Clinical Trial Results:
A Multicenter Study of the Efficacy and Safety of the Human Anti-TNF Monoclonal Antibody Adalimumab in Subjects with Inactive Non-infectious Intermediate Uveitis, Posterior Uveitis, or Panuveitis – Including a Sub-study in Japanese Patients
Summary
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EudraCT number |
2009-016008-22 |
Trial protocol |
FR ES BE PT GB NL DE DK AT IT CZ GR |
Global end of trial date |
14 May 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
29 May 2016
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First version publication date |
29 May 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
M10-880
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01124838 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
AbbVie Deutschland GmbH & Co.KG
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Sponsor organisation address |
AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
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Public contact |
Global Medical Information, AbbVie, 011 800-633-9110,
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Scientific contact |
Andrew Payne, AbbVie, andy.payne@abbvie.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 May 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
14 May 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The objective of this study is to evaluate the efficacy and safety of adalimumab 80 mg loading dose followed by 40 mg dose given every other week subcutaneously starting at Week 1 compared with placebo in patients with inactive non-infectious intermediate uveitis, posterior uveitis, or panuveitis.
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Protection of trial subjects |
The study was conducted in accordance with the protocol, ICH guidelines, applicable regulations and guidelines governing clinical study conduct, and the ethical principles that have their origin in the Declaration of Helsinki and all applicable local regulations.
The investigator or his/her representative explained the nature of the study to the subject, and answered all questions regarding the study. Prior to any study-related screening procedures being performed on the subject, the informed consent statement was reviewed and signed and dated by the subject, the person who administered the informed consent, and any other signatories according to local requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
10 Aug 2010
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 4
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Country: Number of subjects enrolled |
Poland: 11
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Country: Number of subjects enrolled |
Portugal: 3
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
United Kingdom: 18
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Country: Number of subjects enrolled |
Austria: 8
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Country: Number of subjects enrolled |
Belgium: 31
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Country: Number of subjects enrolled |
Czech Republic: 1
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Country: Number of subjects enrolled |
Denmark: 2
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Greece: 2
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Country: Number of subjects enrolled |
Italy: 25
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Country: Number of subjects enrolled |
Argentina: 20
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Country: Number of subjects enrolled |
Australia: 7
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Country: Number of subjects enrolled |
Brazil: 3
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Country: Number of subjects enrolled |
Canada: 11
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Country: Number of subjects enrolled |
Israel: 3
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Country: Number of subjects enrolled |
Japan: 32
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Country: Number of subjects enrolled |
Mexico: 4
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Country: Number of subjects enrolled |
Switzerland: 4
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Country: Number of subjects enrolled |
United States: 61
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Worldwide total number of subjects |
261
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EEA total number of subjects |
116
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
246
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From 65 to 84 years |
15
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85 years and over |
0
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Recruitment
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Recruitment details |
This study includes a Japan sub-study. A total of 261 subjects 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
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Screening 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. | |||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||
Roles blinded |
Investigator, Subject | |||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||||||||||
Arm description |
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. | |||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Administered by subcutaneous injection
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Investigational medicinal product name |
Prednisone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
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.
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Arm title
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Adalimumab | |||||||||||||||||||||||||||||||||
Arm description |
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. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Adalimumab
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Investigational medicinal product code |
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Other name |
Humira
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Administered subcutaneously as an 80 mg loading dose (2 syringes) at Baseline followed by 40 mg eow starting at Week 1.
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Investigational medicinal product name |
Prednisone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
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.
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Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Only includes subjects who enrolled outside of Japan [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Only includes subjects who enrolled in Japan [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Only includes subjects who enrolled in Japan |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Adalimumab
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
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. | ||
Reporting group title |
Adalimumab
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Reporting group description |
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. | ||
Subject analysis set title |
Main Study: Placebo
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects, excluding those enrolled in the Japan sub-study, received placebo subcutaneous injection at
Baseline followed by eow dosing starting at Week 1 for up to 80 weeks or until treatment failure.
