Intravitreal Triamcinolone Acetonide Versus Laser for Diabetic Macular Edema

16:22 EDT 29th August 2014 | BioPortfolio

Summary

The study involves the enrollment of patients over 18 years of age with diabetic macular edema(DME). Patients with one study eye will be randomly assigned (stratified by visual acuity and prior laser) with equal probability to one of the three treatment groups:

1. Laser photocoagulation

2. 1mg intravitreal triamcinolone acetonide injection

3. 4mg intravitreal triamcinolone acetonide injection

For patients with two study eyes (both eyes eligible at the time of randomization), the right eye (stratified by visual acuity and prior laser) will be randomly assigned with equal probabilities to one of the three treatment groups listed above. The left eye will be assigned to the alternative treatment (laser or triamcinolone). If the left eye is assigned to triamcinolone, then the dose (1mg or 4 mg) will be randomly assigned to the left eye with equal probability (stratified by visual acuity and prior laser).

The study drug, triamcinolone acetonide, has been manufactured as a sterile intravitreal injectable by Allergan. Study eyes assigned to an intravitreal triamcinolone injection will receive a dose of either 1mg or 4mg. There is no indication of which treatment regimen will be better.

Patients enrolled into the study will be followed for three years and will have study visits every 4 months after receiving their assigned study treatment. In addition, standard of care post-treatment visits will be performed at 4 weeks after each intravitreal injection.

Description

Diabetic retinopathy is a major cause of visual impairment in the United States. Diabetic macular edema (DME) is a manifestation of diabetic retinopathy that produces loss of central vision. Data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) estimate that after 15 years of known diabetes, the prevalence of diabetic macular edema is approximately 20% in patients with type 1 diabetes mellitus (DM), 25% in patients with type 2 DM who are taking insulin, and 14% in patients with type 2 DM who do not take insulin.

In a review of three early studies concerning the natural history of diabetic macular edema, Ferris and Patz found that 53% of 135 eyes with diabetic macular edema, presumably all involving the center of the macula, lost two or more lines of visual acuity over a two year period. In the Early Treatment Diabetic Retinopathy Study (ETDRS), 33% of 221 untreated eyes available for follow-up at the 3-year visit, all with edema involving the center of the macula at baseline, had experienced a 15 or more letter decrease in visual acuity score (equivalent to a doubling of the visual angle, e.g., 20/25 to 20/50, and termed "moderate visual acuity loss").

In the ETDRS, focal/grid photocoagulation of eyes with clinically significant macular edema (CSME) reduced the risk of moderate visual loss by approximately 50% (from 24% to 12%, three years after initiation of treatment). Therefore, 12% of treated eyes developed moderate visual loss in spite of treatment. Furthermore, approximately 40% of treated eyes that had retinal thickening involving the center of the macula at baseline still had thickening involving the center at 12 months, as did 25% of treated eyes at 36 months.

Although several treatment modalities are currently under investigation, the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are laser photocoagulation, as demonstrated by the ETDRS, and intensive glycemic control, as demonstrated by the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS). In the DCCT, intensive glucose control reduced the risk of onset of diabetic macular edema by 23% compared with conventional treatment. Long-term follow-up of patients in the DCCT show a sustained effect of intensive glucose control, with a 58% risk reduction in the development of diabetic macular edema for the DCCT patients followed in the Epidemiology of Diabetes Interventions and Complications Study.

The frequency of an unsatisfactory outcome following laser photocoagulation in some eyes with diabetic macular edema has prompted interest in other treatment modalities. One such treatment is pars plana vitrectomy. These studies suggest that vitreomacular traction, or the vitreous itself, may play a role in increased retinal vascular permeability. Removal of the vitreous or relief of mechanical traction with vitrectomy and membrane stripping may be followed by substantial resolution of macular edema and corresponding improvement in visual acuity. However, this treatment may be applicable only to a specific subset of eyes with diabetic macular edema. It also requires a complex surgical intervention with its inherent risks, recovery time, and expense. Other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors and antibodies targeted at vascular endothelial growth factor (VEGF) are under investigation. The use of intravitreal corticosteroids is another treatment modality that has generated recent interest.

The optimal dose of corticosteroid to maximize efficacy with minimum side effects is not known. A 4mg dose of Kenalog is principally being used in clinical practice. However, this dose has been used based on feasibility rather than scientific principles.

There is also experience using Kenalog doses of 1mg and 2mg. These doses anecdotally have been reported to reduce the macular edema. There is a rationale for using a dose lower than 4mg. Glucocorticoids bind to glucocorticoid receptors in the cell cytoplasm, and the steroid-receptor complex moves to the nucleus where it regulates gene expression. The steroid-receptor binding occurs with high affinity (low dissociation constant (Kd) which is on the order of 5 to 9 nanomolar). Complete saturation of all the receptors occurs about 20-fold higher levels, i.e., about 100-200 nanomolar. A 4mg dose of triamcinolone yields a final concentration of 7.5 millimolar, or nearly 10,000-fold more than the saturation dose. Thus, the effect of a 1mg dose may be equivalent to that of a 4mg dose, because compared to the 10,000-fold saturation, a 4-fold difference in dose is inconsequential. It is also possible that higher doses of corticosteroid could be less effective than lower doses due to down-regulation of the receptor. The steroid implant studies provide additional justification for evaluating a lower dose, a 0.5mg device which delivers only 0.5 micrograms per day has been observed to have a rapid effect in reducing macular edema.

