Retina Network Coordinating Center 
Institution Name 
Jaeb Center for Health Research, Tampa, FL 
 
Network Chair 
 
Name, degree 
Jennifer K. Sun, MD, MPH 
Title 
Chief, Center for Clinical Eye Research and Trials of the Beetham Eye Institute 
Associate Professor of Ophthalmology, Harvard Medical School 
Institution Name 
Joslin Diabetes Center, Boston, MA 
 
Medical Monitor 
 
Name, degree/Title 
Robert Lindblad, Senior Medical Officer 
Ashraf El Fiky, Medical Officer 
Institution Name 
The EMMES Corporation 
 

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Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20  
 
 
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TABLE OF CONTENTS 
 INTRODUCTION ............................................................................................. 1-1 
1.1 Introduction ........................................................................................................................ 1-1 
1.1.1 Diabetic Macular Edema and Public Health Impact ................................................... 1-1 
1.1.2 Current Treatment for DME ....................................................................................... 1-1 
1.1.3 Photobiomodulation .................................................................................................... 1-2 
1.1.4 Relevent Prior Studies of PBM (670nm) .................................................................... 1-2 
1.1.4.1 Animal Studies ......................................................................................................... 1-2 
1.1.4.2 Clinical Studies in Diabetic Retinopathy ................................................................. 1-6 
1.1.4.3 Clinical Studies in Dry Age-Related Macular Degeneration ................................... 1-7 
1.1.5 Other Blue-Green Light Modulation of Dark Adaptation .......................................... 1-8 
1.1.6 Study Device ............................................................................................................... 1-8 
1.2 Study Rationale .................................................................................................................. 1-8 
1.3 Study Objectives ................................................................................................................ 1-9 
1.4 Potential Risks and Benefits of PBM Device .................................................................... 1-9 
1.4.1 Known Potential Risks .................................................................................................... 1-9 
1.4.2 Known Potential Benefits ............................................................................................... 1-9 
1.4.3 Risk Assessment ............................................................................................................. 1-9 
1.5 General Considerations ...................................................................................................... 1-9 
 STUDY ENROLLMENT AND RANDOMIZATION ................................... 2-1 
2.1 Participant Recruitment and Enrollment ............................................................................ 2-1 
2.1.1 Informed Consent and Authorization Procedures ........................................................... 2-1 
2.2 Participant Inclusion Criteria ............................................................................................. 2-1 
2.2.1 Patient-level Criteria ....................................................................................................... 2-1 
2.2.2 Study Eye Criteria ........................................................................................................... 2-2 
2.2.3 Non-Study Eye ................................................................................................................ 2-3 
2.3 Screening Evaluation ......................................................................................................... 2-4 
2.3.1 Historical Information ..................................................................................................... 2-4 
2.3.2 Screening Procedures ...................................................................................................... 2-4 
2.4 Randomization of Eligible Subjects................................................................................... 2-5 
 RANDOMIZED TRIAL PROCEDURES ...................................................... 3-1 
3.1 Study Device ...................................................................................................................... 3-1 
3.1.1 Home Procedures ........................................................................................................ 3-1 
3.1.2 Primary Outcome Phase .............................................................................................. 3-1 
3.1.3 Post-Outcome Phase ................................................................................................... 3-1 
3.1.4 Device Training .......................................................................................................... 3-1 
3.2 Study Visits and Phone Contacts ....................................................................................... 3-1 
3.2.1 Text Message Reminders ............................................................................................ 3-2 
3.3 Procedures at Study Visits ................................................................................................. 3-2 
3.4 Early Termination Visit ..................................................................................................... 3-3 
3.5 Unscheduled Visits ............................................................................................................ 3-3 
3.5.1 DME Treatment Initiation Visit .................................................................................. 3-3 
3.6 Alternative Treatment for CI-DME ................................................................................... 3-3 
3.7 Participant Access to Study Device at Study Closure ....................................................... 3-4 
 STUDY DEVICES ............................................................................................ 4-1 

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4.1 Description of the Investigational Device .......................................................................... 4-1 
4.2 Study Device Accountability Procedures .......................................................................... 4-1 
4.3 Safety Measures ................................................................................................................. 4-1 
 ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES .......... 5-1 
5.1 Adverse Events .................................................................................................................. 5-1 
5.1.1 Definitions................................................................................................................... 5-1 
5.1.2 Reportable Adverse Events ......................................................................................... 5-2 
5.1.3 Relationship of Adverse Event to Study Device......................................................... 5-2 
5.1.4 Intensity of Adverse Event.......................................................................................... 5-3 
5.1.5 Coding of Adverse Events .......................................................................................... 5-3 
5.1.6 Outcome of Adverse Event ......................................................................................... 5-3 
5.2 Reportable Device Issues ................................................................................................... 5-4 
5.3 Pregnancy Reporting .......................................................................................................... 5-4 
5.4 Timing of Event Reporting ................................................................................................ 5-4 
5.5 Stopping Criteria ................................................................................................................ 5-5 
5.5.1 Participant Discontinuation of Study Device .............................................................. 5-5 
5.5.2 Criteria for Suspending or Stopping Overall Study .................................................... 5-5 
5.6 Independent Safety Oversight ............................................................................................ 5-5 
5.7 Risks ................................................................................................................................... 5-5 
 MISCELLANEOUS CONSIDERATIONS .................................................... 6-1 
6.1 Prohibited Medications, Treatments, and Procedures ........................................................ 6-1 
6.2 Treatment in Non-study Eye .............................................................................................. 6-1 
6.3 Diabetes Management ........................................................................................................ 6-1 
6.4 Participant Compensation .................................................................................................. 6-1 
6.5 Participant Withdrawal ...................................................................................................... 6-1 
6.6 Confidentiality ................................................................................................................... 6-1 
6.6.1 Contact Information Provided to the Coordinating Center ......................................... 6-1 
 STATISTICAL CONSIDERATIONS ............................................................ 7-1 
7.1 Statistical and Analytical Plans .......................................................................................... 7-1 
7.2 Statistical Hypotheses ........................................................................................................ 7-1 
7.3 Sample Size ........................................................................................................................ 7-1 
7.3.1 Outcome Projections: .................................................................................................. 7-1 
7.3.2 Sample Size Estimates ................................................................................................ 7-1 
7.4 Outcome Measures Phase 1 (Baseline to completion of the 4-Month/Primary outcome 
visit) ......................................................................................................................................... 7-2 
7.5 Analysis Cohorts ................................................................................................................ 7-2 
7.6 Analysis of the Primary Efficacy Endpoint(s) ................................................................... 7-3 
7.7 Sensitivity Analysis ........................................................................................................... 7-4 
7.8 Analysis of the Secondary Endpoint(s).............................................................................. 7-4 
7.9 Safety Analyses .................................................................................................................. 7-5 
7.10 Outcome Measures Phase 2 (4 Months Post-Outcome) .................................................. 7-5 
7.11 OCT Angiography Ancillary Study ................................................................................. 7-5 
7.12 Intervention Adherence .................................................................................................... 7-5 
7.13 Protocol Adherence and Retention .................................................................................. 7-6 
7.14 Baseline Descriptive Statistics ......................................................................................... 7-6 
7.15 Device Issues ................................................................................................................... 7-7 

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7.16 Planned Interim Analyses ................................................................................................ 7-7 
7.17 Subgroup Analyses .......................................................................................................... 7-7 
7.18 Multiple Comparisons/Multiplicity ................................................................................. 7-7 
7.19 Additional Tabulations and Analyses .............................................................................. 7-8 
 DATA COLLECTION AND MONITORING ............................................... 8-1 
8.1 Case Report Forms and Device Data ................................................................................. 8-1 
8.2 Study Records Retention.................................................................................................... 8-1 
8.3 Quality Assurance and Monitoring .................................................................................... 8-1 
8.4 Protocol Deviations ............................................................................................................ 8-2 
 ETHICS/PROTECTION OF HUMAN PARTICIPANTS ........................... 9-2 
9.1 Ethical Standard ................................................................................................................. 9-2 
9.2 Institutional Review Boards ............................................................................................... 9-2 
9.3 Informed Consent Process ................................................................................................. 9-2 
9.3.1 Consent Procedures and Documentation .................................................................... 9-2 
9.3.2 Participant and Data Confidentiality ........................................................................... 9-2 
9.3.3 Future Use of Stored Data........................................................................................... 9-3 
 REFERENCES .............................................................................................. 10-1 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
anti-VEGF 
Anti-Vascular Endothelial Growth Factor 
CI-DME 
Central-Involved Diabetic Macular Edema 
CRF 
Case Report Form 
CST 
Central Subfield Thickness 
DME 
Diabetic Macular Edema 
DR 
Diabetic Retinopathy 
DSMC 
Data and Safety Monitoring Committee 
E-ETDRS 
Electronic-Early Treatment Diabetic Retinopathy Study 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
ICH 
International Conference on Harmonization   
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board  
JCHR 
Jaeb Center for Health Research 
LED 
Light Emitting Diode 
OCT 
Optical Coherence Tomography 
PBM 
Photobiomodulation 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
UADE 
Unanticipated Adverse Device Effect 
 
 
 
 

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PROTOCOL SUMMARY 
SUBJECT AREA 
DESCRIPTION 
Title 
A Pilot Study Evaluating Photobiomodulation Therapy for 
Diabetic Macular Edema (DME) 
Précis 
Randomized clinical trial evaluating the effect of 
photobiomodulation compared with sham on central 
subfield thickness (CST) in eyes with central-involved 
DME and good vision.   
Objectives 
This study is being conducted to assess the effects of 
photobiomodulation on CST compared with sham in eyes 
with 
central-involved 
DME 
and 
good 
vision.  
Photobiomodulation is irradiation by light in the far-red 
(FR) to near-infrared (NIR) region of the spectrum (630-
900 nm). 
 
Furthermore, this pilot study is being conducted to 
determine whether the conduct of a pivotal trial has merit 
based on an anatomic outcome and provide information on 
outcome measures needed to design a pivotal trial.   
Study Design 
Randomized, multi-center, sham-controlled clinical trial.  
 
There are two phases of the study; the primary outcome will 
be evaluated at the end of phase 1 (first 4 to 8 months).  At 
the primary outcome visit, participants originally assigned 
to active will end device use and participants originally 
assigned to sham will switch to active.  The switch serves 
two purposes: 
1) to provide participants originally assigned to sham the 
opportunity to receive the active treatment and 
2) to explore the post-outcome effects within treatment 
group.  No statistical comparisons will be performed in 
Phase 2 to compare treatment groups.   
 
Note: This is not a crossover design.  
Number of Sites 
Approximately 40 
Endpoint 
Primary Efficacy Outcome: 
• Mean change in CST from baseline to primary 
outcome visit 

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SUBJECT AREA 
DESCRIPTION 
Key Secondary Efficacy Outcomes: 
Treatment Group Comparisons  
• Mean change in retinal volume from baseline 
primary outcome visit 
• Percentage of eyes with CST below OCT machine- 
and gender-specific threshold for DME at primary 
outcome visit 
• Percentage of eyes receiving alternative treatment 
for DME by primary outcome visit 
• Percentage of eyes with a ≥5 letter loss in visual 
acuity 
• Patient compliance 
• Exploratory assessment of treatment effect after the 
device is stopped or started (see section 7.10 for 
more details) 
Population 
Key Inclusion Criteria 
• Age >18 years 
• Type 1 or type 2 diabetes 
• At least one eye with each of the following: 
• Best corrected E-ETDRS visual acuity letter 
score ≥ 79 (i.e., 20/25 or better)  
• Ophthalmoscopic evidence of central-involved 
DME in study eye confirmed by CST on spectral 
domain OCT: 
 Zeiss Cirrus: ≥290 µm in women, and 
≥305 µm in men 
 Heidelberg 
Spectralis: 
≥305µm 
in 
women, and ≥320 µm in men 
Key Exclusion Criteria 
 
• No history of prior laser, surgical, intravitreous, 
or peribulbar treatment for DME or DR in the 
study eye within the prior 12 months 
o If more than 12 months ago, no more 
than 4 prior intraocular injections  
o Enrollment will be limited to a maximum 
of 15% of the planned sample size with 
any history of anti-VEGF treatment and 
a maximum of 15% with any history of 
PRP.  

