Diabetic Macular EdemaPhase 2PeribulbarNCT00369486
A Pilot Study of Peribulbar Triamcinolone Acetonide for Diabetic Macular Edema
A Phase 2 study testing Focal laser photocoagulation, 40mg triamcinolone and 20mg triamcinolone in people with Diabetic Macular Edema, run by Jaeb Center for Health Research.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Diabetic Macular Edema
- What is being tested?
- Focal laser photocoagulation, 40mg triamcinolone and 20mg triamcinolone
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 113 participants
- Where
- No sites listed yet
- Study dates
- Dec 2004to Oct 2007
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Subject Level Criteria Inclusion
To be eligible, the following inclusion criteria (1-4) must be met:
- Age ≥18 years
- Diagnosis of diabetes mellitus (type 1 or type 2)
- At least one eye meets the study eye criteria
- 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:
- History of chronic renal failure requiring dialysis or kidney transplant.
- 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.
- 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.
- Known allergy to any corticosteroid or any component of the delivery vehicle.
- 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.
- History of steroid-induced intraocular pressure elevation that required IOP-lowering treatment in either eye.
- Warfarin (coumadin) currently being used.
- 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.
- 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
- Best corrected electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity score of ≥69 letters (i.e., 20/40 or better).
- Definite retinal thickening due to diabetic macular edema based on clinical exam.
- Retinal thickness in the Optical Coherence Tomography (OCT) central subfield measuring 250 microns or more.
- 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).
- Media clarity, pupillary dilation, and patient cooperation sufficient for adequate fundus photographs and OCT. Study Eye Exclusion Criteria
- Macular edema is considered to be due to a cause other than diabetic macular edema.
- 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).
- 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.).
- History of prior treatment with intravitreal, peribulbar, or retrobulbar corticosteroids for DME.
- 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.
- History of panretinal scatter photocoagulation (PRP) within 4 months prior to randomization or anticipated need for PRP in the 4 months following randomization.
- History of prior vitrectomy.
- 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.
- History of YAG capsulotomy performed within 2 months prior to randomization.
- Intraocular pressure ≥25 mmHg.
- 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.
- History of prior herpetic ocular infection.
- Exam evidence of ocular toxoplasmosis.
- Exam evidence of pseudoexfoliation. A patient may have two "study eyes" only if both are eligible at the time of randomization.
About this study
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:
Read more
- Focal laser photocoagulation (modified ETDRS technique)
- Posterior peribulbar injection of 40 mg triamcinolone (Kenalog)
- Anterior peribulbar injection of 20 mg triamcinolone
- Posterior peribulbar injection of 40 mg triamcinolone followed after one month by laser
- 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.
Read the detailed 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.
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.
- Conditions
- Diabetic Macular Edema
- Being tested
- Focal laser photocoagulation, 40mg triamcinolone, 20mg triamcinolone, 40mg triamcinolone + laser, 20mg triamcinolone + laser
- Keywords
- diabetic, macular, edema, peribulbar, triamcinolone, acetonide, laser, photocoagulation, intraocular, DME
- Medical subject headings
- Edema
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Focal laser photocoagulationProcedure or surgery
Also called focal/grid laser
Focal laser photocoagulation (modified Early Treatment Diabetic Retinopathy Study technique)
40mg triamcinoloneDrug
Also called Kenalog
Posterior peribulbar injection of 40 mg triamcinolone (Kenalog)
20mg triamcinoloneDrug
Also called Kenalog
Anterior peribulbar injection of 20 mg triamcinolone
40mg triamcinolone + laserDrug
Also called Kenalog, focal/grid photocoagulation
Posterior peribulbar injection of 40 mg triamcinolone followed after one month by laser
20mg triamcinolone + laserDrug
Also called Kenalog, focal/grid photocoagulation
Anterior peribulbar injection of 20 mg triamcinolone followed after one month by laser
| Study group | Role | What they receive |
|---|---|---|
| 1 | Active comparator | Focal laser photocoagulation (modified Early Treatment Diabetic Retinopathy Study (ETDRS) technique) Receives: Procedure: Focal laser photocoagulation |
| 2 | Experimental | Posterior peribulbar injection of 40 mg triamcinolone (Kenalog) Receives: Drug: 40mg triamcinolone |
| 3 | Experimental | Anterior peribulbar injection of 20 mg triamcinolone Receives: Drug: 20mg triamcinolone |
| 4 | Experimental | Posterior peribulbar injection of 40 mg triamcinolone followed after one month by laser Receives: Drug: 40mg triamcinolone + laser |
| 5 | Experimental | Anterior peribulbar injection of 20 mg triamcinolone followed after one month by laser Receives: Drug: 20mg triamcinolone + laser |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Central Subfield Thickening From Baseline Through 34 Weeks
Change in Central Subfield Thickening from Baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology. Negative changes represent a decrease in retinal thickening.
