Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects with Active Ankylosing Spondylitis
Summary
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EudraCT number |
2017-000431-14 |
Trial protocol |
FR DK DE FI CZ GB ES PT NL BE HU PL SE HR IT |
Global end of trial date |
17 Feb 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Feb 2023
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First version publication date |
23 Feb 2023
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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 |
M16-098
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03178487 | ||
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 Services, AbbVie, 001 800-633-9110, abbvieclinicaltrials@abbvie.com
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Scientific contact |
Global Medical Services, AbbVie, 001 800-633-9110, abbvieclinicaltrials@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 |
17 Feb 2022
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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 |
17 Feb 2022
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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 purpose of this study is to evaluate the safety and efficacy of upadacitinib in participants with active ankylosing spondylitis (AS) who have had an inadequate response to at least 2 non-steroidal anti-inflammatory drugs (NSAIDs) or intolerance to or a contraindication for NSAIDs, and who are naïve to biologic disease-modifying anti-rheumatic drugs (bDMARD).
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Protection of trial subjects |
Subject read and understood the information provided about the study and gave written permission.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Oct 2017
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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 |
Australia: 3
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Country: Number of subjects enrolled |
Belgium: 3
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Country: Number of subjects enrolled |
Canada: 5
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Country: Number of subjects enrolled |
Croatia: 1
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Country: Number of subjects enrolled |
Czechia: 36
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Country: Number of subjects enrolled |
Denmark: 1
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Country: Number of subjects enrolled |
Finland: 5
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Country: Number of subjects enrolled |
France: 10
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Country: Number of subjects enrolled |
Germany: 13
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Country: Number of subjects enrolled |
Hungary: 15
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Country: Number of subjects enrolled |
Japan: 13
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Country: Number of subjects enrolled |
Korea, Republic of: 13
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Country: Number of subjects enrolled |
Netherlands: 2
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Country: Number of subjects enrolled |
New Zealand: 6
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Country: Number of subjects enrolled |
Poland: 18
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Country: Number of subjects enrolled |
Portugal: 11
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Country: Number of subjects enrolled |
Spain: 11
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Country: Number of subjects enrolled |
Sweden: 2
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Country: Number of subjects enrolled |
United Kingdom: 5
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Country: Number of subjects enrolled |
United States: 14
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Worldwide total number of subjects |
187
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EEA total number of subjects |
128
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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) |
176
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From 65 to 84 years |
11
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants were enrolled between October 24, 2017, and September 10, 2018 at 62 sites in 20 countries in North America, Eastern and Western Europe, Asia, and Oceania. This study consists of a 14-week double-blind treatment period (Period 1) and a 90-week long-term extension period (Period 2) for participants who completed Period 1. | ||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Eligible participants were randomized in a 1:1 ratio to one of two treatment groups. Randomization was stratified by screening concentrations of high-sensitivity C-reactive protein (hsCRP; ≤ upper limit of normal [ULN] vs > ULN; where the ULN is 2.87 mg/L) and geographical region (USA and Canada, Japan, rest of the world). | ||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Period 1
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||
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 matching placebo orally once a day for 14 weeks in Period 1. | ||||||||||||||||||||||||||||||
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 |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo matching tablets taken orally once a day.
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Arm title
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Upadacitinib 15 mg | ||||||||||||||||||||||||||||||
Arm description |
Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Upadacitinib
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Investigational medicinal product code |
ABT-494
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Other name |
RINVOQ®
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets taken orally once a day.
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Period 2
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Period 2 title |
Period 2
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo / Upadacitinib 15 mg | ||||||||||||||||||||||||||||||
Arm description |
Participants randomized to receive placebo in Period 1 received upadacitinib 15 mg orally once a day for 90 weeks in Period 2. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Upadacitinib
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Investigational medicinal product code |
ABT-494
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Other name |
RINVOQ®
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets taken orally once a day.