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SUBJECT AREA 
DESCRIPTION 
Sample Size 
134 
Treatment Groups 
Random assignment (1:1) to photobiomodulation (PBM) or 
sham  
Participant Duration 
The trial will last up to 12 months for each participant 
(primary outcome at 4 to 8 months and final visit at 8 to 12 
months)  
Protocol Overview 
1. Informed consent will be obtained.  
2. Study eligibility will be assessed. 
3. Prior to randomization, the participant’s willingness 
to proceed into the randomized trial will be 
confirmed. 
4. Eligible eyes (one per participant) will be randomly 
assigned to photobiomodulation or sham.  If a 
participant has two eligible eyes, the eye with the 
greatest CST will be selected as the study eye and 
the non-study eye will be followed to evaluate any 
potential contralateral effect. 
5. Training for at-home use will be performed with the 
randomized device on the day of randomization.   
6. A follow-up phone call is performed at 1 week. 
7. Participants will return for a follow-up visit every 
month for the first ~4 months and then every 2 
months for 4 months after the primary outcome.  
The primary outcome assessment will be at ~4 
months.  
8. Following the primary outcome assessment, 
participants in the active group will end device use 
and participants in the sham group will be given the 
option to switch to the active treatment for the next 
4 months. Participants in both groups who do not 
continue treatment will be given the option to end 
study participation after the primary outcome visit.  
A summary of treatment procedures is included 
below.  
 

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SCHEMATIC OF STUDY DESIGN 
 
Dropped Ineligible
Informed Consent
Baseline Testing
Randomization
PBM
1 Week Phone 
Call
1 Month
2 Month
3 Month
4 Month/
Primary Outcome
Device Use Ends
6 Month/2-month 
Post Outcome
8 Month (Final 
Visit, 4 months 
post-outcome)
Observation 
(Sham)
1 Week Phone 
Call
1 Month
2 Month
3 Month
4 Month/
Primary Outcome
Option to Switch 
to PBM
6 Month/2-month 
Post Outcome
8 Month (Final 
Visit, 4 months 
post-outcome)

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SCHEDULE OF STUDY VISITS AND PROCEDURES 
 
Notes 
Testing is only required for the study eye unless otherwise specified below. 
*Alternative DME treatment (e.g. anti-VEGF) should not be performed unless protocol criteria are met.  If alternative DME treatment is planned at an 
unscheduled visit, study testing must be completed prior to treatment.   
†Visual acuity performed on both eyes at each visit, including protocol refraction on both eyes at baseline, 4-month, and final visit, and on the study eye only 
at all other protocol visits.  
‡Usual care vision may be used if eye has already been dilated when treatment is planned. 
§OCT in both eyes at all visits; OCT may be obtained with Zeiss Cirrus or Heidelberg Spectralis OCT machines only. 
‖Baseline and 4-Month visit only at select sites with OCTA capabilities  
¶Both eyes at baseline visit, study eye only at 4 month and 8-month visits.  Ocular exam at interim visits is at investigator discretion.  In general, an ocular 
exam should be completed if the OCT and/or visual acuity have worsened since baseline.   
**Does not need to be repeated if HbA1c available from within the prior 3 months; if not available, can be performed within 3 weeks after randomization. 
 
Baseline 
1-week 
Phone Call 
Interim Visits  
(1, 2, 3, 6M) 
Primary 
Outcome 
and Final 
Visits 
DME Tx 
Initiation 
Visit* 
Device Training  
X 
 
 
 
 
Randomization 
X 
 
 
 
 
E-ETDRS Best Corrected Visual Acuity† 
X 
 
X 
X 
X‡ 
Spectral Domain OCT§ 
X 
 
X 
X 
X 
OCTA‖ 
X 
 
 
X 
 
Eye Exam¶ 
X 
 
If Needed 
X 
X 
Blood Pressure 
X 
 
 
 
 
HbA1c** 
X 
 
 
 
 
Compliance Assessment  
 
X 
X 
X 
 

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 INTRODUCTION 
1 
1.1 Introduction 
2 
1.1.1 Diabetic Macular Edema and Public Health Impact 
3 
In the United States, an estimated 30.2 million adults have diabetes mellitus (23 million diagnosed, 
4 
7.2 undiagnosed).1 From 2005 to 2008 diabetes was reported to be the leading cause of new cases 
5 
of blindness among adults in the United States.2 Nearly 8 million people over the age of 40 in the 
6 
United States are estimated to have diabetic retinopathy (DR).3  Diabetic macular edema (DME), 
7 
a consequence of retinopathy, is the most common among the conditions that contribute to vision 
8 
loss in persons with diabetes; nearly half of all people with DR will develop DME.4   
9 
1.1.2 Current Treatment for DME 
10 
DME is a manifestation of diabetic retinopathy that produces loss of central vision.  Although prior 
11 
studies have clearly demonstrated that intravitreous anti-VEGF is the most effective monotherapy 
12 
for central-involved DME (CI-DME) and decreased vision10,10-13,11-13, anti-VEGF treatment does 
13 
have disadvantages including the need for recurrent injections as often as once a month and a small 
14 
risk of serious complications, such as endophthalmitis.  Moreover, evidence indicates that DME 
15 
is not satisfactorily resolved in all patients. Thus, there is an ongoing need to identify novel 
16 
therapies that are both effective for DME treatment and that also avoid the potential adverse events 
17 
or costs associated with current ocular interventions. 
18 
Furthermore, baseline cohort characteristics from the Early Treatment Diabetic Retinopathy Study 
19 
(ETDRS) suggest that a substantial percentage of eyes with CI-DME may retain good vision.  At 
20 
baseline in the ETDRS, of all eyes in the focal laser and observation group, center involved 
21 
macular edema on fundus photographs was present in approximately 42% of eyes.  Of these eyes, 
22 
64% had baseline visual acuity ≥ 79 letters (approximately 20/25 or better). (Personal 
23 
communication Adam R. Glassman) Several questions remain regarding treatment of the cohort 
24 
of eyes with CI-DME and good visual acuity. In a review of early studies concerning the natural 
25 
history of DME, Ferris and Patz found that 53% of 135 eyes with DME lost two or more lines of 
26 
visual acuity over a two year period.14 Furthermore, without intervention, 33% of 221 eyes 
27 
included in the Early Treatment Diabetic Retinopathy Study (ETDRS) with central-involved DME 
28 
experienced “moderate visual loss” (defined as a 15 or more letter score decrease in visual acuity) 
29 
over a three year period.15  Thus, there may be rationale for initiating treatment for CI-DME as 
30 
soon as DME meets clinically significant criteria but before vision begins to decline.16  The advent 
31 
of OCT now allows us to determine the presence of and monitor changes in CI-DME with 
32 
increased sensitivity over the fundus photographic grading method used in the ETDRS.  Given the 
33 
potentially large numbers of patients with CI-DME and good vision, and the current lack of 
34 
guidance regarding best treatment practice for this group of eyes, evaluation of a low-risk, non-
35 
invasive treatment alternative to anti-VEGF in this cohort is warranted.   
36 
While focal photocoagulation (direct treatment to microaneurysms and grid treatment to diffuse 
37 
edema) was shown in the ETDRS to reduce the risk of moderate visual loss from DME by 
38 
approximately 50%,17 this direct treatment with high-intensity light also causes retinal scarring 
39 
and loss of photoreceptors.18  More recent studies, however, have found that specific wavelengths 
40 
of low-intensity light that are absorbed by cellular photoreceptor molecules result in activation of 
41 
signaling pathways that cause biological changes on a cellular level without the destructive 
42 
properties found in high-intensity lasers.   
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1.1.3 Photobiomodulation 
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Irradiation by light in the far-red (FR) to near-infrared (NIR) region of the spectrum (630-900 nm) 
45 
collectively termed “photobiomodulation” (PBM) can restore the function of damaged 
46 
mitochondria, upregulate the production of cytoprotective factors, decrease inflammation and 
47 
prevent cell death.  PBM has been applied clinically in the treatment of soft tissue injuries and 
48 
acceleration of wound healing for more than 50 years.  Recent studies have demonstrated that 
49 
FR/NIR photons penetrate diseased tissues including the retina. The therapeutic effects of PBM 
50 
have been hypothesized to result from intracellular signaling pathways triggered when FR/NIR 
51 
photons are absorbed by cellular photo-acceptor molecules, such as mitochondrial cytochrome c 
52 
oxidase, culminating in improved mitochondrial energy metabolism, decreased inflammation and 
53 
cell survival. Investigations in animal models of retinal injury and retinal disease including diabetic 
54 
retinopathy, age-related macular degeneration and retinitis pigmentosa have demonstrated the 
55 
PBM attenuates cell death, protects retinal function and exerts anti-inflammatory actions. An 
56 
increasing number of small clinical studies have documented therapeutic efficacy of PBM in AMD 
57 
and diabetic retinopathy. In addition to wound healing, FR to NIR light (630-1000nm) has now 
58 
been reported to be beneficial in a variety of conditions including recovery from ischemic injury 
59 
to the heart,19 treatment of gingival incisions,20 peripheral nerve repair after trauma,21, 22 and 
60 
treatment of acute soft tissue injuries.23   The FDA approved the use of low-light therapy for carpal 
61 
tunnel syndrome in 2003.24 Far-red light likewise has been found to inhibit production of the 
62 
proinflammatory cytokines, IFN-γ and TNF-α, and to upregulate anti-inflammatory cytokines, IL-
63 
4 and IL-10 in experimental autoimmune encephalomyelitis.25  
64 
FR/NIR light (commonly 660-670 nm) has also has beneficial effects on the retina.  Eells et al.,26 
65 
reported the first direct link between the actions of far-red light on mitochondrial bioenergetics in 
66 
vitro and retinoprotection in vivo using an established model of retinal mitochondrial toxicity, 
67 
methanol intoxication. Accumulation of formic acid generated from methanol oxidation in the 
68 
course of methanol poisoning produces toxic injury to the retina and optic nerve, resulting in 
69 
blindness14 An acute toxic exposure to methanol results in an increase in tissue formic acid 
70 
concentrations, metabolic acidosis and visual toxicity within 72 hours of ingestion.27 Formic acid 
71 
is the mitotoxic metabolite in methanol intoxication.  Formic acid inhibits cytochrome c oxidase 
72 
by reversibly binding to the same site as cyanide and azide14. These studies demonstrated that three 
73 
brief 670 nm LED treatments (160 sec at 25 mW/cm2 producing a fluence 4 J/cm2 at the surface 
74 
of the eye) (Spectralife, Quantum Devices Inc., Barneveld WI) treatments delivered at 5, 25, and 
75 
50 h of methanol intoxication, attenuated the retinotoxic effects of methanol-derived formate. The 
76 
authors documented a significant protection against formate-induced retinal dysfunction during 
77 
the course of intoxication.  670 nm light also protected the retina from the histopathologic changes 
78 
induced by methanol-derived formate.  These findings provided the first link between the actions 
79 
of FR light on mitochondrial oxidative metabolism in vitro and retinoprotection in vivo.  Moreover, 
80 
they were the first studies to suggest that FR PBM had therapeutic potential for the treatment of 
81 
retinal injury and disease.  Subsequent studies have documented retinoprotection in rodent models 
82 
of high intensity light damage, retinitis pigmentosa, diabetic retinopathy and age-related macular 
83 
degeneration.28 
84 
1.1.4 Relevent Prior Studies of PBM (670nm) 
85 
1.1.4.1 Animal Studies 
86 
Diabetes results in increases in oxidative stress in the retina, and increased expression of pro-
87 
inflammatory proteins.  Oxidative stress and proinflammatory proteins in the retina are important 
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in diabetes, because previous studies have shown that vascular lesions of early diabetic retinopathy 
89 
are significantly inhibited in animal models if oxidative stress and inflammatory changes are 
90 
inhibited.29, 30 Consistent with this, diabetic-like concentrations of glucose (20-30 mM) likewise 
91 
result in increased superoxide production, inflammatory biomarker expression, and cell death in 
92 
cultured retinal cells. PBM was able to inhibit these abnormalities in vitro.  
93 
Tang et al.31  investigated the therapeutic efficacy of 670-nm PBM in albino rats (Lewis) which 
94 
had been made diabetic with streptozotocin. With daily 4-minute PBM treatment (6 J/cm2) for 10 
95 
weeks from the onset of diabetes, there was significant inhibition in the diabetes-induced death 
96 
(apoptosis) of retinal ganglion cells (Figure 1), as well as a 50% improvement of the ERG 
97 
amplitude (photopic b wave responses) (Figure 2) (both P < 0.01), indicating both structural and 
98 
functional benefit of PBM in diabetes.31  
99 
  
100 
 
101 
PBM also inhibited the diabetes-induced generation of superoxide (Fig 3), induction of markers of 
102 
inflammation (leukostasis, expression of the Inducible isoform of Nitric Oxide Synthase (iNOS) 
103 
(Fig 4), and preserved MnSOD expression (an enzyme that helps protect against superoxide 
104 
Fig 2. 
Fig 1. 