There has been limited experience using doses greater than 4mg. Jonas' case series reported results using a 25mg dose. However, others have not been able to replicate this dose using the preparation procedure described by Jonas.

In the trial, 4mg and 1mg doses will be evaluated. The former will be used because it is the dose that is currently most commonly used in clinical practice and the latter because there is reasonable evidence for efficacy and the potential for lower risk. Although there is good reason to believe that a 1mg dose will reduce the macular edema, it is possible that the retreatment rate will be higher with this dose compared with 4mg since the latter will remain active in the eye for a longer duration than the former. Insufficient data are available to warrant evaluating a dose higher than 4mg at this time.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Conditions

Diabetic Macular Edema

Intervention

Standard of Care Group, 1mg triamcinolone acetonide, 4mg triamcinolone acetonide

Status

Completed

Source

National Eye Institute (NEI)

Results (where available)

View Results

Links

Clinical Trials [1432 Associated Clinical Trials listed on BioPortfolio]

Intravitreal Triamcinolone Acetonide for Diabetic Macular Edema

Efficacy duration of triamcinolone acetonide (steroid) for treatment of diabetic macular edema. Furthermore, dosage dependency of triamcinolone acetonide comparing a high dosage versus a l...

Intravitreal Injection Versus Sub-Tenon's Infusion of Triamcinolone Acetonide for Refractory Diabetic Macular Edema During Cataract Surgery

Triamcinolone has already been used by different routes of administration to treat diabetic macular edema. In the present study, intravitreal injection (IVI) and posterior sub-Tenon's infu...

Triamcinolone Acetonide as an Adjunctive to VPDT in ARMD.

A 24 - month Study looking at the the changes in visual acuity of patients receiving PDT therapy in conjunction with intravitreal triamcinolone.

Intravitreal Triamcinolone Acetonide for Treatment of Refractory Diffuse Diabetic Macular Edema

Phase I/II study with intravitreal triamcinolone acetonide microspheres(RETAAC)for treatment of diffuse diabetic macular edema unresponsive to laser photocoagulation. Study hypothesis is t...

PST/Laser v. Laser Alone for CSME

Prospective randomized clinical trial comparing Laser Alone v. Laser and posterior sub-tenon injection of triamcinolone acetonide for primary and refractory clinically significant macular...

PubMed Articles [23968 Associated PubMed Articles listed on BioPortfolio]

Differential flow rate of commercially available triamcinolone with and without preservative through small-gauge needles.

To compare the flow rate through different gauge needles of triamcinolone acetonide with benzyl alcohol (TABA) versus preservative-free triamcinolone acetonide injectable suspension (TAIS).

Safety of intravitreal triamcinolone acetonide: an electrophysiologic and histopathological study in rabbits.

To evaluate the retinal safety of various doses of intravitreal triamcinolone acetonide (TA) in rabbits.

Effect of postaurical subcutaneously injection of triamcinolone acetonide for subjective tinnitus.

To determine whether postaurical subcutaneous injection of triamcinolone acetonide is effective for subjective tinnitus refractory to medical treatment.

Sub-Tenon Triamcinolone Acetonide Injections for Topical Medication Intolerance in Chronic Blepharokeratoconjunctivitis.

To report the efficacy of sub-Tenon triamcinolone acetonide (TA) injections for chronic blepharokeratoconjunctivitis (BKC) in 2 patients who were intolerant to topical therapies.

The effect of posterior sub-Tenon's capsule triamcinolone acetonide injection to that of pars plana vitrectomy for diabetic macular edema.

To compare the effect of posterior sub-Tenon's capsule triamcinolone acetonide (STTA) injection to that of pars plana vitrectomy (PPV) for diabetic macular edema (DME).

Medical and Biotech [MESH] Definitions

An esterified form of TRIAMCINOLONE. It is an anti-inflammatory glucocorticoid used topically in the treatment of various skin disorders. Intralesional, intramuscular, and intra-articular injections are also administered under certain conditions.

A synthetic progestational dihydroxy derivative of PROGESTERONE. Its acetonide possesses anti-inflammatory properties.

A glucocorticoid given, as the free alcohol or in esterified form, orally, intramuscularly, by local injection, by inhalation, or applied topically in the management of various disorders in which corticosteroids are indicated. (From Martindale, The Extra Pharmacopoeia, 30th ed, p739)

A glucocorticoid derivative used topically in the treatment of various skin disorders. It is usually employed as a cream, gel, lotion, or ointment. It has also been used topically in the treatment of inflammatory eye, ear, and nose disorders. (From Martindale, The Extra Pharmacopoeia, 30th ed, p732)

The minimum acceptable patient care, based on statutes, court decisions, policies, or professional guidelines.

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