A Study Evaluating the Safety and Efficacy of Upadacitinib in Adults With Active Ankylosing Spondylitis (SELECT-AXIS 1)

• ClinicalTrials.gov Identifier: NCT03178487
• Recruitment Status: Completed
• First Posted: June 7, 2017
• Results First Posted: June 1, 2021
• Last Update Posted: March 21, 2022
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Ankylosing Spondylitis (AS)
• Interventions: Drug: Upadacitinib; Drug: Placebo
• Enrollment: 187

Participant Flow

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 and an ongoing 90-week long-term extension period. Data from period 1 are reported here.
Pre-assignment 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).

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Period Title: Overall Study
Started	94	93
Received Treatment	94	93
Completed [1]	90	89
Not Completed	4	4
Reason Not Completed
Adverse Event	1	1
Withdrawal by Subject	2	1
Lost to Follow-up	1	0
Other	0	2
[1] Completed Period 1

Baseline Characteristics

Arm/Group Title		Placebo	Upadacitinib 15 mg	Total
Arm/Group Description		Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.	Total of all reporting groups
Overall Number of Baseline Participants		94	93	187
Baseline Analysis Population Description		The full analysis set (FAS) includes all randomized participants who received at least one dose of study drug.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	94 participants	93 participants	187 participants
		43.7 (12.07)	47.0 (12.78)	45.4 (12.50)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	94 participants	93 participants	187 participants
	< 40 years	39 41.5%	28 30.1%	67 35.8%
	40 - 64 years	53 56.4%	56 60.2%	109 58.3%
	≥ 65 years	2 2.1%	9 9.7%	11 5.9%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	94 participants	93 participants	187 participants
	Female	25 26.6%	30 32.3%	55 29.4%
	Male	69 73.4%	63 67.7%	132 70.6%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	94 participants	93 participants	187 participants
	Hispanic or Latino	5 5.3%	4 4.3%	9 4.8%
	Not Hispanic or Latino	89 94.7%	89 95.7%	178 95.2%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	94 participants	93 participants	187 participants
	White	76 80.9%	79 84.9%	155 82.9%
	Black or African American	2 2.1%	1 1.1%	3 1.6%
	Asian	16 17.0%	13 14.0%	29 15.5%
Region; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	94 participants	93 participants	187 participants
	USA and Canada	10 10.6%	9 9.7%	19 10.2%
	Western Europe	33 35.1%	30 32.3%	63 33.7%
	Eastern Europe	34 36.2%	36 38.7%	70 37.4%
	Japan	7 7.4%	6 6.5%	13 7.0%
	South Korea	7 7.4%	6 6.5%	13 7.0%
	Australia and New Zealand	3 3.2%	6 6.5%	9 4.8%
Duration Since Ankylosing Spondylitis Diagnosis; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	94 participants	93 participants	187 participants
		6.0 (6.79)	7.8 (10.64)	6.9 (8.94)
Duration of Ankylosing Spondylitis Symptoms; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	94 participants	93 participants	187 participants
		14.0 (9.86)	14.8 (11.64)	14.4 (10.76)
Patient's Global Assessment of Disease Activity (PtGA) [1] [2]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	94 participants	91 participants	185 participants
		6.8 (1.66)	6.6 (1.81)	6.7 (1.73)
		[1] Measure Description: Assessed by the participant using a numeric rating scale (NRS) ranging from 0 (No activity) to 10 (Severe activity).; [2] Measure Analysis Population Description: Participants with available data
Patient's Assessment of Total Back Pain [1] [2]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	94 participants	92 participants	186 participants
		6.7 (1.78)	6.8 (1.77)	6.8 (1.78)
		[1] Measure Description: Total back pain was assessed by the participant on a NRS from 0 (no pain) to 10 (most severe pain),.; [2] Measure Analysis Population Description: Participants with available data
Bath Ankylosing Spondylitis Functional Index [1] [2]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	94 participants	91 participants	185 participants
		5.5 (2.17)	5.4 (2.36)	5.4 (2.26)
		[1] Measure Description: The Bath Ankylosing Spondylitis Functional Index (BASFI) is used to determine the degree of functional limitation in patients with AS. BASFI consists of 10 questions assessing participants' ability to perform activities, each scored on a NRS ranging from 0 (easy to perform activity) to 10 (impossible to perform activity). The overall score is the mean of the 10 items and ranges from 0 to 10 with higher score indicating more functional limitations.; [2] Measure Analysis Population Description: Participants with available data
Inflammation [1] [2]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	94 participants	92 participants	186 participants
		6.7 (1.90)	6.5 (1.99)	6.6 (1.94)
		[1] Measure Description: Inflammation was measured by the mean of the two 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).; [2] Measure Analysis Population Description: Participants with available data
High-sensitivity C-reactive Protein (hsCRP) Level at Screening [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	94 participants	93 participants	187 participants
	> upper limit of normal	68 72.3%	67 72.0%	135 72.2%
	≤ upper limit of normal	26 27.7%	26 28.0%	52 27.8%
		[1] Measure Description: The Screening level of hsCRP was a randomization stratification factor. The hsCRP upper limit of normal (ULN) = 2.87 mg/L.

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Assessment of SpondyloArthritis International Society (ASAS) 40 Response at Week 14
Description	ASAS 40 response was defined as improvement of ≥ 40% relative to Baseline and absolute improvement of ≥ 2 units (on a scale from 0 to 10) in ≥ 3 of the following 4 domains with no deterioration (defined as a net worsening of > 0 units) in the potential remaining domain: Patient's global assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (no activity) to 10 (severe activity);; Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe pain);; 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);; 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).
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who discontinued study drug prior to Week 14 or with missing data at Week 14 were counted as non-responders (non-responder imputation).

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	94	93
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	25.5; (16.7 to 34.3)	51.6; (41.5 to 61.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel (CMH) test adjusting for stratification factor of Screening hsCRP level.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	26.1
	Confidence Interval	(2-Sided) 95%; 12.6 to 39.5
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

2. Secondary Outcome

Title	Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 14
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: Patient's assessment of total back pain (BASDAI Question 2; NRS score 0 [none] - 10 [very severe]); Patient global assessment of disease activity (NRS score 0 [no activity] - 10 [severe activity]); Peripheral pain/swelling (BASDAI Question 3; NRS score 0 [none] - 10 [very severe]); Duration of morning stiffness (BASDAI Question 6; NRS score 0 [0 hours] - 10 [2 or more hours]); High-sensitivity C-reactive protein (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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	84	84
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-0.54; (-0.71 to -0.37)	-1.45; (-1.62 to -1.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.91
	Confidence Interval	(2-Sided) 95%; -1.14 to -0.68
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

3. Secondary Outcome

Title	Change From Baseline in Spondyloarthritis Research Consortium of Canada (SPARCC) Magnetic Resonance Imaging (MRI) Score for the Spine at Week 14
Description	In the SPARCC MRI assessment of the spine, the entire spine is evaluated for active inflammation (bone marrow edema). Six discovertebral units (DVU) representing the 6 most abnormal DVUs were selected to calculate the MRI Spine SPARCC score. For each of the 6 DVUs, 3 consecutive sagittal slices were assessed in 4 quadrants to evaluate the extent of inflammation in all three dimensions. Each quadrant was scored for the presence (1) or absence (0) of edema. If edema was present in at least one 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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set; the following MRI data were included in the analysis: Baseline includes MRI data up to 3 days post first dose of study drug and Week 14 includes MRI data up to first dose of period 2 study drug.

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	60	68
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-0.22; (-2.01 to 1.57)	-6.93; (-8.58 to -5.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.71
	Confidence Interval	(2-Sided) 95%; -9.01 to -4.41
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

4. Secondary Outcome

Title	Percentage of Participants With Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Response at Week 14
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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set; non-responder imputation

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	94	93
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	23.4; (14.8 to 32.0)	45.2; (35.0 to 55.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	P-Value	0.002
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusting for stratification factor of Screening hsCRP level.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	21.8
	Confidence Interval	(2-Sided) 95%; 8.5 to 35.0
	Estimation Comments	Response rate difference = Upadacitinib - Placebo

5. Secondary Outcome

Title	Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) Score
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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	88	88
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-2.67; (-3.58 to -1.75)	-4.20; (-5.12 to -3.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	P-Value	0.016
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.54
	Confidence Interval	(2-Sided) 95%; -2.78 to -0.30
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

6. Secondary Outcome

Title	Percentage of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) Partial Remission
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: Patient's global assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (no activity) to 10 (severe activity);; Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe pain);; 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);; 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).
Time Frame	Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set; non-responder imputation

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	94	93
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	1.1; (0.0 to 3.1)	19.4; (11.3 to 27.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusting for stratification factor of Screening hsCRP level.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	18.3
	Confidence Interval	(2-Sided) 95%; 10.0 to 26.6
	Estimation Comments	Response rate difference = Upadacitinib - Placebo

7. Secondary Outcome

Title	Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 14
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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	86	86
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-1.30; (-1.74 to -0.86)	-2.29; (-2.73 to -1.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	P-Value	0.001
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.00
	Confidence Interval	(2-Sided) 95%; -1.60 to -0.39
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

8. Secondary Outcome

Title	Change From Baseline in Linear Bath Ankylosing Spondylitis Metrology Index (BASMI[Lin]) at Week 14
Description	The BASMI is a composite score based on 5 direct measurements of spinal mobility: cervical rotation (measured in degrees),; tragus to wall distance (in centimeters [cm]); lumbar side flexion (in cm),; lumbar flexion (modified Schober's) (in cm) and; 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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set participants with available data

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	89	89
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-0.14; (-0.29 to 0.01)	-0.37; (-0.52 to -0.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	P-Value	0.030
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.43 to -0.02
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

9. Secondary Outcome

Title	Change From Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at Week 14
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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set participants with Baseline enthesitis; a mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	51	50
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-1.41; (-2.02 to -0.80)	-2.25; (-2.86 to -1.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	P-Value	0.049
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.84
	Confidence Interval	(2-Sided) 95%; -1.68 to -0.00
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

10. Secondary Outcome

Title	Change From Baseline in Work Productivity and Activity Impairment (WPAI) Overall Work Impairment at Week 14
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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis participants who were employed and with available data

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	53	55
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent impairment
	-12.60; (-19.04 to -6.15)	-18.11; (-24.73 to -11.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	P-Value	0.190
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-5.52
	Confidence Interval	(2-Sided) 95%; -13.82 to 2.78
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

11. Secondary Outcome

Title	Change From Baseline in ASAS Health Index (HI) at Week 14
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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	88	88
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-1.38; (-2.11 to -0.65)	-2.75; (-3.48 to -2.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	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.
Statistical Test of Hypothesis	P-Value	0.007
	Comments	This comparison was not tested for statistical significance because the hierarchical testing procedures stopped during the Hochberg procedure.
	Method	Mixed Effect Model Repeated Measurement
	Comments	MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.37
	Confidence Interval	(2-Sided) 95%; -2.37 to -0.37
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

12. Secondary Outcome

Title	Percentage of Participants Achieving an ASAS 20 Response at Week 14
Description	ASAS 20 response was defined as an improvement of ≥ 20% and an absolute improvement of ≥ 1 unit (on a scale of 0 to 10) from Baseline in at least 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: Patient's global assessment of disease activity, measured on a NRS from 0 (no activity) to 10 (severe activity);; Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe pain);; Function, measured by the BASFI which consists of 10 items assessing participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible);; 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 or more duration).
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set; non-responder imputation

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	94	93
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	40.4; (30.5 to 50.3)	64.5; (54.8 to 74.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.001
	Comments	This comparison was not part of the pre-specified multiplicity testing sequence.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusting for stratification factor of Screening hsCRP level.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	24.1
	Confidence Interval	(2-Sided) 95%; 10.2 to 38.0
	Estimation Comments	[Not Specified]
Other Statistical Analysis		Response Rate Difference = Upadacitinib - Placebo

13. Secondary Outcome

Title	Change From Baseline in SPARCC MRI Score for Sacroiliac Joints at Week 14
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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set; the following MRI data were included in the analysis: Baseline includes MRI data up to 3 days post first dose of study drug and Week 14 includes MRI data up to first dose of period 2 study drug.

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	59	68
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-0.22; (-1.47 to 1.04)	-3.91; (-5.05 to -2.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	This comparison was not part of the pre-specified multiplicity testing sequence.
	Method	ANCOVA
	Comments	ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.69
	Confidence Interval	(2-Sided) 95%; -5.31 to -2.08
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

14. Post-Hoc Outcome

Title	Change From Baseline in SPARCC MRI Score for the Spine at Week 14 - Supplementary Analysis
Description	In the SPARCC MRI assessment of the spine, the entire spine is evaluated for active inflammation (bone marrow edema). Six DVUs representing the 6 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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set; the analysis includes all participants with available MRI data collected at Baseline and Week 14

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	88	89
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-0.65; (-2.20 to 0.90)	-6.86; (-8.41 to -5.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.21
	Confidence Interval	(2-Sided) 95%; -8.27 to -4.14
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

15. Post-Hoc Outcome

Title	Change From Baseline in SPARCC MRI Score for Sacroiliac Joints at Week 14 - Supplementary Analysis
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.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set; the analysis includes all participants with available MRI data collected at Baseline and Week 14

Arm/Group Title	Placebo	Upadacitinib 15 mg
Arm/Group Description:	Participants received matching placebo orally once a day for 14 weeks in Period 1.	Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
Overall Number of Participants Analyzed	87	89
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-0.90; (-2.01 to 0.20)	-3.45; (-4.54 to -2.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.55
	Confidence Interval	(2-Sided) 95%; -4.01 to -1.08
	Estimation Comments	Treatment difference = Upadacitinib - Placebo

Adverse Events

Time Frame	14 weeks
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Placebo		Upadacitinib 15 mg
Arm/Group Description	Participants received matching placebo orally once a day for 14 weeks in Period 1.		Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
All-Cause Mortality
	Placebo		Upadacitinib 15 mg
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/94 (0.00%)		0/93 (0.00%)
Serious Adverse Events
	Placebo		Upadacitinib 15 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/94 (1.06%)		1/93 (1.08%)
Cardiac disorders
CARDIOVASCULAR DISORDER † 1	1/94 (1.06%)	1	0/93 (0.00%)	0
Musculoskeletal and connective tissue disorders
SPINAL OSTEOARTHRITIS † 1	0/94 (0.00%)	0	1/93 (1.08%)	1
1 Term from vocabulary, MedDRA (21.1); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Upadacitinib 15 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/94 (14.89%)		19/93 (20.43%)
Gastrointestinal disorders
DIARRHOEA † 1	5/94 (5.32%)	5	5/93 (5.38%)	5
NAUSEA † 1	5/94 (5.32%)	5	1/93 (1.08%)	1
Infections and infestations
NASOPHARYNGITIS † 1	4/94 (4.26%)	4	5/93 (5.38%)	6
Investigations
BLOOD CREATINE PHOSPHOKINASE INCREASED † 1	2/94 (2.13%)	2	8/93 (8.60%)	8
Nervous system disorders
HEADACHE † 1	2/94 (2.13%)	2	5/93 (5.38%)	5
1 Term from vocabulary, MedDRA (21.1); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.

Results Point of Contact

• Name/Title: Global Medical Services
• Organization: AbbVie
• Phone: 800-633-9110
• EMail: abbvieclinicaltrials@abbvie.com

Publications:

van der Heijde D, Song IH, Pangan AL, Deodhar A, van den Bosch F, Maksymowych WP, Kim TH, Kishimoto M, Everding A, Sui Y, Wang X, Chu AD, Sieper J. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet. 2019 Dec 7;394(10214):2108-2117. doi: 10.1016/S0140-6736(19)32534-6. Epub 2019 Nov 12.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Deodhar A, van der Heijde D, Sieper J, Van den Bosch F, Maksymowych WP, Kim TH, Kishimoto M, Ostor A, Combe B, Sui Y, Chu AD, Song IH. Safety and Efficacy of Upadacitinib in Patients With Active Ankylosing Spondylitis and an Inadequate Response to Nonsteroidal Antiinflammatory Drug Therapy: One-Year Results of a Double-Blind, Placebo-Controlled Study and Open-Label Extension. Arthritis Rheumatol. 2022 Jan;74(1):70-80. doi: 10.1002/art.41911. Epub 2021 Nov 12.

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT03178487
• Other Study ID Numbers: M16-098; 2017-000431-14 ( EudraCT Number )
• First Submitted: June 5, 2017
• First Posted: June 7, 2017
• Results First Submitted: May 6, 2021
• Results First Posted: June 1, 2021
• Last Update Posted: March 21, 2022