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damage; not shown) in vivo.31  Daily application of the light therapy was more efficacious than 
105 
every other day administration. 
106 
 
 
107 
While diabetes significantly increased both leukostasis and expression of ICAM-1, they showed 
108 
that PBM essentially prevented both of these abnormalities (Fig 4A and 4B, respectively).31 These 
109 
data indicate that the PBM inhibited at least some key aspects of the diabetes-induced local 
110 
oxidative stress and inflammation in the retina. 
111 
 
112 
More recently, Saliba, et al.32 further tested whether the beneficial effects of PBM for retinal 
113 
disease seen in the aforementioned studies would extend to (i) other species, (ii) in the presence of 
114 
heavy pigmentation (C57Bl/6J mice), and (iii) as an intervention therapy after diabetes onset.  
115 
PBM was applied to pigmented mice for 4 min/day for 10 weeks, starting 4 weeks after the 
116 
induction of diabetes.  The results indicated that PBM significantly reversed the diabetes-induced 
117 
increase in retinal superoxide and leukostasis (Fig 5a and 5b, respectively), and significantly 
118 
inhibited also the diabetes-induced increase in retinal ICAM-1 expression (not shown).  The 
119 
intervention with PBM also significantly inhibited the development of a diabetes-induced defect 
120 
in visual function as measured by spatial frequency threshold (p<0.0001).   
121 
Fig 3. Diabetes (2 months) 
increased superoxide production 
by retina, and this increase was 
inhibited by 4 minutes per day 
PBM. Administration of PBM 
either daily or only three times per 
week both significantly inhibited 
the superoxide generation, but 
daily therapy was more effective. 
Fig 3. 
Fig 4. 

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122 
 
123 
Interestingly, at least some of the beneficial effects of PBM were demonstrated also in a second 
124 
group of mice in which the PBM was unable to directly shine on the eyes, as a result of a lead 
125 
shield covering the head during the PBM to prevent direct irradiation to the eye.     
126 
 
127 
In an effort to determine which retinal cell-types the PBM was affecting, light-induced movement 
128 
of ions into retinal cells was assessed in diabetic and nondiabetic mice using Manganese-enhanced 
129 
MRI. Manganese is used as a surrogate of calcium for these studies, since manganese is known to 
130 
be transported into cells via calcium channels, and unlike calcium, it can be detected by MRI.  
131 
These studies demonstrated that diabetes reduced transport of manganese (and presumably 
132 
calcium) into photoreceptor cells and essentially all other secondary neurons, and PBM treatment 
133 
largely inhibited this except in the presumptive rod inner segment layer. 
134 
 
135 
Most importantly, long-term (8 months) daily application of PBM (670 nm, 4 min/day) recently 
136 
has been shown to inhibit the development of clinically meaningful lesions of early DR in mice.33 
137 
PBM was administered daily from the onset of diabetes, and the daily light therapy significantly 
138 
inhibited the diabetes-induced leakage in each of the 3 layers of the retinal microvasculature (Fig 
139 
7) and degeneration of retinal capillaries (Fig 8), and also significantly inhibited the diabetes-
140 
induced reduction in visual function (visual acuity [spatial frequency threshold] and contrast 
141 
sensitivity; not shown). 
142 
 
143 
Fig 5. 
Fig 6. 

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144 
 
145 
 
146 
 
147 
 
148 
These animal studies provide evidence of beneficial actions of PBM on numerous key early 
149 
changes of diabetic retinopathy, and on clinically meaningful morphologic lesions of the 
150 
retinopathy.  
151 
1.1.4.2 Clinical Studies in Diabetic Retinopathy 
152 
Following the promising results seen in the above-mentioned animal studies, PBM has now been 
153 
evaluated in two small clinical studies of treatment for diabetic macular edema.  Tang, et al. 
154 
reported the results of a non-randomized, consecutive case series that evaluated PBM for non-
155 
center involving DME involving four patients with bilateral edema who were treated in one eye 
156 
and the fellow eye served as the untreated control. After treatment for 160s per day (9 J/cm2) for 
157 
2 to 9 months, thickened areas on spectral domain OCT were reduced by a mean of 20% (±11.7%) 
158 
in the treated eyes and mean change in the untreated eyes was -3% (±8%).34 Percent area of 
159 
thickened retina across the macular region was determined manually on the Spectralis-generated 
160 
color thickness map (Fig 9). 
161 
 
162 
Fig 8. 
Fig 7. 

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163 
Eells et al conducted a randomized prospective study in 10 patients with treatment resistant DME, 
164 
randomized to either standard treatment with continued anti-VEGF alone or anti-VEGF plus PBM.  
165 
Light treatment was administered at a dose of 4.5 J/cm2 three consecutive days per week for 8 
166 
weeks using a 670 nm LED Array (WARP-10, Quantum Devices, Inc., Barneveld, WI) positioned 
167 
2.5 cm from the closed treatment eye. Functional and anatomic assessments were made at baseline, 
168 
8 weeks and 24 weeks. The authors reported a change from baseline at 24 weeks in central retinal 
169 
thickness of -24±5 microns in the PBM group (N=6) and +120±97 microns in the standard 
170 
treatment group (N=4).  Visual acuity also improved by an average of 6±5 letters in the PBM 
171 
group, compared with a 3±4 letter decrease in VA in the standard treated group. No adverse effects 
172 
attributable to 670 nm PBM were noted by the patients or study investigators during the study 
173 
period. Although the sample size is small, the findings show a reduction in DME and an 
174 
improvement in VA following NIR-PBM. Results support the application of NIR-PBM for the 
175 
treatment of DME in eyes refractory to anti-VEGF treatments.  (ARVO 2017 presentation) 
176 
1.1.4.3 Clinical Studies in Dry Age-Related Macular Degeneration  
177 
A clinical study sponsored by the National Eye Institute was recently completed in Toronto under 
178 
the direction of Dr. Robert Devenyi and Dr. Samuel Markowitz (LIGHTSIGHT I, Clinical 
179 
Trials.gov # NCT02725762).35 The LIGHTSITE I study enrolled 30 dry AMD subjects that were 
180 
randomized (1:1) and received either 9 PBM or sham treatments with over 3-4 weeks with a second 
181 
series 6 months from baseline (BL).  Each treatment consisted of exposure to a combination of 
182 
wavelengths of light (590 nm, 670 nm and 850 nm) administered by the LT-300 device. The total 
183 
treatment regimen lasted 4 min minutes per treatment per eye. Dry AMD patients treated with 
184 
PBM demonstrated both functional and anatomical improvements following PBM treatment. 
185 
PBM- treated patients showed reductions in drusen volume and thickness demonstrating potential 
186 
disease-modifying effects on key anatomical disease features. Improvements in Contrast 
187 
Sensitivity and Visual Acuity were seen immediately after the 3 weeks of treatment and were 
188 
maintained out to 3 to 6 months. PBM retreatment times of 6 months are suggested to maintain 
189 
clinical outcome benefits. No device related adverse effects were seen in the study.  
190 
Fig 9. 

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1.1.5 Other Blue-Green Light Modulation of Dark Adaptation  
191 
A recent Phase III clinical trial (CLEOPATRA) examined light-at-night delivered by sleep masks 
192 
as a non-invasive intervention to prevent the progression of diabetic retinopathy and DME39. It is 
193 
important to note key differences between the mechanism of action of retinal exposure to far-red 
194 
(670 nm) light and retinal exposure to blue-green (505 nm) light used in the CLEOPATRA trial. 
195 
Arden and colleagues showed that that blue-green (505nm) light may mitigate the complications 
196 
of diabetic retinopathy by modulating the metabolic activity of the retina.36, 37 Their studies are 
197 
based on evidence that dark-adaptation exacerbates hypoxia in the diabetic retina, acting as a 
198 
powerful stimulus for the overproduction of VEGF and other less well understood factors. Several 
199 
small clinical trials have shown that the prevention of dark adaptation ameliorates clinical signs of 
200 
diabetic retinopathy37,38 The outcome of the CLEOPATRA trial was negative, showing that the 
201 
505nm light mask did not confer long term therapeutic benefit on non-center-involving diabetic 
202 
macular edema.  
203 
 
204 
A significant problem in the CLEOPATRA study was patient compliance. Although earlier studies 
205 
showed short-term improvement in diabetic edema and diabetic retinopathy using 505 nm light 
206 
masks, this study showed that compliance wearing the light masks during sleep is challenging and 
207 
is therefore not a sustainable option. In contrast far-red light treatment is brief lasting only 90 
208 
seconds and should be less burdensome in terms of patient compliance. 
209 
1.1.6 Study Device 
210 
PBM Device 
211 
The advantages of LEDs are that they are compact, lightweight, and can be designed to produce 
212 
many wavelengths and in an array of any shape.  The Warp 10 device used in prior human studies 
213 
is a portable handheld device that emits red colored light of 670nm at a dose of 4.5 J/cm2 at 1 inch.  
214 
The device to be used in this study has been designed by PhotoOptx, LLC (Solon, OH) specifically 
215 
for trial use.  It is worn as a single eye patch to maximize treatment effect.  The active treatment 
216 
version will emit light of 670nm at a dose of 4.5 J/cm2 with an irradiance not greater than 50 
217 
mW/cm2.  The device includes a controller module to collect compliance data, which will be 
218 
downloaded by site personnel at each visit.  The device includes an auto shut off after the desired 
219 
treatment time.   
220 
Sham Device 
221 
The sham device is identical, except that the light will be a blue-filtered white light at a low power.  
222 
The sham device is not expected to have any anatomic effect since the energy of the light in the 
223 
far red to near-infrared/far red spectrum delivered by this device will be minimal and far below 
224 
the thresholds used in previous preclinical and clinical studies to generate cellular or anatomic 
225 
responses in the retina. 
226 
1.2 Study Rationale  
227 
There is evidence from prior preclinical and clinical studies to suggest that PBM may have a 
228 
beneficial effect on DME by inhibiting diabetes-induced oxidative stress and inflammation in the 
229 
retina. PBM is a novel, non-invasive, potentially inexpensive treatment option with low treatment 
230 
burden and no known side effects.  This would be a major public health contribution if this non-
231 
invasive treatment is effective in treating DME and can be implemented into clinical care. 
232 

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The proposed study will evaluate PBM compared with sham for eyes with CI-DME and good 
233 
vision to determine whether there is a short-term effect on CST on OCT.  If there is a short-term 
234 
anatomic effect in these eyes, a larger study would be needed to definitively establish the safety 
235 
and efficacy of this novel treatment for DME.   
236 
1.3 Study Objectives 
237 
This study is being conducted to assess the effects of PBM on CST compared with sham in eyes 
238 
with central-involved DME and good vision. 
239 
Furthermore, this pilot study is being conducted to determine whether the conduct of a pivotal trial 
240 
has merit based on an anatomic outcome and provide information on outcome measures needed to 
241 
design a pivotal trial.  This study is not designed to definitively establish the efficacy of PBM in 
242 
the treatment of DME. 
243 
1.4 Potential Risks and Benefits of PBM Device 
244 
1.4.1 Known Potential Risks 
245 
PBM treatment using LEDs is simple, fast, and non-invasive.  Although no adverse events have 
246 
been reported thus far in the literature, the bright light can be uncomfortable and may cause a 
247 
temporary reduction in the sensitivity of the eye to light, making it difficult to see and distinguish 
248 
colors for a short period after the treatment is stopped (approximately 2 to 5 minutes). The 
249 
participant may also experience a temporary afterimage that fades away in 2 to 5 minutes. 
250 
1.4.2 Known Potential Benefits 
251 
Previous small studies have reported improvement of DME, which could potentially result in 
252 
preservation or improvement of visual acuity. 
253 
1.4.3 Risk Assessment 
254 
LED device has been deemed a non-significant risk device for treatment of eye disorders by the 
255 
FDA during studies using it for treatment of laser eye injuries in military personnel. The dose of 
256 
light falls well within the American National Standards Institute (ANSI) safety standards. 
257 
1.5 General Considerations 
258 
The study is being conducted in compliance with the policies described in the study policies 
259 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with the 
260 
protocol described herein, and with the standards of Good Clinical Practice (GCP). 
261 
 
262 
Details of the examination procedures are provided in study procedure manuals.   
263 
OCT technicians and visual acuity testers, including refractionists, will be masked to treatment 
264 
group at outcome visits.  Study participants will be masked to their treatment group assignment.  
265 
Every effort will be made to keep investigators masked.  Study coordinators who will be involved 
266 
with training and compliance assessment will not be masked to treatment group. 
267 
Data will be directly collected in electronic case report forms, which will be considered the source 
268 
data. 
269 

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There is no restriction on the number of subjects to be enrolled by each site towards the overall 
270 
recruitment goal. 
271 
The protocol does not meet the definition of a significant risk device study. A clinical investigation 
272 
of a similar LED array device was designated a non-significant risk device study for treatment of 
273 
eye disorders by the FDA. The current study device is: 
274 
• Not an implant 
275 
• Not used to support human life  
276 
• Not of substantial importance in treating disease (since there is no current standard care 
277 
treatment for DME with good vision) 
278 
• Does not present potential for serious risk to the health, safety, or welfare of the subject. 
279 
Therefore, the protocol will follow the abbreviated requirements of 21 CFR 812.2(b). 
280 

