CADTH Reimbursement Review

Upadacitinib (Rinvoq)

Sponsor: AbbVie Corporation

Therapeutic area: Ankylosing spondylitis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

NOC = Notice of Compliance.

Note: The sponsor indicated that 30 mg was not submitted for review.

Introduction

Ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis (SpA), is a chronic inflammatory disease primarily involving the spine and the sacroiliac joints (SIJs).^1,2 AS usually begins in young adults (aged < 45 years), with a peak age of onset between the ages of 20 to 30 years. AS is more common among men than among women.¹ Patients with AS exhibit radiographic abnormalities consistent with sacroiliitis. Patients experience back pain and progressive spinal stiffness and may also suffer from extra-articular manifestations such as uveitis, skin psoriasis, and inflammatory bowel disease (IBD). The symptoms of AS and the rate of progression fluctuate with time and can vary substantially between patients. AS negatively affects patients’ health-related quality of life (HRQoL).^1-3 A diagnosis of AS can be made based on clinical features, biological testing, and imaging examinations of the disease.² The modified New York classification criteria for AS have often been applied as a diagnostic instrument.^4,5 A population-based study in Canada published by Haroon et al. showed that the prevalence of AS nearly tripled in Ontario from 1995 to 2010, the 2010 estimate being 0.2%.⁶ In the same study, the annual incidence of AS remained relatively stable, with a rate of 15 per 100,000 individuals.⁶ In 2019, AS was estimated to have affected 300,000 patients in Canada.⁷

The goals of treatment for patients with AS are to maximize long-term HRQoL, control symptoms and inflammation, maintain spinal flexibility and normal posture, reduce functional limitations, maintain work ability, decrease disease complications, and prevent progressive structural damage.^8,9 Several drug classes are used in the pharmacologic therapy of AS. Nonsteroidal anti-inflammatory drugs (NSAIDs), including nonselective and selective cyclooxygenase-2 inhibitors, are the first choice of treatment for adult patients with active AS. Should NSAIDs fail or if there are contraindications, the next line of treatment is a biologic disease-modifying antirheumatic drug (bDMARD), a class that includes inhibitors of tumour necrosis factor (TNF), interleukin-17 (IL-17), and Janus kinase (JAK). Current practice is to start with a TNF inhibitor (TNFi) or IL-17 inhibitor (IL17i). TNFi drugs marketed in Canada for treatment of AS include adalimumab, certolizumab, etanercept, golimumab, and infliximab. IL-17i drugs marketed in Canada for the treatment of AS includes ixekizumab and secukinumab (Table 3). The treatment recommendations for AS and nonradiographic axial SpA are similar.⁸

Upadacitinib is an oral, selective Janus kinase inhibitor (JAKi).¹⁰ JAK inhibitors are also classified as targeted synthetic biologic disease-modifying antirheumatic drugs (tsDMARDs). JAKs are intracellular enzymes that transduce signals from cell surface receptors for cytokines or growth factors involved in a broad range of cellular processes, including inflammatory responses, hematopoiesis, and immune surveillance.¹⁰ Upadacitinib is available as a 15 mg or 30 mg extended-release tablet.¹⁰ Health Canada previously approved indications for upadacitinib for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or are intolerant to methotrexate, adults with active psoriatic arthritis (PsA) who have had an inadequate response or are intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs), and adults and adolescents aged 12 years and older with refractory moderate-to-severe atopic dermatitis (AD) who are not adequately controlled with a systemic treatment (e.g., steroid or biologic) or when use of those therapies is inadvisable.¹⁰ Upadacitinib was previously reviewed by CADTH for the indication of RA in February 2020,¹¹ PsA in August 2021,¹² and AD in June 2022.¹³ The CADTH Canadian Drug Expert Committee (CDEC) has recommended that use of upadacitinib be reimbursed for the indications of RA, PsA, and AD if certain conditions are met.^11-13

