Multicenter Uveitis Steroid Treatment (MUST) Trial

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare the effectiveness of standardized systemic therapy versus fluocinolone acetonide implant therapy for the treatment of severe cases of non-infectious intermediate uveitis, posterior uveitis, or panuveitis.

Detailed Description
-----------------
The MUST trial is a randomized controlled clinical trial comparing two treatments for patients with vision-threatening non-infectious intermediate uveitis, posterior uveitis, or panuveitis: local therapy with fluocinolone acetonide intraocular implant in affected eyes; versus standard therapy: systemic corticosteroid therapy supplemented, when indicated, by corticosteroid-sparing potent immuno-modulator therapy. Study ophthalmologists, clinic coordinators, and patients will not be masked to treatment assignment. Masking will be applied to the determination of visual function at baseline, the six month visit, and thereafter . Patients will be followed until death, participant withdrawal, or a common study closeout. Patients will be seen at baseline, one month after randomization, three months after randomization, and every three months thereafter for data collection. Both ophthalmological and medical data will be collected to evaluate the outcomes of treatment of the uveitis, complications of the uveitis, and complications from therapy itself. Selected laboratory data related to the complications from systemic corticosteroid therapy will be collected. The planned sample size of 250 patients, 125 per treatment group, is expected to give sufficient power to detect clinically important differences in visual acuity outcomes. Patients meeting the eligibility criteria detailed above will be enrolled at approximately 23 clinical centers in the United States, Australia and UK. Patients will be randomized on a 1:1 basis to one of the two treatment groups. The MUST Research Group received additional funding at the completion of the MUST Trial to continue following patients enrolled in the study for an additional 7 years in the MUST Trial Follow-up Study (MUST FS). Since uveitis is often a chronic condition requiring long-term treatment, the objectives of the MUST FS are to evaluate outcomes of the two treatments over a longer period time. The outcomes specified for MUST FS are the same as those specified for the MUST Trial: visual acuity, ocular and systemic side effects of treatment, quality of life, and control of ocular inflammation. The primary analyses will be to compare outcomes between the original randomization groups, i.e., intention-to-treat. Secondary analyses will be based on treatment received. Study visits will be conducted every 6 months in MUST FS as opposed to every 3 months in the MUST Trial. Two analyses are planned for public release, one at 4.5 years and one after 7 years of follow-up. The Data Safety Monitoring Board reviewed and approved the analysis plan.

Official Title
-----------------
Multicenter Uveitis Steroid Treatment (MUST) Trial

Conditions
-----------------
Uveitis

Intervention / Treatment
-----------------
* Drug: fluocinolone acetonide intraocular implant
* Drug: oral corticosteroid with immunosuppressive agents as needed


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 13 years or older Best-corrected visual acuity of hand motions or better in at least one eye with uveitis Intraocular pressure 24 mm Hg or less in all eyes with uveitis Exclusion Criteria: Inadequately controlled diabetes Uncontrolled glaucoma Advanced glaucomatous optic nerve injury A history of scleritis; presence of an ocular toxoplasmosis scar. HIV infection or other immunodeficiency disease for which corticosteroid therapy would be contraindicated according to best medical judgment

Ages Eligible for Study
-----------------
Minimum Age: 13 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Immunosuppressant medication implant | Drug: fluocinolone acetonide intraocular implant<br>* RETISERT™ (fluocinolone acetonide intravitreal implant) 0.59 mg is a sterile implant designed to release fluocinolone acetonide locally to the posterior segment of the eye at a nominal initial rate of 0.6 μg/day, decreasing over the first month to a steady state between 0.3-0.4 μg/day over approximately 30 months.<br>* Other names: NDC 24208-416-01;|
| Active Comparator: 2<br>Systemic corticosteroids with immunosuppressant drugs as needed | Drug: oral corticosteroid with immunosuppressive agents as needed<br>* Prednisone<br>* Other names: other biologics;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Best-corrected Visual Acuity (Change in the Numbers of Letters Read From a Standard ETDRS Eye Chart) From Baseline to 24 Months in Eyes With Uveitis | Best-corrected visual acuity was measured as the number of letters read from standard logarithmic visual acuity charts by study-certified examiners who were masked to treatment. Visual acuity was measured at all study visits. The primary outcome was eye-specific change in visual acuity from baseline to 2-year follow-up. Positive change values indicate improved vision while negative change values indicate vision has gotten worse. A change of 7.5 letters is considered clinically meaningful. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Macular Edema | center point macular thickness >= 240 micrometers assessed on OCT (Stratus OCT-3 [Carl Zeiss Meditec, Dublin, CA]) as graded by Central Reading Center | 24 months | 
| Uveitis Activity | Uveitis activity was determined by clinician assessment at each study visit. The study ophthalmologist evaluated each eye as active, inactive/never had uveitis or cannot assess. | 24 months | 
| Intraocular Pressure - Incident IOP Greater Than or Equal to 30 mm Hg |  | 24 months | 
| Intraocular Pressure - Incident IOP Greater Than or Equal to 24 mm Hg |  | 24 months | 
| Intraocular Pressure - Incident IOP Elevation >= 10 mmHg Above Baseline |  | 24 months | 
| Glaucoma - Incident | Glaucoma was diagnosed by a glaucoma specialist through review of visual fields, clinical data, and fundus images. | 24 months | 
| Intraocular Pressure (IOP) - Incident Use of IOP-lowering Medical Therapy (Percentage of Eyes With Uveitis That Were Not Being Treated With IOP-lowering Medical Therapy at Baseline and Underwent IOP Lowering Therapy During the 24 Month Follow-up. | The percentage of subjects who used topical or systemic treatment for elevated IOP at any time during the 2 year follow-up and were not on IOP-lowering therapy at baseline is reported. | 24 months | 
| Intraocular Pressure - IOP-lowering Surgery |  | 24 months | 
| Cataract - Incident Cataract |  | 24 months | 
| Change in Self-reported Vision-related Function as Measured by the National Eye Institute 25-Item Visual Function Questionnaire (NEI-VFQ 25) Vision Targeted Composite Score From Baseline to 24 Months | The NEI-VFQ 25 measures the effect of visual disability/symptoms with generic health and task-oriented domains. The range for the composite score is 0 to 100; higher scores are associated with better visual function. A change of 4 to 6 points is considered to be a clinically meaningful difference. | 24 months | 
| Change in SF-36 Mental Component Score From Baseline to 24 Months | Self-reported health related QoL was measured with the SF 36 survey. The mental component score for the SF 36 is a summary measure of mental health primarily based on the social functioning, role emotional, mental health and vitality domains. The score is scaled to a population norm with a mean of 50 and standard deviation of 10. Higher scores represent better outcomes. The mean change in scores between baseline and 24 months was calculated for each treatment group. | 24 months | 
| Change in SF-36 Physical Component Score From Baseline to 24 Months | Self-reported health related QoL was measured with the SF 36 survey. The physical component score for the SF 36 is a summary measure of physical health primarily based on the physical functioning, role physical, bodily pain and general health domains of the survey. The score is scaled to a population norm with a mean of 50 and standard deviation of 10. Higher scores represent better outcomes. The mean change in scores between baseline and 24 months was calculated for each treatment group. A 3 to 5 point difference is considered to be clinically meaningful. | 24 months | 
| Hyperlipidemia - Incident | LDL greater than or equal to 160 mg/mL | 24 months | 
| Hypertension Diagnosis Requiring Treatment |  | 24 months | 
| Diabetes Mellitus |  | 24 months | 
| Mortality |  | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
uveitis, non-infectious intermediate uveitis, non-infectious posterior uveitis, non-infectious panuveitis