Intravitreal Dexamethasone vs Bevacizumab in Aboriginal People With DMO

Study Overview
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Brief Summary
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DMO is the most common cause of visual loss in people with diabetes. Regular injections of bevacizumab (Avastin) given as frequently as every month remain the current standard of care for centre-involving DMO; however, this regimen is impractical for many Aboriginal patients. Using Ozurdex implants every 3-6 months could be as effective as the currently used Avastin injections. In order to address this real-world problem, this study seeks to investigate whether it is possible to safely use a long-acting steroid preparation such as the dexamethasone IVT implant (Ozurdex) to manage DMO in Aboriginal patients living in Western Australia.

Detailed Description
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The prevalence of self-reported DM in Aboriginal Australians is reported to be as high as 38%. Despite gradual improvements in underlying social determinants of health, the high morbidity and mortality attributed to DM in Aboriginal populations indicates significant ongoing issues with adherence to screening and treatment regimens. The greater prevalence of DM in the Aboriginal Australian population would be expected to account (at least in part) for the observed complication rates, including DR. DMO is characterised by swelling of the central retina. The hypoxic retinal conditions in diabetic individuals result in structural changes in the vessel walls and a functional impairment of the blood-retinal barrier. The resultant increase in vascular permeability causes retinal oedema, and loss of central vision ensues when oedema involves the macula. Treatment is aimed at reducing visual loss by targeting factors involved in the activated hypoxia pathway, or with laser targeting dysfunctional blood vessels to limit leakage. Laser was the first treatment shown to effectively reduce DMO and improve vision; however, it cannot be applied to the very centre of the macula. More recently, DMO has been shown to respond to intraocular injections with anti-VEGF agents (bevacizumab, ranibizumab, and aflibercept), reducing reliance on laser treatments. Corticosteroids are anti-inflammatory agents with anti-VEGF and anti-proliferative effects. Unfortunately, the increased rates of cataract and elevated IOP are the main adverse effects of the IVT corticosteroid treatments, including triamcinolone, making this a less-appealing option than anti-VEGF agents. However, their efficacy has been demonstrated in a subgroup of pseudophakic patients with DMO, where triamcinolone plus laser treatment was shown to be superior to laser treatment alone, and equivalent to ranibizumab (alone or with laser treatment). First-line treatment with triamcinolone is also the most cost-effective option for pseudophakic patients. Thus, IVT triamcinolone is considered one of the effective adjunct modalities for the treatment of DMO and has emerged as an alternative therapy to anti-VEGF agents for persistent or refractory DMO. Ozurdex (Allergan, Irvine, CA, United States) is a unique biodegradable dexamethasone IVT implant. This slow-release preparation of dexamethasone (a highly potent steroid with a short half-life) has greater long-term efficacy than conventional forms of IVT triamcinolone, with the IVT concentration peaking within 3 months and sustained for up to 6 months post injection. This translates clinically to less frequent injections than conventional treatment with monthly IVT triamcinolone. The geography and population being studied in this trial create some unique challenges, which demand a more flexible study protocol. Longer-acting IVT agents such as Ozurdex have the potential to significantly improve DMO-associated visual morbidity with greater feasibility when used for Aboriginal patients with or at risk of DMO.

Official Title
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A Randomized Clinical Trial of Intravitreal dexamethasOne Versus Bevacizumab in Aboriginal and Torres Strait Islander patientS With Diabetic Macular Oedema (The OASIS Study)

Conditions
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Diabetic Macular Edema, Diabetic Retinopathy

Intervention / Treatment
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* Drug: Dexamethasone intravitreal implant
* Drug: Bevacizumab Injectable Product


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Self-identifying as Aboriginal Australian or Torres Strait Islander Adults aged 18 years and over Diagnosis of DM (type 1 or type 2) BCVA of at best 0.2 LogMAR (20/32) 6/9 in the study eye Pseudophakic, or phakic with significant lens opacity and scheduled to undergo cataract surgery at the time of enrolment Presence of any grade of DR with centre-involving DMO, as defined by clinical examination and OCT scan findings Active DMO: Centre-involving/threatening DMO, as defined by clinical examination and OCT scan findings. At risk of DMO: Patients scheduled for cataract surgery with non-centre involving DMO who are assessed as being at risk of post-operative centre-involving DMO based on clinical examination, OCT scan findings, and Investigator discretion. Exclusion criteria: Intervention: Previous treatment in the study eye including at the time of the first trial treatment with: IVT anti-VEGF injections within the last six weeks; Macular laser treatment within the last four months; IVT triamcinolone or triescence within the last six months; at the time of the first trial treatment. History of open-angle glaucoma or steroid-induced IOP elevation that required IOP-lowering treatment or, IOP ≥25 (Goldmann applanation) on two consecutive clinic visits. Eyes with concurrent ocular pathology other than DMO, or a cataract-causing visual loss, including macular ischaemia as determined by clinical examination and FFA imaging. Women who are breastfeeding, confirmed as pregnant or planning on becoming pregnant in the next 6-12 months. Participants for whom Ozurdex or Avastin treatment are contraindicated as per product information: Active or suspected ocular/periocular infections, including most viral diseases of the cornea and conjunctiva, active epithelia herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. Aphakic eyes with rupture of the posterior lens capsule. Eyes with an anterior chamber intraocular lens and rupture of the posterior lens capsule. Known angina, myocardial infarction, TIA or CVA in the last three months. Known hypersensitivity to any components of these products.

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexamethasone Implant<br>Receive 0.7mg dexamethasone implant (Ozurdex) at baseline visit. Monthly review with repeat administration of intravitreal treatment every three months for DMO and laser as clinically indicated. | Drug: Dexamethasone intravitreal implant<br>* Intravitreal injection of 0.7mg dexamethasone implant<br>* Other names: DEX-implant;|
| Active Comparator: Bevacizumab<br>Receive 1.25mg/0.05ml bevacizumab (Avastin) at baseline visit. Monthly review with repeat administration of intravitreal treatment every one month for DMO and laser as clinically indicated. | Drug: Bevacizumab Injectable Product<br>* Invtravitreal injection of 1.25mg/0.05mL bevacizumab<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in best corrected visual acuity change between treatment arms | The primary outcome measure will be the difference in the BCVA change from baseline to 12 months between treatment arms, with a non-inferiority margin of 0.1 LogMAR (equivalent to one line of Snellen visual acuity). The BCVA will be measured for all study participants at each clinic visit. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best corrected visual acuity loss or gain | The proportion of participants with a BCVA loss or gain of <0.3 LogMAR (termed 'stable BCVA'), a BCVA loss of ≥0.3 LogMAR ('decline in BCVA'), or a BCVA gain of ≥0.3 LogMAR ('gain in BCVA'). | 12 months | 
| Change in central macular thickness | Change in the CMT from baseline to 12 months as measured by OCT. | 12 months | 
| Number of injections | Number of IVT injections given per participant. | 12 months | 
| Appointments attended | Number of appointments attended per participant. | 12 months | 
| Intraocular pressure change | The change in the mean IOP. | 12 months | 
| Intraocular pressure elevation | The number of participants with one or more occasions of IOP elevation >28 mmHg. | 12 months | 
| Intraocular pressure elevation requiring treatment | IOP elevation requiring medical, laser or surgical treatment. | 12 months | 
| Adverse Events | Adverse events (AEs), serious adverse events (SAEs) and serious adverse reactions (SARs) coded according to the National Medical Research Council (2016) safety monitoring and reporting in clinical trials definitions. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic macular edema, Aboriginal, Australian