Subjects continued to receive prednisone orally, 10 - 35 mg/day at study entry followed by a protocol-defined mandatory taper until Week 19.
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Subject analysis set title |
Main Study: Adalimumab
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects, excluding those enrolled in the Japan sub-study, 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. Subjects continued to receive prednisone orally, 10 - 35 mg/day at study entry followed by a protocol-defined mandatory taper until Week 19.
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Subject analysis set title |
Integrated Study (Main + Japan Sub-study): Placebo
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects, including those enrolled in the Main Study and the Japan Sub-study, received placebo
subcutaneous injection at Baseline followed by eow dosing starting at Week 1 for up to 80 weeks or until
treatment failure. Subjects continued to receive prednisone orally, 10 - 35 mg/day at study entry followed by a protocol-defined mandatory taper until Week 19.
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Subject analysis set title |
Integrated Study (Main + Japan Sub-study): Adalimumab
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects, including those enrolled in the Main Study and the Japan Sub-study, 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. Subjects continued to receive prednisone orally, 10 - 35 mg/day at study entry followed by a protocol-defined mandatory taper until Week 19.
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End point title |
Time to Treatment Failure on or After Week 2 | ||||||||||||||||||||
End point description |
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.
The primary analysis was performed in the intent-to-treat (ITT) population which included all randomized subjects recruited outside Japan; 3 subjects at 2 sites were excluded from the ITT due to incomplete efficacy source data and compliance issues. "99999" indicates values not estimable.
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End point type |
Primary
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End point timeframe |
From Baseline until end of study (up to 80 weeks)
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Statistical analysis title |
Primary Analysis - Main Study | ||||||||||||||||||||
Statistical analysis description |
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.
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Comparison groups |
Main Study: Adalimumab v Main Study: Placebo
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Number of subjects included in analysis |
226
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||||||||||
P-value |
= 0.004 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||||
Point estimate |
0.57
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
0.39 | ||||||||||||||||||||
upper limit |
0.84 | ||||||||||||||||||||
Notes [1] - Difference |
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Statistical analysis title |
Additional Analysis – Integrated Study | ||||||||||||||||||||
Statistical analysis description |
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.
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Comparison groups |
Integrated Study (Main + Japan Sub-study): Placebo v Integrated Study (Main + Japan Sub-study): Adalimumab
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Number of subjects included in analysis |
258
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | ||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||||
Point estimate |
0.52
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
0.37 | ||||||||||||||||||||
upper limit |
0.74 | ||||||||||||||||||||
Notes [2] - Difference |
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End point title |
Change in Anterior Chamber (AC) Cell Grade in Each Eye From Baseline to the Final/Early Termination Visit | ||||||||||||||||||||||||||||||
End point description |
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.
This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF)
imputation was used.
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End point type |
Secondary
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End point timeframe |
Baseline and at the Final/Early Termination Visit (up to 80 weeks)
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Notes [3] - Participants with values at both time points [4] - Participants with values at both time points [5] - Participants with values at both time points [6] - Participants with values at both time points |
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Statistical analysis title |
Primary Analysis - Main Study | ||||||||||||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
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Comparison groups |
Main Study: Adalimumab v Main Study: Placebo
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Number of subjects included in analysis |
225
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Analysis specification |
Pre-specified
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Analysis type |
other [7] | ||||||||||||||||||||||||||||||
P-value |
= 0.218 [8] | ||||||||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
-0.14
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.37 | ||||||||||||||||||||||||||||||
upper limit |
0.08 | ||||||||||||||||||||||||||||||
Notes [7] - Difference [8] - From ANOVA of change from baseline to final/early termination visit with treatment as factor adjusted for clustered observations (i.e., observations from each of the subject's eyes). |
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Statistical analysis title |
Additional Analysis - Integrated Study | ||||||||||||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
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Comparison groups |
Integrated Study (Main + Japan Sub-study): Placebo v Integrated Study (Main + Japan Sub-study): Adalimumab
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Number of subjects included in analysis |
257
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Analysis specification |
Pre-specified
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Analysis type |
other [9] | ||||||||||||||||||||||||||||||
P-value |
= 0.164 [10] | ||||||||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
-0.15
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.36 | ||||||||||||||||||||||||||||||
upper limit |
0.06 | ||||||||||||||||||||||||||||||
Notes [9] - Difference [10] - From ANOVA of change from baseline to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors adjusted for clustered observations (i.e., observations from each of the subject's eyes). |
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End point title |
Change in Vitreous Haze (VH) Grade in Each Eye From Baseline to the Final/Early Termination Visit | ||||||||||||||||||||||||||||||
End point description |
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.
