A Pilot Study of Peribulbar Triamcinolone Acetonide for Diabetic Macular Edema

The study involves the enrollment of patients over 18 years of age with diabetic macular edema involving the center of the macula who have not already been given maximal laser treatment.

Patients with one study eye will be randomly assigned (stratified by prior laser) with equal probability to one of five treatment groups:

1. Focal laser photocoagulation (modified ETDRS technique)
2. Posterior peribulbar injection of 40 mg triamcinolone (Kenalog)
3. Anterior peribulbar injection of 20 mg triamcinolone
4. Posterior peribulbar injection of 40 mg triamcinolone followed after one month by laser
5. Anterior peribulbar injection of 20 mg triamcinolone followed after one month by laser

For patients with two study eyes (both eyes eligible at the time of randomization), the right eye (stratified by prior laser) will be randomly assigned with equal probabilities to one of the five treatment groups listed above. If the right eye was assigned to laser only, then the left eye will be assigned to one of the four triamcinolone groups above with equal probability (stratified by prior laser). If the right eye was assigned to receive triamcinolone, then the left eye will receive laser only.

Triamcinolone acetonide will be the corticosteroid utilized in this study. The triamcinolone acetonide preparation to be used is Kenalog. Kenalog is manufactured by Bristol Myers Squibb and is approved by the Food and Drug Administration for intramuscular use for a variety of indications. Peribulbar injections of Kenalog have been used for a wide variety of ocular conditions, particularly uveitis and post-cataract extraction cystoid macular edema, for many years.

Two different triamcinolone regimens will be assessed in the study: 40 mg injected posteriorly and 20 mg injected anteriorly. There is no indication of which treatment regimen will be better. Although the injection behind the eye is more common than the injection near the front of the eye, the injection near the front of the eye has less risk of injuring the eye. However, it is possible that the injection near the front of the eye may increase eye pressure more frequently. Little is known about which of the two injections decreases macular edema and improves vision more often.

Patients enrolled into the study will be followed for three years and will have study visits 1 month, 2 months, 4 months, 8 months and annually after receiving their assigned study treatment. For the first 8 months of the study, patients should only be retreated with their randomized treatment. However, if the patient's visual acuity has decreased by 15 letters or more, then any treatment may be given at the investigator's discretion. After completion of the 8-month visit, treatment is at investigator discretion.

The primary objective of this study is to obtain estimates of efficacy and safety outcomes for each of the treatment groups. These estimates will provide a basis for the sample size estimation and hypothesis generation in a phase III trial.

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.

Diabetic macular edema results from abnormal leakage of macromolecules, such as lipoproteins, from retinal capillaries into the extravascular space followed by an oncotic influx of water into the extravascular space. Abnormalities in the retinal pigment epithelium may also cause or contribute to diabetic macular edema. These abnormalities may allow increased fluid from the choriocapillaries to enter the retina or they may decrease the normal efflux of fluid from the retina to the choriocapillaris. The mechanism of breakdown of the blood retina barrier at the level of the retinal capillaries and the retinal pigment epithelium may be due to changes to tight junction proteins such as occludin.

The increase in retinal capillary permeability and subsequent retinal edema may be the result of a breakdown of the blood retina barrier mediated in part by vascular endothelial growth factor (VEGF), a 45 kD glycoprotein. Aiello et al, demonstrated in an in vivo model that VEGF can increase vascular permeability. Fifteen eyes of 15 albino Sprague-Dawley rats received an intravitreal injection of VEGF. The effect of intravitreal administration of VEGF on retinal vascular permeability was assessed by vitreous fluorophotometry. In all 15 eyes receiving an intravitreal injection of VEGF, a statistically significant increase in vitreous fluorescein leakage was recorded. In contrast, control eyes, which were fellow eyes injected with vehicle alone, did not demonstrate a statistically significant increase in vitreous fluorescein leakage. Vitreous fluorescein leakage in eyes injected with VEGF attained a maximum of 227% of control levels.

Antonetti et al, demonstrated that VEGF may regulate vessel permeability by increasing phosphorylation of tight junction proteins such as occludin and zonula occluden 1. Sprague-Dawley rats were given intravitreal injections of VEGF and changes in tight junction proteins were observed through Western blot analysis. Treatment with alkaline phosphatase revealed that these changes were caused by a change in phosphorylation of tight junction proteins. This model provides, at the molecular level, a potential mechanism for VEGF-mediated vascular permeability in the eye. Similarly, in human non-ocular disease states such as ascites, VEGF has been characterized as a potent vascular permeability factor (VPF).

The normal human retina contains little or no VEGF; however, hypoxia causes upregulation of VEGF production. Vinores et al, using immunohistochemical staining for VEGF, demonstrated that increased VEGF staining was found in retinal neurons and retinal pigment epithelium in human eyes with diabetic retinopathy.

