Uveitis
Conditions
Keywords
uveitis, non-infectious intermediate uveitis, non-infectious posterior uveitis, non-infectious panuveitis
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.
Interventions
DRUGfluocinolone acetonide intraocular implant
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.
DRUGoral corticosteroid with immunosuppressive agents as needed
Prednisone
Sponsors
National Eye Institute (NEI)
JHSPH Center for Clinical Trials
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 24 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Uveitis Activity | 24 months | 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. |
| 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 | 24 months | Glaucoma was diagnosed by a glaucoma specialist through review of visual fields, clinical data, and fundus images. |
| 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. | 24 months | 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. |
| Intraocular Pressure - IOP-lowering Surgery | 24 months | — |
| Macular Edema | 24 months | center point macular thickness \>= 240 micrometers assessed on OCT (Stratus OCT-3 \[Carl Zeiss Meditec, Dublin, CA\]) as graded by Central Reading Center |
| 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 | 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. |
| Change in SF-36 Mental Component Score From Baseline to 24 Months | 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. |
| Change in SF-36 Physical Component Score From Baseline to 24 Months | 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. |
| Hyperlipidemia - Incident | 24 months | LDL greater than or equal to 160 mg/mL |
| Hypertension Diagnosis Requiring Treatment | 24 months | — |
| Diabetes Mellitus | 24 months | — |
| Mortality | 24 months | — |
| Cataract - Incident Cataract | 24 months | — |
Countries
Australia, United Kingdom, United States
Participant flow
Recruitment details
Eligible patients were enrolled at 23 uveitis centers in the US, the United Kingdom and Australia from 6 December 2005 to 9 December 2008.
Pre-assignment details
579 patients were assessed for initial eligibility (e.g. through chart review). Patients who were potentially eligible and interested in joining the trial signed an informed consent and underwent a baseline visit to confirm eligibility. Eligible patients (255) were randomly assigned to systemic treatment or implant treatment.
Participants by arm
| Arm | Count |
|---|---|
| Flucinolone Acetonide Intraocular Implant Local therapy with fluocinolone acetonide 0.59 mg implant (Retisert; Bausch & Lomb Inc.) in each eye with uveitis of sufficient severity to justify treatment with systemic corticosteroids | 129 |
| Standard Systemic Treatment Systemic corticosteroid therapy with immunosuppression as indicated | 126 |
| Total | 255 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 0 |
| Overall Study | Lost to Follow-up | 5 | 8 |
| Overall Study | Missed 2-year visit | 4 | 4 |
Baseline characteristics
| Characteristic | Total | Flucinolone Acetonide Intraocular Implant | Standard Systemic Treatment |
|---|---|---|---|
| Active uveitis | 373 eyes | 192 eyes | 181 eyes |
| Age, Continuous | 46 years STANDARD_DEVIATION 15 | 46 years STANDARD_DEVIATION 15 | 47 years STANDARD_DEVIATION 15 |
| Associated systemic inflammatory disease no | 186 participants | 93 participants | 93 participants |
| Associated systemic inflammatory disease Yes | 69 participants | 36 participants | 33 participants |
| Bilateral uveitis | 224 participants | 116 participants | 108 participants |
| Race/Ethnicity, Customized Black | 66 participants | 35 participants | 31 participants |
| Race/Ethnicity, Customized Hispanic | 33 participants | 18 participants | 15 participants |
| Race/Ethnicity, Customized Other | 14 participants | 4 participants | 10 participants |
| Race/Ethnicity, Customized White | 142 participants | 72 participants | 70 participants |
| Region of Enrollment Australia | 11 participants | 5 participants | 6 participants |
| Region of Enrollment United Kingdom | 31 participants | 15 participants | 16 participants |
| Region of Enrollment United States | 213 participants | 109 participants | 104 participants |
| Sex: Female, Male Female | 191 Participants | 91 Participants | 100 Participants |
| Sex: Female, Male Male | 64 Participants | 38 Participants | 26 Participants |
| Site of uveitis Intermediate | 97 participants | 50 participants | 47 participants |
| Site of uveitis Posterior or Panuveitis | 158 participants | 79 participants | 79 participants |
| Visual acuity 20/200 or worse | 74 eyes | 39 eyes | 35 eyes |
| Visual acuity 20/40 or better | 238 eyes | 116 eyes | 122 eyes |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 113 / 129 | 113 / 126 |
| serious Total, serious adverse events | 75 / 129 | 47 / 126 |
Outcome results
Primary
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.