Currently, the Health Canada–approved upadacitinib indication of interest for this review is for the treatment of adults with active AS who have had an inadequate response to a bDMARD or when use of such a therapy is inadvisable. The recommended dose regimen is a 15 mg tablet administered orally once daily. Upadacitinib may be used as monotherapy or in combination with NSAIDs. (Table 3). The sponsor’s reimbursement request is identical to the Health Canada–approved indication.¹⁰

The objective of this review is to review the beneficial and harmful effects of upadacitinib (extended-release tablets, 15 mg and 30 mg), 15 mg once daily, administered orally, for the treatment of adult patients with active AS who have had an inadequate response to a bDMARD or when use of those therapies is inadvisable. Upadacitinib may be used as monotherapy or in combination with NSAIDs.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

This section was prepared by CADTH staff based on the input provided by patient groups.

Two responses to CADTH’s call for patient input for this review were received from Arthritis Consumer Experts (ACE) and through a joint submission from the Canadian Arthritis Patient Alliance (CAPA), Arthritis Society Canada, the Canadian Spondylitis Association (CSA), and Creaky Joints Canada. ACE, CAPA, Arthritis Society Canada, CSA, and Creaky Joints Canada serve individuals living with arthritis, including AS, and their caregivers, health care providers, and community members.

Patient perspectives from the joint input were obtained from a survey shared via email, social media, and the 4 organizations’ websites from October 12, 2022, to October 30, 2022. Patient perspectives from the ACE input were obtained from an ACE Survey Monkey platform.

Among the 264 joint survey participants living with AS, 9 had direct experience with upadacitinib and close to 90% indicated they live with back pain, while 72% have back pain, 86% have joint stiffness, and 51% experienced sore heels and feet. Patient respondents were also faced with other symptoms of AS, such as anxiety and depression (52% of respondents), bowel inflammation (49%), psoriasis (35%), migraine (32%), uveitis (31%), osteoporosis (23%), and heart problems (11%). Most survey participants rated their disease severity at 59 out of 100. In addition, patients reported having trouble managing symptoms, including fatigue, difficulty concentrating, stress, mobility issues, and loss of appetite. Similarly, respondents from the ACE patient input described experiencing fatigue, mobility issues, weight gain, and constant pain, and indicated that the disease affects their quality of life, daily activities, and mood. Caregivers of patient respondents from the ACE input also stated that the disease affected their quality of life as they must pay attention to time management.

The joint patient input stated that, during an AS flare, which is a period of worsening symptoms, patients may have difficulties performing day-to-day activities. Patient respondents with AS reported that the disease severely affects all aspects of their lives, from their physical and mental health to their family life, self-esteem, work, intimacy, and participation in social and leisure activities.

According to the joint patient input, many treatments are available to manage AS, including NSAIDs, corticosteroids, conventional synthetic DMARDs (csDMARDs), and bDMARDs. The joint patient input stated that the effectiveness and tolerance of these treatments varies significantly among patients, with more than 40% of patient respondents indicating that they had an inadequate response to currently available treatments. The joint patient input indicated that some patients had to change their medication after a short period of time; others did not respond adequately to currently available treatments. In addition, the joint patient input stated that side effects of current AS medications were another major concern for people living with AS. Fatigue, nausea and vomiting, increased risk of infections, liver toxicity, and weight gain can all affect patient adherence to medication and their daily activities.

According to the patient respondents from the ACE patient input, currently available treatments can manage their disease symptoms. However, concerns were raised regarding the cost of the medications, side effects, and the need to change medications due to decreased effectiveness within a short period of time.

The joint patient input highlighted that other treatment options, such as medical cannabis and/or nonpharmacological approaches to managing AS symptoms, are challenging to access because they are not reimbursed, not offered, or require lengthy waits. According to the joint patient input, health care providers need to consider many factors to determine the most effective treatment, such as side effects, mode of administration, time required for treatment, travel, patient preferences, and cost.

Nine respondents from the joint input reported having experience with upadacitinib. Positive aspects of treatment with upadacitinib reported by patient respondents included the simple route of administration, improved disease symptoms, mobility, and better quality of life with more energy. Few patient respondents experienced more frequent infections and headaches while being treated with upadacitinib.