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  STUDY ENROLLMENT AND RANDOMIZATION 
281 
2.1 Participant Recruitment and Enrollment 
282 
A minimum of 134 eyes (one per participant) are expected to be randomized.  Participants who 
283 
have signed consent and started the screening process may be permitted to continue into the trial, 
284 
if eligible, even if the randomization goal has been reached. 
285 
Study participants will be recruited from approximately 40 clinical centers in the United States.  
286 
All eligible participants will be included without regard to gender, race, or ethnicity.  There is no 
287 
restriction on the number of participants to be enrolled by each site toward the overall recruitment 
288 
goal. 
289 
2.1.1 Informed Consent and Authorization Procedures 
290 
Potential eligibility may be assessed as part of a routine-care examination.  Before completing any 
291 
procedures or collecting any data that are not part of usual care, written informed consent will be 
292 
obtained. 
293 
The study protocol will be discussed with the potential study participant by study staff.  The 
294 
potential study participant will be given the Informed Consent Form to read.  Potential study 
295 
participants will be encouraged to discuss the study with family members and their personal 
296 
physicians(s) before deciding whether to participate in the study. 
297 
As part of the informed consent process, each participant will be asked to sign an authorization for 
298 
release of personal information.  The investigator, or his or her designee, will review the study-
299 
specific information that will be collected and to whom that information will be disclosed.  After 
300 
speaking with the participant, questions will be answered about the details regarding authorization.  
301 
A separate signature section will be used to collect whether or not the participant agrees to be 
302 
randomly assigned to receive text message reminders (see section 3.2.1). 
303 
A participant is considered enrolled when the informed consent form has been signed. Once a 
304 
study participant is randomized, that participant will be counted regardless of whether the assigned 
305 
treatment is received.  Thus, the investigator must not proceed to randomize an individual until 
306 
he/she is convinced that the individual is eligible, will accept assignment to either of the two 
307 
treatment groups, and will be compliant with device use.   
308 
2.2 Participant Inclusion Criteria 
309 
2.2.1 Patient-level Criteria 
310 
Inclusion 
311 
To be eligible for the randomized trial, the following inclusion criteria must be met: 
312 
1. Age ≥ 18 years  
313 
• Subjects <18 years old are not being included because DME is so rare in this age group 
314 
that the diagnosis may be questionable.  
315 
2. Diagnosis of diabetes mellitus (type 1 or type 2)  
316 
• Any one of the following will be considered to be sufficient evidence that diabetes is 
317 
present:  
318 
 Current regular use of insulin for the treatment of diabetes. 
319 
 Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes. 
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 Documented diabetes by American Diabetes Association and/or the World Health 
321 
Organization criteria.  
322 
3. At least one eye meets the study eye criteria listed in section 2.2.2. 
323 
4. Able and willing to provide informed consent. 
324 
 
325 
Exclusion 
326 
A study participant is not eligible if any of the following exclusion criteria are present:  
327 
 
328 
5. History of chronic renal failure requiring dialysis or kidney transplant. 
329 
6. A condition that, in the opinion of the investigator, would preclude participation in the study 
330 
(e.g., unstable medical status that might preclude completion of follow-up).  
331 
7. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months 
332 
prior to randomization or plans to do so in the next 4 months. 
333 
8. Participation in an investigational trial that involved treatment within 30 days of randomization 
334 
with any drug/device that has not received regulatory approval for the indication being studied. 
335 
• Note: study participants cannot participant in another investigational trial that involves 
336 
treatment with an investigational drug or device while participating in the study. 
337 
9. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). 
338 
• If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual can 
339 
become eligible.  
340 
10. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization. 
341 
• These drugs should not be used during the study. 
342 
11. For women of child-bearing potential: pregnant or intending to become pregnant within the 
343 
next 8 months. 
344 
• Women who are potential study participants should be questioned about the potential for 
345 
pregnancy.  Investigator judgment is used to determine when a pregnancy test is needed. 
346 
12. Individual is expecting to move out of the area during the 8 months of the study. 
347 
2.2.2 Study Eye Criteria 
348 
To be eligible, the study participant must have at least one eye meeting all of the inclusion criteria 
349 
and none of the exclusion criteria listed below. 
350 
 
351 
A participant can have only one study eye.  If a participant has two eligible eyes, the eye with the 
352 
greatest central subfield will be selected as the study eye and the non-study eye will be followed 
353 
to evaluate any potential contralateral effect. 
354 
 
355 
The eligibility criteria for a study eye are as follows: 
356 
Inclusion 
357 
a. Best corrected E-ETDRS visual acuity letter score ≥ 79 (i.e., 20/25 or better)  
358 
b. Ophthalmoscopic evidence of central-involved DME, confirmed by CST on spectral domain 
359 
OCT: 
360 

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 Zeiss Cirrus: ≥290µm in women, and ≥305µm in men 
361 
 Heidelberg Spectralis: ≥305µm in women, and ≥320µm in men 
362 
c. Media clarity, pupillary dilation, and study participant cooperation sufficient for adequate 
363 
OCT. 
364 
 
365 
Exclusion 
366 
d. Macular edema is considered to be due to a cause other than DME.  
367 
• An eye should not be considered eligible if: (1) the macular edema is considered to be 
368 
related to ocular surgery such as cataract extraction or (2) clinical exam and/or 
369 
investigator assessment of OCT suggests that vitreoretinal interface abnormalities (e.g., a 
370 
taut posterior hyaloid or epiretinal membrane) are contributing to the macular edema. 
371 
e. An ocular condition is present such that, in the opinion of the investigator, any visual acuity 
372 
loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment 
373 
abnormalities, dense subfoveal hard exudates, nonretinal condition).  
374 
f. An ocular condition is present (other than DME) that, in the opinion of the investigator, might 
375 
affect visual acuity during the course of the study or require intraocular treatment (e.g., vein 
376 
occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.) 
377 
g. Cataract is present that, in the opinion of the investigator, may alter visual acuity during the 
378 
course of the study.  
379 
h. History of major ocular surgery (including cataract, scleral buckle, any intraocular surgery, 
380 
etc.) within prior 4 months or major ocular surgery anticipated during the study period. 
381 
i. Any history of prior laser or other surgical, intravitreal, or peribulbar treatment for DME or 
382 
DR (such as PRP, focal/grid macular photocoagulation, intravitreal or peribulbar 
383 
corticosteroids, or anti-VEGF) within the prior 12 months. 
384 
• If treatment was given more than 12 months prior, no more than 4 prior intraocular 
385 
injections  
386 
• Enrollment will be limited to a maximum of 15% of the planned sample size with any 
387 
history of anti-VEGF treatment and a maximum of 15% with any history of PRP.  
388 
j. Anticipated need to treat DME or DR during the study period (Note: any DME treatment 
389 
during the study must follow criteria in section 3.6).  
390 
k. History of topical steroid or NSAID treatment within 30 days prior to randomization. 
391 
l. History of YAG capsulotomy performed within 2 months prior to randomization 
392 
m. Any history of vitrectomy. 
393 
n. Aphakia  
394 
o. Uncontrolled glaucoma 
395 
2.2.3 Non-Study Eye 
396 
Subjects can have only one study eye. There are no eligibility or exclusion criteria with respect to 
397 
the non-study eye. 
398 
 
399 

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2.3 Screening Evaluation 
400 
2.3.1 Historical Information 
401 
After informed consent has been signed, a potential participant will be evaluated for study 
402 
eligibility through the elicitation of a medical history and performance of an ocular examination 
403 
by study personnel to screen for exclusionary conditions. 
404 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
405 
date per investigator discretion.   
406 
All testing does not need to be completed on the same day provided it is within the windows 
407 
specified below.   
408 
2.3.2  Screening Procedures 
409 
The following procedures are needed to confirm eligibility and/or serve as baseline measures for 
410 
the randomized trial:   
411 
• If a procedure has been performed using the study technique and by study certified 
412 
personnel as part of usual care, then it does not need to be repeated specifically for the 
413 
study if it was performed within the defined time windows specified below.  
414 
• The testing procedures are detailed in the DRCR Retina Network procedures manuals.  
415 
Visual acuity testing, ocular exam, and OCT will be performed by DRCR Retina Network 
416 
certified personnel. 
417 
• OCTs meeting DRCR Retina Network criteria for manual grading will be sent to a reading 
418 
center, but study participant eligibility is determined by the site (i.e., individuals deemed 
419 
eligible by the investigator will be randomized without pre-randomization reading center 
420 
confirmation). 
421 
1. Self-reported demographics (date of birth, sex, race and ethnicity) 
422 
2. Medical history (pre-existing medical conditions, concomitant medications, as well as ocular 
423 
diseases, surgeries, and treatment) 
424 
 Medical history will be obtained by medical charts if available at the enrolling site; 
425 
otherwise, it will be self-reported 
426 
3. Electronic-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester 
427 
(including protocol refraction) in study eye only (within prior 14 days of randomization). 
428 
4. Spectral-Domain OCT using Zeiss Cirrus or Heidelberg Spectralis in both eyes (within prior 
429 
14 days of randomization).  
430 
5. Ocular examination on each eye including slit lamp, measurement of intraocular pressure, lens 
431 
assessment, and dilated ophthalmoscopy (within prior 14 days of randomization).  
432 
6. OCT angiography on the study eye (within prior 14 days of randomization). 
433 
 Only obtained by a subset of sites with OCT angiography capabilities.   
434 
7. Measurement of blood pressure. 
435 
8. Laboratory Testing- HbA1c. 
436 

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• HbA1c does not need to be repeated if available in the prior 3 months.  If not available at 
437 
the time of randomization, the individual may be enrolled but the test must be obtained 
438 
within 3 weeks after randomization.   
439 
2.4 Randomization of Eligible Subjects  
440 
1. Prior to randomization, the study participant’s understanding of the trial, compliance with 
441 
device use, willingness to accept the assigned treatment group, and commitment to the follow-
442 
up schedule will be reconfirmed. 
443 
 
444 
2. Randomization is completed on the DRCR.net website.   
445 
• Study participants will be assigned randomly (stratified by site and intravitreous treatment* 
446 
in the non-study eye) with equal probability to one of two treatment groups:  
447 
o Active treatment (670nm wavelength) device  
448 
o Sham (broad spectrum white light) device  
449 
 
450 
*Randomization will be stratified by site and recent (within 4 months) or planned intravitreous 
451 
treatment in the non-study eye, including intravitreous anti-VEGF and steroid 
452 
 
453 
3. For participants who consent, a second randomization will determine whether the   participant 
454 
will receive periodic text message reminders regarding device compliance.   
455 
• Randomization is completed on the DRCR.net website and will be stratified by assigned 
456 
treatment group. 
457 
 
458 
Once a study participant is randomized, that participant will be counted regardless of whether the 
459 
assigned treatment is received.  Thus, the investigator must not proceed to randomize an individual 
460 
until he/she is convinced that the individual is eligible and will accept whichever treatment group 
461 
is assigned through randomization. 
462 
 
463 

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3-1 
 RANDOMIZED TRIAL PROCEDURES 
464 
3.1 Study Device 
465 
3.1.1 Home Procedures 
466 
While a device is assigned, the study participant will be required to use the device twice daily 
467 
(once in the morning and once before bed) for 90 seconds each. Participants will be provided with 
468 
instructions to take home for proper device use and the required timing of treatments. 
469 
 
470 
3.1.2 Primary Outcome Phase 
471 
Each participant will receive the type of device for home use based on their treatment group 
472 
assignment (the participant will remain masked to whether the device is emitting active or sham 
473 
treatment): 
474 
o Active treatment (670nm wavelength) device twice a day for 90 seconds 
475 
o Sham (broad spectrum white light) device twice a day for 90 seconds 
476 
 
477 
The primary outcome phase will last until completion of the ‘4-month’ visit, which could be up to 
478 
8 months post-randomization (see visit windows below).  If the visit is not completed by 8 months, 
479 
the participant will be instructed to discontinue device use, return the study device as soon as they 
480 
are able, and study participation will be ended. 
481 
 
482 
3.1.3 Post-Outcome Phase 
483 
At the 4-month visit, all participants will be unmasked to their treatment group assignment.   
484 
 
485 
Participants originally assigned to Sham who have not already received alternative DME treatment 
486 
(see section 3.6) will return the original device and have the option to receive the active treatment 
487 
group device for the next 4 months.    
488 
 
489 
Participants originally assigned to Active who have not received alternative treatment will return 
490 
the original device and have the option to complete the remaining follow-up visits without device 
491 
use. 
492 
 