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Arm title
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Upadacitinib 15 mg / Upadacitinib 15 mg | ||||||||||||||||||||||||||||||
Arm description |
Participants randomized to receive upadacitinib in Period 1 continued to receive upadacitinib 15 mg orally once a day for 90 weeks in Period 2. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Upadacitinib
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Investigational medicinal product code |
ABT-494
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Other name |
RINVOQ®
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets taken orally once a day.
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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 matching placebo orally once a day for 14 weeks in Period 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Upadacitinib 15 mg
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Reporting group description |
Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 matching placebo orally once a day for 14 weeks in Period 1. | ||
Reporting group title |
Upadacitinib 15 mg
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Reporting group description |
Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1. | ||
Reporting group title |
Placebo / Upadacitinib 15 mg
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Reporting group description |
Participants randomized to receive placebo in Period 1 received upadacitinib 15 mg orally once a day for 90 weeks in Period 2. | ||
Reporting group title |
Upadacitinib 15 mg / Upadacitinib 15 mg
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Reporting group description |
Participants randomized to receive upadacitinib in Period 1 continued to receive upadacitinib 15 mg orally once a day for 90 weeks in Period 2. |
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End point title |
Percentage of Participants With Assessment of SpondyloArthritis International Society (ASAS) 40 Response at Week 14 | ||||||||||||
End point description |
ASAS 40 response was defined as improvement of ≥ 40% relative to Baseline and absolute improvement of ≥ 2 units in ≥ 3 of the following 4 domains with no deterioration (a net worsening of > 0 units) in the potential remaining domain:
1) Patient's global assessment of disease activity, measured on a NRS from 0 - 10 (severe activity);
2) Pain, measured by the total back pain NRS from 0 - 10 (most severe pain);
3) Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI), consisting of 10 items assessing participants' ability to perform activities each on an NRS from 0 (easy) - 10 (impossible);
4) Inflammation, measured by the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none/0 hours) to 10 (very severe/≥ 2 hours duration).
Participants with missing data or who discontinued study drug prior to Week 14 were counted as non-responders.
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End point type |
Primary
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End point timeframe |
Baseline and Week 14
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Notes [1] - Full analysis set (all randomized participants who received at least one dose of study drug) [2] - Full analysis set |
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Statistical analysis title |
Primary Analysis | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
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Number of subjects included in analysis |
187
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
< 0.001 [4] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Response Rate Difference | ||||||||||||
Point estimate |
26.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
12.6 | ||||||||||||
upper limit |
39.5 | ||||||||||||
Notes [3] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. [4] - Cochran-Mantel-Haenszel (CMH) test adjusting for stratification factor of Screening hsCRP level. |
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End point title |
Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 14 | ||||||||||||
End point description |
ASDAS is a composite index to assess disease activity in Ankylosing Spondylitis. ASDAS combines the following 5 disease activity variables using a weighted formula:
1. Patient's assessment of total back pain (BASDAI Question 2; NRS from 0 - 10 [very severe])
2. Patient global assessment of disease activity (NRS from 0 [no activity] - 10 [severe activity])
3. Peripheral pain/swelling (BASDAI Question 3; NRS from 0 - 10 [very severe])
4. Duration of morning stiffness (BASDAI Question 6; NRS from 0 [0 hours] - 10 [2 or more hours])
5. hs-CRP in mg/L.
The overall score ranges from 0 with no defined upper score; published ranges for disease activity states as defined by the ASDAS include Inactive disease (ASDAS < 1.3) and very high disease (ASDAS > 3.5). A negative change from Baseline score indicates improvement in disease activity.
A mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 14
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Notes [5] - Full analysis set; MMRM including all observed longitudinal data up to Week 14 [6] - Full analysis set; MMRM including all observed longitudinal data up to Week 14 |
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Statistical analysis title |
Analysis of Change from Baseline in ASDAS | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
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Number of subjects included in analysis |
168
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Analysis specification |
Pre-specified
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Analysis type |
superiority [7] | ||||||||||||
P-value |
< 0.001 [8] | ||||||||||||
Method |
Mixed Effect Model Repeated Measurement | ||||||||||||
Parameter type |
Least Squares (LS) Mean Difference | ||||||||||||
Point estimate |
-0.91
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.14 | ||||||||||||
upper limit |
-0.68 | ||||||||||||
Notes [7] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. [8] - MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates. |
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End point title |
Change From Baseline in Spondyloarthritis Research Consortium of Canada (SPARCC) Magnetic Resonance Imaging (MRI) Score for the Spine at Week 14 | ||||||||||||
End point description |
The entire spine was evaluated for active inflammation (bone marrow edema) and 6 discovertebral units (DVU) representing the most abnormal DVUs were selected to calculate the SPARCC MRI Spine score. For each of the 6 DVUs, 3 consecutive sagittal slices were assessed in 4 quadrants to evaluate the extent of inflammation in three dimensions. Each quadrant was scored for the presence (1) or absence (0) of edema. If edema was present in at least 1 quadrant of a DVU slice, it was also scored for intensity and depth of the edema representing that slice: An additional score of 1 was assigned if an intense signal was seen in any quadrant on a DVU slice. Slices that included a lesion demonstrating continuous increased signal of depth ≥ 1 cm extending from the endplate were scored as an additional 1 per slice. The maximum (worst) overall score for all 6 DVUs is 108.
MRI data up to 3 days post first dose (for Baseline) and up to first dose of period 2 for Week 14 were included in the anlaysis.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 14
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Notes [9] - Full analysis set with available MRI data during pre-specified time window [10] - Full analysis set with available MRI data during pre-specified time window |
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Statistical analysis title |
Analysis of Change in SPARCC MRI Spine Score | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
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Number of subjects included in analysis |
128
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Analysis specification |
Pre-specified
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Analysis type |
superiority [11] | ||||||||||||
P-value |
< 0.001 [12] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-6.71
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-9.01 | ||||||||||||
upper limit |
-4.41 | ||||||||||||
Notes [11] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. [12] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate. |
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End point title |
Percentage of Participants With Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Response at Week 14 | ||||||||||||
End point description |
The BASDAI assesses disease activity by asking the participant to answer 6 questions (each on an 11 point numeric rating scale [NRS]) pertaining to symptoms experienced for the past week. For Questions 1 to 5 (level of fatigue/tiredness, level of AS neck, back or hip pain, level of pain/swelling in joints, other than neck, back or hips, level of discomfort from any areas tender to touch or pressure, and level of morning stiffness), the response is from 0 (none) to 10 (very severe); for Question 6 (duration of morning stiffness), the response is from 0 (0 hours) to 10 (≥ 2 hours). The overall BASDAI score ranges from 0 to 10. Lower scores indicate less disease activity.
A BASDAI 50 response is defined as improvement of 50% or more from Baseline in BASDAI score.
Participants with missing data or who discontinued study drug prior to Week 14 were counted as non-responders.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 14
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Notes [13] - Full analysis set [14] - Full analysis set |
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Statistical analysis title |
Analyis of BASDAI 50 Response | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
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Number of subjects included in analysis |
187
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Analysis specification |
Pre-specified
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Analysis type |
superiority [15] | ||||||||||||
P-value |
= 0.002 [16] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Response Rate Difference | ||||||||||||
Point estimate |
21.8
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
8.5 | ||||||||||||
upper limit |
35 | ||||||||||||
Notes [15] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including BASDAI 50; within the group, the allocated α was adjusted based on the magnitude of p values. [16] - Cochran-Mantel-Haenszel test adjusting for stratification factor of Screening hsCRP level. |
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End point title |
Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) Score | ||||||||||||
End point description |
The ASQoL consists of 18 items related to quality of life, including the impact of pain on sleep, mood, motivation, ability to cope, activities of daily living, independence, relationships, and social life. Each item is answered as yes (scored as 1) or no (scored as 0).
Scores are summed to obtain the overall score which ranges from 0 to 18, where higher scores indicate a worse quality of life. A negative change from Baseline in ASQoL indicates improvement in quality of life.
A mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 14
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Notes [17] - Full analysis set; MMRM including all observed longitudinal data up to Week 14 [18] - Full analysis set; MMRM including all observed longitudinal data up to Week 14 |
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Statistical analysis title |
Analysis of Change from Baseline in ASQoL Score | ||||||||||||
Comparison groups |
Upadacitinib 15 mg v Placebo
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Number of subjects included in analysis |
176
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Analysis specification |
Pre-specified
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||||||||||||
Analysis type |
superiority [19] | ||||||||||||
P-value |
= 0.16 [20] | ||||||||||||
Method |
Mixed Effect Model Repeated Measurement | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-1.54
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.78 | ||||||||||||
upper limit |
-0.3 | ||||||||||||
Notes [19] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including ASQoL; within the group, the allocated α was adjusted based on the magnitude of p values. [20] - MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates. |
|
|||||||||||||
End point title |
Percentage of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) Partial Remission | ||||||||||||
End point description |
ASAS partial remission (PR) is defined as an absolute score of ≤ 2 units on a 0 to 10 scale for each of the four following domains:
1) Patient's global assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (no activity) to 10 (severe activity);
2) Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe pain);
3) Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which consists of 10 items assessing participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible);
4) Inflammation, measured by the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none/0 hours) to 10 (very severe/2 hours or more duration).
Participants with missing data or who discontinued study drug prior to Week 14 were counted as non-responders.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 14
|
||||||||||||
|
|||||||||||||
Notes [21] - Full analysis set [22] - Full analysis set |
|||||||||||||
Statistical analysis title |
Analysis of ASAS Partial Remission | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
|
||||||||||||
Number of subjects included in analysis |
187
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [23] | ||||||||||||
P-value |
< 0.001 [24] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Response Rate Difference | ||||||||||||
Point estimate |
18.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
10 | ||||||||||||
upper limit |
26.6 | ||||||||||||
Notes [23] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including ASAS PR; within the group, the allocated α was adjusted based on the magnitude of p values. [24] - Cochran-Mantel-Haenszel test adjusting for stratification factor of Screening hsCRP level. |
|
|||||||||||||
End point title |
Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 14 | ||||||||||||
End point description |
The Bath Ankylosing Spondylitis Functional Index is a validated index to determine the degree of functional limitation in patients with AS. BASFI consists of 10 questions assessing participants' ability to perform activities such as putting on socks, bending, reaching, getting up from the floor or an armless chair, standing, climbing and other physical activities. Each item is scored on a NRS ranging from 0 (easy to perform an activity) to 10 (impossible to perform an activity). The overall score is the mean of the 10 items and ranges from 0 to 10 with higher scores indicating more functional limitations. A negative change from Baseline in BASFI indicates improvement.
A mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 14
|
||||||||||||
|
|||||||||||||
Notes [25] - Full analysis set; MMRM including all observed longitudinal data up to Week 14 [26] - Full analysis set; MMRM including all observed longitudinal data up to Week 14 |
|||||||||||||
Statistical analysis title |
Analysis of Change from Baseline in BASFI | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
|
||||||||||||
Number of subjects included in analysis |
172
|
||||||||||||
Analysis specification |
Post-hoc
|
||||||||||||
Analysis type |
superiority [27] | ||||||||||||
P-value |
= 0.001 [28] | ||||||||||||
Method |
Mixed Effect Model Repeated Measurement | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.6 | ||||||||||||
upper limit |
-0.39 | ||||||||||||
Notes [27] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including BASFI; within the group, the allocated α was adjusted based on the magnitude of p values. [28] - MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates. |
|
|||||||||||||
End point title |
Change From Baseline in Linear Bath Ankylosing Spondylitis Metrology Index (BASMI[Lin]) at Week 14 | ||||||||||||
End point description |
The BASMI is a composite score based on 5 direct measurements of spinal mobility:
1) cervical rotation (measured in degrees),
2) tragus to wall distance (in centimeters [cm]),
3) lumbar side flexion (in cm),
4) lumbar flexion (modified Schober's) (in cm), and
5) intermalleolar distance (in cm).
Each measurement is converted to a linear score between 0 and 10. The total BASMI score is the average of the 5 scores and ranges from 0 to 10; the higher the BASMI score the more severe the patient's limitation of movement due to their ankylosing spondylitis. A negative change from Baseline indicates improvement.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 14
|
||||||||||||
|
|||||||||||||
Notes [29] - Full analysis set participants with available data [30] - Full analysis set participants with available data |
|||||||||||||
Statistical analysis title |
Analysis of Change from Baseline in BASMI(lin) | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
|
||||||||||||
Number of subjects included in analysis |
178
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [31] | ||||||||||||
P-value |
= 0.03 [32] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.22
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.43 | ||||||||||||
upper limit |
-0.02 | ||||||||||||
Notes [31] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including BASMI(lin); within the group, the allocated α was adjusted based on the magnitude of p values. [32] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate. |
|
|||||||||||||
End point title |
Change From Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at Week 14 | ||||||||||||
End point description |
The MASES evaluation was conducted to assess the presence or absence of enthesitis (inflammation of the entheses, or sites where tendons or ligaments insert into the bone) at 13 different sites (first costochondral joint left/right, seventh costochondral joint left/right, posterior superior iliac spine left/right, anterior superior iliac spine left/right, iliac crest left/right, fifth lumbar spinous process, and proximal insertion of Achilles tendon left/right. Each site was scored for presence (1) or absence (0) of enthesitis. The MASES is the sum of the 13 site scores, and ranges from 0 to 13, with higher scores indicating more inflammation of the entheses.
A mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases
up to Week 14 was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 14
|
||||||||||||
|
|||||||||||||
Notes [33] - Full analysis set participants with Baseline enthesitis; MMRM including all observed data to Week 14 [34] - Full analysis set participants with Baseline enthesitis; MMRM including all observed data to Week 14 |
|||||||||||||
Statistical analysis title |
Analysis of Change from Baseline in MASES | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
|
||||||||||||
Number of subjects included in analysis |
101
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [35] | ||||||||||||
P-value |
= 0.049 [36] | ||||||||||||
Method |
Mixed Effect Model Repeated Measurement | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.84
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.68 | ||||||||||||
upper limit |
0 | ||||||||||||
Notes [35] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including MASES; within the group, the allocated α was adjusted based on the magnitude of p values. [36] - MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates. |
|
|||||||||||||
End point title |
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Overall Work Impairment at Week 14 | ||||||||||||
End point description |
The Work Productivity and Activity Impairment Questionnaire: Axial Spondyloarthritis, Version 2.0 (WPAI-Axial Spondyloarthritis) measures the effect of overall health and specific symptoms on productivity at work and outside of work. It consists of 6 questions. Respondents were asked about time missed from work and time while at work during which productivity was impaired in the past seven days. Results of WPAI are expressed as a percentage of impairment from 0 to 100, with higher percentages indicating greater impairment and less productivity. Overall Work Impairment indicates the percentage of overall work impairment due to health problems. A negative change from Baseline indicates improvement.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 14
|
||||||||||||
|
|||||||||||||
Notes [37] - Full analysis participants who were employed and with available data [38] - Full analysis participants who were employed and with available data |
|||||||||||||
Statistical analysis title |
Analysis of Change in WPAI Overall Work Impairment | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
|
||||||||||||
Number of subjects included in analysis |
108
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [39] | ||||||||||||
P-value |
= 0.19 [40] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-5.52
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-13.82 | ||||||||||||
upper limit |
2.78 | ||||||||||||
Notes [39] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including WPAI; within the group, the allocated α was adjusted based on the magnitude of p values. [40] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate. |
|
|||||||||||||
End point title |
Change From Baseline in ASAS Health Index (HI) at Week 14 | ||||||||||||
End point description |
The ASAS HI measures functioning and health across 17 aspects of health in patients with AS, including pain, emotional functions, sleep, sexual function, mobility, self care, and community life. Each of the 17 questions is answered by the participant as "I agree" (score = 1) or "I disagree" (score = 0). The responses to the 17 dichotomous items are summed up to give a total score ranging from 0 to 17, where a higher score indicates a worse health status. A negative change from Baseline indicates improvement.
A mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 14
|
||||||||||||
|
|||||||||||||
Notes [41] - Full analysis set; MMRM including all observed longitudinal data up to Week 14 [42] - Full analysis set; MMRM including all observed longitudinal data up to Week 14 |
|||||||||||||
Statistical analysis title |
Analysis of Change from Baseline in ASAS HI | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
|
||||||||||||
Number of subjects included in analysis |
176
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [43] | ||||||||||||
P-value |
= 0.007 [44] | ||||||||||||
Method |
Mixed Effect Model Repeated Measurement | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-1.37
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.37 | ||||||||||||
upper limit |
-0.37 | ||||||||||||
Notes [43] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. ASAS HI was to be evaluated only if the group of endpoints tested by Hochberg procedure were all significant. [44] - MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates. |
|
|||||||||||||
End point title |
Percentage of Participants Achieving an ASAS 20 Response at Week 14 | ||||||||||||
End point description |
ASAS 20 response was defined as improvement of ≥ 20% and an absolute improvement of ≥ 1 unit from Baseline in ≥ 3 of the following 4 domains, with no deterioration (defined as a worsening of ≥ 20% and a net worsening of ≥ 1 units [on a scale of 0 to 10]) in the remaining domain:
1) Patient's global assessment of disease activity, measured on a NRS from 0 - 10 (severe activity);
2) Pain, measured by the total back pain NRS from 0 - 10 (most severe pain);
3) Function, measured by the BASFI, consisting of 10 items assessing participants' ability to perform activities each on an NRS from 0 (easy) - 10 (impossible);
4) Inflammation, measured by the mean of the 2 morning stiffness-related BASDAI NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none/0 hours) to 10 (very severe/≥ 2 hours duration).
Participants with missing data or who discontinued study drug prior to Week 14 were counted as non-responders.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 14
|
||||||||||||
|
|||||||||||||
Notes [45] - Full analysis set [46] - Full analysis set |
|||||||||||||
Statistical analysis title |
Analysis of ASAS 20 Response | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
|
||||||||||||
Number of subjects included in analysis |
187
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [47] | ||||||||||||
P-value |
= 0.001 [48] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Response Rate Difference | ||||||||||||
Point estimate |
24.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
10.2 | ||||||||||||
upper limit |
38 | ||||||||||||
Notes [47] - This comparison was not part of the pre-specified multiplicity testing sequence. [48] - Cochran-Mantel-Haenszel test adjusting for stratification factor of Screening hsCRP level. |
|
|||||||||||||
End point title |
Change From Baseline in SPARCC MRI Score for Sacroiliac Joints at Week 14 | ||||||||||||
End point description |
In the SPARCC MRI assessment of the sacroiliac (SI) joints 6 consecutive sacroiliac joint image coronal slices representing the largest proportion of the synovial compartment of the SI joints were assessed for edema, intensity and depth of edema.
Each SI joint (left and right) was divided into quadrants for a total of 8 SI scoring locations. Each quadrant was scored for the presence (1) or absence (0) of edema, intensity of edema (a score of 1 was assigned for each SI joint (left and right) if an intense signal was seen in any quadrant of that joint for each slice), and a lesion was graded as deep (score of 1) if there was homogeneous and unequivocal increase in signal extending over a depth of at least 1 cm from the articular surface of the SI joint in any quadrant.
The total maximum score for all SI joints across 6 slices is 72.
MRI data up to 3 days post first dose (for Baseline) and up to first dose of period 2 for Week 14 were included in the anlaysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 14
|
||||||||||||
|
|||||||||||||
Notes [49] - Full analysis set with available MRI data during pre-specified time window [50] - Full analysis set with available MRI data during pre-specified time window |
|||||||||||||
Statistical analysis title |
Analysis of Change in SPARCC MRI SI Joint Score | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
|
||||||||||||
Number of subjects included in analysis |
127
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [51] | ||||||||||||
P-value |
< 0.001 [52] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-3.69
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-5.31 | ||||||||||||
upper limit |
-2.08 | ||||||||||||
Notes [51] - This comparison was not part of the pre-specified multiplicity testing sequence. [52] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate. |
|
|||||||||||||
End point title |
Change From Baseline in SPARCC MRI Score for the Spine at Week 14 - Supplementary Analysis | ||||||||||||
End point description |
The entire spine was evaluated for active inflammation (bone marrow edema). Six DVUs representing the most abnormal DVUs were selected to calculate the SPARCC MRI spine score. For each DVU, 3 consecutive sagittal slices were assessed in 4 quadrants to evaluate the extent of inflammation in all dimensions. Each quadrant was scored for the presence (1) or absence (0) of edema. If edema was present in at least 1 quadrant of a DVU slice, it was also scored for intensity and depth of the edema representing that slice: An additional score of 1 was assigned if an intense signal was seen in any quadrant on a DVU slice. Slices that included a lesion demonstrating continuous increased signal of depth ≥ 1 cm extending from the endplate were scored as an additional 1 per slice. The maximum (worst) overall score for all 6 DVUs is 108.
A supplemental post-hoc SPARCC MRI analysis included all MRI data collected at nominal visits at Baseline and Week 14.
|
||||||||||||
End point type |
Post-hoc
|
||||||||||||
End point timeframe |
Baseline and Week 14
|
||||||||||||
|
|||||||||||||
Notes [53] - Full analysis set participants with available MRI data at Baseline and Week 14 [54] - Full analysis set participants with available MRI data at Baseline and Week 14 |
|||||||||||||
Statistical analysis title |
Supplementary Analysis of SPARCC MRI Spine Score | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
|
||||||||||||
Number of subjects included in analysis |
177
|
||||||||||||
Analysis specification |
Post-hoc
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.001 [55] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-6.21
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-8.27 | ||||||||||||
upper limit |
-4.14 | ||||||||||||
Notes [55] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate. |
|
|||||||||||||
End point title |
Change From Baseline in SPARCC MRI Score for Sacroiliac Joints at Week 14 - Supplementary Analysis | ||||||||||||
End point description |
In the SPARCC MRI assessment of the sacroiliac joints 6 consecutive sacroiliac joint image coronal slices representing the largest proportion of the synovial compartment of the SI joints were assessed for edema, intensity and depth of edema.
Each SI joint (left and right) was divided into quadrants for a total of 8 SI scoring locations. Each quadrant was scored for the presence (1) or absence (0) of edema, intensity of edema (a score of 1 was assigned for each SI joint (left and right) if an intense signal was seen in any quadrant of that joint for each slice), and a lesion was graded as deep (score of 1) if there was homogeneous and unequivocal increase in signal extending over a depth of at least 1 cm from the articular surface of the SI joint in any quadrant. The total maximum score for all SI joints across 6 slices is 72.
A supplemental post-hoc SPARCC MRI analysis was done to include all MRI data collected at nominal visits at Baseline and Week 14.
|
||||||||||||
End point type |
Post-hoc
|
||||||||||||
End point timeframe |
Baseline and Week 14
|
||||||||||||
|
|||||||||||||
Notes [56] - Full analysis set participants with available MRI data at Baseline and Week 14 [57] - Full analysis set participants with available MRI data at Baseline and Week 14 |
|||||||||||||
Statistical analysis title |
Supplmentary Analysis of SPARCC MRI SI Joint Score | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 15 mg
|
||||||||||||
Number of subjects included in analysis |
176
|
||||||||||||
Analysis specification |
Post-hoc
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.001 [58] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-2.55
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-4.01 | ||||||||||||
upper limit |
-1.08 | ||||||||||||
Notes [58] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Period 1: From the first dose of study drug to Week 14.
Period 1+2: Week 14 to 30 days after last dose (94 weeks) for subjects initially assigned to placebo;
Week 1 to 30 days after last dose (108 weeks) for subjects initially assigned to upadacitinib.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
Period 1: Placebo
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Reporting group description |
Participants received matching placebo orally once a day for 14 weeks in Period 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Period 1: Upadacitinib 15 mg
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Reporting group description |
Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Period 1+2: Upadacitinib 15 mg
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Reporting group description |
Participants originally assigned to placebo received upadacitinib 15 mg from Week 14 to Week 104. Participants originally assigned to upadacitinib received upadacitinib 15 mg from Week 0 to Week 104. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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12 Sep 2017 |
●Removed upadacitinib 30 mg QD dose from study plan.
●Updated Phase from 2b/3 to Phase 2/3.
●Clarified definition of inadequate response to NSAIDs required for enrollment.
●Updated number of sites from 120 to 107.
●Updated subject enrollment from 228 to 170.
●Modified Period 2 study design from blinded to open-label with only one dose (15 mg).
●Allowed earlier option of rescue therapy (Week 16 for concomitant pain medications and Week 20 for certain csDMARDs).
●Allowed earlier discontinuation of study drug, and assessment of ASAS 20 from Week 16.
●Updated results from other clinical trials in benefits and risks.
●Updated references to spondyloarthritis to specify axial manifestation.
●Removed statement on subject enrollment after target number reached.
●Updated tuberculosis testing and prophylaxis information.
●Updated schedule for subjects still participating in the study but discontinued study drug.
●Updated contraception requirements for females.
●Updated purpose and assessment of x-ray, MRI, and low-dose computed tomography.
●Updated requirements for local hsCRP testing.
●Updated Hepatitis B infection definition and testing requirements.
●Clarified the impact of corticosteroid injections on swollen joint and dactylitis assessments.
●Added embolic and thrombotic events to the Adverse Events (AE) of Special Interest and added a Supplemental CRF.
●Updated safety assessments to reference Common Terminology Criteria.
●Updated AE collection for subjects continuing in the study but discontinued study drug.
●Updated supplemental information to be collected for certain cardiovascular, herpes zoster, and thrombotic/embolic AEs.
●Updated SUSAR reporting reference.
●Updated pregnancy information to be collected.
●Updated toxicity management guidelines for serum creatinine and creatine phosphokinase and added gastrointestinal perforation.
●Updated the timeframe for product complaint reporting.
●Updated multiplicity control and statistical power. |
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20 Dec 2019 |
● Added events of deep vein thrombosis (DVT) and pulmonary embolism (PE) to the adverse events that have been observed in subjects who receive JAK inhibitors, including upadacitinib.
● Added management of thrombosis events.
● Added management of herpes zoster and a recommendation for periodic skin examination for subjects who are at increased risk for skin cancer.
● Amended the wording for subjects who experience a study drug interruption > 7 consecutive days during Weeks 1 through 14 (Period 1) or > 30 consecutive days during Period 2 to allow the Investigator to decide if the drug should be re-started; previous wording required that upadacitinib be permanently discontinued if interruptions of those lengths occurred. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |