Examining the Relationship Between Diabetic Macular Edema and Obstructive Sleep Apnea: Prevalence, Association and Impact.
Conditions: Diabetic Macular Edema, Sleep Apnea, Non Proliferative Diabetic Retinopathy
Sponsor: Uptown Eye Specialists

 
DME-OSA Study 
 
 
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PROTOCOL: DME-OSA 
PRIMARY INVESTIGATOR: Dr. Sohel Somani 
CO-INVESTIGATOR: Dr. Alan Kosaric, Dr. M.R. Goolam Hussain 
 
PRTOCOL TITLE: Examining the relationship between Diabetic Macular Edema and Obstructive 
Sleep Apnea: prevalence, association and impact. 
 
SHORT TITLE: DME-OSA study 
 
INTRODUCTION 
Study Rationale 
Obstructive sleep apnea (OSA) is a well-studied disease affecting millions of North Americans. 
OSA causes intermittent episodes of hypoxemia which may cause hypertension in some 
patients. Increased severity of OSA is linked with an increased chance of developing coronary 
artery disease, heart failure, arrhythmias, and stroke, which may lead to sudden death. OSA can 
also cause daytime fatigue and random onset of sleep, which can cause serious harm to the 
patient if engaging in an activity requiring a high level of mental focus (i.e. driving). OSA can also 
impact a patient’s response to medications and surgery; general anesthesia can worsen OSA 
due to its impact on the upper airway increasing complications post-surgery. Most OSA patients 
are undiagnosed; many do not consider snoring or other symptoms as cause for concern, 
adjusting to maintain an adequate lifestyle. However, undiagnosed OSA can lead to severe 
comorbidities and possibly the demise of the patient.  
 
OSA has been found to affect up to 86% of type 2 diabetic patients [1, 2]. Chronic intermittent 
hypoxia (CIH) is a feature of OSA that has shown to increase insulin resistance [3]. A causal link 
between OSA and diabetes has yet to be established; however, the prevalence of diabetes in 
OSA patients is significantly higher (15%) compared to the general population (3%)[4]. In 
essence, the relationship has been shown to be bidirectional (i.e. OSA patients are more likely 
to develop diabetes and diabetic patients are more likely to develop OSA than the general 
population). 
 
Based on this relationship, researchers sought out to identify whether a correlation exists 
between microvascular complications of diabetes, such as diabetic retinopathy (DR) and OSA. A 
Japanese study identified a 29% and 48% prevalence of OSA among patients with non-
proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) 
respectively; the difference in prevalence being significant[5]. The authors suggest a potential 
relationship between OSA and the development of PDR. In another study at Oxford, West et al 
(2010) identified a 24% prevalence of OSA in men with Type II diabetes, indicating that OSA and 
HbA1c were the only significant predictors of retinopathy[6]. However, another study describes 
the relationship between DR and OSA as statistically insignificant[7].  
 
A review of the literature has shown there to be limited studies looking at the relationship 
between OSA and diabetic maculopathy[8]. One study identified a 65% prevalence of OSA 
among patients with clinically significant macular edema (CSME)[9]. However, the authors did 

 
DME-OSA Study 
 
 
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not find a statistical significance between the severity of maculopathy and the severity of OSA. 
Another study identified no difference between retinopathy in patients with or without OSA 
(39% vs. 38%) but did find an association between maculopathy in patients with OSA compared 
to those without (22% vs. 13%) but this was not statistically significant[7]. The results of both 
these studies are limited by the use of a home sleep studies rather than an overnight sleep 
study. Treating OSA with continuous positive airway pressure (CPAP) has shown to improve 
visual acuity in DME patients but no changes in macular thickness was observed[10]. 
 
The current literature lacks a thorough analysis of the relationship of DME and OSA. Of the few 
studies that assess macular edema and OSA, home sleep studies were conducted. In this study 
protocol, we aim to have patients thoroughly evaluated in an overnight sleep lab monitored by 
a sleep specialist. Furthermore, appropriate interventions will be carried out if positive OSA is 
identified. 
 