493 
3.1.4 Device Training 
494 
On the day of randomization, a device will be provided to the participant according to their 
495 
randomized assignment.  In order for investigators to remain masked, clinical site coordinators 
496 
will instruct study participants regarding the proper use of the device.  The eyelid must be closed 
497 
for the duration of the treatment.  The participant must turn the device on and it will stop 
498 
automatically. The study participant will be asked to demonstrate proper use in the office, which 
499 
will be considered the initial treatment. The participant will be instructed to complete the second 
500 
treatment that day before bed.  
501 
 
502 
3.2 Study Visits and Phone Contacts 
503 
A phone call is completed by site personnel within approximately one week of randomization (5 
504 
to 14 days) to emphasize compliance with device use and answer any questions. 
505 
 
506 
Scheduled follow-up visits will occur at the following times (time from randomization unless 
507 
otherwise noted): 
508 

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509 
Visit 
Target Date 
Target Window 
(around Target Date) 
Allowable Window 
(around Target Date) 
1 Month  
4 weeks 
± 1 week 
± 2 weeks 
2 Month 
8 weeks 
± 1 week 
± 2 weeks 
3 Month 
12 weeks 
± 1 week 
± 2 weeks 
4 Month/Primary 
Outcome Visit* 
16 weeks 
± 2 weeks  
-4 weeks/+16 weeks 
~6 Month/2-month 
post outcome 
8 weeks after 4-
Month visit  
± 2 weeks  
± 4 weeks 
~8 Month/4-month 
post outcome 
16 weeks after 4-
Month visit  
± 2 weeks  
-8 weeks/+12 weeks 
*Key visit 
510 
 
511 
The goal will be for all participants to complete all scheduled visits.  However, participants who 
512 
(because of unforeseen circumstances) are unable or unwilling to return for all follow-up visits 
513 
will be permitted to return for key visits only as an alternative to withdrawal from the study.  
514 
Participants who are not using a device during the post-outcome phase but have not received 
515 
alternative treatment will be given the option to continue study visits or end study participation 
516 
early. 
517 
 
518 
Additional phone contacts may be performed as needed. 
519 
3.2.1 Text Message Reminders 
520 
For participants randomly assigned to text message reminders, periodic messages will be sent by 
521 
the Coordinating Center with a reminder to comply with the study device schedule. 
522 
3.3 Procedures at Study Visits 
523 
The following procedures will be performed in both groups at each visit, unless otherwise 
524 
specified: 
525 
1. E-ETDRS visual acuity testing (best corrected) in each eye. 
526 
• A protocol refraction in the study eye is required at each visit.  Refraction in the non-study 
527 
eye is only required at the 4 and 8 month visits.  When a refraction is not performed, the 
528 
most recently performed refraction is used for the testing. 
529 
2. Spectral-Domain OCT using Zeiss Cirrus or Heidelberg Spectralis in both eyes  
530 
• The same machine type (Cirrus or Spectralis) used at baseline should be used during 
531 
follow-up. 
532 
3. Ocular exam in the study eye, including slit lamp examination with lens assessment, 
533 
measurement of intraocular pressure, and dilated ophthalmoscopy.  
534 
• Required at Primary Outcome and 4-Month Post Outcome visits only. Otherwise, 
535 
ocular exam is at investigator discretion.  In general, an ocular exam should be 
536 
completed if the OCT and/or visual acuity have worsened since baseline (e.g. more 
537 
than 10% increase in CSF thickness or 5 letter loss in VA). 
538 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
3-3 
4. OCT angiography on the study eye if obtained at baseline (4 month/primary outcome visit 
539 
only) 
540 
• Only obtained by a subset of sites with OCT angiography capabilities.   
541 
• See procedure manual for more details on acquisition, including which fields to collect 
542 
on a given OCT angiography system. 
543 
5. Compliance assessment 
544 
• The site personnel will download the compliance data and re-emphasize the importance 
545 
of compliance with device use 
546 
All of the testing procedures do not need to be performed on the same day, provided that they are 
547 
completed within the time window of a visit.  If data from a testing procedure is unusable (ex. if 
548 
OCT is ungradable), the participant may be asked to repeat the procedure during an additional 
549 
visit, whether part of usual care or solely to repeat the procedure. 
550 
3.4 Early Termination Visit  
551 
Study participants who request to withdraw will be asked to have a final closeout visit at which 
552 
the testing described for study visits will be performed.   
553 
3.5 Unscheduled Visits 
554 
Additional visits may occur as required for usual care of the study participant. Testing procedures 
555 
at unscheduled visits are at investigator discretion.  However, it is recommended that procedures 
556 
that are performed should follow the standard DRCR Retina Network protocol for each procedure. 
557 
3.5.1 DME Treatment Initiation Visit 
558 
Participants for whom alternative treatment for DME is planned for the first time at an unscheduled 
559 
visit (e.g. anti-VEGF or corticosteroid intravitreous injection, PRP, focal/grid laser, or vitrectomy) 
560 
will be asked to complete the study procedures above before the treatment is administered.  Usual 
561 
care vision (e.g. Snellen charts) will be acceptable if the eye is already dilated when treatment is 
562 
planned. 
563 
3.6 Alternative Treatment for CI-DME 
564 
Treatment for CI-DME must not be given unless one of the following criteria have been met or 
565 
protocol chair approval is obtained: 
566 
o 1) at least 10 letter decrease in visual acuity from baseline presumed to be from 
567 
DME at a single visit or  
568 
o 2) 5 to 9 letter decrease in visual acuity from baseline presumed to be from DME 
569 
at two-consecutive visits at least 21 days apart. 
570 
Once criteria are met, alternative treatment is at the discretion of the investigator as part of usual 
571 
care.  If alternative treatment is given, study device use will be discontinued and participation in 
572 
the study will be discontinued following the 4-month/primary outcome visit (or next study visit, if 
573 
after 4 months).   
574 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
3-4 
3.7 Participant Access to Study Device at Study Closure 
575 
The study device is not commercially available and must be returned at the end of the study.  
576 
Participants who withdraw from the study (or do not return for the final visit within the allowable 
577 
window) will be asked to return the device as soon as possible. 
578 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
4-1 
 STUDY DEVICES 
579 
4.1 Description of the Investigational Device 
580 
The device to be evaluated is the PhotoOptx, LLC Retilux Eye Patch. It is worn as a single eye 
581 
patch to maximize treatment effect.  The active treatment version will emit light of 670nm at a 
582 
dose of 4.5 J/cm2 with an irradiance not greater than 50 mW/cm2.  The device includes a controller 
583 
module to collect compliance data.   
584 
The sham version is identical, except that the light will be a broad spectrum white light at a low 
585 
power.   
586 
The investigators have determined that use of the LED device in this protocol meets the criteria 
587 
for the study to be classified as a non-significant risk device study as it does not meet any of the 
588 
criteria from section 812.3 (m) of the FDA investigational device exemption regulation 21 CFR 
589 
812.  As such an IDE is not required. 
590 
4.2 Study Device Accountability Procedures 
591 
Device accountability procedures will be detailed in the coordinator manual. 
592 
4.3 Safety Measures 
593 
The device includes an auto shut off after the desired treatment time.   
594 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
5-1 
595 
 ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES  
596 
5.1 Adverse Events 
597 
5.1.1 Definitions 
598 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
599 
relationship between the adverse event and the device(s) under investigation (see section 5.1.2 for 
600 
reportable adverse events for this protocol) 
601 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
602 
• Results in death. 
603 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
604 
become life-threatening, is not necessarily considered a serious adverse event). 
605 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
606 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability 
607 
to conduct normal life functions (sight threatening). 
608 
• Is a congenital anomaly or birth defect. 
609 
• Is considered a significant medical event by the investigator based on medical judgment (e.g., 
610 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
611 
the outcomes listed above). 
612 
In general, an ocular adverse event should be reported as serious (considered sight threatening) if 
613 
it meets one of the following criteria: 
614 
1. It causes a decrease of ≥ 30 letters in visual acuity compared with the last visual acuity 
615 
measurement prior to onset (e.g. central retinal artery occlusion) 
616 
2. In the opinion of the investigator, it requires prompt surgical intervention (e.g. vitrectomy, 
617 
vitreous tap, intravitreous antibiotics) to prevent permanent loss of sight.  Examples include 
618 
endophthalmitis or rhegmatogenous retinal detachment. 
619 
Ocular adverse events that require eventual surgical intervention would not be considered serious. 
620 
Ocular adverse events that do not have the potential to result in permanent loss of sight also would 
621 
not be considered serious. 
622 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
623 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
624 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
625 
protocol, or any other unanticipated serious problem associated with a device that relates to the 
626 
rights, safety, or welfare of participants (21 CFR 812.3(s)). 
627 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which the 
628 
device may have caused or to which the device may have contributed (Note that an Adverse Event 
629 
Form is to be completed in addition to a Device Deficiency or Issue Form). 
630 
Device Complaints and Malfunctions: A device complication or complaint is something that 
631 
happens to a device or related to device performance, whereas an adverse event happens to a 
632 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
5-2 
participant.  A device complaint may occur independently from an AE, or along with an AE.  An 
633 
AE may occur without a device complaint or there may be an AE related to a device complaint.   
634 
A device malfunction is any failure of a device to meet its performance specifications or otherwise 
635 
perform as intended.  Performance specifications include all claims made in the labeling for the 
636 
device.  The intended performance of a device refers to the intended use for which the device is 
637 
labeled or marketed. (21 CFR 803.3).  Note: for reporting purposes, sites will not be asked to 
638 
distinguish between device complaints and malfunctions. 
639 
5.1.2 Reportable Adverse Events 
640 
For this protocol, a reportable adverse event includes any untoward medical occurrence that meets 
641 
one of the following criteria: 
642 
1) An ocular adverse event in the study eye 
643 
2) A serious adverse event 
644 
3) An Adverse Device Effect as defined in section 5.1.1, unless excluded from reporting 
645 
in section 5.2 
646 
4) A systemic adverse event occurring in association with a study procedure  
647 
All reportable Adverse Events—whether volunteered by the participant, discovered by study 
648 
personnel during questioning, or detected through physical examination, laboratory test, or other 
649 
means—will be reported on an adverse event form online.  Each adverse event form is reviewed 
650 
by the Medical Monitor to verify the coding and the reporting that is required. 
651 
5.1.3 Relationship of Adverse Event to Study Device 
652 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
653 
by determining if there is a reasonable possibility that the adverse event may have been caused by 
654 
the study device. 
655 
To ensure consistency of adverse event causality assessments, investigators should apply the 
656 
following general guideline when determining whether an adverse event is related: 
657 
Yes 
658 
There is a plausible temporal relationship between the onset of the adverse event and the study 
659 
intervention, and the adverse event cannot be readily explained by the participant’s clinical state, 
660 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern of 
661 
response to the study intervention; and/or the adverse event abates or resolves upon discontinuation 
662 
of the study intervention or dose reduction and, if applicable, reappears upon re-challenge. 
663 
No 
664 
Evidence exists that the adverse event has an etiology other than the study intervention (e.g., 
665 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
666 
medication); and/or the adverse event has no plausible temporal relationship to study intervention. 
667 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
5-3 
5.1.4 Intensity of Adverse Event 
668 
The intensity of an adverse event will be rated on a three point scale: (1) mild, (2) moderate, or (3) 
669 
severe.  It is emphasized that the term severe is a measure of intensity: thus a severe adverse event 
670 
is not necessarily serious.  For example, itching for several days may be rated as severe, but may 
671 
not be clinically serious. 
672 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
673 
participant’s daily activities. 
674 
• MODERATE: Usually causes a low level of inconvenience or concern to the participant and 
675 
may interfere with daily activities, but is usually ameliorated by simple therapeutic measures. 
676 
• SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic drug 
677 
therapy or other treatment. 
678 
5.1.5 Coding of Adverse Events 
679 
Adverse events will be coded using the MedDRA dictionary.  The Medical Monitor will review 
680 
the investigator’s assessment of causality and may agree or disagree.  Both the investigator’s and 
681 
Medical Monitor’s assessments will be recorded.  The Medical Monitor will have the final say in 
682 
determining the causality. 
683 
Adverse events considered related to the study device that continue after the participant’s 
684 
discontinuation or completion of the study will be followed until their medical outcome is 
685 
determined or until no further change in the condition is expected. 
686 
5.1.6 Outcome of Adverse Event 
687 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
688 
• COMPLETE RECOVERY/RESOLVED – The participant recovered from the AE/SAE 
689 
without sequelae.  Record the AE/SAE stop date. 
690 
• RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized 
691 
without change in the event anticipated.  Record the AE/SAE stop date. 
692 
• FATAL – A fatal outcome is defined as the SAE that resulted in death.  Only the event that 
693 
was the cause of death should be reported as fatal.  AEs/SAEs that were ongoing at the time of 
694 
death; however, were not the cause of death, will be recorded as “resolved” at the time of death. 
695 
• ONGOING – An ongoing AE/SAE is defined as the event was ongoing with an undetermined 
696 
outcome. 
697 
• An ongoing outcome for which further improvement or worsening is possible will 
698 
require follow-up by the site in order to determine the final outcome of the AE/SAE. 
699 
• An ongoing outcome that is medically stable (further change not expected) will be 
700 
documented as such and will not require additional follow-up.   
701 
• The outcome of an ongoing event at the time of death that was not the cause of death, 
702 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
703 
date. 
704 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
5-4 
If any reported adverse events classified as UADEs are ongoing with further improvement or 
705 
worsening possible when a participant completes the study (or withdraws), the event will be 
706 
followed until it is either resolved or medically stable, even after the subject has completed all 
707 
applicable study visits/contacts. For all other adverse events, data collection will end at the time 
708 
the participant completes the study. Note: participants should continue to receive appropriate 
709 
medical care for an adverse event after their participation in the study ends.  
710 
5.2 Reportable Device Issues 
711 
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of 
712 
whether an adverse event occurred, except in the following circumstances. 
713 
The following device issues are anticipated and will not be reported on a Device Issue Form but 
714 
will reported as an Adverse Event if the criteria for AE reporting described above are met: 
715 
• Device issues clearly addressed in the user guide manual that do not require additional 
716 
troubleshooting 
717 
• Brightness of light 
718 
• Mild to moderate photo blanching or color distortion immediately following use that resolves  
719 
5.3 Pregnancy Reporting 
720 
If pregnancy occurs, device use will be discontinued immediately and participation in the study 
721 
will be discontinued following the 4-month visit (or next study visit, if after 4 months).  The 
722 
occurrence of pregnancy will be reported on an AE Form. 
723 
5.4 Timing of Event Reporting 
724 
SAEs and UADEs must be reported to the Coordinating Center within 24 hours via completion of 
725 
the online adverse event form. 
726 
The Coordinating Center will notify all participating investigators of any adverse event that is 
727 
serious, related, and unexpected. Notification will be made within 10 days after the Coordinating 
728 
Center becomes aware of the event. 
729 
Each principal investigator is responsible for reporting serious study-related adverse events and 
730 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
731 
Ethics Committee. 
732 
Upon receipt of a UADE report, JCHR will investigate the UADE and if indicated, report the 
733 
results of the investigation to the sites’ IRBs, and the FDA within 10 working days of JCHR 
734 
becoming aware of the UADE per 21CFR 812.46(b) (2).  The Medical Monitor must determine if 
735 
the UADE presents an unreasonable risk to participants.  If so, the Medical Monitor must ensure 
736 
that all investigations, or parts of investigations presenting that risk, are terminated as soon as 
737 
possible but no later than 5 working days after the Medical Monitor makes this determination and 
738 
no later than 15 working days after first receipt notice of the UADE. 
739 
In the case of a device malfunction, it should be reported to JCHR by site personnel and the 
740 
information will be forwarded to PhotoOptx, LLC, to be handled by their complaint management 
741 
system. 
742 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
5-5 
5.5 Stopping Criteria 
743 
5.5.1 Participant Discontinuation of Study Device 
744 
Rules for discontinuing study device use are described below. 
745 
• The investigator believes it is unsafe for the participant to continue on the intervention.  This 
746 
could be due to the development of a new medical condition or worsening of an existing 
747 
condition; or participant behavior contrary to the indications for use of the device that imposes 
748 
on the participant’s safety 
749 
• The participant requests that the treatment be stopped 
750 
• Participant pregnancy 
751 
Even if the study device system is discontinued, the participant will be encouraged to remain in 
752 
the study through the 4-month primary outcome visit. Participants who are not using a device 
753 
during the post-outcome phase but have not received alternative treatment will be given the option 
754 
to continue study visits or end study participation early. 
755 
5.5.2 Criteria for Suspending or Stopping Overall Study 
756 
Study activities could be suspended if the manufacturer of the study device requires stoppage of 
757 
device use for safety reasons (e.g. product recall).  The affected study activities may resume if the 
758 
underlying problem can be corrected by a protocol or system modification that will not invalidate 
759 
the results obtained prior to suspension. 
760 
The Data and Safety Monitoring Committee (DSMC) will be informed of any unanticipated 
761 
adverse device events that occur during the study and will review compiled safety data at periodic 
762 
intervals.  The DSMC will request suspension of study activities or stoppage of the study if deemed 
763 
necessary based on the totality of safety data available. 
764 
The study may be discontinued by the Executive Committee (with approval of the DSMC) prior 
765 
to the preplanned completion of follow-up for all study participants. 
766 
5.6 Independent Safety Oversight 
767 
A DSMC will approve the protocol, template informed consent form, and substantive amendments 
768 
and provide independent monitoring of adverse events.  Cumulative adverse event data are 
769 
tabulated semi-annually for review by the DSMC.  Following each DSMC data review, a summary 
770 
will be provided to IRBs.  A list of specific adverse events to be reported expeditiously to the 
771 
DSMC will be compiled and included as part of the DSMC Monitoring Plan document.   
772 
5.7 Risks 
773 
While no known adverse events have been reported thus far in the literature, the bright light can 
774 
be uncomfortable and may cause a temporary reduction in the sensitivity of the eye to light, making 
775 
it difficult to see and distinguish colors for a short period after the treatment is stopped. The 
776 
participant may also experience a temporary afterimage that should fade away. 
777 
Many of the testing procedures in this study are part of daily ophthalmologic practice in the United 
778 
States and pose few if any known risks.  
779 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
5-6 
• Dilating eye drops will be used as part of the exam.  There is a small risk of inducing a narrow-
780 
angle glaucoma attack from the pupil dilation.  However, all participants will have had prior 
781 
pupil dilation usually on multiple occasions and therefore the risk is extremely small.   
782 
 
