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Study Title and Description

Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial.



Key Questions Addressed
1 How are the efficacy and safety of corticosteroid implants for chronic non-infectious uveitis?
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Primary Publication Information
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TitleData
Title Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial.
Author Kempen JH., Altaweel MM., Holbrook JT., Jabs DA., Louis TA., Sugar EA., Thorne JE.
Country Ocular Inflammation Service, The University of Pennsylvania, Philadelphia, Philadelphia, PA 19104, USA.
Year 2011
Numbers Pubmed ID: 21840602

Secondary Publication Information
There are currently no secondary publications defined for this study.


Extraction Form: Corticosteroid implants for chronic non-infectious uveitis 2016
Arms
Number Title Description Comments
1 Fluocinolone acetonide surgical FA implant (0.59 mg) placement
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2 Standard-of-care "systemic therapy following expert guidelines"
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Design Details
Question... Follow Up Answer Follow-up Answer
Page 1916-26
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Study design parallel-group, randomized controlled trial
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Number randomized
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Total 255 participants (479 eyes)
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FA implant group 129 participants (245 eyes)
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Standard-of-care group 126 participants (234 eyes)
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Number analyzed
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Total_1 255 participants (479 eyes)
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FA implant group_1 129 participants (245 eyes)
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Standard-of-care group_1 126 participants (234 eyes)
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Exclusions and loss to follow-up
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Total_2 23 participants
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FA implant group_2 11 participants
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Standard-of-care group_2 12 participants
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Study follow-up 24 months
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Country Australia, United Kingdom, United States
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Age (mean +/- SD, range) 46.3 +/- 15.0, 34 to 56 years
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Gender
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Overall
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Women 192/255 participants (75%)
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Men 63/255 participants (25%)
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By group not reported
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Inclusion criteria "1. Age 13 years or older2. Diagnosis of noninfectious intermediate uveitis, posterior uveitis, or panuveitis by a MUST-certified ophthalmologist3. Active uveitis of a degree for which systemic corticosteroid therapy is indicated in the judgment of a MUST-certified ophthalmologist or such uveitis active within the last 60 days as determined either by examination by a MUST-certified ophthalmologist or by review of ophthalmic medical records by a MUST-certified ophthalmologist4. Uveitis with or without an associated systemic disease is acceptable; however, the systemic disease must not be sufficiently active that it dictates therapy with oral corticosteroids or immunosuppressive agents at the time of study entry5. Best-corrected visual acuity of hand movements or better in at least 1 eye with uveitis6. Baseline intraocular pressure of 24 mm Hg or less in all eyes with uveitis7. Collection of required baseline data within 10 days before randomization8. Signed informed consent"
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Exclusion criteria "1. Use of a fluocinolone acetonide implant within the last 3 years2. Diabetes mellitus that is inadequately controlled, according to best medical judgment3. A known allergy to a required study medication4. Uncontrolled glaucoma
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5. Advanced glaucomatous optic nerve injury meeting the following criteria (1) for patients able to undertake a Humphrey visual field analysis, depression of 2 points or more within 10 degrees of fixation by at least 10 dB, mean deviation worse than –15 dB, or both; (2) for patients unable to undertake a Humphrey visual field analysis, vertical cup-to-disc ratio [1]0.96. A history of scleritis (because of concerns regarding the potential for scleral melting with local corticosteroid therapy)7. Presence of an ocular toxoplasmosis scar8. Pregnancy9. Current breastfeeding10. Known human immunodeficiency virus infection or other immunodeficiency disease for which corticosteroid therapy would be contraindicated according to best medical judgment11. Patients for whom participation in the trial would constitute a risk exceeding the potential benefits of study participation, in the judgment of the treating physician12. Medical problems or drug or alcohol dependence problems sufficient to prevent adherence to treatment and study procedures"
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Participants with unilateral and asymmetric bilateral disease were included For participants with unilateral disease, the affected eye was the study eye. For participants with asymmetric bilateral disease, both eyes were study eyes.
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FA implant surgical FA implant (0.59 mg) placement
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Standard-of-care &";systemic therapy following expert guidelines&";"Most cases had active inflammation at baseline and received 1 mg/kg/day up to 60 mg/day of prednisone until either the uveitis was controlled or 4 weeks had elapsed. After control was achieved, prednisone was tapered per study guidelines. Cases already suppressed at baseline began by tapering from their initial prednisone dose. Immunosuppression was indicated for (1) failure to initially control inflammation using corticosteroids; (2) corticosteroid-sparing in cases consistently reactivating before reaching a prednisone dose of 10 mg/day; and (3) specific high-risk uveitis syndromes. When indicated, clinicians selected the approved immunosuppressant most suitable for each patient; administration and monitoring for toxicity followed guidelines.8 Uveitis experts regularly monitored treatment regimens for protocol compliance at site visits." P1917
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General procedures ophthalmologic examination
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Primary outcome change in best-corrected visual acuity from baseline
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Secondary outcome(s) patient-reported quality of life, ophthalmologist-graded uveitis activity, and local and systemic complications of uveitis or therapy
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Other outcomes(s) hyperlipidemia diagnosis requiring treatment, cumulative over 24 months, hypertension diagnosis requiring treatment, cumulative through 24 months, diabetes mellitus, cumulative through 24 months, osteoporosis, cumulative through 24 months, white blood cell count < 2500/microliter, cumulative through 24 months, elevated liver enzymes, cumulative through 24 months, elevated creatinine, cumulative through 24 months, cancer diagnosis through 24 months, death through 24 months
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Measurements taken outcomes assessed at 1 month after enrollment, 3 months after enrollment, and then at 3-month intervals until 24 months
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Unit of analysis mix of individuals and eyes (one eye of 31 participants (12%) and both eyes of 224 participants (88%), respectively, were study eyes)