This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF) imputation was used.
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End point type |
Secondary
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End point timeframe |
Baseline and Final/Early Termination Visit (up to 80 weeks)
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Notes [11] - Participants with values at both time points [12] - Participants with values at both time points [13] - Participants with values at both time points [14] - Participants with values at both time points |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Primary Analysis - Main Study | ||||||||||||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||||||||||||
Comparison groups |
Main Study: Adalimumab v Main Study: Placebo
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
225
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other [15] | ||||||||||||||||||||||||||||||
P-value |
= 0.07 [16] | ||||||||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
-0.13
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.28 | ||||||||||||||||||||||||||||||
upper limit |
0.01 | ||||||||||||||||||||||||||||||
Notes [15] - Difference [16] - From ANOVA of change from baseline to final/early termination visit with treatment as factor adjusted for clustered observations. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Additional Analysis - Integrated Study | ||||||||||||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||||||||||||
Comparison groups |
Integrated Study (Main + Japan Sub-study): Placebo v Integrated Study (Main + Japan Sub-study): Adalimumab
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
257
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other [17] | ||||||||||||||||||||||||||||||
P-value |
= 0.016 [18] | ||||||||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
-0.17
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.31 | ||||||||||||||||||||||||||||||
upper limit |
-0.03 | ||||||||||||||||||||||||||||||
Notes [17] - Difference [18] - From ANOVA of change from baseline to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors adjusted for clustered observations. |
|
|||||||||||||||||||||||||||||||
End point title |
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 | ||||||||||||||||||||||||||||||
End point description |
Using corrective lenses based on that visit's refraction testing, subject's best corrected visual acuity was
measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR chart.
This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF)
imputation was used.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Final/Early Termination Visit (up to 80 weeks)
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Notes [19] - Participants with values at both time points [20] - Participants with values at both time points [21] - Participants with values at both time points [22] - Participants with values at both time points |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Primary Analysis - Main Study | ||||||||||||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||||||||||||
Comparison groups |
Main Study: Placebo v Main Study: Adalimumab
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
225
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other [23] | ||||||||||||||||||||||||||||||
P-value |
= 0.096 [24] | ||||||||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
-0.04
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.08 | ||||||||||||||||||||||||||||||
upper limit |
0.01 | ||||||||||||||||||||||||||||||
Notes [23] - Difference [24] - From ANOVA of change from baseline to final/early termination visit with treatment as factor adjusted for clustered observations. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Additional Analysis - Integrated Study | ||||||||||||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||||||||||||
Comparison groups |
Integrated Study (Main + Japan Sub-study): Placebo v Integrated Study (Main + Japan Sub-study): Adalimumab
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
257
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other [25] | ||||||||||||||||||||||||||||||
P-value |
= 0.044 [26] | ||||||||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
-0.04
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.09 | ||||||||||||||||||||||||||||||
upper limit |
0 | ||||||||||||||||||||||||||||||
Notes [25] - Difference [26] - From ANOVA of change from baseline to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors adjusted for clustered observations. |
|
|||||||||||||||||||||
End point title |
Time to Optimal Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 2 | ||||||||||||||||||||
End point description |
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.