783 
Additional risks are minor and/or infrequent and include: 
784 
• Pain, bruising, redness, or infection from baseline blood draw 
785 
• Loss of confidentiality 
786 
 
787 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
6-1 
 MISCELLANEOUS CONSIDERATIONS 
788 
6.1 Prohibited Medications, Treatments, and Procedures 
789 
Alternative treatment for DME will not be permitted unless protocol criteria in section 3.6 are met 
790 
or treatment is discussed with and approved by the Protocol Chair or Coordinating Center 
791 
designee. 
792 
6.2 Treatment in Non-study Eye 
793 
Treatment of DR or DME in the non-study eye is at investigator discretion.  
794 
6.3 Diabetes Management 
795 
Diabetes management is left to the study participant’s medical care provider. 
796 
6.4 Participant Compensation 
797 
Participant compensation will be specified in the informed consent form. 
798 
6.5 Participant Withdrawal 
799 
Participation in the study is voluntary, and a participant may withdraw at any time.  If a study 
800 
participant is considering withdrawal from the study, the principal investigator should personally 
801 
speak to the individual about the reasons and every effort should be made to accommodate him or 
802 
her.  
803 
The goal for the study is to have as few losses to follow-up as possible. The Coordinating Center 
804 
will assist in the tracking of study participants who cannot be contacted by the site. The 
805 
Coordinating Center will be responsible for classifying a study participant as lost to follow-up. For 
806 
participants who withdraw, their data up until the time of withdrawal will be used. 
807 
6.6 Confidentiality 
808 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
809 
used instead of their name.  Protected health information gathered for this study will be shared 
810 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL.  De-identified 
811 
participant information may also be provided to research sites involved in the study. 
812 
6.6.1 Contact Information Provided to the Coordinating Center 
813 
The Coordinating Center will be provided with contact information for each study participant.  
814 
Permission to obtain such information will be included in the Informed Consent Form.  The contact 
815 
information will be maintained in a secure database and will be maintained separately from the 
816 
study data. 
817 
Phone contact from the Coordinating Center will be made with each study participant in the first 
818 
month after enrollment.  Additional phone contacts from the Coordinating Center will be made if 
819 
necessary to facilitate the scheduling of the study participant for follow-up visits.  A participant-
820 
oriented newsletter and a study logo item may be sent once.  For participants randomly assigned 
821 
to text message reminders, periodic messages will be sent by the Coordinating Center with a 
822 
reminder to comply with the study device schedule. 
823 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
6-2 
Study participants will be provided with a summary of the study results in a newsletter format after 
824 
completion of the study by all study participants.  
825 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
7-1 
 STATISTICAL CONSIDERATIONS 
826 
7.1 Statistical and Analytical Plans 
827 
The approach to sample size calculation and statistical analyses are summarized below.  A detailed 
828 
statistical analysis plan will be written and finalized prior to the first review of study outcome data 
829 
by the Data and Safety Monitoring Committee.  The analysis plan synopsis in this chapter contains 
830 
the framework of the anticipated final analysis plan. 
831 
7.2 Statistical Hypotheses 
832 
A test of superiority will be used in evaluating the following hypotheses for the primary outcome: 
833 
Null Hypothesis (H0): There is no difference in the mean change in CST from baseline to 4 months 
834 
between photobiomodulation (PBM) and sham groups. 
835 
Alternative Hypothesis (Ha): There is a difference in the mean change in CST from baseline to 4 
836 
months between PBM and sham groups. 
837 
Similar hypothesis tests will be conducted for all secondary, exploratory, and safety outcomes. 
838 
7.3 Sample Size 
839 
7.3.1 Outcome Projections:  
840 
To estimate the standard deviation (SD) of change in OCT CST, data from the DRCR Retina 
841 
Network Protocol A (Treatment for Central-Involved Diabetic Macular Edema in Eyes with Very 
842 
Good Visual Acuity) was used.  The Protocol A cohort of eyes with 20/25 baseline visual acuity 
843 
and central subfield thickening treated with modified-ETDRS laser was used for the estimation.  
844 
In protocol A, 42 eyes in the modified-ETDRS laser group completed a visit within 4 months of 
845 
randomization.  The SD of change in CST adjusted for baseline CST in these eyes was 50 microns 
846 
(personal communication, Adam Glassman).  The mean change in CST was -2 microns.  
847 
The expected change and standard deviation of CST in an untreated group is unknown at this time. 
848 
7.3.2 Sample Size Estimates  
849 
Table 1 shows total sample size estimates under several scenarios. These calculations assume a 
850 
Type I error rate of 5%, 90% power, and a two-sided test of superiority (see Section 7.6) with a 
851 
null hypothesis of no difference between the groups (see Section 7.2). 
852 
 