As the above discussion suggests, attenuation of the effects of VEGF provides a rationale for treatment of macular edema associated with diabetic retinopathy. Corticosteroids, a class of substances with anti-inflammatory properties, have been demonstrated to inhibit the expression of the VEGF gene. In a study by Nauck et al, the platelet-derived growth-factor (PDGF) induced expression of the VEGF gene in cultures of human aortic vascular smooth muscle cells was abolished by corticosteroids in a dose-dependent manner. A separate study by Nauck et al demonstrated that corticosteroids abolished the induction of VEGF by the pro-inflammatory mediators PDGF and platelet-activating factor (PAF) in a time and dose-dependent manner. This study was performed using primary cultures of human pulmonary fibroblasts and pulmonary vascular smooth muscle cells.

As discussed above, corticosteroids have been experimentally shown to down regulate VEGF production and possibly reduce breakdown of the blood-retinal barrier. Similarly, steroids have anti-angiogenic properties possibly due to attenuation of the effects of VEGF. Both of these steroid effects have been utilized. For example, triamcinolone acetonide is often used clinically as a periocular injection for the treatment of cystoid macular edema (CME) secondary to uveitis or as a result of intraocular surgery. In animal studies, intravitreal triamcinolone acetonide has been used in the prevention of proliferative vitreoretinopathy and retinal neovascularization. Intravitreal triamcinolone acetonide has been used clinically in the treatment of proliferative vitreoretinopathy and choroidal neovascularization.

Eligibility Criteria:
Subject Level Criteria Inclusion

To be eligible, the following inclusion criteria (1-4) must be met:

1. Age ≥18 years
2. Diagnosis of diabetes mellitus (type 1 or type 2)
3. At least one eye meets the study eye criteria
4. Able and willing to provide informed consent.

   Study Level Exclusion Criteria

   A patient is not eligible if any of the following exclusion criteria (5-13) are present:
5. History of chronic renal failure requiring dialysis or kidney transplant.
6. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control). Patients in poor glycemic control who, within the last 4 months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next 4 months should not be enrolled.
7. Participation in an investigational trial within 30 days of study entry that involved treatment with any drug that has not received regulatory approval at the time of study entry.
8. Known allergy to any corticosteroid or any component of the delivery vehicle.
9. History of systemic (e.g., oral, IV, IM, epidural, bursal) corticosteroids within 4 months prior to randomization or topical, rectal, or inhaled corticosteroids in current use more than 2 times per week.
10. History of steroid-induced intraocular pressure elevation that required IOP-lowering treatment in either eye.
11. Warfarin (coumadin) currently being used.
12. Blood pressure \> 180/110 (systolic above 180 OR diastolic above 110). If blood pressure is brought below 180/110 by anti-hypertensive treatment, patient can become eligible.
13. Patient is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the next 8 months.

    The patient must have at least one eye meeting all of the inclusion criteria (a-e) and none of the exclusion criteria (f-t) listed below:

    Study Eye Inclusion Criteria
    1. Best corrected electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity score of ≥69 letters (i.e., 20/40 or better).
    2. Definite retinal thickening due to diabetic macular edema based on clinical exam.
    3. Retinal thickness in the Optical Coherence Tomography (OCT) central subfield measuring 250 microns or more.
    4. Maximal laser has not already been given and investigator believes that either peribulbar steroids or laser may benefit the eye (note: subjects may be enrolled without having received prior macular laser).
    5. Media clarity, pupillary dilation, and patient cooperation sufficient for adequate fundus photographs and OCT.

       Study Eye Exclusion Criteria
    6. Macular edema is considered to be due to a cause other than diabetic macular edema.
    7. An ocular condition is present such that, in the opinion of the investigator, visual acuity would not improve from resolution of macular edema (e.g., foveal atrophy, pigmentary changes, dense subfoveal hard exudates, nonretinal condition).
    8. An ocular condition is present (other than diabetes) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass Syndrome, etc.).
    9. History of prior treatment with intravitreal, peribulbar, or retrobulbar corticosteroids for DME.
    10. History of focal/grid macular photocoagulation within 15 weeks (3.5 months) prior to randomization. Note: Patients are not required to have had prior macular photocoagulation to be enrolled.
    11. History of panretinal scatter photocoagulation (PRP) within 4 months prior to randomization or anticipated need for PRP in the 4 months following randomization.

    m. History of prior vitrectomy.

    n. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 6 months or anticipated within the next 6 months following randomization.

    o. History of YAG capsulotomy performed within 2 months prior to randomization.

    p. Intraocular pressure ≥25 mmHg.

    q. History of open-angle glaucoma (either primary open-angle glaucoma or other cause of open-angle glaucoma; note: angle-closure glaucoma is not an exclusion). A history of ocular hypertension is not an exclusion as long as (1) intraocular pressure is \<25 mm Hg, (2) the patient is using no more than one topical glaucoma medication, (3) the most recent visual field, performed within the last 12 months, is normal (if abnormalities are present on the visual field they must be attributable to the patient's diabetic retinopathy), and (4) the optic disc does not appear glaucomatous. Note: if the intraocular pressure is 22 to \<25 mm Hg, then the above criteria for ocular hypertension eligibility must be met.

    r. History of prior herpetic ocular infection.

    s. Exam evidence of ocular toxoplasmosis.

    t. Exam evidence of pseudoexfoliation.

    A patient may have two "study eyes" only if both are eligible at the time of randomization.