Time frame: 24 months
Population: The primary analysis was an intention-to-treat analysis; analysis was conducted as randomized. Data from the 255 randomized participants were used in the analytic model. 232 of the 255 completed the 2 year outcome visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flucinolone Acetonide Implant | 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 | 6.0 letters | Standard Error 1.4 |
| Systemic Therapy | 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 | 3.2 letters | Standard Error 1.4 |
Comparison: Null hypothesis: There will be no difference in change in visual acuity between treatment groups.~Assuming 67% bilateral disease, between eye correlation of 0.4, SD of 16 letters' change over 2 years and two-sided type 1 error rate of .05, a sample size of 250 provided 91% power (assuming 10% crossover) to detect a treatment difference of 7.5 standard ETDRS letters' change in visual acuity from baseline to 24 months.p-value: 0.1695% CI: [-1.16, 6.68]Generalized estimating equations, linear
Secondary
Cataract - Incident Cataract
Time frame: 24 months
Population: Eyes with uveitis, not participants, were analyzed. Eyes with prevalent complications or missing data at enrollment were were excluded from the risk set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Cataract - Incident Cataract | 90.7 percentage of eyes with uveitis at risk |
| Systemic Therapy | Cataract - Incident Cataract | 44.9 percentage of eyes with uveitis at risk |
p-value: <0.000195% CI: [2.21, 7.67]Cox proportional hazards w/ RE
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flucinolone Acetonide Implant | 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 | 11.44 units on a scale (composite score) | Standard Error 1.67 |
| Systemic Therapy | 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 | 6.80 units on a scale (composite score) | Standard Error 1.58 |
p-value: 0.04395% CI: [0.14, 9.15]GEE, linear
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flucinolone Acetonide Implant | Change in SF-36 Mental Component Score From Baseline to 24 Months | 2.55 units on a scale | Standard Error 1.11 |
| Systemic Therapy | Change in SF-36 Mental Component Score From Baseline to 24 Months | -1.1 units on a scale | Standard Error 1.15 |
p-value: 0.02395% CI: [0.49, 6.76]GEE, linear
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flucinolone Acetonide Implant | Change in SF-36 Physical Component Score From Baseline to 24 Months | 1.15 units on a scale | Standard Error 0.83 |
| Systemic Therapy | Change in SF-36 Physical Component Score From Baseline to 24 Months | -1.8 units on a scale | Standard Error 0.9 |
p-value: 0.01695% CI: [0.54, 5.36]Generalized Estimating Equations
Secondary
Diabetes Mellitus
Time frame: 24 months
Population: Participants with prevalent complications or missing data at enrollment were excluded from the risk set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Diabetes Mellitus | 1.0 percentage of participants |
| Systemic Therapy | Diabetes Mellitus | 3.6 percentage of participants |
p-value: 0.2495% CI: [0.03, 2.44]Regression, Cox
Secondary
Glaucoma - Incident
Glaucoma was diagnosed by a glaucoma specialist through review of visual fields, clinical data, and fundus images.
