Uveitis
Conditions
Keywords
inflammation of uvea
Brief summary
A study comparing the safety and efficacy of adalimumab compared with placebo in patients with active uveitis.
Interventions
BIOLOGICALAdalimumab
Administered subcutaneously as an 80 mg loading dose (2 syringes) at Baseline followed by a 40 mg dose eow starting at Week 1.
DRUGPrednisone
Administered orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper schedule in which all participants continuing in the study were to discontinue prednisone no later than Week 15.
DRUGPlacebo
Administered by subcutaneous injection
Sponsors
AbbVie (prior sponsor, Abbott)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is at least 18 years of age. * Subject is diagnosed with non-infectious intermediate-, posterior-, or panuveitis. * Subject must have active disease at the Baseline visit as defined by the presence of at least 1 of the following parameters in at least one eye despite at least 2 weeks of maintenance therapy with oral prednisone ≥ 10 mg/day to ≤ 60 mg/day (or oral corticosteroid equivalent): * Active, inflammatory, chorioretinal and/or inflammatory retinal vascular lesion * ≥ 2+ anterior chamber cells (Standardization of Uveitis Nomenclature \[SUN\] criteria) * ≥ 2+ vitreous haze (National Eye Institute \[NEI\]/SUN criteria) * Subject is on oral prednisone ≥ 10 mg/day to ≤ 60 mg/day (or oral corticosteroid equivalent) for at least 2 weeks prior to Screening and remains on the same dose from Screening to Baseline visit. * Subject with documented prior adequate response to oral corticosteroids (equivalent of oral prednisone up to 1 mg/kg/day). * Subjects who do not have previous, active or latent tuberculosis (TB). Only one TB test is required to allow the subject in the study. Subjects with either negative purified protein derivative (PPD) (\< 5 mm of induration) or negative QuantiFERON®-TB Gold test (or interferon-gamma release assay (IGRA) equivalent) are eligible. Subjects with a repeat indeterminate QuantiFERON®-TB Gold test (or IGRA equivalent) result are not eligible. Note, that only one TB screening test is allowed and required. A repeat QuantiFERON® TB Gold test (or IGRA equivalent) is not permitted if the PPD skin test is positive. The TB screening tests are diagnostic tests. In the event of a negative TB screening test, the results are to be interpreted in the context of the patient's epidemiology, history, exam findings, etc. and it is the responsibility of the investigator to determine if a patient has previous, active or latent tuberculosis or not. Under no circumstances can a patient with a positive PPD result or positive QuantiFERON®-TB Gold test (or IGRA equivalent) enter the study.
Exclusion criteria
* Subject with isolated anterior uveitis. * Subject with prior inadequate response to high-dose oral corticosteroids * Subject with confirmed or suspected infectious uveitis, including but not limited to infectious uveitis due to TB, cytomegalovirus (CMV), Human T-Lymphotropic Virus Type 1 (HTLV-1), Whipple's disease, Herpes Zoster virus (HZV), Lyme disease, toxoplasmosis and herpes simplex virus (HSV). * Subject with serpiginous choroidopathy. * Subject with corneal or lens opacity that precludes visualization of the fundus or that likely requires cataract surgery during the duration of the trial. * Subject with intraocular pressure of ≥ 25 mmHg and on ≥ 2 glaucoma medications or evidence of glaucomatous optic nerve injury. * Subject with Best Corrected Visual Acuity (BCVA) less than 20 letters (Early Treatment Diabetic Retinopathy Study) in at least one eye at the Baseline Visit. * Subject with intermediate uveitis or panuveitis that has signs of intermediate uveitis (e.g.presence or history of snowbanking or snowballs) and symptoms and/or magnetic resonance imaging (MRI) findings suggestive of a demyelinating disease such as multiple sclerosis. All subjects with intermediate uveitis or panuveitis that have signs of intermediate uveitis (e.g., presence or history of snowbanking or snowballs) must have had a brain MRI within 90 days prior to the Baseline Visit. * Subject has previous exposure to anti-tumor necrosis factor (TNF) therapy or any biologic therapy (except intravitreal anti-vascular endothelial growth factor \[VEGF\] therapy) with a potential therapeutic impact on non-infectious uveitis. * If entering the study on 1 concomitant immunosuppressive therapy, dose has been increased within the last 28 days prior to Baseline visit or is not within the following allowable doses at the Baseline visit: * Methotrexate (MTX) ≤ 25 mg per week * Cyclosporine ≤ 4 mg/kg per day * Mycophenolate mofetil ≤ 2 grams per day or an equivalent drug to mycophenolate mofetil (e.g. mycophenolic acid) at an equivalent dose approved by the Medical Monitor. * Azathioprine ≤ 175 mg per day * Tacrolimus (oral formulation) ≤ 8 mg per day * Subject has received Retisert® (glucocorticosteroids implant) within 3 years prior to the Baseline visit or that has had complications related to the device. Subject has had Retisert® (glucocorticosteroids implant) removed within 90 days prior to the Baseline visit or has had complications related to the removal of the device. * Subject has received intraocular or periocular corticosteroids within 30 days prior to Baseline visit. * Subject with proliferative or severe non-proliferative diabetic retinopathy or clinically significant macular edema due to diabetic retinopathy. * Subject with neovascular/wet age-related macular degeneration * Subject with abnormality of vitreo-retinal interface (i.e., vitreomacular traction, epiretinal membranes, etc.) with the potential for macular structural damage independent of the inflammatory process. * Subject with severe vitreous haze that precludes visualization of the fundus at the Baseline visit. * Subject has received Ozurdex® (dexamethasone implant) within 6 months prior to the Baseline visit. * Subject has received intravitreal anti-VEGF therapy within 45 days of the Baseline visit for Lucentis® (ranibizumab) or Avastin® (bevacizumab) or within 60 days of the Baseline visit for anti-VEGF Trap (aflibercept). * Subject has received intravitreal methotrexate within 90 days prior to the Baseline visit * Subject on systemic carbonic anhydrase inhibitor within 1 week prior to Screening visit. * Subject with macular edema as the only sign of uveitis. * Subject with a history of scleritis. * Subject with intolerance to high-dose oral corticosteroids (equivalent of oral prednisone 1 mg/kg/day or 60 to 80 mg/day). * Subject on cyclophosphamide within 30 days prior to the Baseline visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure on or After Week 6 | From Baseline until end of study (up to 80 weeks) | Time to treatment failure was analyzed using Kaplan-Meier methods. Treatment failures on or after Week 6 were counted as events. Dropouts for reasons other than treatment failure at any time during the study were censored at the dropout date. To be considered a treatment failure, ≥ 1 of these criteria had to be present in at least 1 eye: * New active, inflammatory chorioretinal or retinal vascular lesions relative to Baseline * Inability to achieve ≤ 0.5+ at Week 6 or a 2-step increase relative to best state achieved at all visits after Week 6 in anterior chamber cell grade or vitreous haze grade * Worsening of best corrected visual acuity by ≥ 15 letters relative to best state achieved. Per protocol, the primary analysis was performed in the Main Study population which included all randomized participants recruited outside Japan; for completeness results are also reported below for the Integrated dataset which includes participants recruited in Japan. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | From Baseline to Week 6 and Final/Early Termination Visit (up to 80 weeks) | Vitreous haze was measured using dilated indirect ophthalmoscopy (DIO) and assessed by the Investigator according to National Eye Institute (NEI) and SUN criteria: Grade 0: No evident vitreous haze; Grade 0.5+: Slight blurring of the optic disc margin because of the haze; normal striations and reflex of the nerve fiber layer cannot be visualized; Grade 1+: Permits a better definition of both the optic nerve head and the retinal vessels (compared to higher grades); Grade 2+: Permits better visualization of the retinal vessels (compared to higher grades); Grade 3+: Permits the observer to see the optic nerve head, but the borders are quite blurry; Grade 4+: Optic nerve head is obscured. |
| Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | From Baseline to Week 6 and Final/Early Termination Visit (up to 80 weeks) | Using corrective lenses based on that visit's refraction testing, participant's best corrected visual acuity was measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR chart. |
| Time to Optical Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 6 | From Baseline until the Final Visit (up to 80 weeks) | Optical coherence tomography was performed at every visit using 1 of 3 approved machines. Images were evaluated by a central reader. Macular edema was defined as cystoid macular edema. OCT evidence of macular edema on or after Week 6 was to be counted as an event. Dropouts due to reasons other than OCT evidence of macular edema were to be considered as censored observations at the time of dropping out. |
| Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Baseline to Week 6 and Final/Early Termination Visit (up to 80 weeks) | Central retinal thickness was measured using optical coherence tomography and assessed by a central reader. |
| Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | From Baseline to Week 6 and at the Final/Early Termination Visit (up to 80 weeks) | Slit lamp examinations were conducted at each visit to assess AC cell count. The number of AC cells observed within a 1 mm × 1 mm slit beam was used to determine the grade according to the Standardization of Uveitis Nomenclature (SUN) criteria: Grade 0 = \< 1 cell; Grade 0.5+ = 1-5 cells; Grade 1+ = 6-15 cells; Grade 2+ = 16-25 cells; Grade 3+ = 26-50 cells; Grade 4+ = \> 50 cells. |
| Change in VFQ-25 Distance Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks) | The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The distance vision subscore is calculated from the answers to 3 distance vision-related questions and ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning. |
| Change in VFQ-25 Near Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks) | The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The distance vision subscore is calculated from the answers to 3 near vision-related questions and ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning. |
| Change in VFQ-25 Ocular Pain Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks) | The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The ocular pain subscore is calculated from the answers to 2 ocular pain-related questions and ranges from 0 to 100, where higher scores or increases in score indicate less pain. |
| Change in Visual Functioning Questionnaire 25 (VFQ-25) Composite Score From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks) | The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The overall composite score ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning. |
Participant flow
Recruitment details
This study includes a Japan sub-study. 239 participants with active non-infectious intermediate uveitis, posterior uveitis, or panuveitis were randomized worldwide, including 223 participants at 67 sites in Australia, Europe, Israel, Latin America, and North America (Main Study), and 16 participants randomized at 7 sites in Japan (Japan sub-study).
Pre-assignment details
Participants were randomized in a 1:1 ratio double-masked fashion stratified by baseline immunosuppressant usage. Participants recruited in the Japan sub-study were randomized in a separate stratum with no stratification by baseline immunosuppressant usage. Study completion was defined as meeting treatment failure or reaching study Week 80.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo subcutaneous injection at Baseline followed by eow dosing starting at Week 1 for up to 80 weeks or until treatment failure. Participants continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15. | 120 |
| Adalimumab Participants received adalimumab 80 mg subcutaneous loading dose at Baseline followed by 40 mg doses eow starting at Week 1 for a maximum of 80 weeks or until treatment failure. Participants continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15. | 119 |
| Total | 239 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 10 |
| Overall Study | Lack of Efficacy | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Miscellaneous Reasons | 3 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | Adalimumab |
|---|---|---|---|
| Age, Continuous | 43.19 years STANDARD_DEVIATION 14.331 | 43.33 years STANDARD_DEVIATION 14.872 | 43.46 years STANDARD_DEVIATION 15.458 |
| Age, Customized 40 - 64 years | 54 participants | 110 participants | 56 participants |
| Age, Customized < 40 years | 56 participants | 103 participants | 47 participants |
| Age, Customized ≥ 65 years | 10 participants | 26 participants | 16 participants |
| Diagnosis Behcet's | 4 participants | 18 participants | 14 participants |
| Diagnosis Birdshot Choroidopathy | 21 participants | 45 participants | 24 participants |
| Diagnosis Idiopathic | 50 participants | 90 participants | 40 participants |
| Diagnosis Multifocal Choroiditis And Panuveitis | 5 participants | 13 participants | 8 participants |
| Diagnosis Other | 14 participants | 23 participants | 9 participants |
| Diagnosis Sarcoid | 12 participants | 24 participants | 12 participants |
| Diagnosis Vogt Koyanagi Harada | 14 participants | 26 participants | 12 participants |
| Duration of Uveitis | 58.56 months STANDARD_DEVIATION 85.308 | 49.90 months STANDARD_DEVIATION 71.66 | 41.18 months STANDARD_DEVIATION 53.53 |
| Eye Affected Both | 111 participants | 217 participants | 106 participants |
| Eye Affected Left | 5 participants | 11 participants | 6 participants |
| Eye Affected Right | 4 participants | 11 participants | 7 participants |
| Race/Ethnicity, Customized American Indian/Alaskan Native | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 10 participants | 22 participants | 12 participants |
| Race/Ethnicity, Customized Black | 12 participants | 23 participants | 11 participants |
| Race/Ethnicity, Customized Multi Race | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 5 participants | 11 participants | 6 participants |
| Race/Ethnicity, Customized White | 91 participants | 180 participants | 89 participants |
| Sex: Female, Male Female | 73 Participants | 139 Participants | 66 Participants |
| Sex: Female, Male Male | 47 Participants | 100 Participants | 53 Participants |
| Type of Uveitis Intermediate | 24 participants | 49 participants | 25 participants |
| Type of Uveitis Panuveitis | 58 participants | 114 participants | 56 participants |
| Type of Uveitis Posterior | 38 participants | 76 participants | 38 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 61 / 120 | 71 / 119 |
| serious Total, serious adverse events | 5 / 120 | 16 / 119 |
Outcome results
Primary
Time to Treatment Failure on or After Week 6
Time to treatment failure was analyzed using Kaplan-Meier methods. Treatment failures on or after Week 6 were counted as events. Dropouts for reasons other than treatment failure at any time during the study were censored at the dropout date. To be considered a treatment failure, ≥ 1 of these criteria had to be present in at least 1 eye: * New active, inflammatory chorioretinal or retinal vascular lesions relative to Baseline * Inability to achieve ≤ 0.5+ at Week 6 or a 2-step increase relative to best state achieved at all visits after Week 6 in anterior chamber cell grade or vitreous haze grade * Worsening of best corrected visual acuity by ≥ 15 letters relative to best state achieved. Per protocol, the primary analysis was performed in the Main Study population which included all randomized participants recruited outside Japan; for completeness results are also reported below for the Integrated dataset which includes participants recruited in Japan.
Time frame: From Baseline until end of study (up to 80 weeks)
Population: The intent-to-treat (ITT) population which included all randomized participants; 6 participants at 2 sites were excluded from the ITT due to incomplete efficacy source data and compliance issues.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Main Study: Placebo | Time to Treatment Failure on or After Week 6 | 3.0 months |
| Main Study: Adalimumab | Time to Treatment Failure on or After Week 6 | 5.6 months |
| Integrated Study (Main + Japan Sub-study): Placebo | Time to Treatment Failure on or After Week 6 | 3.0 months |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Time to Treatment Failure on or After Week 6 | 4.8 months |
Comparison: The primary analysis of the primary endpoint was performed on Main Study data, excluding the Japanese sub-study. The statistical test was performed at a 2-sided significance level of 0.05. The hazard ratio of adalimumab versus placebo was calculated using proportional hazards regression with treatment as factor.p-value: <0.00195% CI: [0.36, 0.7]Log Rank
Comparison: An additional analysis of the primary endpoint was performed using the Integrated Study data (Main Study + Japan sub-study). The statistical test was performed at a 2-sided significance level of 0.05. The hazard ratio of adalimumab versus placebo was calculated using proportional hazards regression with treatment and race (Japanese versus non-Japanese) as factors.p-value: <0.00195% CI: [0.4, 0.76]Log Rank
Secondary
Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
Slit lamp examinations were conducted at each visit to assess AC cell count. The number of AC cells observed within a 1 mm × 1 mm slit beam was used to determine the grade according to the Standardization of Uveitis Nomenclature (SUN) criteria: Grade 0 = \< 1 cell; Grade 0.5+ = 1-5 cells; Grade 1+ = 6-15 cells; Grade 2+ = 16-25 cells; Grade 3+ = 26-50 cells; Grade 4+ = \> 50 cells.
Time frame: From Baseline to Week 6 and at the Final/Early Termination Visit (up to 80 weeks)
Population: Intent-to-treat population with values at both time points (best state achieved prior to Week 6 and at least 1 post-week 6 value); last observation carried forward (LOCF) imputation was used; participants with no values after Week 6 were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study: Placebo | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.59 units on a scale | Standard Deviation 0.935 |
| Main Study: Placebo | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.69 units on a scale | Standard Deviation 1.067 |
| Main Study: Adalimumab | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.35 units on a scale | Standard Deviation 0.763 |
| Main Study: Adalimumab | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.36 units on a scale | Standard Deviation 0.746 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.65 units on a scale | Standard Deviation 1.039 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.56 units on a scale | Standard Deviation 0.913 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.36 units on a scale | Standard Deviation 0.727 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.35 units on a scale | Standard Deviation 0.744 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.01195% CI: [-0.51, -0.07]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.01995% CI: [-0.46, -0.04]ANOVA
Secondary
Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
Using corrective lenses based on that visit's refraction testing, participant's best corrected visual acuity was measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR chart.
Time frame: From Baseline to Week 6 and Final/Early Termination Visit (up to 80 weeks)
Population: Intent-to-treat population with values at both time points; last observation carried forward (LOCF) imputation was used; participants with no values after Week 6 were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study: Placebo | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.13 logMAR | Standard Deviation 0.32 |
| Main Study: Placebo | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.12 logMAR | Standard Deviation 0.169 |
| Main Study: Adalimumab | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.07 logMAR | Standard Deviation 0.16 |
| Main Study: Adalimumab | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.04 logMAR | Standard Deviation 0.143 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.13 logMAR | Standard Deviation 0.328 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.11 logMAR | Standard Deviation 0.179 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.05 logMAR | Standard Deviation 0.145 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.07 logMAR | Standard Deviation 0.164 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.00395% CI: [-0.11, -0.02]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.00895% CI: [-0.1, -0.02]ANOVA
Secondary
Change in VFQ-25 Distance Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The distance vision subscore is calculated from the answers to 3 distance vision-related questions and ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning.
Time frame: Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks)
Population: Intent-to-treat population with values at both time points; last observation carried forward (LOCF) imputation was used; participants with no values after Week 6 were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study: Placebo | Change in VFQ-25 Distance Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -5.64 units on a scale | Standard Deviation 14.654 |
| Main Study: Adalimumab | Change in VFQ-25 Distance Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -3.77 units on a scale | Standard Deviation 13.414 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in VFQ-25 Distance Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -5.72 units on a scale | Standard Deviation 14.531 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in VFQ-25 Distance Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -4.42 units on a scale | Standard Deviation 13.871 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.34695% CI: [-2.03, 5.75]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.49695% CI: [-2.47, 5.09]ANOVA
Secondary
Change in VFQ-25 Near Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The distance vision subscore is calculated from the answers to 3 near vision-related questions and ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning.
Time frame: Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks)
Population: Intent-to-treat population with values at both time points; last observation carried forward (LOCF) imputation was used; participants with no values after Week 6 were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study: Placebo | Change in VFQ-25 Near Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -8.09 units on a scale | Standard Deviation 17.754 |
| Main Study: Adalimumab | Change in VFQ-25 Near Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -2.97 units on a scale | Standard Deviation 16.784 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in VFQ-25 Near Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -7.65 units on a scale | Standard Deviation 17.808 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in VFQ-25 Near Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -3.52 units on a scale | Standard Deviation 16.494 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.03695% CI: [0.34, 9.9]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.07795% CI: [-0.45, 8.72]ANOVA
Secondary
Change in VFQ-25 Ocular Pain Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The ocular pain subscore is calculated from the answers to 2 ocular pain-related questions and ranges from 0 to 100, where higher scores or increases in score indicate less pain.
Time frame: Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks)
Population: Intent-to-treat population with values at both time points; last observation carried forward (LOCF) imputation was used; participants with no values after Week 6 were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study: Placebo | Change in VFQ-25 Ocular Pain Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -12.62 units on a scale | Standard Deviation 21.435 |
| Main Study: Adalimumab | Change in VFQ-25 Ocular Pain Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -2.60 units on a scale | Standard Deviation 15.342 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in VFQ-25 Ocular Pain Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -12.39 units on a scale | Standard Deviation 20.841 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in VFQ-25 Ocular Pain Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -3.56 units on a scale | Standard Deviation 16.056 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: <0.00195% CI: [4.86, 15.19]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%p-value: <0.00195% CI: [3.88, 13.79]ANOVA
Secondary
Change in Visual Functioning Questionnaire 25 (VFQ-25) Composite Score From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The overall composite score ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning.
Time frame: Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks)
Population: Intent-to-treat population with values at both time points; last observation carried forward (LOCF) imputation was used; participants with no values after Week 6 were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study: Placebo | Change in Visual Functioning Questionnaire 25 (VFQ-25) Composite Score From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -5.50 units on a scale | Standard Deviation 11.968 |
| Main Study: Adalimumab | Change in Visual Functioning Questionnaire 25 (VFQ-25) Composite Score From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -1.30 units on a scale | Standard Deviation 10.98 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in Visual Functioning Questionnaire 25 (VFQ-25) Composite Score From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -5.34 units on a scale | Standard Deviation 11.899 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in Visual Functioning Questionnaire 25 (VFQ-25) Composite Score From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | -1.68 units on a scale | Standard Deviation 10.924 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.0195% CI: [1.02, 7.38]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.01995% CI: [0.62, 6.71]ANOVA
Secondary
Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
Vitreous haze was measured using dilated indirect ophthalmoscopy (DIO) and assessed by the Investigator according to National Eye Institute (NEI) and SUN criteria: Grade 0: No evident vitreous haze; Grade 0.5+: Slight blurring of the optic disc margin because of the haze; normal striations and reflex of the nerve fiber layer cannot be visualized; Grade 1+: Permits a better definition of both the optic nerve head and the retinal vessels (compared to higher grades); Grade 2+: Permits better visualization of the retinal vessels (compared to higher grades); Grade 3+: Permits the observer to see the optic nerve head, but the borders are quite blurry; Grade 4+: Optic nerve head is obscured.
Time frame: From Baseline to Week 6 and Final/Early Termination Visit (up to 80 weeks)
Population: Intent-to-treat population with values at both time points; last observation carried forward (LOCF) imputation was used; participants with no values after Week 6 were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study: Placebo | Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.45 units on a scale | Standard Deviation 0.781 |
| Main Study: Placebo | Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.33 units on a scale | Standard Deviation 0.666 |
| Main Study: Adalimumab | Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.11 units on a scale | Standard Deviation 0.559 |
| Main Study: Adalimumab | Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.13 units on a scale | Standard Deviation 0.648 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.49 units on a scale | Standard Deviation 0.815 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.34 units on a scale | Standard Deviation 0.675 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right Eye | 0.16 units on a scale | Standard Deviation 0.648 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left Eye | 0.11 units on a scale | Standard Deviation 0.547 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: <0.00195% CI: [-0.43, -0.11]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: <0.00195% CI: [-0.43, -0.12]ANOVA
Secondary
Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
Central retinal thickness was measured using optical coherence tomography and assessed by a central reader.
Time frame: Baseline to Week 6 and Final/Early Termination Visit (up to 80 weeks)
Population: Intent-to-treat population with values at both time points; last observation carried forward (LOCF) imputation was used; participants with no values after Week 6 were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study: Placebo | Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left eye (n=100, 100, 107, 108) | 20.2 percent change | Standard Deviation 52.01 |
| Main Study: Placebo | Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right eye (n=102, 101, 108, 109) | 22.0 percent change | Standard Deviation 62.48 |
| Main Study: Adalimumab | Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right eye (n=102, 101, 108, 109) | 8.2 percent change | Standard Deviation 25.78 |
| Main Study: Adalimumab | Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left eye (n=100, 100, 107, 108) | 9.6 percent change | Standard Deviation 29.76 |
| Integrated Study (Main + Japan Sub-study): Placebo | Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right eye (n=102, 101, 108, 109) | 21.7 percent change | Standard Deviation 60.75 |
| Integrated Study (Main + Japan Sub-study): Placebo | Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left eye (n=100, 100, 107, 108) | 19.0 percent change | Standard Deviation 50.57 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Left eye (n=100, 100, 107, 108) | 13.9 percent change | Standard Deviation 53.95 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit | Right eye (n=102, 101, 108, 109) | 14.5 percent change | Standard Deviation 57.05 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.0295% CI: [-20.9, -1.8]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.42895% CI: [-17.7, 7.5]Chi-squared, Corrected
Secondary
Time to Optical Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 6
Optical coherence tomography was performed at every visit using 1 of 3 approved machines. Images were evaluated by a central reader. Macular edema was defined as cystoid macular edema. OCT evidence of macular edema on or after Week 6 was to be counted as an event. Dropouts due to reasons other than OCT evidence of macular edema were to be considered as censored observations at the time of dropping out.
Time frame: From Baseline until the Final Visit (up to 80 weeks)
Population: Intent to treat population with no macular edema at Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Main Study: Placebo | Time to Optical Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 6 | 6.2 months |
| Main Study: Adalimumab | Time to Optical Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 6 | 11.1 months |
| Integrated Study (Main + Japan Sub-study): Placebo | Time to Optical Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 6 | 3.7 months |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Time to Optical Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 6 | 9.2 months |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.23195% CI: [0.39, 1.26]Log Rank
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.19195% CI: [0.38, 1.21]Log Rank