A Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Anti-TNFα Naive Participants With Active Radiographic Axial Spondyloarthritis

ASAS 20 defined as improvement from baseline of >= 20% and with an absolute improvement from baseline of 1 on a 0 to 10cm scale in at least 3 of following 4 domains:Patient's global assessment (0 to 10cm; 0=very well,10=very poor),total back pain(0 to 10cm; 0=no pain,10=most severe pain),Bath Ankylosing Spondylitis Functional Index (BASFI) (self-assessment represented as mean(0 to 10 cm; 0=easy to 10=impossible) of 10 questions,8 of which relate to participant's functional anatomy and 2 relate to participant's ability to cope with everyday life, Inflammation (0 to 10cm;0=none,10=very severe);absence of deterioration from baseline(>= 20% and worsening of at least 1 on a 0 to 10 cm scale) in the potential remaining domain. ASAS 20 response based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rules(consider non-responder at Week 20 and 24),non-responder[NRI] (missing responses at post baseline visit imputed as non-responder).

BASDAI used to measure ankylosing spondylitis (AS) disease severity. Consists of 6 questions: fatigue,spinal pain,arthralgia (joint pain) or swelling, enthesitis (inflammation of tendons, ligaments),morning stiffness(MS) (2 questions:duration, severity). Each question is easy to answer 10cm VAS, 0(none),10(very severe) and for the last question related to morning stiffness duration: 0(0 hours), 10(2 or more hours). In order to give each 5 symptoms equal weight, mean of 2 questions about MS added to total of remaining 4 scores,final BASDAI score(ranging 0-10) is average of overall total score. Higher BASDAI indicates more severe AS symptom. 50% improvement from baseline based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rule(consider non-responder at W20 and 24),non-responder[NRI] (missing responses at post baseline visit imputed as non-responder).

The BASFI is composed with 10 questions (each question is answered with a visual analogue scale 0-10 cm) to assess the disease severity, including the first 8 questions regarding to functional anatomy related activities and the remaining 2 questions related to daily activities of AS participants. Each question is a 10cm VAS with a value between 0 (easy) and 10 (impossible). The final BASFI score is the mean of the 10 scores. The BASFI score is the average of the 10 responses and has a possible minimum value of 0 and a possible maximum value of 10. Higher BASFI score indicates more severe functional limitations of the participant due to AS. Early escape rule was applied (measurement value at Week 20 and Week 24 was set as missing).

ASDAS includes CRP milligram per liter(mg/L); four additional self-reported items (rated on 0-10cm VAS or 0-10 numerical rating scale [NRS]) included are total back pain (TBP), duration of morning stiffness (DMS), peripheral pain/swelling and patient global assessment(PGA). ASDAS scores calculated as: ASDAS(CRP) = (0.121*TBP) + (0.110*participant global) + (0.073*peripheral pain/swelling) + (0.058* DMS) + (0.579*Ln(CRP+1). The disease activity, TBP, and peripheral pain/swelling on a numeric rating scale (from 0 [normal] to 10 [very severe]) and DMS on a numeric rating scale (0 to 10, with 0 being none and 10 representing a duration of =>2 hours). Inactive disease is defined as an ASDAS score <1.3. ASDAS (CRP) Inactive Disease is based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rules(consider non-responder at Week 20 and 24), NRI(missing responses at post baseline visit imputed as non-responder).

Change from baseline in hsCRP levels were reported. hsCRP is a sensitive laboratory assay for serum levels of C-Reactive Protein, which is a biomarker of inflammation. Early escape rule was applied(measurement value at Week 20 and Week 24 was set as missing).

Assessment of enthesitis was performed in the following 7 domains: 1) 1st costochondral joint left and right, 2) 7th costochondral joint left and right, 3) posterior superior iliac spine left and right, 4) anterior superior iliac spine left and right, 5) iliac crest left and right, 6) 5th lumbar spinous process and 7) proximal insertion of Achilles tendon left and right. Entheses were scored as either 0 (nontender) or 1 (tender) yielding total MASES ranging from 0 (no tenderness) to 13 (worst possible score; severe tenderness). Early escape rule was applied (measurement value at Week 20 and Week 24 was set as missing).

