Uveitis
Conditions
Keywords
Uveitis
Brief summary
A study comparing the safety and efficacy of adalimumab compared with. placebo in adults with inactive non-infectious intermediate uveitis, posterior uveitis, or panuveitis.
Interventions
DRUGAdalimumab
Administered subcutaneously as an 80 mg loading dose (2 syringes) at Baseline followed by 40 mg eow starting at Week 1.
DRUGPrednisone
Administered orally, 10 - 35 mg/day at study entry followed by a protocol-defined mandatory taper schedule in which all subjects continuing in the study were to discontinue prednisone no later than Week 19.
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 99 Years
Healthy volunteers
No
Inclusion criteria
* Subject is diagnosed with non-infectious intermediate, posterior, or panuveitis. * Subject that for ≥ 28 days prior to the Baseline visit has inactive disease and is taking ≥ 10 mg of oral prednisone to maintain this inactive state and fulfillment of all 3 of the following criteria based on the Investigator's clinical judgment at the Screening and Baseline visits for both eyes: * Subject without active, inflammatory chorioretinal and/or inflammatory retinal vascular lesions. * Subject with anterior chamber cell grade ≤ 0.5+ according to Standardization of Uveitis Nomenclature (SUN) criteria. * Subject with vitreous haze grade ≤ 0.5+ according to National Eye Institute (NEI)/SUN criteria. * Subject is on oral prednisone 10 to 35 mg/day (or oral corticosteroid equivalent) at Baseline and the dose has not been increased in the past 28 days or decreased in the past 14 days. * Subject must have a documented history of experiencing at least one disease flare within 18 months of the Screening visit. This flare has to occur during or up to a maximum of 28 days after tapering off the oral corticosteroid therapy. * 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 confirmed or suspected infectious uveitis, including but not limited to infectious uveitis due to TB, cytomegalovirus (CMV), Lyme disease, toxoplasmosis, human T-lymphotropic virus type 1 (HTLV-1) infection, Whipple's disease, herpes zoster virus (HZV) 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 (ETDRS \[Early Treatment Diabetic Retinopathy Study\]) 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 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. * Subject on concomitant immunosuppressive therapy other than methotrexate, cyclosporine, mycophenolate mofetil or an equivalent drug to mycophenolate mofetil (e.g., mycophenolic acid), azathioprine or tacrolimus within 28 days of Baseline or has discontinued an immunosuppressive therapy including methotrexate, cyclosporine, mycophenolate mofetil or an equivalent drug to mycophenolate mofetil (e.g., mycophenolic acid), azathioprine or tacrolimus within 28 days of Baseline. * If entering the study on one concomitant immunosuppressive therapy, dose has not been stable for at least 28 days prior to the 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 Retisert® (glucocorticosteroids implant) within 3 years prior to the Baseline visit or has had complications related to the device. Subject has had Retisert® (glucocorticosteroid implant) removed within 90 days prior to the Baseline visit or has had complications related to removal of the device. * Subject has received intraocular or periocular corticosteroids within 90 days prior to the 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 cystoid macular edema unless the retinal changes are persistent, residual and stable as defined by the SUN criteria (persistent is \> 3 months duration). * Subject has received Ozurdex® (dexamethasone implant) within 6 months prior to the Baseline visit. * Subject has received intravitreal methotrexate within 90 days 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 on systemic carbonic anhydrase inhibitor within 1 week prior to Screening visit. * Subject with a history of scleritis. * 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 2 | From Baseline until end of study (up to 80 weeks) | Treatment failure was defined by the occurrence of a uveitis flare (the inability to maintain disease control). To be considered treatment failure, ≥ 1 of these criteria had to be present in at least 1 eye at Week 2 or all other visits: * New active, inflammatory chorioretinal, and/or inflammatory retinal vascular lesions relative to Baseline * 2-step increase relative to Baseline in anterior chamber cell grade or vitreous haze grade * Worsening of best corrected visual acuity by ≥ 15 letters relative to baseline. Time to treatment failure was analyzed using the Kaplan-Meier method. Dropouts for reasons other than treatment failure at any time during the study were censored at the drop out date. 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 Baseline to the Final/Early Termination Visit | Baseline 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 Baseline to the Final/Early Termination Visit | Baseline 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. On the logMAR scale, 0 is equivalent to 20/20 visual acuity, the range of normal vision is considered to be from -0.2 - 0.1; higher values indicate visual impairment. |
| Time to Optimal Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 2 | 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 2 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 Baseline to the Final/Early Termination Visit. | Baseline and Final/Early Termination Visit (up to 80 weeks) | Central retinal thickness was measured using OCT and assessed by a central reader. |
| Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline to the Final/Early Termination Visit | Baseline 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 Subscore Distance Vision From Baseline to the Final/Early Termination Visit | Baseline 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 Subscore Near Vision From Baseline to the Final/Early Termination Visit | Baseline 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 near 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 Subscore Ocular Pain From Baseline to the Final/Early Termination Visit | Baseline 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 form the answers to 2 eye pain 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) Total Score From Baseline to the Final/Early Termination Visit | Baseline 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. A total of 261 adults with inactive non-infectious intermediate uveitis, posterior uveitis or panuveitis were randomized at 72 study sites worldwide; 229 participants at 62 study sites in Australia, Israel, Latin America, North America, and Europe (Main Study), and 32 participants at 10 study sites in Japan.