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Sample size calculation "By assuming bilateral disease in 67% of patients, a between eye correlation of 0.4, a standard deviation of 16 letters' change over 2 years, and a 2-sided type 1 error rate of 0.05, a sample size of 250 provided 91% power (assuming 10% crossover) to detect a treatment difference of 7.5 standard Early Treatment of Diabetic Retinopathy Study letters' change in visual acuity from baseline to 24 months, a difference similar to that which drove widespread use of expensive new retinal treatments in other trials that tested them. One interim analysis using the O'Brien-Fleming-spending function was conducted; the nominal type 1 error rate was 0.049 for the final analysis."
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Study dates December 2005 to December 2008
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Funding sources National Eye Institute, Research to Prevent Blindness, Paul and Evanina Mackall Foundation. Bausch and Lomb provided &";support to the study in the form of a donation of a limited number of fluocinolone implants to patients who were &hellip; uninsured or otherwise unable to pay for the implants&";
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Declaration of interest "Dr Kempen is a consultant for Alcon Laboratories, Allergan Pharmaceutical Corporation, Lux Biosciences Inc, and Sanofi Pasteur SA. Dr Jabs is a consultant for Abbott Laboratories, Alcon Laboratories, Allergan Pharmaceutical Corporation, Corcept Therapeutics, Genentech Inc, Genzyme Corporation, GlaxoSmithKline, Novartis Pharmaceutical Corporation, Roche Pharmaceuticals, and Applied Genetic Technologies Corporation. Dr Louis is a consultant for Bristol-Myers Squibb, Medtronic Inc, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr Thorne is a consultant for Heron Evidence Ltd, and Allergan. Drs Altaweel, Holbrook, and Sugar have no conflicts of interest."
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Trial registry NCT00132691 (clinicaltrials.gov)
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Publication language English
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Number analyzed at 24 months' follow-up
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Countries
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Overall_1
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FA implant group_3
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Women_1
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Men_1
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Standard-of-care group_3
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Women_2
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Men_2
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More severely affected eyes were treated with systemic therapy for greater than or equal to 1 month
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Less severely affected eyes with
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Study eyes at time of enrolment
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Primary outcomes
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Secondary outcomes
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Measurements taken, specify intervals at which outcomes assessed
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Funding source
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Random sequence generation (selection bias):Authors' judgement Low risk
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Random sequence generation (selection bias):Support for judgement &";Patients were randomized to implant or systemic therapy; patients with bilateral uveitis were assigned to receive implants in each eye meeting eligibility criteria. Randomization (1:1 ratio) was by variable length, permuted blocks within 2 strata (clinical center, intermediate vs posterior or panuveitis), with assignments produced by Stata 11.0 (StataCorp 2009, Stata Statistical Software: Release 11; StataCorp LP, College Station, TX).&"; P1917
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Allocation concealment (selection bias):Authors' judgement Low risk
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Allocation concealment (selection bias):Support for judgement &";After data entry confirmed a subject's eligibility and stratum, the study Web site revealed the next treatment assignment.&"; P1917
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Masking of participants and personnel (performance bias):Authors' judgement High risk
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Masking of participants and personnel (performance bias):Support for judgement &";Study-certified visual acuity examiners measured best-corrected visual acuity as the number of letters read from standard logarithmic visual acuity charts; 14 change in this measure from baseline to 24 months was the primary outcome.&"; P1917 &";Other than at the 1- and 3-month visits, when postoperative signs were expected to be visible, visual acuity examiners were masked.&"; P1917 &";Secondary outcomes included patient-reported quality of life, ophthalmologist-graded uveitis activity, and local and systemic complications of uveitis or therapy. Reading Center graders and glaucoma specialists assessing ocular complications were masked. Participants, ophthalmologists, and coordinators were unmasked.&"; P1916
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Masking of outcome assessment (detection bias):Authors' judgement High risk
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Masking of outcome assessment (detection bias):Support for judgement &";Study-certified visual acuity examiners measured best-corrected visual acuity as the number of letters read from standard logarithmic visual acuity charts; 14 change in this measure from baseline to 24 months was the primary outcome.&"; P1917 &";Other than at the 1- and 3-month visits, when postoperative signs were expected to be visible, visual acuity examiners were masked.&"; P1917 &";Secondary outcomes included patient-reported quality of life, ophthalmologist-graded uveitis activity, and local and systemic complications of uveitis or therapy. Reading Center graders and glaucoma specialists assessing ocular complications were masked. Participants, ophthalmologists, and coordinators were unmasked.&"; P1916
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Incomplete outcome data (attrition bias):Authors' judgement Unclear risk
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Incomplete outcome data (attrition bias):Support for judgement &";Among patients randomized, 232 (435 eyes with uveitis; 91%) completed visual acuity measurement at the 24-month follow-up visit. Overall, 4415 of 4790 study visits (92%) were completed for the primary outcome through 24 months.&"; P1919 &";Analyses were conducted 'as randomized.'&"; P1918
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Selective reporting (reporting bias):Authors' judgement Low risk
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Selective reporting (reporting bias):Support for judgement All outcomes defined in trial registry were reported.
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Other bias:Authors' judgement Unclear risk
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Other bias:Support for judgement The study was federally funded, although the device manufacturer &";Bausch & Lomb provided support to the study in the form of donation of fluocinolone implants for patients randomized to implant therapy who were uninsured or otherwise unable to pay for implants, or were located at a site where implants could not be purchased (e.g., in the United Kingdom).&"; P1926 &";A representative of the National Eye Institute participated in the conduct of the study, including the study design and the collection, management, analysis, and interpretation of the data, and in the review and approval of this manuscript.&"; P1926
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Results & Comparisons


Results Data
Outcome: Mean difference in BCVA      Population: All Participants
Time Point Measure Fluocinolone acetonide Standard-of-care


12 months

N Analyzed 215 eyes 225 eyes
Mean 4.61 3.33
SD 1.38 1.23
SE


24 months

N Analyzed 212 223
Mean 6.03 3.23
SD 1.41 1.41
SE
Outcome: Mean difference in quality of life      Population: All Participants
Time Point Measure Fluocinolone acetonide Standard-of-care


12 months

N Analyzed NR NR
Mean 12.13 4.86
SD 1.60 1.38
SE


24 months

N Analyzed NR NR
Mean 11.44 6.80
SD 1.67 1.58
SE

Adverse Events
Arm or Total Title Description Proportion of adverse events Comments
Fluocinolone acetonide cataract formation/progression through 24 months 49/54
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Standard-of-care 22/50
Fluocinolone acetonide cataract surgery through 24 months 113/140
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Standard-of-care 39/125
Fluocinolone acetonide elevated intraocular pressure > 10 mmHg through 24 months 122/235
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Standard-of-care 36/230
Fluocinolone acetonide endophthalmitis through 24 months 3/237
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Standard-of-care 0/230
Fluocinolone acetonide retinal tear or retinal detachment through 24 months 5/236
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Standard-of-care 1/230
Fluocinolone acetonide IOP-lowering surgery through 24 months 61/233
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Standard-of-care 8/226
Fluocinolone acetonide hypotony through 24 months 19/228
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Standard-of-care 13/218