STUDY OBJECTIVES 
Our study aims to answer more definitively the relationship between OSA and DME on three 
levels: 
 
1. What is the prevalence and correlation of OSA in a DME population? 
 
We hypothesize a relationship does exist based on previous studies of DME and OSA (65% 
prevalence of OSA among DME patients). However, this study diagnosed OSA using a home 
sleep study, which is not considered to be a true gold standard test in sleep medicine 
research. We aim to identify the presence of OSA using the gold standard testing of an 
overnight sleep study to determine the prevalence of OSA in the DME population. Further, 
we will attempt to determine if there is a correlation of OSA by comparing it to non-DME 
patients who have NPDR. 
 
2. Is there an association of severity between OSA and DME? 
 
The second clinical question entails whether the severity of OSA is correlated with the 
severity of DME. The mechanism of OSA action on diabetic microvascular complications 
may involve increased inflammatory responses and oxidative stress pathways such as 
increased advanced glycation end products[11, 12]. Thus, we hypothesize that the 
increased severity of OSA will be positively correlated with increased severity of DME. By 
comparing the gold standard metric of severity index of OSA (Apnea-hypopnea index) to 
DME metrics (LogMAR Snellen vision and CRT) at the baseline of both disease diagnoses, we 
can determine severity association. 
 
3. Is there any impact on OSA treatment (i.e. CPAP) on DME treatment? 
 
Only one study has attempted to identify if OSA treatment can enhance DME outcomes. 
Mason et al (2012) found a significant improvement of visual acuity among OSA treatment 
patients but their macular thickness was not significantly different. We aim to further 

 
DME-OSA Study 
 
 
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explore this relationship by comparing the results of DME treatment 1 year following CPAP 
initiation. The specific metrics of DME treatment (Vision, CRT, number of injections) will be 
compared to pre-CPAP data to determine what the impact of CPAP was (if any) on DME 
treatment metrics. Further, we aim to compare the one-year post-CPAP DME treatment 
metrics against one-year non-CPAP/non-OSA patients to determine the relative impact 
against a control group.   
 
We hypothesize that CPAP users demonstrate an improvement on Vision and CRT metrics 
compared to prior to initiation of CPAP. We further hypothesis that CPAP users and non-
CPAP users have equivalent visual acuity, CRT, and number of injections due to the 
neutralization effect (i.e. OSA neutralized by CPAP). 
 
In summary: 
Question 1: Is there a correlation between DME and OSA? 
 
DME + 
DME - / NPDR + 
OSA + 
 
 
OSA - 
 
 
 
Question 2: Is there a relationship between the severity of DME (CRT and vision) and OSA (AHI 
index)? 
 
 
 
 
 
 
 
Question 3: Does treating OSA result in improving DME metrics, and does it neutralize the 
outcomes at 1 year compared to OSA negatives. 
 
 
 
 
 
 
 
 
 
 
 
 
OSA 
DME 
DME 
OSA + 
OSA - 
Equivalent DME status 12 months later 

 
DME-OSA Study 
 
 
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INVESTIGATIONAL PLAN 
Study Design 
A 12 month, non-randomized, controlled, prospective study evaluating the relationship 
between diabetic macular edema (DME) and obstructive sleep apnea (OSA). Investigational 
sites will have Ethics Review Board approval prior to enrolling patients. 
 
All subjects who meet eligibility criteria will be consecutively offered enrollment into the study 
until the study has fulfilled all enrollment requirements, or terminated by the Primary 
Investigator. The study will be initiated upon Ethics review and approval. 
 