The Bath Ankylosing Spondylitis Metrology Index linear function is a combined index of 5 clinical measurements (performed by the Joint Assessor) which reflect axial mobility in the AS patient. The measurements to assess mobility are: 1)Tragus-to-wall; 2)Modified Schober (lumbar flexion); 3)Cervical rotation angle; 4)Lateral spinal flexion; 5)Intermalleolar distance. The BASMI linear result is the average of the 5 assessments and ranges from 0 to 10. The higher the BASMI score the more severe the patient's limitation of movement due to their AS. Early escape rule was applied (measurement value was set as missing).

The ASQoL is a self-administered health-related quality of life (HRQOL) instrument. It consists of 18 items requesting a Yes or No response to questions related to the impact of the disease/condition (including pain) on sleep, mood, motivation, ability to cope, activities of daily living, independence, relationships, and social life. A score of 1 is given to a response of "yes" on each item and all item scores are summed to a total score with a range of 0 to 18. Higher scores indicate worse HRQOL. Early escape rule was applied (measurement value was set as missing).

The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). Early escape rule was applied (measurement value was set as missing).

The Medical Outcome Study health measure SF-36 questionnaire is a well-validated and widely used quality-of-life instrument. It is a self-administered survey that consists of 8 multi-item scales: The 4 subscales of the SF-36 comprises the PCS score (physical functioning, role-physical, bodily pain, and general health) and the 4 subscales of the SF-36 comprises the MCS score(vitality, social functioning, role-emotional, and mental health). PCS and MCS are scored from 0 to 100 with higher scores indicating better health (worst value is 0 and best value is 100), which are scored using a norm-based system where linear transformations are performed to transform scores to a mean of 50 and standard deviation of 10. Early escape rule was applied (measurement value at Week 20 and Week 24 was set as missing).

The BASDAI is used to measure the ankylosing spondylitis (AS) disease severity. It consists of 6 questions: fatigue, spinal pain, arthralgia (joint pain) or swelling, enthesitis (inflammation of tendons and ligaments), and morning stiffness (2 questions: duration, severity). Each question is an easy to answer 10 centimeter (cm) visual analog scale (VAS), with 0 being none, and 10 being very severe and for the last question relating to morning stiffness duration: 0(0 hours), 10(2 or more hours). Change from baseline in inflammation was assessed by calculating the average of the Last 2 Questions of the BASDAI Concerning Morning Stiffness. Early escape rule was applied (measurement value was set as missing).

Sleep problems were assessed using the 12-item MOS-SS, a generic instrument designed to assess six dimensions of sleep: Sleep disturbance, Somnolence, Sleep adequacy, Snoring, Awaken short of breath or headache, and Quantity of sleep(QS)/optimal sleep(OS) during the past 4 weeks. The six dimensions were also used to generate the composite Sleep Problems Index (SPI). An increase in score from baseline represents improvement. Sleep disturbance, snoring, somnolence, awaken short of breath, sleep problems index have score ranges from 0(no sleep problems) to 100 (greater sleep problems), negative change indicates improvement. Sleep adequacy scored 0 (least sleep adequacy) to 100 (better sleep adequacy), positive change indicates improvement. Quantity of sleep is scored 0 (less quantity of sleep) to 24 (greater quantity of sleep), positive change indicates improvement. Early escape rule was applied (measurement value was set as missing).

Sleep problems were assessed using the 12-item MOS-SS, a generic instrument designed to assess six dimensions of sleep: Sleep disturbance, Somnolence, Sleep adequacy, Snoring, Awaken short of breath or headache, QS/OS during past W4. 6 dimensions used to generate composite SPI. Increase in score from baseline represents improvement. Sleep adequacy scored 0 (least sleep adequacy[SA]) to 100 (better SA), positive change indicates improvement. QS is scored 0 (less QS) to 24 (greater QS), positive change indicates improvement. Single-item QS asks participants to estimate average number of hours they slept each night during past 4W (0-24 hours) and transformed into dichotomous OS Score, reported 7 (or 8) hours of sleep considered Optimal. OS is scored Yes if average hours of sleep is in range of 7-8 hours. Early escape rule was applied (measurement value was set as missing).

ASAS 40 components included Patient's global assessment (0 to 10cm; 0=very well,10=very poor),total back pain (0 to 10cm; 0=no pain,10=most severe pain), BASFI (self-assessment represented as mean (0 to 10 cm; 0=easy to 10=impossible) of 10 questions, 8 of which relate to participant's functional anatomy and 2 relate to participant's ability to cope with everyday life), Inflammation (0 to 10cm;0=none,10=very severe). Percentage of Participants With at least a 40% improvement from baseline in each of the ASAS components was calculated.

BASDAI used to measure the AS disease severity. It consists of 6 questions: fatigue, spinal pain, arthralgia (joint pain) or swelling, enthesitis (inflammation of tendons and ligaments), and morning stiffness (2 questions: duration and severity). Each question is an easy to answer cm VAS with 0 being none, and 10 being very severe and for the last question relating to morning stiffness duration: 0(0 hours), 10(2 or more hours). In order to give each of the 5 symptoms equal weight, mean of 2 questions about morning stiffness will be added to total of remaining 4 scores, final BASDAI score (ranging 0-10) is average of overall total score. Higher BASDAI score indicates more severe AS symptom. 20 %,50%, 70%,90% improvement from baseline in BASDAI based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rules(consider non-responder at Week 20 and 24), NRI(missing responses at post baseline visit imputed as non-responders).

The BASDAI is used to measure the ankylosing spondylitis (AS) disease severity. It consists of 6 questions: fatigue, spinal pain, arthralgia (joint pain) or swelling, enthesitis (inflammation of tendons and ligaments), and morning stiffness (2 questions: duration and severity). Each question is an easy to answer 10 centimeter (cm) visual analog scale (VAS), with 0 being none, and 10 being very severe and for the last question relating to morning stiffness duration: 0(0 hours), 10(2 or more hours). In order to give each of the 5 symptoms equal weight, the mean of the 2 questions about morning stiffness will be added to the total of the remaining 4 scores, and the final BASDAI score (ranging 0-10) is the average of the overall total score. Higher BASDAI score indicates more severe AS symptom. Early escape rule was applied (measurement value at Week 20 and Week 24 was set as missing).

ASAS 40 defined as improvement from baseline of greater than or equal to (>=) 40% and with an absolute improvement from baseline of at least 2 on 0 to10cm scale in at least 3 of following 4 domains: Patient's global assessment (0 to 10cm; 0=very well,10=very poor),total back pain (0 to 10cm; 0=no pain,10=most severe pain), BASFI (self-assessment represented as mean (0 to 10 cm; 0=easy to 10=impossible) of 10 questions, 8 of which relate to participant's functional anatomy and 2 relate to participant's ability to cope with everyday life), Inflammation (0 to 10cm;0=none,10=very severe); no worsening at all from baseline in remaining domain. ASAS40 response based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rules(consider non-responder at Week 20 and 24),non-responder[NRI] (missing responses at post baseline visit imputed as non-responder).

ASAS 20 defined as improvement from baseline of greater than or equal to (>=) 20% and with an absolute improvement from baseline of 1 on a 0 to 10 cm scale in at least 3 of following 4 domains: Patient's global assessment (0 to 10cm; 0=very well,10=very poor),total back pain (0 to 10cm; 0=no pain,10=most severe pain), BASFI (self-assessment represented as mean (0 to 10 cm; 0=easy to 10=impossible) of 10 questions, 8 of relate to participant's functional anatomy and 2 relate to participant's ability to cope with everyday life), Inflammation (0 to 10cm;0=none,10=very severe); absence of deterioration (>= 20% and worsening of at least 1 on a 0 to 10 cm scale) from baseline in the potential remaining domain. ASAS20 response based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rules(consider non-responder at Week 20 and 24),non-responder[NRI] (missing responses at post baseline visit imputed as non-responder).

Low level of disease activity was measured by criteria for ASAS partial remission, defined as a value below 2 on a scale of 0 to 10 cm in each of the 4 ASAS domains: patient's global assessment of disease activity, total back pain, function (BASFI), inflammation. ASAS partial remission response based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rules(consider non-responder at Week 20 and 24),non-responder[NRI] (missing responses at post baseline visit imputed as non-responder).

ASAS 5/6 is defined as a >=20% improvement in any 5 of the 6 domains of pain (VAS 0 to 10), patient global (VAS 0 to 10), function (BASFI score), morning stiffness (from BASDAI), hsCRP, and spine mobility (lumbar side flexion). ASAS 5/6 response is based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rules(consider non-responder at Week 20 and 24),non-responder[NRI] (missing responses at post baseline visit imputed as non-responder).

ASDAS includes CRP mg/L; 4 additional self-reported items (rated 0-10cm VAS or 0-10 numerical rating scale [NRS]) included are total back pain (TBP), duration of morning stiffness (DMS), peripheral pain/swelling and patient global assessment (PGA). ASDAS scores calculated as: ASDAS(CRP) = (0.121*TBP)+(0.110*PGA) + (0.073*peripheral pain(PP)/swelling)+(0.058* duration of morning stiffness)+(0.579*Ln(CRP+1)). The disease activity, TBP, and PP/swelling on a NRS(0[normal]-10[very severe]and DMS on NRS(0 to 10, 0 being none and 10 representing a duration=>2 hours). The scores were categorized as: inactive disease (< 1.3), moderate (1.3 - < 2.1), high (2.1 - 3.5) and very high disease activity (> 3.5). The calculated score can be from 0 to no defined upper limit. A negative number indicates a reduction in the score which indicates decrease in disease activity. Early escape rule was applied (measurement value was set as missing).

ASDAS includes CRP mg/L; four additional self-reported items (rated on 0-10cm VAS or 0-10 numerical rating scale [NRS]) included are total back pain (TBP), duration of morning stiffness (DMS), peripheral pain/swelling and patient global assessment (PGA). ASDAS scores calculated as: ASDAS(CRP) = (0.121*total back pain) + (0.110*participant global) + (0.073*peripheral pain/swelling) + (0.058* duration of morning stiffness) + (0.579*Ln(CRP+1)). The disease activity, TBP, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and DMS on a numeric rating scale (0 to 10, with 0 being none and 10 representing a duration of =>2 hours). Inactive disease is defined as an ASDAS score <1.3. ASDAS (CRP) Inactive Disease is based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rules(consider non-responder at Week 20 and 24), NRI(missing responses at post baseline visit imputed as non- responders).

ASDAS includes CRP mg/L; four additional self-reported items (rated on 0-10cm VAS or 0-10 numerical rating scale [NRS]) included are total back pain (TBP), duration of morning stiffness (DMS), peripheral pain/swelling and patient global assessment (PGA). ASDAS scores calculated as: ASDAS(CRP) = (0.121*TBP) + (0.110*participant global) + (0.073*peripheral pain/swelling) + (0.058* DMS) + (0.579*Ln(CRP+1)). The disease activity, TBP, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and DMS on a numeric rating scale (0 to 10, with 0 being none and 10 representing a duration of =>2 hours). Major improvement in ASDAS is defined as a decrease from baseline >=2.0. ASDAS (CRP) major improvement (decrease >=2.0) is based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rules(consider non-responder at Week 20 and 24), NRI(missing responses at post baseline visit imputed as non- responders).

ASDAS includes CRP mg/L; four additional self-reported items (rated on 0-10cm VAS or 0-10 NRS) included are TBP, duration of DMS, peripheral pain/swelling and patient global assessment (PGA). ASDAS scores calculated as: ASDAS(CRP) = (0.121*TBP) + (0.110*participant global) + (0.073*peripheral pain/swelling) + (0.058*DMS) + (0.579*Ln(CRP+1)). The disease activity, TBP, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and DMS on a numeric rating scale (0 to 10, with 0 being none and 10 representing a duration of =>2 hours). Clinically important improvement in ASDAS is defined as a decrease from baseline >=1.1. ASDAS (CRP) clinical important improvement (decrease >=1.1) is based on imputed data using treatment failure(consider non-responders at and after treatment failure),early escape rules(consider non-responder at Week 20 and 24), NRI(missing responses at post baseline visit imputed as non- responders).

The BASFI is composed with 10 questions (each question is answered with a visual analogue scale 0-10 cm) to assess the disease severity, including the first 8 questions regarding to functional anatomy related activities and the remaining 2 questions related to daily activities of AS participants. Each question is a 10cm VAS with a value between 0 (easy) and 10 (impossible). The final BASFI score is the mean of the 10 scores. The BASFI score is the average of the 10 responses and has a possible minimum value of 0 and a possible maximum value of 10. Higher BASFI score indicates more severe functional limitations of the participant due to AS. Early escape rule was applied (measurement value at Week 20 and Week 24 was set as missing).

Chest expansion is the difference, in centimeter (cm), between the circumference of the chest in maximal inspiration and maximal expiration. It is measured at the level of the fourth intercostal space in males, and just below the breasts in females. Early escape rule was applied (measurement value at Week 20 and Week 24 was set as missing).

The total back pain and nighttime back pain was measured on a VAS (0 to 10 cm; 0 = no pain, 10 = most severe pain). Early escape rule was applied (measurement value at Week 20 and Week 24 was set as missing).

Participants assessed their disease activity using a 10 cm visual analog scale, with responses ranging from 0 (very well) to 10 (very poor). Early escape rule was applied (The measurement value at Week 20 and Week 24 was set as missing).

The EQ-5D questionnaire is a brief, generic health-related quality of life assessment (HRQOL) that can also be used to incorporate participant preferences into health economic evaluations. The EQ-5D questionnaire assesses HRQOL in terms of degree of limitation on 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and as overall health using a visual analog scale with response options ranging from 0 (worst imaginable health) to 100 (best imaginable health). Lower scores indicate worsening. Early escape rule was applied (measurement value at Week 20 and Week 24 was set as missing).

The EuroQol-5 is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing death. Early escape rule was applied (measurement value at Week 20 and Week 24 was set as missing).

The study used MRI with fat-saturating techniques such as short tau inversion recovery (STIR) to look for the presence of bone marrow edema. The Berlin modification of Ankylosing Spondylitis spine MRI score for activity (ASspiMRI-a) scoring technique assesses inflammation in each of the 23 disc vertebral units (DVU), capturing edema and erosion. Scores for each DVU range from 0-3 (0=normal; 1=minor bone marrow edema [less than or equal to 25% of DVU; 3=severe bone marrow edema (more that 50% of DVU)]. The composite score ranges from 0 to 69, with higher scores indicating more severe inflammation.

The WPAI-SHP is a 6-item questionnaire used to assess the degree to which a specified health problem (here "AS") affected work attendance, work productivity and productivity in non-work regular activities. Patients are asked to consider the past 7 days prior to each questionnaire day. The questionnaire asks: current employment status, hours worked, hours missed from work for any reason other than AS, hours missed from work due to AS, degree to which AS affected work productivity, and degree to a which AS affected non-work regular activities. Four component scores were then calculated: percent work time missed due to AS; percent impairment while working due to AS, percent overall work impairment due to AS, and percent non-work activity impairment due to AS. The computed percentage range for each sub-scale was from 0-100, with higher numbers indicating greater impairment and less productivity. change from baseline in percent work time missed due to AS for each study arm are reported.

WPAI-SHP is 6-item questionnaire used to assess the degree to which a specified health problem ("AS") affected work attendance, work productivity and productivity in non-work regular activities. Patients are asked to consider the past 7 days prior to each questionnaire day. The questionnaire asks: current employment status, hours worked, hours missed from work for any reason other than AS, hours missed from work due to AS, degree to which AS affected work productivity, and degree to a which AS affected non-work regular activities. Four component scores were then calculated: percent work time missed due to AS; percent impairment while working due to AS, percent overall work impairment due to AS, and percent non-work activity impairment due to AS. The computed percentage range for each sub-scale was from 0-100, with higher numbers indicating greater impairment and less productivity. change from baseline in percent impairment while working due to AS for each study arm are reported.

WPAI-SHP is 6-item questionnaire used to assess the degree to which a specified health problem (AS) affected work attendance, work productivity and productivity in non-work regular activities. Patients are asked to consider the past 7 days prior to each questionnaire day. Questionnaire asks: current employment status, hours worked, hours missed from work for any reason other than AS, hours missed from work due to AS, degree to which AS affected work productivity, and degree to a which AS affected non-work regular activities. Four component scores were then calculated: percent work time missed due to AS; percent impairment while working due to AS, percent overall work impairment due to AS, percent non-work activity impairment due to AS. The computed percentage range for each sub-scale was from 0-100, with higher numbers indicating greater impairment and less productivity. change from baseline in percent overall work impairment due to AS for each study arm are reported.

WPAI-SHP is6-item questionnaire used to assess the degree to which a specified health problem (AS) affected work attendance, work productivity and productivity in non-work regular activities. Patients are asked to consider the past 7 days prior to each questionnaire day. The questionnaire asks: current employment status, hours worked, hours missed from work for any reason other than AS, hours missed from work due to AS, degree to which AS affected work productivity, and degree to a which AS affected non-work regular activities. Four component scores were then calculated: percent work time missed due to AS; percent impairment while working due to AS, percent overall work impairment due to AS, and percent non-work activity impairment due to AS. The computed percentage range for each sub-scale was from 0-100, with higher numbers indicating greater impairment and less productivity. change from baseline in percent non-work activity impairment due to AS for each study arm are reported.