Pre-assignment details
Participants were randomized in a 1:1 ratio double-masked fashion using baseline immunosuppressant (IMM) usage as the stratification factor. Participants in the Japan sub-study were randomized in a separate stratum with no stratification by baseline IMM usage. Study completion is 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 every other week (eow) dosing starting at Week 1 for up to 80 weeks or until treatment failure. Participants continued to receive prednisone orally, 10 to 35 mg/day at study entry followed by a protocol-defined mandatory taper until Week 19. | 130 |
| 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, 10 - 35 mg/day at study entry followed by a protocol-defined mandatory taper until Week 19. | 131 |
| Total | 261 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 11 |
| Overall Study | Lack of Efficacy | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Miscellaneous | 4 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Adalimumab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 43.18 years STANDARD_DEVIATION 12.719 | 43.20 years STANDARD_DEVIATION 13.36 | 43.22 years STANDARD_DEVIATION 14.026 |
| Age, Customized < 65 years | 125 participants | 246 participants | 121 participants |
| Age, Customized ≥ 65 years | 6 participants | 15 participants | 9 participants |
| Diagnosis Behcet's | 10 participants | 17 participants | 7 participants |
| Diagnosis Birdshot Choroidopathy | 15 participants | 31 participants | 16 participants |
| Diagnosis Idiopathic | 33 participants | 78 participants | 45 participants |
| Diagnosis Multifocal Choroiditis and Panuveitis | 5 participants | 7 participants | 2 participants |
| Diagnosis Other | 12 participants | 22 participants | 10 participants |
| Diagnosis Sarcoid | 22 participants | 42 participants | 20 participants |
| Diagnosis Vogt Koyanagi Harada | 34 participants | 64 participants | 30 participants |
| Duration of Uveitis | 58.35 months STANDARD_DEVIATION 61.834 | 58.85 months STANDARD_DEVIATION 63.185 | 59.36 months STANDARD_DEVIATION 64.753 |
| Eye Affected Both | 126 participants | 248 participants | 122 participants |
| Eye Affected Left | 3 participants | 6 participants | 3 participants |
| Eye Affected Right | 2 participants | 7 participants | 5 participants |
| History of Infectious Uveitis No | 131 participants | 261 participants | 130 participants |
| History of Infectious Uveitis Yes | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized American Indian/Alaskan Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 19 participants | 38 participants | 19 participants |
| Race/Ethnicity, Customized Black | 6 participants | 14 participants | 8 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 | 9 participants | 14 participants | 5 participants |
| Race/Ethnicity, Customized White | 96 participants | 192 participants | 96 participants |
| Sex: Female, Male Female | 75 Participants | 158 Participants | 83 Participants |
| Sex: Female, Male Male | 56 Participants | 103 Participants | 47 Participants |
| Type of Uveitis Intermediate | 17 participants | 47 participants | 30 participants |
| Type of Uveitis Intermediate/Posterior | 2 participants | 3 participants | 1 participants |
| Type of Uveitis Panuveitis | 71 participants | 134 participants | 63 participants |
| Type of Uveitis Posterior | 41 participants | 77 participants | 36 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 78 / 130 | 88 / 131 |
| serious Total, serious adverse events | 10 / 130 | 8 / 131 |
Outcome results
Primary
Time to Treatment Failure on or After Week 2
Treatment failure was defined by the occurrence of a uveitis flare (the inability to maintain disease control). To be considered treatment failure, ≥ 1 of these criteria had to be present in at least 1 eye at Week 2 or all other visits: * New active, inflammatory chorioretinal, and/or inflammatory retinal vascular lesions relative to Baseline * 2-step increase relative to Baseline in anterior chamber cell grade or vitreous haze grade * Worsening of best corrected visual acuity by ≥ 15 letters relative to baseline. Time to treatment failure was analyzed using the Kaplan-Meier method. Dropouts for reasons other than treatment failure at any time during the study were censored at the drop out date. 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; 3 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 2 | 8.3 months |
| Main Study: Adalimumab | Time to Treatment Failure on or After Week 2 | NA months |
| Integrated Study (Main + Japan Sub-study): Placebo | Time to Treatment Failure on or After Week 2 | 5.6 months |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Time to Treatment Failure on or After Week 2 | NA 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: 0.00495% CI: [0.39, 0.84]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: [0.37, 0.74]Log Rank