PATIENT SELECTION 
 
Key Inclusion Criteria 
 18 years of age or greater 
 Ability to understand and provide written consent 
 Type II diabetes patients and evidence of Diabetic Retinopathy 
 Patients with and without DME 
 Able and willing to comply with all treatment and follow-up procedures 
 
Key Exclusion Criteria 
 Contraindications to Eylea including: stroke within the past month, ocular or periocular 
infection, active intraocular inflammation, hypersensitivity to Eylea and/or its excipients. 
 Contraindication to CPAP including: severe bullous lung disease, pneumothorax, 
pathologically low blood pressure, dehydration, cerebrospinal fluid leak, recent cranial 
surgery, or trauma 
 Any other types of retinal diseases such as retinal detachment 
 Any other types of macular disease such as age-related macular degeneration 
 Mental capacity to comply is impaired (i.e. dementia) 
 Pregnant or breastfeeding women 
 Participation in any drug or device clinical investigation within 30 days prior to entry into 
the study 
 
Subject Enrollment 
The subject must satisfy all eligibility criteria to enroll. The subject is considered enrolled in the 
study at the time the first anti-VEGF injection is administered. 
 
Subject Completion 
The subject has completed the entire study after 12 months of receiving routine injections to 
the study eye and has initiated CPAP treatment, if applicable, for at least 3 months.  
 
Subject Withdrawal 

 
DME-OSA Study 
 
 
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A subject may discontinue from the study prior to the final study visit due to voluntary 
withdrawal or death. Prior to discontinuing a subject who voluntarily withdraws, every effort 
should be made to contact the subject, schedule a final study visit, and obtain as much follow-
up data as possible. Discontinued subjects who withdraw consent should be followed outside of 
the study protocol according to the Investigator’s normal standard of care. The Investigator 
may withdraw a patient for rescheduling appointments that prevent them from following the 
protocol’s injection schedule. 
 
Premature patient withdrawal from the study 
Patients will be withdrawn from the study under the following circumstance: 
 Withdrawal of study informed consent 
 Patient exhibits one or more contraindications to Eylea or CPAP as described in the 
exclusion criteria or develops an unexpected AE with respect to the study treatment 
(either Eylea or CPAP if applicable) 
 Worsening of diabetic macular edema despite optimal Eylea dosing (requiring a second 
line rescue medication or procedure) 
 Patient develops a new retinal or macular disease along the course of the study 
 Patient becomes pregnant or begins breastfeeding 
 Patient’s mental status and capacity becomes significantly altered (i.e. develops 
dementia) 
 Patient switches treatments 
 Patient non-compliance defined as missing at least 2 consecutive study visits 
 
If premature withdrawal occurs for the reasons described above, the investigator should make 
every effort to record the primary reason for a patient’s premature withdrawal from the study 
on the Study Completion CRM. 
 
Lost to Follow-up 
Subjects who do not return for their routine injections or must reschedule due to personal 
reasons may be considered lost to follow-up. All follow-up attempts will be documented and 
kept with the subject’s source documentation. 
 
PLANNED STUDY PERIOD AND DURATION OF TREATMENT 
 
The duration of the study, including the time to recruit all subjects, will be up to 12 months. 
Eligible subjects who are enrolled in the study will be seen for up to 12 months. 
 
Early Study Termination 
If during the study, the primary investigator determines that the study should be stopped 
prematurely, the study will be terminated or suspended and appropriate notification will be 
given to the investigator(s) and patients. 
 
 

 
DME-OSA Study 
 
 
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PROTOCOL 
 
Design 
Subjects eligible for the inclusion in the study will be grouped based on their diagnosis: DME & 
OSA positive, DME positive only, OSA positive only, and DME & OSA negative.  
 
All DME positive patients (irrespective of OSA status) will receive the standard of care 
treatment with anti-VEGF using Eylea in a standardized treat and extend protocol. 
 
Patients above the age of 65, the Eylea product is covered under the public health plan (ODB). 
Patients under the age of 65, the Eylea product will be provided by the patient’s private plan. In 
the absence of such a plan, the Eylea product will be provided at no cost to the patient. CPAP 
machines will need to be purchased by the patient if they are diagnosed with sleep apnea and 
their private plans do not cover it. All DME negative patients will not be receiving Eylea. All DME 
positive patients will receive Eylea until resolution of DME. This is not a drug trial, hence no 
placebo or randomization issues that affect accountability is applicable. 
 