Measured: 4, 8, 17, 34 weeks
Change in Visual Acuity Letter Score From Baseline Through 34 Weeks
Change in visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the electronic Early Treatment for Diabetic Retinopathy Study(E-ETDRS) technique. Letter score best value = 97 and worst value = 0; an increase in a letter score by 10 is considered clinically significant. Negative changes represent a worsening in visual acuity.
Measured: 4, 8, 17, and 34 weeks
Mean Visual Acuity Letter Score at Each Follow-up Visit
Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) mean visual acuity letter score: best value = 97; letter score worst value = 0
Measured: 4, 8, 17, and 34 weeks
Secondary outcomes (3)
Persistence/Recurrence of Diabetic Macular Edema (DME) Either Retreated or Meeting Criteria for Retreatment at 17 Weeks
Number of eyes that were retreated at 17 weeks. According to the protocol, primary criterion for retreatment was central subfield thickness >=250 microns or macular edema was still present according to the investigator's judgment.
Measured: 17 weeks
Reduction of ≥ 50% in Retinal Thickening in the Central Subfield From Baseline Through 34 Weeks
Number of eyes that had a reduction in central subfield retinal thickness by ≥ 50% at each follow-up. Change in Central Subfield Thickening from Baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology.
Measured: 4, 8, 17, 34 weeks
Central Subfield Thickness <250 Microns From Baseline Through 34 Weeks
Primary criterion for retreatment is central subfield thickness >=250 microns. Central subfield thickness of <250 microns indicates no need for retreatment. Change in Central Subfield Thickening from Baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology.
Measured: 4, 8, 17, 34 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Aug 2006 (estimated)
- Study startDec 2004
- Primary completionJun 2006
- Study completionOct 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Diabetic Macular EdemaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 113 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jaeb Center for Health Research
- Sponsor type
- University, hospital or other
- Collaborators
- National Eye Institute (NEI)
- Investigators
- Emily Chew, M.D., Study chair, National Eye Institute (NEI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00369486
- Sponsor's protocol ID
- NEI-104
- Other IDs
- U10EY018817-03, U10EY014229-07, U10EY014231-09
- Acronym
- Peribulbar
- Status last verified
- Aug 2016
- First submitted
- 25 Aug 2006
- Last updated
- 26 Aug 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Chew EY, Glassman AR, Beck RW, Bressler NM, Fish GE, Ferris FL, Kinyoun JL; Diabetic Retinopathy Clinical Research Network. Ocular side effects associated with peribulbar injections of triamcinolone acetonide for diabetic macular edema. Retina. 2011 Feb;31(2):284-9. doi: 10.1097/IAE.0b013e3181f049a8.
PubMed 20948459Diabetic Retinopathy Clinical Research Network; Chew E, Strauber S, Beck R, Aiello LP, Antoszyk A, Bressler N, Browning D, Danis R, Fan J, Flaxel C, Friedman S, Glassman A, Kollman C, Lazarus H. Randomized trial of peribulbar triamcinolone acetonide with and without focal photocoagulation for mild diabetic macular edema: a pilot study. Ophthalmology. 2007 Jun;114(6):1190-6. doi: 10.1016/j.ophtha.2007.02.010.
PubMed 17544778Gangaputra S, Almukhtar T, Glassman AR, Aiello LP, Bressler N, Bressler SB, Danis RP, Davis MD; Diabetic Retinopathy Clinical Research Network. Comparison of film and digital fundus photographs in eyes of individuals with diabetes mellitus. Invest Ophthalmol Vis Sci. 2011 Aug 3;52(9):6168-73. doi: 10.1167/iovs.11-7321.
PubMed 21571677
Study at a glance
From the registry record, last updated by the sponsor on 26 Aug 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study of Peribulbar Triamcinolone Acetonide for Diabetic Macular Edema
- ClinicalTrials.gov ID
- NCT00369486
- Acronym / sponsor ID
- Peribulbar / NEI-104
- Conditions
- Diabetic Macular Edema
- Keywords
- diabetic, macular, edema, peribulbar, triamcinolone, acetonide, laser, photocoagulation
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 113 participants (actual)
- Lead sponsor
- Jaeb Center for Health ResearchUniversity, hospital or other
- Collaborators
- National Eye Institute (NEI)
- Study start
- Dec 2004
- Primary completion
- Jun 2006 (actual)
- Study completion
- Oct 2007 (actual)
- First posted
- 29 Aug 2006 (estimated)
- Results
- Posted 14 Jun 2011
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Focal laser photocoagulation (modified ETDRS technique)
- Posterior peribulbar injection of 40 mg triamcinolone (Kenalog)
- Anterior peribulbar injection of 20 mg triamcinolone
- Posterior peribulbar injection of 40 mg triamcinolone followed after one month by laser
- 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.