Secondary
Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline 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: Baseline and at the Final/Early Termination Visit (up to 80 weeks)
Population: Intent-to-treat population with a Baseline and at least one post-baseline value; last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study: Placebo | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline to the Final/Early Termination Visit | Left eye | 0.57 units on a scale | Standard Deviation 1.001 |
| Main Study: Placebo | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline to the Final/Early Termination Visit | Right eye | 0.53 units on a scale | Standard Deviation 0.963 |
| Main Study: Adalimumab | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline to the Final/Early Termination Visit | Right eye | 0.40 units on a scale | Standard Deviation 0.927 |
| Main Study: Adalimumab | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline to the Final/Early Termination Visit | Left eye | 0.41 units on a scale | Standard Deviation 0.969 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline to the Final/Early Termination Visit | Left eye | 0.61 units on a scale | Standard Deviation 1.005 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline to the Final/Early Termination Visit | Right eye | 0.60 units on a scale | Standard Deviation 0.992 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline to the Final/Early Termination Visit | Left eye | 0.46 units on a scale | Standard Deviation 0.996 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline to the Final/Early Termination Visit | Right eye | 0.44 units on a scale | Standard Deviation 0.95 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.21895% CI: [-0.37, 0.08]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.16495% CI: [-0.36, 0.06]ANOVA
Secondary
Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Baseline 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. On the logMAR scale, 0 is equivalent to 20/20 visual acuity, the range of normal vision is considered to be from -0.2 - 0.1; higher values indicate visual impairment.
Time frame: Baseline and Final/Early Termination Visit (up to 80 weeks)
Population: Intent-to-treat population with a Baseline and at least one post-baseline value; last observation carried forward (LOCF) imputation was used.
| 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 Baseline to the Final/Early Termination Visit | Left eye | 0.06 logMAR | Standard Deviation 0.239 |
| Main Study: Placebo | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Baseline to the Final/Early Termination Visit | Right eye | 0.02 logMAR | Standard Deviation 0.198 |
| Main Study: Adalimumab | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Baseline to the Final/Early Termination Visit | Right eye | -0.01 logMAR | Standard Deviation 0.165 |
| Main Study: Adalimumab | Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Baseline to the Final/Early Termination Visit | Left eye | 0.01 logMAR | Standard Deviation 0.251 |
| 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 Baseline to the Final/Early Termination Visit | Left eye | 0.07 logMAR | Standard Deviation 0.23 |
| 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 Baseline to the Final/Early Termination Visit | Right eye | 0.04 logMAR | Standard Deviation 0.216 |
| 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 Baseline to the Final/Early Termination Visit | Left eye | 0.02 logMAR | Standard Deviation 0.241 |
| 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 Baseline to the Final/Early Termination Visit | Right eye | 0.00 logMAR | Standard Deviation 0.169 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.09695% CI: [-0.08, 0.01]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.04495% CI: [-0.09, 0]ANOVA
Secondary
Change in VFQ-25 Subscore Distance Vision From Baseline 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 and Final/Early Termination Visit (up 80 weeks)
Population: Intent-to-treat population with a Baseline and at least one post-baseline value; last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study: Placebo | Change in VFQ-25 Subscore Distance Vision From Baseline to the Final/Early Termination Visit | 0.76 units on a scale | Standard Deviation 16.248 |
| Main Study: Adalimumab | Change in VFQ-25 Subscore Distance Vision From Baseline to the Final/Early Termination Visit | 2.64 units on a scale | Standard Deviation 17.165 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in VFQ-25 Subscore Distance Vision From Baseline to the Final/Early Termination Visit | 0.60 units on a scale | Standard Deviation 15.978 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in VFQ-25 Subscore Distance Vision From Baseline to the Final/Early Termination Visit | 2.96 units on a scale | Standard Deviation 17.121 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.40195% CI: [-2.53, 6.29]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.25695% CI: [-1.73, 6.45]ANOVA