 
853 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
7-2 
Table 1: Total Sample Size Under Various Assumptions for True Mean Change and 
854 
Standard Deviation 
855 
Mean 
Treatment 
Group 
Difference, 
microns 
Change in Central Subfield Standard Deviation, microns  
(adjusted for baseline) 
40 
50 
60 
70 
20 
172 
266 
382 
518 
30 
78 
120 
172 
232 
40 
46 
68 
98 
132 
Assuming an effective standard deviation of 50 microns and a true difference in mean CST of 30 
856 
microns, the required total sample size is 120 eyes to achieve 90% power.  Sample size will be 
857 
increased to 134 eyes to account for 10% lost to follow-up.   
858 
7.4 Outcome Measures Phase 1 (Baseline to completion of the 4-Month/Primary outcome 
859 
visit) 
860 
Primary Efficacy Endpoint(s): Mean change in CST from baseline 
861 
Secondary Efficacy Endpoint(s): 
862 
• Mean change in retinal volume from baseline 
863 
• Percentage of eyes with CST below OCT machine and gender-specific threshold for DME 
864 
• Percentage of eyes receiving alternative treatment for DME* 
865 
• Percentage of eyes with a 5-letter loss in visual acuity from baseline 
866 
• Mean change in visual acuity from baseline* 
867 
• Patient compliance* 
868 
*Outcomes marked with an asterisk will include descriptive statistics only and not statistical 
869 
comparisons of treatment groups 
870 
To ensure that statistical outliers do not have undue impact on analyses of continuous outcomes, 
871 
change in continuous outcomes from baseline will be truncated to ± 3 standard deviations based 
872 
on the overall mean and standard deviation at primary outcome visit from both treatment groups 
873 
combined. Analyses to be conducted on these outcomes are detailed in Section 7.8. 
874 
7.5 Analysis Cohorts 
875 
• Intention-To-Treat (ITT) Analysis Cohort: all randomized participants irrespective of 
876 
treatment received, analyzed according to treatment assignment 
877 
• Safety Analysis Cohort: all randomized participants irrespective of treatment received, 
878 
analyzed according to treatment assignment 
879 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
7-3 
• Per-Protocol Analysis Cohort: participants who complete primary outcome visit, 70% or 
880 
more of prescribed sessions of treatment, and do not receive an alternative treatment for 
881 
DME  
882 
The primary analysis will follow the intention-to-treat principle. It will include all randomized 
883 
participants. The data from the ITT cohort will be analyzed according to the group to which the 
884 
participants were assigned through randomization, regardless of treatment actually received. 
885 
A per-protocol analysis will be performed to provide additional information regarding the 
886 
magnitude of the treatment effect. The per-protocol analysis will only be performed if more than 
887 
10% of randomized participants would be excluded by these criteria. The intention-to-treat 
888 
analysis is considered primary and if the results of the per-protocol analysis and intention-to-treat 
889 
give inconsistent results, exploratory analyses will be performed to evaluate possible factors 
890 
contributing to the differences.  
891 
7.6 Analysis of the Primary Efficacy Endpoint(s) 
892 
The primary outcome of mean change in CST on OCT is a continuous variable. The primary 
893 
analysis will consist of a treatment group comparison of mean change in CST from baseline using 
894 
analysis of covariance, with adjustment for baseline CST and randomization stratification factor. 
895 
Eyes that receive treatment for DME (see section 3.6) will have the last OCT measurement prior 
896 
to treatment used for the primary analysis. OCTs can be obtained from either Spectralis or Cirrus 
897 
images. Values from these machines cannot be used interchangeably. OCT values will be 
898 
converted to a common value for reporting and analyses.  The estimated treatment-group 
899 
difference, 95% confidence interval and 2-sided P value will be obtained using robust variance 
900 
estimation. The assumptions of linearity, normality, and homoscedasticity will be verified using 
901 
graphical methods. Serious violations may be addressed by transformation of dependent and/or 
902 
independent variables, non-parametric transformation, categorizing continuous covariates, and/or 
903 
excluding covariates. Transformation of the dependent variable will be used to obtain valid p-
904 
values while ensuring statistical model assumptions are met.  However, mean treatment group 
905 
differences, rather than results based on transformed outcomes will be reported for clinical 
906 
interpretation.  Change in CST will be truncated at ±3 SD to improve robustness of the treatment 
907 
comparison to CST change outliers. 
908 
Markov chain Monte Carlo (MCMC) multiple imputation will be used to handle missing data for 
909 
eyes not treated with an alternative DME treatment. The imputation model will be stratified by 
910 
treatment group and include the CST measured at randomization visit and change in CST from 
911 
baseline at all monthly interim visits up to the primary outcome visit along with the randomization 
912 
stratification factor of recent or planned intravitreous treatment in the non-study eye.  MCMC 
913 
imputation will be used to estimate treatment group differences, 95% confidence intervals, and P 
914 
values; observed data will be used to estimate within treatment group changes.   
915 
A sensitivity analysis including observed data from participants completing the primary outcome 
916 
visit (no imputation of missing data) also will be conducted (i.e., complete-case analysis).   In 
917 
addition, a sensitivity analysis including observed data from participants completing the primary 
918 
outcome visit within -4 weeks and +8 weeks of the target date will be conducted.  Status of 
919 
intravitreous treatment in the non-study eye (recent or planned versus none) will be included as a 
920 
covariate because it is a randomization stratification factor. Eyes that receive an alternative 
921 
treatment for DME will be handled in the same manner as in the primary analysis. If the analyses 
922 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
7-4 
of imputed and observed data differ substantially, then exploratory analyses will be performed to 
923 
evaluated factors that may have contributed to the differences. A separate sensitivity analysis will 
924 
be conducted where no data truncation on outlying values for change in CST will be performed. 
925 
7.7 Sensitivity Analysis 
926 
An additional sensitivity analysis will be performed, where OCT measurements taken after an eye 
927 
receives an alternative treatment for DME will be considered as missing and will be imputed using 
928 
multiple imputation stratified by treatment group. The imputation model will include an additional 
929 
variable indicating whether the eye receives an alternative treatment, in addition to all variables 
930 
specified in the primary imputation model.  
931 
7.8 Analysis of the Secondary Endpoint(s) 
932 
The ITT analysis cohort will be used for all secondary outcomes unless otherwise specified.  Eyes 
933 
that receive treatment for DME (see section 3.6) will have the last measurement prior to treatment 
934 
used for the secondary analysis unless otherwise specified. Unless otherwise specified, missing 
935 
data will be imputed with multiple imputation. The imputation model will be stratified by treatment 
936 
group and include the baseline value of the outcome, the randomization stratification factor, and 
937 
change in the outcome for the available time points.   
938 
Change in retinal volume from baseline is a continuous variable and will be analyzed using 
939 
analysis of covariance. The analysis will include adjustment for baseline CST, baseline retinal 
940 
volume, and the randomization stratification factor. The estimated treatment-group difference, 
941 
95% confidence interval and 2-sided P value will be presented. The assumptions of linearity, 
942 
normality, and homoscedasticity will be verified using graphical methods. Serious violations may 
943 
be addressed by transformation of dependent and/or independent variables, non-parametric 
944 
methods, categorizing continuous covariates, and/or excluding covariates.  
945 
The percentage of eyes with CST below OCT machine and gender-specific threshold for DME at 
946 
the primary outcome visit is a binary variable that will be analyzed with logistic regression with 
947 
robust variance estimation. Baseline CST and the randomization stratification factor will be 
948 
included as covariates.  
949 
The percentage of eyes receiving an alternative treatment for DME before the primary outcome 
950 
visit will be reported. Only participants receiving alternative treatment or completing the primary 
951 
outcome visit without receiving alternative treatment will be included. Statistical comparison 
952 
between treatment groups will not be performed. 
953 
The percentages of eyes with 5-or-more-letter decrease from randomization at primary outcome 
954 
visit is a binary variable that will be compared between treatment groups using logistic regression 
955 
with robust variance estimation. Baseline visual acuity and randomization stratification factor will 
956 
be included as covariates.  The mean change in visual acuity will also be reported; however, 
957 
statistical comparison between treatment groups for the mean change will not be performed.    
958 
For each logistic regression analysis, the odds ratio for the treatment group effect, 95% confidence 
959 
interval, and P value will be presented.  
960 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
7-5 
7.9 Safety Analyses 
961 
All reportable adverse events will be categorized as study eye or systemic. All events will be 
962 
tabulated by treatment group in a listing of each reported Medical Dictionary for Regulatory 
963 
Activities (MedDRA) term and summarized over each MedDRA System Organ Class. All 
964 
randomized participants will be included in safety analyses. 
965 
Since there are no known risks of the device, there are no pre-specified safety outcomes of interest. 
966 
However, the frequency of each ocular adverse event occurring at least once per eye and each 
967 
systemic event occurring at least once per participant will be calculated.  
968 
In addition, the following will be tabulated by treatment group: 
969 
• For each MedDRA System Organ Class, percentage of participants with at least one 
970 
serious event  
971 
• Number of adverse events thought by investigator to be related to treatment 
972 
No formal statistical comparisons will be performed for reported adverse events. 
973 
7.10 Outcome Measures Phase 2 (4 Months Post-Outcome) 
974 
The following post-switch effects on DME from completion of the 4-month/primary outcome visit 
975 
to the final visit will be tabulated separately within each treatment group:  
976 
• Duration of effect on DME after active treatment is stopped  
977 
o Mean change in CST between 4-month and the final visit 
978 
o Mean change in retinal volume between 4-month and the final visit 
979 
o Percentage of eyes with CST below OCT machine and gender-specific threshold 
980 
for DME at final visit 
981 
• Effect on DME in eyes previously receiving sham that switch to active 
982 
o Mean change in CST between 4-month and the final visit 
983 
o Mean change in retinal volume between 4-month and the final visit Percentage of 
984 
eyes with CST below OCT machine and gender-specific threshold for DME at the 
985 
final visit 
986 
• Patient compliance 
987 
For continuous outcomes, median and interquartile ranges and/or means and standard deviations 
988 
will be reported to describe the data. Only participants with available CST at the primary outcome 
989 
visit that did not already receive alternative DME treatment will be included. No statistical 
990 
comparisons will be performed in Phase 2 to compare treatment groups.   
991 
7.11 OCT Angiography Ancillary Study 
992 
At a subset of sites with OCT angiography capabilities, images will be taken at baseline and 4 
993 
months to explore whether there are changes in any features evident on OCT angiography. 
994 
7.12 Intervention Adherence 
995 
For the primary analyses at the end of Phase 1, adherence will be defined as compliance with 
996 
device use during the primary outcome phase. An exploratory dose response analysis will be 
997 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
7-6 
performed to evaluate whether there appears to be an association of compliance (defined as the 
998 
total number of sessions of the study device use during the primary outcome phase) versus 
999 
magnitude of treatment effect (defined as the change in OCT CST from baseline at primary 
1000 
outcome visit). The distribution of the total number of sessions will be described using summary 
1001 
statistics and graphical methods. A scatter plot with a regression line will be constructed to 
1002 
examine for evidence of dose-response, separately for each treatment group. If there is evidence 
1003 
of a dose-response effect in either or both groups, an analysis of covariance will be performed 
1004 
including treatment, compliance, and the interaction between treatment group and compliance to 
1005 
test for evidence that the dose-response effect is limited to the active treatment group. If the 
1006 
interaction between compliance and treatment group is significant, a stratified analysis will be 
1007 
performed to evaluate the potential association between compliance and treatment effect within 
1008 
each treatment group. Model assumptions will be checked, and transformation or categorization 
1009 
of compliance will be used if there is evidence of non-linearity in the dose response. It is 
1010 
recognized that the study is not powered to detect a definitive dose-response association existing 
1011 
only in the active treatment group and that lack of significance is not necessarily an indication that 
1012 
the association does not exist. It is also recognized that compliance may be affected by both 
1013 
measured and unmeasured post-randomization factors, including efficacy of masking and 
1014 
perceived effects of the treatment; hence, the observed dose-response associations may be biased. 
1015 
 
1016 
If compliance lessens over time during the primary outcome phase, an exploratory analysis will 
1017 
investigate whether there appears to be any association of compliance versus magnitude of 
1018 
treatment effect over those months. 
1019 
 
1020 
For Phase 2, adherence will be evaluated in a similar fashion for those using the device to assess 
1021 
whether compliance affects the post-switch effect within group, specifically: 
1022 
• For the initial treated group, whether there is an association between compliance during 
1023 
phase 1 and duration of treatment effect in phase 2. 
1024 
• For the initial sham group, whether there is an association between compliance during 
1025 
phase 2 and treatment effect in phase 2.   
1026 
 