This endpoint was only analyzed in subjects without macular edema at Baseline. "99999" indicates
values not estimable.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
From Baseline until the Final Visit (up to 80 weeks)
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [27] - Subjects without macular edema at Baseline [28] - Subjects without macular edema at Baseline [29] - Subjects without macular edema at Baseline [30] - Subjects without macular edema at Baseline |
|||||||||||||||||||||
Statistical analysis title |
Primary Analysis - Main Study | ||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%. The hazard ratio of adalimumab versus placebo was calculated using
proportional hazards regression with treatment as factor.
|
||||||||||||||||||||
Comparison groups |
Main Study: Placebo v Main Study: Adalimumab
|
||||||||||||||||||||
Number of subjects included in analysis |
185
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [31] | ||||||||||||||||||||
P-value |
= 0.491 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||||
Point estimate |
0.75
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.34 | ||||||||||||||||||||
upper limit |
1.69 | ||||||||||||||||||||
Notes [31] - Difference |
|||||||||||||||||||||
Statistical analysis title |
Additional Analysis - Integrated Study | ||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%. The hazard ratio of adalimumab versus placebo was calculated using
proportional hazards regression with treatment and race (Japanese versus non-Japanese) as factors.
|
||||||||||||||||||||
Comparison groups |
Integrated Study (Main + Japan Sub-study): Placebo v Integrated Study (Main + Japan Sub-study): Adalimumab
|
||||||||||||||||||||
Number of subjects included in analysis |
208
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [32] | ||||||||||||||||||||
P-value |
= 0.185 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||||
Point estimate |
0.6
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.28 | ||||||||||||||||||||
upper limit |
1.28 | ||||||||||||||||||||
Notes [32] - Difference |
|
|||||||||||||||||||||||||||||||
End point title |
Percent Change in Central Retinal Thickness in Each Eye From Baseline to the Final/Early Termination Visit | ||||||||||||||||||||||||||||||
End point description |
Central retinal thickness was measured using OCT and assessed by a central reader.
This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF)
imputation was used.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Final/Early Termination Visit (up to 80 weeks)
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Notes [33] - Participants with values at both time points [34] - Participants with values at both time points [35] - Participants with values at both time points [36] - Participants with values at both time points |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Primary Analysis - Main Study | ||||||||||||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||||||||||||
Comparison groups |
Main Study: Adalimumab v Main Study: Placebo
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
222
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other [37] | ||||||||||||||||||||||||||||||
P-value |
= 0.451 [38] | ||||||||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
-2.3
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-8.5 | ||||||||||||||||||||||||||||||
upper limit |
3.8 | ||||||||||||||||||||||||||||||
Notes [37] - Difference [38] - From ANOVA of change from baseline to final/early termination visit with treatment and OCT machine as factors adjusted for clustered observations. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Additional Analysis - Integrated Study | ||||||||||||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||||||||||||
Comparison groups |
Integrated Study (Main + Japan Sub-study): Placebo v Integrated Study (Main + Japan Sub-study): Adalimumab
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
254
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other [39] | ||||||||||||||||||||||||||||||
P-value |
= 0.174 [40] | ||||||||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
-3.9
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-9.7 | ||||||||||||||||||||||||||||||
upper limit |
1.8 | ||||||||||||||||||||||||||||||
Notes [39] - Difference [40] - From ANOVA of change from baseline to final/early termination visit with treatment, race (Japanese versus non-Japanese) and OCT machine as factors adjusted for clustered observations. |
|
|||||||||||||||||||||
End point title |
Change in Visual Functioning Questionnaire 25 (VFQ-25) Total Score From Baseline to the Final/Early Termination Visit | ||||||||||||||||||||
End point description |
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.