All patients (irrespective of DME status) will be sent to a sleep lab to identify OSA status. OSA 
positive patients will be provided the standard of care (i.e. CPAP) treatment. CPAP machines 
will be prescribed and the patient will be responsible to purchase the machine using provincial 
and/or private insurance, or personal funds.   
 
Study Size 
All groups to include 150 patients total (i.e. 75 DME positive, 75 DME negative) 
 
Participating Sites 
The clinical trial will be conducted at up to 3 investigative sites located in Canada. The study will 
be conducted by Investigators who are determined by the Primary Investigator to be suitably 
qualified by training and experience to conduct this study in compliance with all applicable 
good clinical practices (GCPs). Each investigative site (except the sleep lab) will attempt to 
enroll a minimum of 10 subjects. In the event that selected sites do not meet full enrollment, 
the Primary Investigator may decide to increase enrollment as needed at other currently active 
sites and/or additional site(s) may be added to satisfy the enrollment requirements of the 
study. The primary Investigator will monitor other sites through monthly review of all CRMs to 
ensure proper documentation (consent, CRM, etc) and protocol adherence. 
 
Study methods 
Subjects who meet eligibility criteria will be seen according to the following schedule (unless 
discontinued or lost to follow-up) and must adhere to the following schedule: 
 
Visit 1: Baseline DME Treatment or NPDR diagnosis (if not DME) 
Visit 2: Diagnosis of OSA – Overnight sleep study + consult 
Visit 3: 6-month visit post DME initial treatment  
Visit 4: 12-month visit post DME initial treatment in the OSA- group and at least 3 
months post CPAP initiation in the OSA+ group 

 
DME-OSA Study 
 
 
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NPDR 
DME - 
DME + 
OSA testing 
OSA - 
OSA + 
OSA - 
OSA + 
CPAP initiation 
CPAP initiation  
1 year follow up post-DME initiation 
3+ months  
3+ months  
Baseline measurements 
1. Snellen Vision 
2. CRT 
3. #injections 
Study 
Visit#2: 
 
6 month 
f/u 
Study Visit#3: 
 
12-month f/u 
(final) 

 
DME-OSA Study 
 
 
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Table 1 
 
 
BCVA  best-corrected visual acuity; CRT  Central Retinal Thickness; OCT  Optical 
Coherence Tomography ESS  Epworth Sleepiness Scale; SSS  Stanford Sleepiness Scale; AHI 
 Apnea-hypopnea index; OAI  Overall arousal index; ODI  Oxygen desaturation index 
 
Table 2 
  
Visit 1 
Visit 2 Dx of OSA 
  
Baseline DME treatment or NPDR dx 
(if not DME) 
Diagnostic 
RAPD 
  
N/A 
AR 
  
Pachymetry (CCT) 
  
IOP 
  
PENTACAM topography 
  
Cornea SPK 
  
Upper eyelid papillary conjunctivitis 
  
Eyelid elasticity score 
  
OCT RNFL 
  
VF 
  
Vitals: BP, HR, O2 
N/A 
  
Ethnicity 
  
Age 
  
Sex 
  
Neck circumference 
  
Height 
  
Weight 
  
BMI 
  

 
DME-OSA Study 
 
 
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Duration of diabetes 
  
Past Medical History 
  
Past Surgical History 
  
Medications 
  
Waist Circumference 
  
Smoking 
  
Alcohol 
  
 
RAPD  relative afferent pupillary defect; AR  autorefractor; RNFL  retinal nerve fiber 
layer; VF  Visual field; IOP  intraocular pressure; CCT  central corneal thickness;; SPK  
superficial punctate keratitis 
 
During each visit, the intraocular pressure and perfusion of the optic nerve head will be 
monitored for patient safety. 
 
Visual acuity testing is a primary marker of efficacy and subject safety, as any decline in this 
parameter triggers a clinical evaluation for cause.  During each study visit, patients will also 
have an opportunity to report of any safety issues. 
 