1027 
In addition, for each phase the effect of text message reminders will be evaluated by assessing 
1028 
compliance within each treatment group.  Compliance will be defined as the total number of 
1029 
sessions of the study device use during each phase divided by the total number of possible 
1030 
treatment sessions.  This analysis will consist of a comparison between those receiving texts and 
1031 
those not received texts of mean compliance using analysis of covariance, with adjustment for 
1032 
treatment. Only participants who have been randomly assigned to receive or not receive text 
1033 
messages will be included in this analysis.   
1034 
7.13 Protocol Adherence and Retention 
1035 
Protocol deviations and visit completion rates (excluding deaths) will be tabulated for each 
1036 
treatment group. 
1037 
7.14 Baseline Descriptive Statistics 
1038 
Baseline characteristics will be tabulated by treatment group and summary statistics appropriate 
1039 
to the distribution will be reported. 
1040 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
7-7 
7.15 Device Issues 
1041 
Number of reported device issues will be tabulated by treatment group. 
1042 
7.16 Planned Interim Analyses 
1043 
There is no formal interim analysis planned for this study. The Data and Safety Monitory 
1044 
Committee (DSMC) will review tabulated safety and outcome data approximately every 6 months 
1045 
while the study is ongoing. 
1046 
7.17 Subgroup Analyses 
1047 
Subgroup analyses/assessments of effect modification (interaction) will be conducted for the 
1048 
primary outcome. Since there is no strong prior rationale for potential subgroup effects, these 
1049 
analyses will be considered exploratory and hypothesis generating, rather than definitive. It is 
1050 
recognized that the study is not powered to detect subgroup effects and that lack of significance is 
1051 
not necessarily an indication that subgroup effects do not exist. Additionally, interpretation of the 
1052 
analyses will depend on whether the primary analysis demonstrates a significant treatment group 
1053 
difference; in the absence of such a difference, subgroup analyses will be interpreted with caution. 
1054 
The general approach for these exploratory analyses will be to add an interaction term for the 
1055 
subgroup factor by treatment into the primary analysis model. 
1056 
Subgroup analyses will use observed data (no imputation) from participants who complete the 
1057 
primary outcome visit without missing CST data. Exploratory subgroup analysis will evaluate the 
1058 
effects of the following baseline factors: 
1059 
• Prior DME treatment: yes vs. no 
1060 
• Intravitreous treatment in non-study eye: recent (within 4 months) or planned  
1061 
• Lens status: phakic vs. pseudophakic 
1062 
• Baseline CST: continuous and categorical (dichotomized based on a clinically relevant cut 
1063 
point or an approximate median value) 
1064 
• Hemoglobin A1c: continuous and <7.5% vs. ≥7.5% 
1065 
• Iris color: blue, brown, or other 
1066 
Subgroup analyses will only be conducted if there are at least 20 eyes in each subgroup for each 
1067 
treatment group. There are no data to suggest that the treatment effect will vary by sex or 
1068 
race/ethnicity. However, both of these factors will be evaluated in exploratory subgroup analyses 
1069 
as mandated by NIH guidelines. Subgroup factors will be analyzed as continuous/ordinal variables 
1070 
where possible. 
1071 
7.18 Multiple Comparisons/Multiplicity 
1072 
Due to the large number of outcomes evaluated, only P < .05 will be considered of interest and 
1073 
warranting further exploration. It is recognized that this does not completely control the Type I 
1074 
error rate. There will be no other adjustments made for multiple comparisons or multiple testing. 
1075 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
7-8 
7.19 Additional Tabulations and Analyses 
1076 
To evaluate the potential contralateral effect, visual acuity, OCT measurements, and treatment for 
1077 
DME in non-study eyes will be tabulated at primary outcome visit by the treatment group assigned 
1078 
to the study eye. These outcomes will be analyzed and presented similarly to the primary and 
1079 
secondary analyses as specified above for the study eyes, with the exception that no imputation 
1080 
will be performed for missing data. 
1081 
This pilot study is being conducted to determine whether the conduct of a pivotal trial has merit 
1082 
based on an anatomic outcome and to provide information on outcome measures needed to design 
1083 
a pivotal trial. If the results of this study support proceeding with a pivotal trial after evaluation of 
1084 
all the data and discussion within DRCR, information from this study will contribute to designing 
1085 
the pivotal trial. The standard deviation of the difference in visual acuity will be used in the sample 
1086 
size calculation of the pivotal trial. Patient compliance (for example, the proportion of enrolled 
1087 
participants that are randomized and the proportion of randomized participants who comply with 
1088 
the use of the study device post-randomization) will also aid in the design of the pivotal trial.  
1089 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
8-1 
 DATA COLLECTION AND MONITORING 
1090 
8.1 Case Report Forms and Device Data 
1091 
The main study data are collected through electronic case report forms (CRFs).  Compliance data 
1092 
are collected via electronic device data files obtained from the study device.  When data are directly 
1093 
collected in electronic case report forms, this will be considered the source data.  Each participating 
1094 
site will maintain appropriate medical and research records for this trial, in compliance with ICH 
1095 
E6 and regulatory and institutional requirements for the protection of confidentiality of 
1096 
participants. 
1097 
8.2 Study Records Retention 
1098 
Study documents should be retained for a minimum of 3 years following the NIH grant cycle for 
1099 
which the last visit was completed (expected to be December 31, 2026) or 2 years after the last 
1100 
approval of a marketing application in an ICH region and until there are no pending or 
1101 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since 
1102 
the formal discontinuation of clinical development of the investigational product, whichever is 
1103 
later.  These documents should be retained for a longer period, however, if required by local 
1104 
regulations.  No records will be destroyed without the written consent of JCHR, if applicable.  It 
1105 
is the responsibility of JCHR to inform the investigator when these documents no longer need to 
1106 
be retained. 
1107 
8.3 Quality Assurance and Monitoring 
1108 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1109 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1110 
conducted and data are generated, documented and reported in compliance with the protocol, Good 
1111 
Clinical Practice (GCP) and the applicable regulatory requirements.  Adverse events will be 
1112 
prioritized for monitoring. 
1113 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1114 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical Investigations 
1115 
— A Risk-Based Approach to Monitoring” (August 2013).  Study conduct and monitoring will 
1116 
conform with 21 Code of Federal Regulations (CFR) 812. 
1117 
The data of most importance for monitoring at the site are participant eligibility and adverse events.  
1118 
Therefore, the RBM plan will focus on these areas.  As much as possible, remote monitoring will 
1119 
be performed in real-time with on-site monitoring performed to evaluate the verity and 
1120 
completeness of the key site data.  Elements of the RBM may include: 
1121 
• Qualification assessment, training, and certification for sites and site personnel 
1122 
• Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
1123 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1124 
review of entered data and edits, statistical monitoring, study closeout 
1125 
• On-site monitoring (site visits): source data verification, site visit report 
1126 
• Device accountability 
1127 
• Communications with site staff 
1128 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
8-2 
• Patient retention and visit completion 
1129 
• Quality control reports 
1130 
• Management of noncompliance 
1131 
• Documenting monitoring activities 
1132 
• Adverse event reporting and monitoring 
1133 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1134 
order to maintain current and personal knowledge of the study through review of the records, 
1135 
comparison with source documents, observation and discussion of the conduct and progress of the 
1136 
study. 
1137 
8.4 Protocol Deviations 
1138 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1139 
requirements.  The noncompliance may be either on the part of the participant, the investigator, or 
1140 
the study site staff.  As a result of deviations, corrective actions are to be developed by the site and 
1141 
implemented promptly. 
1142 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements.  Further 
1143 
details about the handling of protocol deviations will be included in the monitoring plan. 
1144 
 
1145 
 
 
1146 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
9-2 
 ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
1147 
9.1 Ethical Standard 
1148 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1149 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
1150 
CFR Part 56, and/or the ICH E6. 
1151 
9.2 Institutional Review Boards 
1152 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1153 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1154 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
1155 
require review and approval by the IRB before the changes are implemented to the study.  All 
1156 
changes to the consent form will be IRB approved; a determination will be made regarding whether 
1157 
previously consented participants need to be re-consented. 
1158 
9.3 Informed Consent Process 
1159 
9.3.1 Consent Procedures and Documentation 
1160 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
1161 
study and continues throughout the individual’s study participation.  Extensive discussion of risks 
1162 
and possible benefits of participation will be provided to the participants and their families.  
1163 
Consent forms will be IRB-approved, and the participant will be asked to read and review the 
1164 
document.  The investigator will explain the research study to the participant and answer any 
1165 
questions that may arise.  All participants will receive a verbal explanation in terms suited to their 
1166 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
1167 
research participants.  Participants will have the opportunity to carefully review the written consent 
1168 
form and ask questions prior to signing. 
1169 
The participants should have the opportunity to discuss the study with their family members and 
1170 
their personal physicians(s) or think about it prior to agreeing to participate.  The participant will 
1171 
sign the informed consent document prior to any procedures being done specifically for the study.  
1172 
The participants may withdraw consent at any time throughout the course of the trial.  A copy of 
1173 
the informed consent document will be given to the participants for their records.  The rights and 
1174 
welfare of the participants will be protected by emphasizing to them that the quality of their 
1175 
medical care will not be adversely affected if they decline to participate in this study. 
1176 
9.3.2 Participant and Data Confidentiality 
1177 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and 
1178 
the JCHR and their agents.  This confidentiality is extended to cover biological samples in addition 
1179 
to the clinical information relating to participants.  Therefore, the study protocol, documentation, 
1180 
data, and all other information generated will be held in strict confidence.  No information 
1181 
concerning the study, or the data will be released to any unauthorized third party without prior 
1182 
written approval of the JCHR. 
1183 
The study monitor, other authorized representatives of the JCHR, or representatives of the IRB 
1184 
may inspect all documents and records required to be maintained by the investigator, including but 
1185 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
9-3 
not limited to, and medical records (office, clinic, or hospital).  The clinical study site will permit 
1186 
access to such records. 
1187 
The study participant’s contact information will be securely stored at each clinical site for internal 
1188 
use during the study.  At the end of the study, all records will continue to be kept in a secure 
1189 
location for as long a period as dictated by local IRB and Institutional regulations. 
1190 
Separately from any research data, the coordinating center for the study, the Jaeb Center for Health 
1191 
Research (JCHR) in Tampa, Florida, will be provided with participant contact information to aid 
1192 
in study retention efforts. Study participant’s contact information will be securely stored and will 
1193 
be destroyed at the end of the study. 
1194 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
1195 
will be transmitted to and stored at JCHR.  This will be stored separately from the participant’s 
1196 
contact or direct identifying information.  For research purposes, individual participants and their 
1197 
research data will be identified by a unique study identification number.  The study data entry and 
1198 
study management systems used by clinical sites and by JCHR research staff will be secured and 
1199 
password protected.  At the end of the study, all study databases will be de-identified and archived 
1200 
at JCHR. 
1201 
To further protect the privacy of study participants, a Certificate of Confidentiality is available 
1202 
from the NIH.  This certificate protects identifiable research information from forced disclosure.  
1203 
It allows the investigator and others who have access to research records to refuse to disclose 
1204 
identifying information on research participation in any civil, criminal, administrative, legislative, 
1205 
or other proceeding, whether at the federal, state, or local level.  By protecting researchers and 
1206 
institutions from being compelled to disclose information that would identify research participants, 
1207 
Certificates of Confidentiality help achieve the research objectives and promote participation in 
1208 
studies by helping assure confidentiality and privacy to participants. 
1209 
9.3.3 Future Use of Stored Data 
1210 
 Data collected for this study will be analyzed and stored at the Jaeb Center for Health Research.  
1211 
After the study is completed, the de-identified, archived data will be made publicly available, for 
1212 
use by other researchers including those outside of the study.  Permission for future use of the data 
1213 
will be included in the informed consent. 
1214 
 
1215 

Jaeb Center for Health Research 
Protocol AE - Photobiomodulation Study v4.0 3-31-20_Clean20   
10-1 
 REFERENCES 
1216 
1. 
National Diabetes Statistics Report, 2017. Estimates of diabetes and its burden in the 
1217 
United 
States. 
 
https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-
1218 
statistics-report.pdf. 
1219 
2. 
Centers for Disease Control and Prevention. National Diabetes Fact Sheet.  
1220 
https://www.cdc.gov/visionhealth/pdf/factsheet.pdf, Accessed March 21, 2011. 
1221 
3. 
Vision problems in the U.S.: Prevalence of adult vision impairment and age-related eye 
1222 
disease in America.  http://www.visionproblemsus.org/. Accessed 16 November 2016. 
1223 
4. 
National 
Eye 
Institute. 
Facts 
about 
diabetic 
eye 
disease.  
1224 
https://nei.nih.gov/health/diabetic/retinopathy. 
1225 
5. 
Centers for Disease Control and Prevention. State-specific incidence of diabetes among 
1226 
adults--participating states, 1995-1997 and 2005-2007. MMWR Morb Mortal Wkly Rep. 
1227 
2008;57(43):1169-73. 
1228 
6. 
International 
Diabetes 
Federation: 
Facts 
and 
figures.  
1229 
http://www.idf.org/worlddiabetesday/toolkit/gp/facts-figures Accessed 26 September 
1230 
2016. 
1231 
7. 
Varma R, Bressler NM, Doan QV, et al. Prevalence of and risk factors for diabetic macular 
1232 
edema in the United States. JAMA Ophthalmol. 2014;132(11):1334-40. 
1233 
8. 
Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 
1234 
2012;366(13):1227-39. 
1235 
9. 
Aiello LP. Angiogenic pathways in diabetic retinopathy. N Engl J Med. 2005;353:839-41. 
1236 
10. 
Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating 
1237 
ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic 
1238 
macular edema. Ophthalmology. 2010;117(6):1064-77 e35. 
1239 
11. 
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: 
1240 
Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 
1241 
2012;119(4):789-801. 
1242 
12. 
Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic 
1243 
macular edema. Ophthalmology. 2014;121(11):2247-54. 
1244 
13. 
Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study ranibizumab 
1245 
monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. 
1246 
Ophthalmology. 2011;118(4):615-25. 
1247 
14. 
Ferris FL, 3rd, Patz A. Macular edema. A complication of diabetic retinopathy. Surv 
1248 
Ophthalmol. 1984;28 Suppl:452-61. 
1249 
15. 
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for 
1250 
diabetic macular edema: ETDRS report number 4. Int Ophthalmol Clin. 1987;27(4):265-
1251 
72. 
1252 
16. 
American Academy of Ophthalmology. Preferred Practice Patterns: Diabetic Retinopathy.  
1253 
http://www.guideline.gov/summary/summary.aspx?doc_id=13502 Accessed Accessed 
1254 
November 9, 2009. 
1255 
17. 
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for 
1256 
diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. 
1257 
Arch Ophthalmol. 1985;103(12):1796-806. 
1258 
18. 
Maeshima K, Utsugi-Sutoh N, Otani T, Kishi S. Progressive enlargement of scattered 
1259 
photocoagulation scars in diabetic retinopathy. Retina. 2004;24(4):507-11. 
1260 
19. 
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