This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF)
imputation was used.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Final/Early Termination Visit (up 80 weeks)
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [41] - Participants with values at both time points [42] - Participants with values at both time points [43] - Participants with values at both time points [44] - Participants with values at both time points |
|||||||||||||||||||||
Statistical analysis title |
Primary Analysis - Main Study | ||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||
Comparison groups |
Main Study: Placebo v Main Study: Adalimumab
|
||||||||||||||||||||
Number of subjects included in analysis |
224
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [45] | ||||||||||||||||||||
P-value |
= 0.16 [46] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||
Point estimate |
2.12
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.84 | ||||||||||||||||||||
upper limit |
5.08 | ||||||||||||||||||||
Notes [45] - Difference [46] - From ANOVA of change from baseline to final/early termination visit with treatment as a factor. |
|||||||||||||||||||||
Statistical analysis title |
Additional Analysis - Integrated Study | ||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||
Comparison groups |
Integrated Study (Main + Japan Sub-study): Placebo v Integrated Study (Main + Japan Sub-study): Adalimumab
|
||||||||||||||||||||
Number of subjects included in analysis |
256
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [47] | ||||||||||||||||||||
P-value |
= 0.205 [48] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||
Point estimate |
1.77
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.97 | ||||||||||||||||||||
upper limit |
4.52 | ||||||||||||||||||||
Notes [47] - Difference [48] - From ANOVA of change from baseline to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors. |
|
|||||||||||||||||||||
End point title |
Change in VFQ-25 Subscore Distance Vision From Baseline to the Final/Early Termination Visit | ||||||||||||||||||||
End point description |
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.
This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF)
imputation was used.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Final/Early Termination Visit (up 80 weeks)
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [49] - Participants with values at both time points [50] - Participants with values at both time points [51] - Participants with values at both time points [52] - Participants with values at both time points |
|||||||||||||||||||||
Statistical analysis title |
Primary Analysis - Main Study | ||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||
Comparison groups |
Main Study: Placebo v Main Study: Adalimumab
|
||||||||||||||||||||
Number of subjects included in analysis |
224
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [53] | ||||||||||||||||||||
P-value |
= 0.401 [54] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||
Point estimate |
1.88
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-2.53 | ||||||||||||||||||||
upper limit |
6.29 | ||||||||||||||||||||
Notes [53] - Difference [54] - From ANOVA of change from baseline to final/early termination visit with treatment as a factor. |
|||||||||||||||||||||
Statistical analysis title |
Additional Analysis - Integrated Study | ||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||
Comparison groups |
Integrated Study (Main + Japan Sub-study): Placebo v Integrated Study (Main + Japan Sub-study): Adalimumab
|
||||||||||||||||||||
Number of subjects included in analysis |
256
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [55] | ||||||||||||||||||||
P-value |
= 0.256 [56] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||
Point estimate |
2.36
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-1.73 | ||||||||||||||||||||
upper limit |
6.45 | ||||||||||||||||||||
Notes [55] - Difference [56] - From ANOVA of change from baseline to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors. |
|
|||||||||||||||||||||
End point title |
Change in VFQ-25 Subscore Near Vision From Baseline to the Final/Early Termination Visit | ||||||||||||||||||||
End point description |
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.
This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF)
imputation was used.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Final/Early Termination Visit (up 80 weeks)
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [57] - Participants with values at both time points [58] - Participants with values at both time points [59] - Participants with values at both time points [60] - Participants with values at both time points |
|||||||||||||||||||||
Statistical analysis title |
Primary Analysis - Main Study | ||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||
Comparison groups |
Main Study: Placebo v Main Study: Adalimumab
|
||||||||||||||||||||
Number of subjects included in analysis |
224
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [61] | ||||||||||||||||||||
P-value |
= 0.967 [62] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||
Point estimate |
-0.1
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-4.81 | ||||||||||||||||||||
upper limit |
4.61 | ||||||||||||||||||||
Notes [61] - Difference [62] - From ANOVA of change from baseline to final/early termination visit with treatment as a factor. |
|||||||||||||||||||||
Statistical analysis title |
Additional Analysis - Integrated Study | ||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||
Comparison groups |
Integrated Study (Main + Japan Sub-study): Placebo v Integrated Study (Main + Japan Sub-study): Adalimumab
|
||||||||||||||||||||
Number of subjects included in analysis |
256
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [63] | ||||||||||||||||||||
P-value |
= 0.714 [64] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||
Point estimate |
-0.87
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-5.53 | ||||||||||||||||||||
upper limit |
3.79 | ||||||||||||||||||||
Notes [63] - Difference [64] - From ANOVA of change from baseline to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors. |
|
|||||||||||||||||||||
End point title |
Change in VFQ-25 Subscore Ocular Pain From Baseline to the Final/Early Termination Visit | ||||||||||||||||||||
End point description |
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 eye pain questions and ranges from 0 to 100, where higher scores or increases in score indicate less pain.
