Intravitreal Dexamethasone vs Bevacizumab in Aboriginal People With DMO

Diabetic Retinopathy Clinical Trial

— OASIS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04619303
• Other study ID #: OASIS
• Status: Completed
• Phase: Phase 4
• Start date: February 7, 2017
• Est. completion date: February 14, 2020

Study information

• Verified date: November 2020
• Source: Lions Eye Institute, Perth, Western Australia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 59
• Est. completion date: February 14, 2020
• Est. primary completion date: February 14, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Diabetic Macular Edema
• Diabetic Retinopathy
• Edema
• Macular Edema

Intervention

Drug:
• Dexamethasone intravitreal implant
Intravitreal injection of 0.7mg dexamethasone implant
• Bevacizumab Injectable Product
Invtravitreal injection of 1.25mg/0.05mL bevacizumab

Locations

Country	Name	City	State
Australia	Broome Regional Aboriginal Medical Service	Broome	Western Australia
Australia	Derby Hospital	Derby	Western Australia
Australia	Fitzroy Crossing Hospital	Fitzroy Crossing	Western Australia
Australia	Halls Creek Health Service	Halls Creek	Western Australia
Australia	Bega Garnbirringu Health Service	Kalgoorlie	Western Australia
Australia	Nickol Bay Hospital	Karratha	Western Australia
Australia	Ord Valley Aboriginal Health Service	Kununurra	Western Australia
Australia	Laverton Hospital	Laverton	Western Australia
Australia	Derbarl Yerrigan Health Service Inc.	Perth	Western Australia
Australia	Lions Eye Institute Midland	Perth	Western Australia
Australia	Lions Eye Institute Nedlands	Perth	Western Australia
Australia	Mawarnkarra Health Service	Roebourne	Western Australia
Australia	Wirraka Maya Health Service Aboriginal Corporation	South Hedland	Western Australia

Sponsors (3)

Lead Sponsor	Collaborator
Lions Eye Institute, Perth, Western Australia	Allergan, Lions Outback Vision

Country where clinical trial is conducted

Australia, 

References & Publications (23)

Al Dhibi HA, Arevalo JF. Clinical trials on corticosteroids for diabetic macular edema. World J Diabetes. 2013 Dec 15;4(6):295-302. doi: 10.4239/wjd.v4.i6.295. Review. — View Citation

Boyer DS, Faber D, Gupta S, Patel SS, Tabandeh H, Li XY, Liu CC, Lou J, Whitcup SM; Ozurdex CHAMPLAIN Study Group. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina. 2011 May;31(5):915-23. doi: 10.1097/IAE.0b013e318206d18c. — View Citation

Cetin EN, Yildirim C. Adjuvant treatment modalities to control macular edema in diabetic patients undergoing cataract surgery. Int Ophthalmol. 2013 Oct;33(5):605-10. doi: 10.1007/s10792-012-9695-1. Epub 2012 Dec 18. Review. — View Citation

Chang-Lin JE, Attar M, Acheampong AA, Robinson MR, Whitcup SM, Kuppermann BD, Welty D. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci. 2011 Jan 5;52(1):80-6. doi: 10.1167/iovs.10-5285. — View Citation

Chen E, Looman M, Laouri M, Gallagher M, Van Nuys K, Lakdawalla D, Fortuny J. Burden of illness of diabetic macular edema: literature review. Curr Med Res Opin. 2010 Jul;26(7):1587-97. doi: 10.1185/03007995.2010.482503. Review. — View Citation

Chew EY, Benson WE, Remaley NA, Lindley AA, Burton TC, Csaky K, Williams GA, Ferris FL 3rd. Results after lens extraction in patients with diabetic retinopathy: early treatment diabetic retinopathy study report number 25. Arch Ophthalmol. 1999 Dec;117(12):1600-6. — View Citation

Dewan V, Lambert D, Edler J, Kymes S, Apte RS. Cost-effectiveness analysis of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2012 Aug;119(8):1679-84. doi: 10.1016/j.ophtha.2012.01.049. Epub 2012 Apr 13. — View Citation

Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. — View Citation

Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, Ferris FL 3rd, Friedman SM, Glassman AR, Miller KM, Scott IU, Stockdale CR, Sun JK. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010 Jun;117(6):1064-1077.e35. doi: 10.1016/j.ophtha.2010.02.031. Epub 2010 Apr 28. — View Citation

Dutra Medeiros M, Postorino M, Navarro R, Garcia-Arumí J, Mateo C, Corcóstegui B. Dexamethasone intravitreal implant for treatment of patients with persistent diabetic macular edema. Ophthalmologica. 2014;231(3):141-6. doi: 10.1159/000356413. Epub 2013 Dec 19. — View Citation

Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, Glassman AR, Scott IU, Stockdale CR, Sun JK; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):609-14. doi: 10.1016/j.ophtha.2010.12.033. — View Citation

Haller JA, Kuppermann BD, Blumenkranz MS, Williams GA, Weinberg DV, Chou C, Whitcup SM; Dexamethasone DDS Phase II Study Group. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol. 2010 Mar;128(3):289-96. doi: 10.1001/archophthalmol.2010.21. — View Citation

Hariprasad SM, Mieler WF, Grassi M, Green JL, Jager RD, Miller L. Vision-related quality of life in patients with diabetic macular oedema. Br J Ophthalmol. 2008 Jan;92(1):89-92. Epub 2007 Jun 21. — View Citation

Kaidonis G, Mills RA, Landers J, Lake SR, Burdon KP, Craig JE. Review of the prevalence of diabetic retinopathy in Indigenous Australians. Clin Exp Ophthalmol. 2014 Dec;42(9):875-82. doi: 10.1111/ceo.12338. Epub 2014 May 5. Review. — View Citation

Klein R, Klein BE. Blood pressure control and diabetic retinopathy. Br J Ophthalmol. 2002 Apr;86(4):365-7. — View Citation

Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, Boos CJ, Xing W, Egan C, Peto T, Bunce C, Leslie RD, Hykin PG. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology. 2010 Jun;117(6):1078-1086.e2. doi: 10.1016/j.ophtha.2010.03.045. Epub 2010 Apr 22. — View Citation

Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985 Dec;103(12):1796-806. — View Citation

Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology. 1995 Apr;102(4):647-61. — View Citation

Wong J, Molyneaux L, Constantino M, Twigg SM, Yue DK. Timing is everything: age of onset influences long-term retinopathy risk in type 2 diabetes, independent of traditional risk factors. Diabetes Care. 2008 Oct;31(10):1985-90. doi: 10.2337/dc08-0580. Epub 2008 Jul 15. — View Citation

Wong TY, Mwamburi M, Klein R, Larsen M, Flynn H, Hernandez-Medina M, Ranganathan G, Wirostko B, Pleil A, Mitchell P. Rates of progression in diabetic retinopathy during different time periods: a systematic review and meta-analysis. Diabetes Care. 2009 Dec;32(12):2307-13. doi: 10.2337/dc09-0615. — View Citation

Xie J, Arnold AL, Keeffe J, Goujon N, Dunn RA, Fox S, Taylor HR. Prevalence of self-reported diabetes and diabetic retinopathy in indigenous Australians: the National Indigenous Eye Health Survey. Clin Exp Ophthalmol. 2011 Aug;39(6):487-93. doi: 10.1111/j.1442-9071.2011.02502.x. Epub 2011 Mar 24. — View Citation

Zalewski D, Raczynska D, Raczynska K. Five-month observation of persistent diabetic macular edema after intravitreal injection of Ozurdex implant. Mediators Inflamm. 2014;2014:364143. doi: 10.1155/2014/364143. Epub 2014 Feb 10. — View Citation

Zucchiatti I, Lattanzio R, Querques G, Querques L, Del Turco C, Cascavilla ML, Bandello F. Intravitreal dexamethasone implant in patients with persistent diabetic macular edema. Ophthalmologica. 2012;228(2):117-22. doi: 10.1159/000336225. Epub 2012 Feb 3. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Change in central macular thickness	Change in the CMT from baseline to 12 months as measured by OCT.	12 months
Secondary	Number of injections	Number of IVT injections given per participant.	12 months
Secondary	Appointments attended	Number of appointments attended per participant.	12 months
Secondary	Intraocular pressure change	The change in the mean IOP.	12 months
Secondary	Intraocular pressure elevation	The number of participants with one or more occasions of IOP elevation >28 mmHg.	12 months
Secondary	Intraocular pressure elevation requiring treatment	IOP elevation requiring medical, laser or surgical treatment.	12 months
Secondary	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

External Links

•   Australian Bureau of Statistics. Diabetes in Australia: A Snapshot, 2007-08. Cat. no. 4820.0.
•   The health and welfare of Australia's Aboriginal and Torres Strait Islander peoples 2008