Table 3: DME positive patients will receive a minimum of 6 injections with the first five 
occurring at 1-month intervals and the sixth occurring two months after the fifth. Further 
injections will be provided at the discretion of the ophthalmologist in according to the treat and 
extend protocol of Eylea. Data for Visits 1 and 4 in Table 1 will be collected at the first and sixth 
injections whereas the other injection visits will be treated as regular office visits and not study 
visits.  
DME EYLEA TREATMENT 
 
INJECTION 1 
Collect data 
INJECTION 2 
n/a 
INJECTION 3 
n/a 
INJECTION 4 
n/a 
INJECTION 5 
n/a 
INJECTION 6 
Collect data 
 
 
ADVERSE EVENTS 
Throughout the course of the study, all efforts will be made to remain alert to possible AEs. If 
an AE occurs, the first concern will be the safety of the subject and appropriate medical 
intervention will be made. All ocular AEs that occur in the study eye and all systemic AEs (both 
ocular and non-ocular) will be collected. Non-serious non-ocular AEs will not be reported. The 
collection of AEs begins at the time the subject is enrolled into the study. 
 
Common adverse events to Eylea to be reported include: conjunctival hemorrhage, eye pain, 
cataract, and vitreous floaters. Adverse events to CPAP may include: drying of the nose, mouth, 
or throat, nosebleed, bloating, ear or sinus discomfort, eye irritation, or skin rashes. 

 
DME-OSA Study 
 
 
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Serious Unexpected Adverse Drug Reaction Reporting 
During the course of a clinical trial, the sponsor shall inform the Minister of any serious 
unexpected adverse drug reaction in respect of the drug that has occurred inside or outside 
Canada as follows: 
(a) if it is neither fatal nor life threatening, within 15 days after becoming aware of the 
information; and 
(b) if it is fatal or life threatening, within seven days after becoming aware of the 
information. 
The sponsor shall, within eight days after having informed the Minister under paragraph (1)(b), 
submit to the Minister a complete report in respect of that information that includes an 
assessment of the importance and implication of any findings made. 
The AE's that will be reported are those that are NOT associated or described in the product 
monograph - as these will truly be "unexpected" in nature. 
--- 
To ensure patient safety, every SAE (serious adverse event), regardless of suspected causality, 
occurring after the patient has provided informed consent and until 30 days after the patient 
has stopped study participation (defined as time of last injection of Eylea) must be reported to 
Bayer within 24 hours of learning of its occurrence. 
 
Any SAEs experienced after this 30-day period should only be reported to Bayer if the 
investigator suspects causal relationship to Eylea. 
 
Recent episodes, complications, or progression of initial SAE must be reported as follow-up to 
the original episode, regardless of when the event occurs. This report must be submitted within 
24 hours of the investigator receiving the follow-up information. An SAE that is considered 
completely unrelated to a previously reported one should be reported separately as a new 
event.  
  
Information about all SAEs is collected and recorded on the Serious Adverse event Report Form. 
The investigator must assess the relationship of any SAE to Eylea, complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the local Bayer 
Druga Safety and Epidemiology Department. The telephone an telecopy number of the contact 
persons in the local department of Clinical Safety and Epidemiology, specific to the site, are 
listed in the investigator folder provided to each site. The original copy of the SAE Report Form 
and the fax confirmation sheet must be kept with the case report form documentation at the 
study site. 
 

 
DME-OSA Study 
 
 
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Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated and whether the patient 
continued or withdrew from study participation.  
 
If the SAE is not previously documented in the local product label or package insert (new 
occurrence) and is thought to be related to Eylea, a Drug Safety and Epidemiology Department 
associate may urgently require further information from the investigator for Health Authority 
reporting. 
 
Any device problem reports (as described in Health Canada Guidance Document for Mandatory 
Problem Reporting for Medical Devices) related to the CPAP device will be reported promptly to 
the manufacturer. 
 