Patient respondents from the joint patient input stated that management of AS can be improved by having access to affordable treatments that have a simple administration route (e.g., pills), fewer adverse effects and infection rates, and are able to reduce disease-related symptoms, enhance their quality of life, and allow them to pursue their daily activities. The ACE input noted that patient respondents value additional treatment options with fewer adverse events (AEs) and improved pain control and remission rates.

Clinician Input

This section was prepared by CADTH staff based on input from the clinical expert consulted by CADTH.

The clinical expert consulted by CADTH for this review indicated that not all patients respond to available treatments. The Assessment in SpondyloArthritis international Society 40% improvement (ASAS40) is a common primary end point in clinical trials, which corresponds to a 40% improvement in 3 out of 4 domains (patient global assessment, total back pain, Bath Ankylosing Spondylitis Functional Index [BASFI], and morning stiffness) with an absolute improvement of at least 2 domains and no worsening of the remaining domains. Roughly 40% of patients are able to achieve this response in clinical trials. Response rates to more stringent measures, such as Assessment of SpondyloArthritis international Society (ASAS) partial remission (PR) or Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (ID), are much lower. Roughly 10% of patients with AS also have IBD. While a TNFi can be effective in treating both, many patients with severe IBD do not respond to a TNFi even at a high dose (infliximab 10 mg/kg every 4 weeks) or initially respond but experience loss of efficacy or have to stop due to side effects (i.e., drug-induced psoriasis, lupus, or multiple sclerosis). IL-17i drugs would be contraindicated in these patients, leaving few options available to patients. Roughly half of patients experience a loss in efficacy with their first biologic within 3 to 5 years. When patients fail a biologic, clinicians often consider switching to a different mechanism of action. In the event of a secondary loss of effect, clinicians can consider switching within class. Additionally, some patients may have a contraindication to available therapies. With a TNFi, clinicians are cautious in patients with a personal or family history of multiple sclerosis, lupus, or drug-induced psoriasis. With an IL-17i, clinicians would try to avoid prescribing such a drug to patients with a history of IBD. Finally, no oral bDMARD options are available, and many patients are young, may enjoy travelling, or have an aversion to needles.

The clinical expert consulted by CADTH for this review indicated that treatment data from the upadacitinib trials in axial SpA show treatment response rates that appear to be comparable to those of other biologic drugs, such as TNFi or IL-17i options. Because JAKi options do not appear to work through a TNF or IL-17 pathway, an alternative mechanism of action would be ideal for these patients. Upadacitinib has been shown to reduce objective markers of inflammation such as C-reactive protein (CRP) and bone marrow edema in the SIJ and spine on MRI. Bone marrow edema has been shown to be a strong predictor of future syndesmophyte formation. If a patient requires escalation in therapy, clinicians will decide whether a TNFi, IL-17i, or JAKi would be most appropriate and initiate therapy. Currently the approved Health Canada label calls for use of these drugs if a previous biologic has failed or if other biologics are unsuitable; most rheumatologists were disappointed with that decision and were hoping to use this drug as a first-line DMARD in the appropriate patients. As upadacitinib was recently shown to be effective for nonradiographic axial SpA in a study with a sufficient sample size, the expectation is that the sponsor will want to get Health Canada approval for use as a first-line drug under this indication. The drug under review would provide further options to treat patients due to contraindications to a TNFi or IL-17i, previous failures to these drugs, convenience to patients in the form of an oral option, and efficacy in patients with both IBD and axial SpA. Patients should first try 2 NSAIDs for 2 to 4 weeks unless there is a contraindication. If they still have high disease activity, DMARDs are expected to be a first-line option available to patients, along with a TNFi and IL-17i. With the current Health Canada indication of a second-line drug, patients who have previously failed a biologic or who have a contraindication would be able to use it. From a safety perspective, most rheumatologists are comfortable with using this drug as a first-line biologic as it has been approved to treat RA.

The clinical expert consulted by CADTH for this review indicated that any patient with active AS would likely benefit from treatment with upadacitinib. Patients who also have active IBD, prefer an oral option, or have failed or have a contraindication to a TNFi or IL-17i may also benefit. Patients with high disease activity are in most in need of an intervention. Elevated CRP and bone marrow edema on MRI may be predictive of a greater response, but many patients with neither of these will also respond very well. The diagnosis of AS involves characteristic clinical findings in conjunction with identifying sacroiliitis in a pelvic X-ray. There can be quite a lot of interreader reliability issues, especially with early disease. Many rheumatologists typically confirm a diagnosis with MRI of the SIJ before proceeding with a bDMARD. The probability of under or overdiagnosis is largely related to the experience of the clinician. Most cases are straightforward, and convincing imaging and clinical features — and possibly a positive test for human leukocyte antigen B27 (HLA-B27) — can help a rheumatologist make a definitive diagnosis. The experience of the radiologist reading the X-ray, CT, or MRI scan is also important. Predictors of treatment response would be early onset of symptoms, male gender, elevated CRP, and degree of bone marrow edema seen on MRI.

The clinical expert consulted by CADTH for this review indicated that clinicians typically follow up with a patient after 3 months of therapy. If there is absolutely no response, clinicians would consider switching to a different drug. If there is a partial response, clinicians may wait for up to 6 months to determine the benefit. In daily practice, treatment response is measured by improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or ASDAS. Typically, a BASDAI improvement of 2 points or a 50% reduction is a reasonable response. Clinicians would see patients every 3 to 6 months to ensure stability of their disease. In clinical trials, clinicians would want to see an ASAS40 and a statistically significant improvement in other measures, such as ASDAS inadequate response, CRP, MRI, Assessment of SpondyloArthritis international Society Health Index (ASAS HI), Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire, or Linear Bath Ankylosing Spondylitis Metrology Index (BASFI). The clinical expert consulted by CADTH for this review indicated that clinicians would discontinue the medication if patients were developing side effects such as infections. If a patient’s symptoms were to recur, clinicians may consider switching the patient to another medication if clinicians were convinced that this was due to active disease. The clinical expert consulted by CADTH for this review indicated that a rheumatologist would be needed to confirm a diagnosis, treat, and monitor patients with AS. If other manifestations are involved, they may be co-followed by ophthalmology, gastroenterology, and dermatology.

Clinician Group Input

The Canadian Rheumatology Association (CRA) provided clinical input. Two clinicians who are members of the Spondylarthritis Research Consortium of Canada (SPARCC) executive committee and were involved in the 2014 CRA/SPARCC treatment recommendations contributed to these submissions.

Clinician group input indicated that there is an unmet need for the treatment of patients with AS for the following reasons: not all patients respond to currently available treatments; medications become less effective more frequently, which requires a switch to another medication; various adverse effects of the current therapies; persistence of constant spinal pain; and active extra-articular manifestations are common. The lack of orally administrated options can also affect compliance and adherence to a treatment plan.

The views of the clinician group were consistent overall with those of the clinical expert consulted by CADTH. The clinician group indicated that the most essential treatment goals are reducing pain and improving function.

The group advocated for NSAIDs as first-line pharmacologic therapy for AS and a TNFi or IL-17i as a first-line biologic therapy when NSAIDs are insufficient. Other classes of biologic treatments, such as a JAKi or other tsDMARD, could be used if initial treatments fail.

Clinician input suggested that patients would benefit more from upadacitinib, a selective JAKi for axial SpA, given its unique mechanism of action and oral administration, which are considered ideal options for many patients, particularly those who have failed treatment with continuous NSAIDs and who continue to have high measures of disease activity. However, people with severe active infections, acute or chronic, and people with severe hepatic disorders may not be suitable for upadacitinib use.

Drug Program Input

The drug plans identified considerations for initiation of therapy as a jurisdictional implementation issue. The clinical expert consulted by CADTH provided responses to the drug program implementation questions (Table 4).

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

Two manufacturer-sponsored, 14-week, double-blind, randomized controlled trials (RCTs), Study 944 (N = 420) and Study 098 (N = 187), are included in this review. The 2 trials evaluated the efficacy and safety of upadacitinib 15 mg administered orally once daily compared to placebo in patients with active AS. Study 944 was conducted in patients with AS who responded inadequately or were intolerant to 1 or 2 bDMARDs. Study 098 was conducted in patients with AS who responded inadequately or were intolerant to 2 or more NSAIDs but were bDMARD-naive. The primary outcome in both trials was the proportion of patients meeting the ASAS40 response criteria at week 14. The key secondary outcomes (multiplicity-controlled) included change from baseline in ASDAS; change from baseline in MRI SPARCC score (spine); Bath Ankylosing Spondylitis Disease Activity Index 50% improvement (BASDAI50) response; Assessment in SpondyloArthritis international Society 20% improvement (ASAS20) response; ID (ASDAS score < 1.3); change from baseline in patient assessment of total back pain; change from baseline in patient assessment of nocturnal back pain; low disease activity (LDA) (ASDAS score < 2.1); change from baseline in the BASFI); PR; change from baseline in ASQoL; change from baseline in ASAS HI; change from baseline in the Linear Bath Ankylosing Spondylitis Metrology Index (BASMIlin); and change from baseline in the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES).

Both Study 944 and Study 098 study included 4 periods: a screening period, a double-blinded treatment period (for 14 weeks), an extended treatment period (up to week 104), and a posttreatment follow-up period (30 days after last visit). Both Study 944 and Study 098 were conducted in multiple countries, including Canada, the US, Europe, Australia, New Zealand, and Asian countries. Study 944 also included Mexico and countries from South America. Results of the extension phase at week 52 of ||| ||||| ||| ||||||| |||||| ||| ||| Study 098) as well as week 104 for Study 098 are also presented in this report. Study 944 is ongoing. The long-term efficacy and safety outcome at week 104 in Study 944 was not available at the time of this review. Study 098 was complete.

Efficacy Results

Key efficacy and safety results at week 14 are summarized in Table 2.

Clinical response (e.g., ASAS40) at week 14: In Study 944, the proportions of patients achieving ASAS40 were 44.5% and 18.2% in the upadacitinib (15 mg, oral, once daily) and placebo groups, respectively. The mean between-groups difference (upadacitinib versus placebo) was 26.4% (95% confidence interval [CI], 17.9% to 34.9%; P < 0.0001). In Study 098, the proportions of patients achieving ASAS40 were 51.6% and 25.5% in the upadacitinib (15 mg, oral, once daily) and placebo groups, respectively. The mean between-groups difference (upadacitinib versus placebo) was 26.1% (95% CI, 12.6% to 39.5%; P < 0.001). According to the clinical expert CADTH consulted for this review, ASAS20 at week 12 has been considered an acceptable clinical response for bDMARD trials in patients with AS. Therefore, ASAS40 at week 14 represents a more substantial clinical improvement, and more recent trials have utilized this as the primary end point.

Measures of AS symptoms (e.g., total back pain) at week 14: In Study 944, the means of changes from baseline for total back pain were −3.00 (95% CI, −3.30 to −2.70) and −1.47 (95% CI, −1.77 to −1.16) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −1.53 (95% CI, −1.96 to −1.11; P < 0.0001). In Study 098, the means of changes from baseline for total back pain were −3.21 ||||| ||||||| |||||| and −1.68 ||||| ||||||| |||||| in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was |||||| |||||| ||||| || |||||| |||||||. The improvement in total back pain may be considered clinical meaningful (or useful) || |||| |||||||.

Function and disability (i.e., BASFI) at week 14: In Study 944, the means of changes from baseline for BASFI were −2.26 (95% CI, −2.53 to −2.00) and −1.09 (95% CI, −1.35 to −0.83) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −1.17 (95% CI, −1.55 to −0.80; P < 0.0001). In Study 098, the means of changes from baseline for BASFI were −2.29 (95% CI, −2.73 to −1.85) and −1.30 (95% CI, −1.74 to −0.86) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −1.00 (95% CI, −1.60 to 0.39; P < 0.001). The improvement in the BASFI was considered clinical meaningful.

HRQoL (ASQoL) at week 14: In Study 944, the means of changes from baseline for ASQoL were −5.10 (95% CI, −5.69 to −4.52) and −2.03 (95% CI, −2.62 to −1.44) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −3.07 (95% CI, −3.90 to −2.24; P < 0.0001). In Study 098, the mean changes from baseline for ASQoL were −4.20 (95% CI, −5.12 to −3.29) and −2.67 (95% CI, −3.58 to −1.75) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −1.54 (95% CI, −2.78 to 0.30; P < 0.016). The improvement in ASQoL was considered clinical meaningful in Study 944, but not in Study 098.

Work productivity (i.e., Work Productivity Activity Impairment–Spondyloarthritis [WPAI-SpA] Overall Work Impairment) at week 14: In Study 944, the means of changes from baseline for WPAI Overall Work Impairment were ||||| |||||||| ||||||| ||| |||||| |||||||| |||||| in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was |||||| |||||| |||||| || |||||| || ||||||| ||||| |||||||| ||||| || ||||| ||| ||| |||||||| |||| || |||||||||||| ||||||||||| ||| ||||||||||| |||||||||||| ||||||| |||||||||| In Study 098, the means of changes from baseline for WPAI Overall Work Impairment were −18.11 (95% CI, −24.73 to −11.50) and −12.60 (95% CI, −19.04 to −6.15) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −5.52 (95% CI, −13.82 to 2.78; P = 0.19 [not statistically significant]).

ASDAS (CRP): In Study 944, the means of changes from baseline for ASDAS (CRP) were −1.52 (95% CI, −1.64 to −1.39) and −0.49 (95% CI, −0.62 to −0.37) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −1.02 (95% CI, −1.20 to −0.85; P < 0.0001). In Study 098, the means of changes from baseline for ASDAS (CRP) were −1.45 (95% CI, −1.62 to −1.28) and −0.54 (95% CI, −0.71 to −0.37) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −0.91 (95% CI, −1.14 to −0.68; P < 0.001). A cut-off of 1.1 or higher is considered a clinically important improvement, which was seen in Study 944 but not in Study 098.

BASDAI50 at week 14: In Study 944, the proportions of patients achieving BASDAI50 were 43.1% and 16.7% in the upadacitinib and placebo groups, respectively. The mean between-groups difference (upadacitinib versus placebo) was 26.4% (95% CI, 18.0% to 34.8%; P < 0.0001). In Study 098, the proportions of patients achieving BASDAI50 at week 14 were in 45.2% and 23.4% in the upadacitinib and placebo groups, respectively. The mean between-groups difference (upadacitinib versus placebo) was 21.8% (95% CI, 8.5% to 35.0%; P = 0.002). A BASDI50 response was considered clinical meaningful in both studies.

MRI SPARCC Index (spine) at week 14: In Study 944, the means of changes from baseline for MRI SPARCC Index (spine) were −3.95 (95% CI, −5.06 to −2.83) and −0.04 (95% CI, −1.14 to 1.06) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −3.90 (95% CI, −5.47 to −2.33; P < 0.0001). In Study 098, the means of changes from baseline for MRI SPARCC Index (spine) were −6.93 (95% CI, −8.58 to −5.28) and −0.22 (95% CI, −2.01 to 1.57) in the upadacitinib 15 mg, oral, once-daily and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −6.71 (95% CI, −9.01 to −4.41; P < 0.001). The improvement of MRI SPARCC Index (spine) was considered clinical meaningful in Study 098 but not in Study 944.

MASES at week 14: In Study 944, the means of changes from baseline for MASES were −2.6 (95% CI, −3.0 to −2.2) and −1.1 (95% CI, −1.5 to −0.8) in the upadacitinib 15 mg, oral, once-daily and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −1.50 (95% CI, −2.00 to −0.90; P < 0.0001). However, whether the improvement in MASES in Study 944 is clinical meaningful remains unclear. In Study 098, at week 14, the means of changes from baseline for MASES were −2.25 (95% CI, −2.86 to −1.64) and −1.41 (95% CI, −2.02 to −0.80) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −0.84 (95% CI, −1.68 to 0.00; P < 0.049, which was considered not significant).