This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF)
imputation was used.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Final/Early Termination visit (up to 80 weeks)
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [65] - Participants with values at both time points [66] - Participants with values at both time points [67] - Participants with values at both time points [68] - Participants with values at both time points |
|||||||||||||||||||||
Statistical analysis title |
Primary Analysis - Main Study | ||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the
significance level of 5%.
|
||||||||||||||||||||
Comparison groups |
Main Study: Placebo v Main Study: Adalimumab
|
||||||||||||||||||||
Number of subjects included in analysis |
224
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [69] | ||||||||||||||||||||
P-value |
= 0.83 [70] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||
Point estimate |
0.56
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-4.56 | ||||||||||||||||||||
upper limit |
5.68 | ||||||||||||||||||||
Notes [69] - Difference [70] - From ANOVA of change from baseline to final/early termination visit with treatment as a factor. |
|||||||||||||||||||||
Statistical analysis title |
Additional Analysis - Integrated Study | ||||||||||||||||||||
Statistical analysis description |
The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
|
||||||||||||||||||||
Comparison groups |
Integrated Study (Main + Japan Sub-study): Placebo v Integrated Study (Main + Japan Sub-study): Adalimumab
|
||||||||||||||||||||
Number of subjects included in analysis |
256
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [71] | ||||||||||||||||||||
P-value |
= 0.842 [72] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Mean Difference | ||||||||||||||||||||
Point estimate |
-0.49
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-5.32 | ||||||||||||||||||||
upper limit |
4.34 | ||||||||||||||||||||
Notes [71] - Difference [72] - From ANOVA of change from baseline to final/early termination visit with treatment and race (Japanese vs. non-Japanese) as factors. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From the first study drug administration until 70 days following the last study drug administration or
until rollover into the extension study. Median duration of treatment was 147 days in the placebo arm
and 245 days in the adalimumab arm.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Adalimumab
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
24 Mar 2010 |
Substantial changes included:
● Revised efficacy variables to reflect updated scientific approach and statistical analyses
● Inclusion Criteria No. 3 and throughout protocol: changed "active" to active "inflammatory" chorioretinal and/or "inflammatory" retinal vascular lesion
● Increase the maximum allowable stable dose for an inactive uveitis patient to include up to 35 mg.
● Exclusion Criteria No. 9: changed BCVA worse than 20/400 to 20/200 and logMar from "> 1.34" to "> 1.0"
● Exclusion Criteria No. 10: added "All subjects with intermediate uveitis must have had a prior brain magnetic resonance imaging (MRI) at time of or after diagnosis of intermediate uveitis"
● Exclusion Criteria No. 14: changed dose of mycophenolate mofetil from ≤ 2 "mg" to ≤ 2 "gm"
● Concomitant Therapy: added text regarding concomitant and prohibited therapies to provide additional clarification regarding the use of topical or systemic corticosteroids
● Japan Sub-study: added active Hepatitis C and positive or indeterminate β-D-glucan as an exclusion criteria
● Japan Sub-study: Analysis of Efficacy: removed the following sentence: "An additional analysis the Time to Treatment Failure will be compared between the adalimumab group and the placebo group in the Japan ITT dataset using a log-rank test" as agreed upon with Japan's Pharmaceuticals and Medical Devices Agency (PMDA), the primary analysis will be performed on the integrated ITT dataset and a statistical test to compare the treatment groups in the Japan ITT dataset is not necessary.
|
||
23 Apr 2010 |
Substantial changes included:
● Best Corrected Visual Acuity Testing: Removed the requirement that the individual performing refraction and BCVA testing not be the Principal Investigator or the same person entering data on the eCRFs based on updated visual acuity requirements.