Detailed 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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| 1 | Active comparator | Procedure: Focal laser photocoagulationFocal laser photocoagulation (modified Early Treatment Diabetic Retinopathy Study (ETDRS) technique) |
| 2 | Experimental | Drug: 40mg triamcinolonePosterior peribulbar injection of 40 mg triamcinolone (Kenalog) |
| 3 | Experimental | Drug: 20mg triamcinoloneAnterior peribulbar injection of 20 mg triamcinolone |
| 4 | Experimental | Drug: 40mg triamcinolone + laserPosterior peribulbar injection of 40 mg triamcinolone followed after one month by laser |
| 5 | Experimental | Drug: 20mg triamcinolone + laserAnterior peribulbar injection of 20 mg triamcinolone followed after one month by laser |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Focal laser photocoagulationAlso: focal/grid laserFocal laser photocoagulation (modified Early Treatment Diabetic Retinopathy Study technique) | Procedure or surgery | 1 |
| 40mg triamcinoloneAlso: KenalogPosterior peribulbar injection of 40 mg triamcinolone (Kenalog) | Drug | 2 |
| 20mg triamcinoloneAlso: KenalogAnterior peribulbar injection of 20 mg triamcinolone | Drug | 3 |
| 40mg triamcinolone + laserAlso: Kenalog, focal/grid photocoagulationPosterior peribulbar injection of 40 mg triamcinolone followed after one month by laser | Drug | 4 |
| 20mg triamcinolone + laserAlso: Kenalog, focal/grid photocoagulationAnterior peribulbar injection of 20 mg triamcinolone followed after one month by laser | Drug | 5 |
Primary outcome
Change in Central Subfield Thickening From Baseline Through 34 Weeks
Time frame: 4, 8, 17, 34 weeks
Change in Central Subfield Thickening from Baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology. Negative changes represent a decrease in retinal thickening.
Change in Visual Acuity Letter Score From Baseline Through 34 Weeks
Time frame: 4, 8, 17, and 34 weeks
Change in visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the electronic Early Treatment for Diabetic Retinopathy Study(E-ETDRS) technique. Letter score best value = 97 and worst value = 0; an increase in a letter score by 10 is considered clinically significant. Negative changes represent a worsening in visual acuity.
Mean Visual Acuity Letter Score at Each Follow-up Visit
Time frame: 4, 8, 17, and 34 weeks
Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) mean visual acuity letter score: best value = 97; letter score worst value = 0
3 secondary outcomes
Persistence/Recurrence of Diabetic Macular Edema (DME) Either Retreated or Meeting Criteria for Retreatment at 17 Weeks
Time frame: 17 weeks
Reduction of ≥ 50% in Retinal Thickening in the Central Subfield From Baseline Through 34 Weeks
Time frame: 4, 8, 17, 34 weeks
Central Subfield Thickness <250 Microns From Baseline Through 34 Weeks
Time frame: 4, 8, 17, 34 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Aug 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 20948459Chew EY, Glassman AR, Beck RW, Bressler NM, Fish GE, Ferris FL, Kinyoun JL; Diabetic Retinopathy Clinical Research Network. Ocular side effects associated with peribulbar injections of triamcinolone acetonide for diabetic macular edema. Retina. 2011 Feb;31(2):284-9. doi: 10.1097/IAE.0b013e3181f049a8.
- Results publication: PubMed 17544778Diabetic Retinopathy Clinical Research Network; Chew E, Strauber S, Beck R, Aiello LP, Antoszyk A, Bressler N, Browning D, Danis R, Fan J, Flaxel C, Friedman S, Glassman A, Kollman C, Lazarus H. Randomized trial of peribulbar triamcinolone acetonide with and without focal photocoagulation for mild diabetic macular edema: a pilot study. Ophthalmology. 2007 Jun;114(6):1190-6. doi: 10.1016/j.ophtha.2007.02.010.
- Derived from this study: PubMed 21571677Gangaputra S, Almukhtar T, Glassman AR, Aiello LP, Bressler N, Bressler SB, Danis RP, Davis MD; Diabetic Retinopathy Clinical Research Network. Comparison of film and digital fundus photographs in eyes of individuals with diabetes mellitus. Invest Ophthalmol Vis Sci. 2011 Aug 3;52(9):6168-73. doi: 10.1167/iovs.11-7321.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Emily Chew, M.D. study chair
National Eye Institute (NEI)
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Focal laser photocoagulation, 40mg triamcinolone and 20mg triamcinolone in people with Diabetic Macular Edema, run by Jaeb Center for Health Research.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Aug 2016. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Jun 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Central Subfield Thickening From Baseline Through 34 Weeks (time frame: 4, 8, 17, 34 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00369486, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Aug 2016.