STATISTICAL METHODS 
 
Primary Clinical Endpoints 
 Presence of DME and OSA 
 DME: Snellen Visual Acuity 
 OSA: Apnea-hypopnea index 
 
Primary Safety Endpoints 
 Incidence of cumulative adverse events (AEs; evaluated at all visits) 
 
Secondary Clinical Endpoints 
 DME: CRT, # of injections 
 OSA: compliance 
 
Tertiary Clinical Endpoint 
 The International Clinical Disease Severity Scale for Diabetic Retinopathy [13] based on 
clinical exam or colour fundus photography: 
o No DR 
o Mild Retinopathy 
o Moderate Retinopathy 
o Severe Retinopathy 
 Hemoglobin A1c 
 
Randomization 
Randomization is not applicable to this study. 
 
Sample size 
150 patients – 75 DME positive, 75 DME negative 
Estimates based off 65% prevalence in DME+ patients and 29% in NPDR+. 

 
DME-OSA Study 
 
 
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DME + 
DME -/NPDR + 
OSA + 
48 
21 
OSA - 
27 
54 
 
 
Statistical analysis 
Assuming the prevalence of OSA as 65% in DME+ patients and 29% in DME-/NPDR+, a sample 
size of 75 patients in both DME+ and DME- group provides >99% power to detect correlations 
between DME and OSA (Research Question 1), with a two sided test controlling type I error as 
0.05. A slight over power here due to the considerations of research Question 3 in comparing 
DME metrics (i.e., Snellen VA for sample size calculation) between OSA+ (CPAP+) and OSA- 
(CPAP-) patients: assuming a SD of 2 lines in Snellen VA (based on extrapolation from the 
RISE/RIDE paper), and the same prevalence as given above (65% and 29%), a sample size of 75 
patients in both DME+ and DME- groups would provide 85% power to detect a difference in 
Snellen VA of 1 line between OSA+ and OSA- patients, in a 2 sided test with type I error 
controlled as 0.05. The research Question 2 is more exploratory and not considered in the 
sample size calculation. 
 
APPENDIX 
 
Description of procedures: 
Vision (Snellen BCVA): measuring visual acuity using a typical Snellen chart providing vision as 
20/100, 20/50, etc. This value is converted to a logarithmic scale (i.e. LogMAR BCVA) 
Central Retinal Thickness (CRT): Central retinal thickness is measured using an optical 
coherence tomography to ensure no damage to retinal occurs 
Fundus exam: assessment of the retina, optic nerve head, blood vessels, and other features of 
the eye. 
Relative afferent pupillary defect (RAPD): a condition in which pupils respond differently to 
light stimuli shone in one eye at a time due to unilateral or asymmetrical disease of the retina 
or optic nerve 
Autorefractor (AR): provides an objective measurement of a person’s refractive error and 
prescription for glasses or contact lenses 
Retinal Nerve Fiber Layer (RNFL): evaluating the retinal nerve fiber layer is essential in 
understanding the patient’s current ocular diseases and potential future occurrences. 
Visual Field (VF): entire area that the patient is able to see when their eyes are fixed in one 
position 
Intraocular Pressure (IOP): fluid pressure inside the eye 
Central Corneal Thickness (CCT): measures the thickness of the cornea using corneal 
pachymetry 
Superficial Punctate Keratitis (SPK): evaluating presence or absence of SPK, an eye disorder 
casued by death of small groups of cells on the surface of the cornea 
 
 
Epsworth Sleepiness Scale (ESS): measures a person’s general level of daytime sleepiness 

 
DME-OSA Study 
 
 
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Stanford Sleepiness Scale (SSS): measures how alert a person is feeling in the moment 
Apnea-Hypopnea index (AHI): index used to indicate the severity of sleep apnea 
Overall arousal index (OAI): an intrusion or disturbance in your sleep pattern as measured by 
EEG brain wave activity 
Oxygen desaturation index (ODI): number of times per hour of sleep that the blood’s oxygen 
level drop by a certain degree from baseline 
 
 
 
 
 

 
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