● Handling/Processing of Samples: added "Blood samples for Adalimumab and anti-adalimumab antibody (AAA) analysis will be collected by venipuncture into appropriately labeled evacuated serum collection tubes without gel separator at the required visits. Blood samples for Adalimumab analysis will also be obtained if a subject is discontinued from the study. Sufficient blood will be collected to provide approximately 1 mL serum. Allow the blood to clot for 30 minutes at room temperature before centrifugation."
● Collection of Samples for Analysis: Revised the number of pharmacokinetic (PK) and AAA samples that will be collected. |
||
10 Jun 2010 |
Substantial changes included:
● Inclusion Criterion No. 5 – Revised sentence to read "Subject must have a history of experiencing a disease flare while tapering off their oral corticosteroid therapy within the past 18 months" to provide correct interpretation of the appropriate subject population to be included.
● Efficacy Variables – Removed "3 lines" throughout the protocol when assessing Best Corrected Visual Acuity to provide clarification that worsening of BCVA will be based on the number of letters.
● Added text to indicate that information collected on AC cell count/grade would not only be a component of the primary endpoint but also be evaluated as a secondary efficacy variable.
● Exclusion Criterion No. 2: Added Human T Lymphotropic Virus Type 1 (HTLV-1) infection, Whipple's disease and HZV (herpes zoster virus).
● Prohibited Therapy: Added "anti-vascular endothelial growth factor (VEGF) therapy" and "periocular, intraocular or intravitreal injections."
|
||
11 Feb 2011 |
Substantial changes included:
Inclusion Criterion:
● Added requirement for ≥10 mg oral prednisone for 90 days prior to Baseline
● Added option to use QuantiFERON®-TB Gold for TB screening
● Removed text requiring reading of purified protein derivative (PPD) test at study site and added text indicating TB screening tests are performed locally and annually
● Added instruction for TB prophylaxis
● Added instruction that subjects with documented completion of Center for Disease Control (CDC) recommended prophylaxis may conditionally be permitted to enroll
● Added increase of screening period up to 45 days if a subject is required to receive ≥ 28 days of TB prophylaxis
Exclusion Criteria:
● Exclude subjects with 1 immunosuppressive therapy with dose that has not been stable for at least 28 days or who are on a dose outside of the allowed range listed
● Exclude subjects with macular edema due to diabetic retinopathy
● Changed description of demyelinating disease
● Expanded and clarified description of exclusionary infections
● Clarified that subjects with an active systemic viral infection or any active viral infection are excluded
● Added exclusion criterion that allows the prior use of intravitreal anti-VEGF therapy provided a 3 month washout period from Baseline is observed
● Added Ozurdex® (dexamethasone implant) and intravitreal methotrexate as prohibited therapy
● Exclude marijuana use including medical marijuana in the previous 12 months
● Exclude hepatitis B surface antigen positive subjects
● Removed requirement that Screening visit fundus photo is evaluated prior to the Baseline visit Removed central reader's precedence if assessment differs from investigator's assessment
● Added diagnosis of lupus like syndrome, multiple sclerosis or demyelinating disease and non-compliance with TB therapy as discontinuation criteria
● Added criteria that age-related eye disease study (AREDS) classification does not apply to subjects with pseudophakia |
||
16 Feb 2011 |
Substantial changes included:
● Clarified that methotrexate, cyclosporine, mycophenolate mofetil or azathioprine cannot be discontinued within 28 days prior to the Baseline visit.
|
||
21 Mar 2011 |
Substantial Changes included:
● Added text to exclude use of systemic carbonic anhydrase inhibitor within 1 week prior to Screening visit and as prohibited therapy.
● Provided details of the nature of syphilis confirmatory testing.
● Added instruction to evaluate subjects for treatment failure criteria at Unscheduled visits (as applicable) and complete Unscheduled visit activities per the investigator's clinical judgment.
