Diabetic Macular Edema - Obstructive Sleep Apnea Relationship Study

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the relationship between DME and obstructive sleep apnea (OSA). OSA impacts millions of North Americans, many of whom are undiagnosed. The investigators aim to evaluate if a relationship exists between the two diseases, whether or not the severity of OSA impacts the severity of DME, and whether treating OSA results in better treatment outcomes for DME. The study will involve the standard of care provided for both DME (involving anti-VEGF injections) and OSA (involving continuous positive airway pressure [CPAP] machine).Approximately 150 subjects are expected to be enrolled in this study. In summary: Question 1: Is there a correlation between DME and 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.

Detailed Description
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A 12 month, non-randomized, controlled, prospective study evaluating the relationship between diabetic macular edema (DME) and obstructive sleep apnea (OSA). 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. All patients will undergo baseline ophthalmologic examinations as part of a regular clinic visit including best-corrected visual acuity, intraocular pressure, slit lamp exam, dilated retinal exam, fluorescein angiography and optical coherence tomography (OCT). Diagnosis of diabetic macular edema will be confirmed with standard domain OCT. Diagnosis of OSA will be confirmed through gold standard of overnight polysomnography. During each visit, the intraocular pressure and perfusion of the optic nerve head will be monitored for patient safety. 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. The investigators 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, the investigators will attempt to determine if there is a correlation of OSA by comparing it to non-DME patients who have NPDR. 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. 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, the investigators can determine severity association. 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, the investigators 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.

Official Title
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Examining the Relationship Between Diabetic Macular Edema and Obstructive Sleep Apnea: Prevalence, Association and Impact.

Conditions
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Diabetic Macular Edema, Sleep Apnea, Non Proliferative Diabetic Retinopathy

Intervention / Treatment
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* Drug: Aflibercept 40 MG/ML [Eylea]
* Diagnostic Test: OSA diagnostic test - overnight sleep study
* Device: CPAP therapy for OSA positive patients


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| DME positive, OSA positive<br>Visit 1: Baseline DME Treatment. Includes first EYELEA(aflibercept) injection. (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 to ensure the DME is resolved by the end of the study.) Each injection is 2 mg (0.05 mL). Visit 2: Diagnosis of OSA - Overnight sleep study Visit 3: 1 month follow up post-CPAP initiation Visit 4: 6-month visit post DME initial treatment Visit 5: 2-3 month follow up - titration study (at sleep lab) Visit 6: 12-month visit post DME initial treatment in the OSA- group and at least 3 months post CPAP initiation in the OSA+ group Visit 7: 12-month sleep apnea follow up | Drug: Aflibercept 40 MG/ML [Eylea]<br>* Intravitreal injection, form of anti-VEGF therapy<br>Diagnostic Test: OSA diagnostic test - overnight sleep study<br>* Overnight with specialist care in hospital - heart, lung and brain activity monitored.<br>Device: CPAP therapy for OSA positive patients<br>* positive airway pressure ventilator, applies mild air pressure in a continuous basis to keep the airways continuously open in patients who are able to breath spontaneously on their own.<br>|
| DME positive, OSA negative<br>Visit 1: Baseline DME Treatment Includes first EYELEA(aflibercept) injection. (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 to ensure the DME is resolved by the end of the study.) Each injections is 2 mg (0.05 mL). Visit 2: Diagnosis of OSA - Overnight sleep study 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 | Drug: Aflibercept 40 MG/ML [Eylea]<br>* Intravitreal injection, form of anti-VEGF therapy<br>Diagnostic Test: OSA diagnostic test - overnight sleep study<br>* Overnight with specialist care in hospital - heart, lung and brain activity monitored.<br>|
| DME negative (NPDR positive), OSA positive<br>no injections needed. Visit 1: Baseline NPDR diagnosis Sleep lab visits Visit 2: Diagnosis of OSA - Overnight sleep study Visit 3: 1 month follow up post-CPAP initiation Visit 4: 2-3 month follow up - titration study Visit 5: 12-month sleep apnea follow up | Diagnostic Test: OSA diagnostic test - overnight sleep study<br>* Overnight with specialist care in hospital - heart, lung and brain activity monitored.<br>Device: CPAP therapy for OSA positive patients<br>* positive airway pressure ventilator, applies mild air pressure in a continuous basis to keep the airways continuously open in patients who are able to breath spontaneously on their own.<br>|
| DME negative (NPDR positive), OSA negative<br>no injections needed. Visit 1: Baseline NPDR diagnosis Visit 2: Diagnosis of OSA - Overnight sleep study | Diagnostic Test: OSA diagnostic test - overnight sleep study<br>* Overnight with specialist care in hospital - heart, lung and brain activity monitored.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of DME |  | First visit, 0 months | 
| Presence of OSA |  | First visit, 0 months | 
| Snellen visual acuity |  | 12 months | 
| Apnea-Hypopnea Index |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central Retinal Thickness | for DME +ve patients | 12 months | 
| Number of injections | for DME +ve patients | 7 months + | 
| CPAP compliance | for OSA+ patients | 12 months |