Time frame: 24 months
Population: Eyes, not participants, were analyzed. Eyes with prevalent complications or missing data at enrollment were were excluded from the risk set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Glaucoma - Incident | 16.5 percentage of eyes with uveitis at risk |
| Systemic Therapy | Glaucoma - Incident | 4.0 percentage of eyes with uveitis at risk |
p-value: 0.000895% CI: [1.82, 9.63]Cox proportional hazards w/ RE
Secondary
Hyperlipidemia - Incident
LDL greater than or equal to 160 mg/mL
Time frame: 24 months
Population: Number of participants at risk were included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Hyperlipidemia - Incident | 9.8 percentage of participants at risk |
| Systemic Therapy | Hyperlipidemia - Incident | 11.0 percentage of participants at risk |
p-value: 0.8495% CI: [0.39, 2.15]Regression, Cox
Secondary
Hypertension Diagnosis Requiring Treatment
Time frame: 24 months
Population: Participants with prevalent complications or missing data at enrollment were excluded from the risk set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Hypertension Diagnosis Requiring Treatment | 4.6 percentage of participants |
| Systemic Therapy | Hypertension Diagnosis Requiring Treatment | 10.5 percentage of participants |
p-value: 0.1395% CI: [0.13, 1.29]Regression, Cox
Secondary
Intraocular Pressure - Incident IOP Elevation >= 10 mmHg Above Baseline
Time frame: 24 months
Population: Eyes, not participants, were analyzed. Eyes with prevalent complications or missing data at enrollment were were excluded from the risk set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Intraocular Pressure - Incident IOP Elevation >= 10 mmHg Above Baseline | 51.8 percentage of eyes with uveitis at risk |
| Systemic Therapy | Intraocular Pressure - Incident IOP Elevation >= 10 mmHg Above Baseline | 15.5 percentage of eyes with uveitis at risk |
p-value: <0.000195% CI: [2.78, 6.58]Cox proportional hazards with RE
Secondary
Intraocular Pressure - Incident IOP Greater Than or Equal to 24 mm Hg
Time frame: 24 months
Population: Eyes, not participants, were analyzed. Eyes with prevalent complications or missing data at enrollment were were excluded from the risk set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Intraocular Pressure - Incident IOP Greater Than or Equal to 24 mm Hg | 53.1 percentage of eyes with uveitis at risk |
| Systemic Therapy | Intraocular Pressure - Incident IOP Greater Than or Equal to 24 mm Hg | 18.7 percentage of eyes with uveitis at risk |
p-value: <0.000195% CI: [2.34, 5.5]Cox proportional hazards w/ RE
Secondary
Intraocular Pressure - Incident IOP Greater Than or Equal to 30 mm Hg
Time frame: 24 months
Population: Eyes, not participants, were analyzed. Eyes with prevalent complications or missing data at enrollment were were excluded from the risk set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Intraocular Pressure - Incident IOP Greater Than or Equal to 30 mm Hg | 32.8 percentage of eyes with uveitis at risk |
| Systemic Therapy | Intraocular Pressure - Incident IOP Greater Than or Equal to 30 mm Hg | 6.3 percentage of eyes with uveitis at risk |
p-value: <0.000195% CI: [3.32, 11.15]Cox proportional hazards w/ RE
Secondary
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.
Time frame: 24 months
Population: Eyes, not participants, were analyzed. Eyes with prevalent complications or missing data at enrollment were were excluded from the risk set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | 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. | 61.1 percentage of eyes with uveitis at risk |
| Systemic Therapy | 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. | 20.1 percentage of eyes with uveitis at risk |
p-value: <0.000195% CI: [2.67, 6.47]Cox proportional hazards w/ RE
Secondary
Intraocular Pressure - IOP-lowering Surgery
Time frame: 24 months
Population: Eyes, not participants, were analyzed. Eyes with prevalent complications or missing data at enrollment were were excluded from the risk set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Intraocular Pressure - IOP-lowering Surgery | 26.2 percentage of eyes with uveitis at risk |
| Systemic Therapy | Intraocular Pressure - IOP-lowering Surgery | 3.7 percentage of eyes with uveitis at risk |
p-value: <0.000195% CI: [3.39, 20.82]Cox proportional hazards w/ RE
Secondary
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
Time frame: 24 months
Population: All eyes with uveitis were included in the analysis (245 eyes of the 129 participants randomized to implant therapy and 234 eyes of the 126 participants randomized to systemic therapy)..
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Macular Edema | 22 percentage of eyes with uveitis |
| Systemic Therapy | Macular Edema | 30 percentage of eyes with uveitis |
p-value: 0.07195% CI: [0.34, 1.03]GEE, logistic
Secondary
Mortality
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Mortality | 1.6 percentage of participants |
| Systemic Therapy | Mortality | 0 percentage of participants |
Secondary
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.
Time frame: 24 months
Population: All eyes with uveitis were included in the analysis (245 eyes of the 129 participants randomized to implant therapy and 234 eyes of the 126 participants randomized to systemic therapy).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flucinolone Acetonide Implant | Uveitis Activity | 12 percentage of eyes with uveitis |
| Systemic Therapy | Uveitis Activity | 29 percentage of eyes with uveitis |
p-value: 0.00195% CI: [0.13, 0.6]GEE, logistic