● Added instruction to use the same fundus camera throughout the study per subject.
|
||
24 Aug 2011 |
Substantial changes included:
● Changed period of inactive disease and minimum length of time the subject must be taking ≥ 10 mg of oral prednisone to 28 days prior to Baseline
● Removed allowance for subjects with positive TB tests except if a subject received Bacille Calmette-Guérin (BCG) vaccination or has history of an ulcerative reaction to a PPD skin test. If the PPD test is positive, the QuantiFERON®-TB Gold test must be performed. If the QuantiFERON®-TB Gold test is negative, the subject is eligible
● Added to criterion to require an MRI report completed within 90 days prior to Baseline to include a statement that reveals no hint of demyelinating disease such as multiple sclerosis for subjects who have intermediate uveitis or panuveitis that have signs of intermediate uveitis
● Clarified that immunosuppressive therapy including methotrexate, cyclosporine, mycophenolate mofetil or azathioprine should not be discontinued within 28 days prior to Baseline
● Modification to exclude subjects who received Retisert® within 3 years prior to Baseline or had complications related to the device. Added exclusion for those subjects who had Retisert® removed within 90 days prior to Baseline or complications related to device removal
• Changed exclusion of subjects with macular edema due to diabetic retinopathy to subjects with clinically significant macular edema due to diabetic retinopathy
● Modified that both Fluorescent Treponemal Antibody (FTA) and Rapid Plasma Reagin (RPR) must be tested, and if positive the subject would be excluded
● Exclude subjects with macular edema as the only sign of uveitis
● Exclude subjects with a history of scleritis
• Exclude subjects who require TB Prophylaxis
• Added “any TB-prophylaxis therapy” and “Retisert®" to list of prohibited medications
● Dilated Indirect Ophthalmoscopy: Added instruction to record the number of lesions, the location(s), size(s) and whether the lesions are active or inactive with a retinal drawing |
||
15 Mar 2012 |
Substantial changes included:
● Clarified that at least one disease flare must occur within 18 months of Screening and that this flare has to occur during or up to a maximum of 28 days after tapering off the oral corticosteroid therapy.
● Revised language to include subjects with either negative PPD (< 5 mm of induration) or negative QuantiFERON®-TB Gold test (or Interferon-Gamma Release Assay [IGRA] equivalent) as eligible. Only 1 TB test is permitted to allow the subject in the study. Subjects with a repeat indeterminate QuantiFERON®-TB Gold test (or IGRA equivalent) result are not eligible. Added that subjects with "previous" TB are also not eligible for this study.
● Reduced the number of letters a subject must read for BCVA to 20 letters.
● Added tacrolimus as an acceptable concomitant immunosuppressant.
● Created Exclusion to allow prior use of cyclophosphamide provided a 30 day washout prior to Baseline is observed. Added chlorambucil and cyclophosphamide to prohibited concomitant medication list.
● Exclude subjects with cystoid macular edema unless the documented retinal changes are persistent, residual and stable as defined by the SUN criteria (persistent is > 3 months duration).
● Reduced intravitreal anti-VEGF therapy washout periods for Lucentis® (ranibizumab) or Avastin® (bevacizumab) to 45 days of Baseline or for anti-VEGF Trap (Aflibercept) for 60 days of Baseline.
● Changed to allow refractive laser surgery, retinal laser photocoagulation or neodymium-doped yttrium aluminium garnet (Nd:YAG) capsulotomy laser ≥ 30 days prior to Baseline visit.
|
||
21 Dec 2012 |
● Ranked secondary variables.
● Added language and new requirements regarding malignancy in patients who are 30 years old or younger.
● Adverse Event Reporting changed to require non-serious events of malignancy in subjects 30 or younger to be reported to Abbvie within 24 hours of site awareness. |
||
24 Jun 2013 |
Substantial changes included:
● Removed interim analyses and reduced the total number of treatment failures to complete the study.
● Added Rituxan® (rituximab) as prohibited therapy.
● Added subjects with optic neuritis are exclusionary.
● Added Stelara® (ustekinumab), Benlysta® (belimumab), and corticosteroids with the exceptions of protocol specified prednisone taper and the protocol specified corticosteroid eyedrop taper as prohibited medications.
|
||
19 Feb 2014 |
Substantial changes included:
• Increase the number of Treatment Failures from currently planned 76 to approximately 96 to ensure approximately 80% statistical power.
|
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |