Trial Outcomes & Findings for A Study Evaluating the Safety and Efficacy of Upadacitinib in Adults With Active Ankylosing Spondylitis (NCT NCT03178487)

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.

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).

Participants with available data

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).

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 score 0 \[none\] - 10 \[very severe\]) 2. Patient global assessment of disease activity (NRS score 0 \[no activity\] - 10 \[severe activity\]) 3. Peripheral pain/swelling (BASDAI Question 3; NRS score 0 \[none\] - 10 \[very severe\]) 4. Duration of morning stiffness (BASDAI Question 6; NRS score 0 \[0 hours\] - 10 \[2 or more hours\]) 5. 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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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).

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.

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.

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.