Secondary
Change in VFQ-25 Subscore Near Vision From Baseline 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 near 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 and Final/Early Termination Visit (up 80 weeks)
Population: Intent-to-treat population with a Baseline and at least one post-baseline value; last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study: Placebo | Change in VFQ-25 Subscore Near Vision From Baseline to the Final/Early Termination Visit | 3.98 units on a scale | Standard Deviation 17.397 |
| Main Study: Adalimumab | Change in VFQ-25 Subscore Near Vision From Baseline to the Final/Early Termination Visit | 3.88 units on a scale | Standard Deviation 18.302 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in VFQ-25 Subscore Near Vision From Baseline to the Final/Early Termination Visit | 3.73 units on a scale | Standard Deviation 17.17 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in VFQ-25 Subscore Near Vision From Baseline to the Final/Early Termination Visit | 2.89 units on a scale | Standard Deviation 50.503 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.96795% CI: [-4.81, 4.61]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.71495% CI: [-5.53, 3.79]ANOVA
Secondary
Change in VFQ-25 Subscore Ocular Pain From Baseline 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 form the answers to 2 eye pain questions and ranges from 0 to 100, where higher scores or increases in score indicate less pain.
Time frame: Baseline and Final/Early Termination Visit (up 80 weeks)
Population: Intent-to-treat population with a Baseline and at least one post-baseline value; last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study: Placebo | Change in VFQ-25 Subscore Ocular Pain From Baseline to the Final/Early Termination Visit | 2.87 units on a scale | Standard Deviation 17.233 |
| Main Study: Adalimumab | Change in VFQ-25 Subscore Ocular Pain From Baseline to the Final/Early Termination Visit | 3.42 units on a scale | Standard Deviation 21.32 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in VFQ-25 Subscore Ocular Pain From Baseline to the Final/Early Termination Visit | 2.60 units on a scale | Standard Deviation 17.339 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in VFQ-25 Subscore Ocular Pain From Baseline to the Final/Early Termination Visit | 2.15 units on a scale | Standard Deviation 21.689 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.8395% CI: [-4.56, 5.68]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.84295% CI: [-5.32, 4.34]ANOVA
Secondary
Change in Visual Functioning Questionnaire 25 (VFQ-25) Total Score From Baseline 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 and Final/Early Termination Visit (up 80 weeks)
Population: Intent-to-treat population with a Baseline and at least one post-baseline value; last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study: Placebo | Change in Visual Functioning Questionnaire 25 (VFQ-25) Total Score From Baseline to the Final/Early Termination Visit | 1.24 units on a scale | Standard Deviation 10.698 |
| Main Study: Adalimumab | Change in Visual Functioning Questionnaire 25 (VFQ-25) Total Score From Baseline to the Final/Early Termination Visit | 3.36 units on a scale | Standard Deviation 11.73 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in Visual Functioning Questionnaire 25 (VFQ-25) Total Score From Baseline to the Final/Early Termination Visit | 1.00 units on a scale | Standard Deviation 10.225 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in Visual Functioning Questionnaire 25 (VFQ-25) Total Score From Baseline to the Final/Early Termination Visit | 2.79 units on a scale | Standard Deviation 12.018 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.1695% CI: [-0.84, 5.08]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.20595% CI: [-0.97, 4.52]ANOVA
Secondary
Change in Vitreous Haze (VH) Grade in Each Eye From Baseline 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: Baseline and Final/Early Termination Visit (up to 80 weeks)
Population: Intent-to-treat population with a Baseline and at least one post-baseline value; last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study: Placebo | Change in Vitreous Haze (VH) Grade in Each Eye From Baseline to the Final/Early Termination Visit | Left eye | 0.33 units on a scale | Standard Deviation 0.733 |
| Main Study: Placebo | Change in Vitreous Haze (VH) Grade in Each Eye From Baseline to the Final/Early Termination Visit | Right eye | 0.27 units on a scale | Standard Deviation 0.605 |
| Main Study: Adalimumab | Change in Vitreous Haze (VH) Grade in Each Eye From Baseline to the Final/Early Termination Visit | Right eye | 0.18 units on a scale | Standard Deviation 0.604 |
| Main Study: Adalimumab | Change in Vitreous Haze (VH) Grade in Each Eye From Baseline to the Final/Early Termination Visit | Left eye | 0.16 units on a scale | Standard Deviation 0.601 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in Vitreous Haze (VH) Grade in Each Eye From Baseline to the Final/Early Termination Visit | Right eye | 0.36 units on a scale | Standard Deviation 0.729 |
| Integrated Study (Main + Japan Sub-study): Placebo | Change in Vitreous Haze (VH) Grade in Each Eye From Baseline to the Final/Early Termination Visit | Left eye | 0.35 units on a scale | Standard Deviation 0.749 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in Vitreous Haze (VH) Grade in Each Eye From Baseline to the Final/Early Termination Visit | Left eye | 0.18 units on a scale | Standard Deviation 0.614 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Change in Vitreous Haze (VH) Grade in Each Eye From Baseline to the Final/Early Termination Visit | Right eye | 0.18 units on a scale | Standard Deviation 0.602 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.0795% CI: [-0.28, 0.01]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.01695% CI: [-0.31, -0.03]ANOVA
Secondary
Percent Change in Central Retinal Thickness in Each Eye From Baseline to the Final/Early Termination Visit.
Central retinal thickness was measured using OCT and assessed by a central reader.
Time frame: Baseline and Final/Early Termination Visit (up to 80 weeks)
Population: Intent-to-treat population with a Baseline and at least one post-baseline value; last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study: Placebo | Percent Change in Central Retinal Thickness in Each Eye From Baseline to the Final/Early Termination Visit. | Left eye (N = 107, 114, 122, 130) | 6.4 percent change | Standard Deviation 20.67 |
| Main Study: Placebo | Percent Change in Central Retinal Thickness in Each Eye From Baseline to the Final/Early Termination Visit. | Right eye (N = 108, 113, 124, 129) | 7.7 percent change | Standard Deviation 28.88 |
| Main Study: Adalimumab | Percent Change in Central Retinal Thickness in Each Eye From Baseline to the Final/Early Termination Visit. | Right eye (N = 108, 113, 124, 129) | 5.4 percent change | Standard Deviation 34.83 |
| Main Study: Adalimumab | Percent Change in Central Retinal Thickness in Each Eye From Baseline to the Final/Early Termination Visit. | Left eye (N = 107, 114, 122, 130) | 4.5 percent change | Standard Deviation 29.82 |
| Integrated Study (Main + Japan Sub-study): Placebo | Percent Change in Central Retinal Thickness in Each Eye From Baseline to the Final/Early Termination Visit. | Right eye (N = 108, 113, 124, 129) | 9.9 percent change | Standard Deviation 30.79 |
| Integrated Study (Main + Japan Sub-study): Placebo | Percent Change in Central Retinal Thickness in Each Eye From Baseline to the Final/Early Termination Visit. | Left eye (N = 107, 114, 122, 130) | 6.3 percent change | Standard Deviation 19.75 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Percent Change in Central Retinal Thickness in Each Eye From Baseline to the Final/Early Termination Visit. | Right eye (N = 108, 113, 124, 129) | 3.9 percent change | Standard Deviation 33.34 |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Percent Change in Central Retinal Thickness in Each Eye From Baseline to the Final/Early Termination Visit. | Left eye (N = 107, 114, 122, 130) | 5.2 percent change | Standard Deviation 29.91 |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.45195% CI: [-8.5, 3.8]ANOVA
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.17495% CI: [-9.7, 1.8]ANOVA
Secondary
Time to Optimal Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 2
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 2 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 Optimal Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 2 | NA months |
| Main Study: Adalimumab | Time to Optimal Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 2 | NA months |
| Integrated Study (Main + Japan Sub-study): Placebo | Time to Optimal Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 2 | NA months |
| Integrated Study (Main + Japan Sub-study): Adalimumab | Time to Optimal Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 2 | NA months |
Comparison: The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.p-value: 0.49195% CI: [0.34, 1.69]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: 0.18595% CI: [0.28, 1.28]Log Rank