A Multicentre Randomised Clinical Trial of Laser Treatment Plus Intravitreal Triamcinolone for Diabetic Macular Oedema

Study Overview
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Brief Summary
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This study is likely to identify an improved and economical treatment for diabetic macular oedema, one of the commonest causes of blindness both in Australia and the rest of the world.The specific aims of the study are to test the following hypotheses: That intravitreal triamcinolone followed by laser treatment results in a greater improvement in visual acuity than placebo followed by laser treatment of eyes with macular oedema secondary to diabetes; That intravitreal triamcinolone followed by laser treatment results in greater degree of resolution of macular oedema than placebo followed by laser treatment of eyes with macular oedema secondary to diabetes; That intravitreal triamcinolone followed by laser treatment results in a reduced requirement for further laser treatment to control diabetic macular oedema than placebo followed by laser treatment; That intravitreal triamcinolone followed laser has a manageable and acceptable safety profile in eyes with diabetic macular edema.

Detailed Description
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A 25 fold increase in the risk of going blind on diagnosis of diabetes is one of the most daunting threats that people with diabetes face. Stimulated by several uncontrolled, anecdotal reports, we are already conducting a randomized clinical trial of intravitreal triamcinolone for the treatment of diabetic macular edema which is refractory to conventional laser treatment. The analysis of the 3 month data from this study has already unequivocally demonstrated that the treatment very significantly reduces or eliminates macular oedema in the short term and results in improved visual acuity. Thus intravitreal triamcinolone may represent the most significant development in the prevention of blindness in people with diabetes since the introduction of laser treatment. It is also a highly cost-effective intervention that can be administered by general ophthalmologists. The next question to be answered, which will be addressed directly by the present study, is whether there is a significant, synergistic beneficial effect when intravitreal steroids are combined with current therapy (laser). This study represents the second major project to be undertaken by the Australian Retinal Collaboration (ARC). The ARC aims to set the highest attainable standards for investigator-initiated clinical research in retinal diseases in Australia. Having enrolled and treated more than the target of 120 patients, we are currently completing an RCT of laser induced chorioretinal anastomosis for central retinal vein occlusion, an innovative Australian concept for a severe and otherwise untreatable disease. The proposed study is likely to identify an improved and economical treatment for one of the commonest causes of blindness both in Australia and the rest of the world. Intravitreal triamcinolone is also an intervention which has generated intense interest internationally, and one for which members of the ARC are acknowledged pioneers. Successful implementation of the study proposed, which is feasible, is highly likely to have an immediate and direct effect on the prevention of vision impairment and blindness in people with diabetes

Official Title
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Phase II/III Multicentre Randomised Clinical Trial of Laser Treatment Plus 4 mg Intravitreal Triamcinolone Injection to Reduce Diabetic Macular Oedema

Conditions
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Diabetic Macular Oedema

Intervention / Treatment
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* Drug: Triamcinolone acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Diagnosis of diabetes mellitus types 1 or 2 Diabetic macular oedema affecting the fovea in one or both eyes (phakic or pseudophakic) for which laser treatment is indicated in the opinion of the investigator Best corrected visual acuity of 19-68 letters (6/12 -6/120) Definite macular oedema on clinical examination involving the centre of the macula Retinal thickness > 250 micron in central 1mm subfield on OCT Investigator is comfortable deferring macular laser treatment for 6 weeks Exclusion Criteria: Glaucoma which is uncontrolled or is controlled but with glaucomatous field defects Loss of vision due to other causes (e.g. age related macular degeneration, myopic macular degeneration, retinal vein occlusion) Macular oedema due to other causes including vitreous traction An ocular condition that would prevent visual acuity improvement despite resolution of oedema (such as foveal atrophy) Previous treatment IVTA within 6 months or with peribulbar TA within 3 months Cataract surgery within the last 6 months Retinal laser treatment within the last 4 months High risk PDR at baseline or laser therapy cannot be delayed for 6 weeks on retina History of herpes viral disease in study eye Media opacity including cataract that already precludes adequate macular photography and laser treatment, or cataract that is likely to preclude an adequate view within 2 years Known allergies to triamcinolone acetate Patient is already receiving systemic steroid treatment Intercurrent severe disease such as septicemia, any condition which would affect follow-up or photographic documentation (e.g. geographical, psycho-social) History of chronic renal failure requiring dialysis or renal transplant Blood pressure >180/110 mmHg

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: Triple


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Triamcinolone acetate|Eyes assigned to IVTA received an intravitreal injection of 0.1 ml of Kenacort 40© [40mg/ml triamcinolone acetonide, Bristol-Myers Squibb pharmaceuticals, Australia] on the day of the baseline visual acuity measurement under sterile conditions in a minor procedures area as an outpatient procedure. Eyes assigned to placebo were prepared in the same way but had the barrel of the syringe without a needle pushed firmly against the eye to simulate an injection.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of eyes showing an improvement of visual acuity by 10 letters on a LogMAR chart compared with the pre-injection level 24 months after treatment | At 24 months, improvement of ≥10 LogMAR letters was seen in 15/42 (36%) eyes treated with IVTA plus laser compared with 7/42 (17%) eyes treated with laser only (p=0.047, odds ratio 2.79, 95% CI, 1.01, 7.67). | 24 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of laser treatments required for the treatment of macular oedema during the course of the study. | At least 1 retreatment was required in the second year of the study in 29/42 (69%) of IVTA plus laser treated eyes compared with 19/42 (45%) laser only eyes (p=0.187). | 24 month | 
| Change in retinal thickness demonstrated on optical coherence tomography (OCT) | There was no difference in the mean CMT (346.8μm ± 114.9SD vs 372.6μm ± 154.2SD, comparing IVTA plus laser vs laser only, p=0.349) or mean logMAR visual acuity (56.1 ± 15.7SD vs 54.5 ± 16.1SD letters, p=0.439). | 24 month | 
| The incidence of moderate or severe side effects related to the procedure of intravitreal injection or related to the drug | Cataracts were removed from 17/28 (61%) of phakic IVTA plus laser-treated eyes vs. 0/27 (0%) laser only eyes (p<0.001). Treatment for elevated intraocular pressure was required in 27/42 (64%) of the IVTA plus laser eyes compared with 10/42 (24%) laser only eyes (p<0.001) | 24 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic macular oedema, Triamcinolone acetate, Intravitreal injection, Clinical trial, Laser treatment