BASMI at week 14: In Study 944, the means of changes from baseline for the BASMI were −0.48 (95% CI, −0.58 to −0.38) and −0.16 (95% CI, −0.26 to −0.06) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −0.32 (95% CI, −0.46 to −0.18; P < 0.0001). However, whether the improvement in the BASMI shown in Study 944 is clinical meaningful remains unclear. In Study 098, the means of changes from baseline for BASMI were −0.37 (95% CI, −0.52 to −0.21) and −0.14 (95% CI, −0.29 to 0.01) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −0.22 (95% CI, −0.43 to −0.02; P < 0.03, which was considered not significant).

Efficacy reported in extension phase: The efficacy achieved at week 14 appeared to be maintained at 52 weeks ||| |||| |||||||| and week 104 (for Study 098).

Harms Results

The overall frequency of patients with treatment-emergent adverse events (TEAEs) in patients treated with upadacitinib appeared to be low, but higher compared to those in the placebo group in both Study 944 (40.8% verus 36.8%, respectively) and in Study 098 (62.4% versus 55.3%) by week 14. In Study 944, no TEAEs occurred in at least 5% of patients in either of the arms. In Study 098, the most common TEAEs (> 5% of patients in either of the treatment groups) had increased levels of blood creatine phosphokinase (CPK), diarrhea, nasopharyngitis, headache, and nausea. The overall frequency of patients with serious adverse events (SAEs) by week 14 seemed to be very low (< 3%) in both studies by week 14. It was noted that no patients withdrew due to AEs in the upadacitinib group in Study 944. In Study 098, patient withdrawal due to adverse event (WDAE) was also very low (< 3%). No deaths were reported by week 14 in either of the studies. The incidence of notable harms identified in this review (including serious infection, anemia, neutropenia, lymphopenia, thrombocytopenia, malignancies, thrombosis including increased platelets, elevation of CPK, other gastrointestinal SAEs, hypersensitivity, acne, and folliculitis) was also low. No major adverse cardiac event (MACE), gastrointestinal perforation, hepatotoxicity, dyslipidemia, opportunistic infection excluding tuberculosis, herpes zoster, or active case of tuberculosis was reported in either of the studies. Based on the input from the clinical expert CADTH consulted for this review, the TEAEs reported in both Study 944 and Study 098 were commonly observed in other upadacitinib clinical trials for RA, PsA, and AD. Notable harms were unremarkable.

For the extension phase, the proportion of patients with a TEAE was not reported in either study. Instead, the number of TEAEs and the number of TEAE person-years were provided. The clinical expert CADTH consulted for the review indicated that the safety profiles of upadacitinib for AS over |||| || || ||||| ||| and over week 104 were consistent with that observed by week 14, with no new safety signals reported. The overall observed AEs aligned with the known safety profile of upadacitinib. No new safety signals were identified between week 14 and week 104.

Table 2: Summary of Key Results From Pivotal and Protocol-Selected Studies (at Week 14)

AE = adverse event; ASAS20 = Assessment of SpondyloArthritis international Society 20% improvement; ASAS40 = Assessment of SpondyloArthritis international Society 40% improvement; ASDAS = Ankylosing Spondylitis Disease Activity Score; ASQoL = ankylosing spondylitis quality of life; BASDAI50 = Bath Ankylosing Spondylitis Disease Activity Index 50% improvement; BASFI = Bath Ankylosing Spondylitis Functional Index; CFB = change from baseline; CI = confidence interval; CPK = creatine phosphokinase; CRP = C-reactive protein; FAS = full analysis set; MI = multiple imputation; NRI = nonresponder imputation; PBO = placebo; q.d. = once daily; SAE = serious adverse event; TEAE = treatment-emergent adverse event; SPARCC = Spondyloarthritis Research Consortium of Canada; UPA = upadacitinib; vs. = versus; WDAE = withdrawal due to adverse event including death.

Notes: NRI-MI is nonresponder imputation incorporating multiple imputations to handle missing data due to COVID-19. Standard deviations of the mean for baseline and week 14 were not available from the sponsor.

^an is calculated by N and MI-aggregated response rate (%).

^bTreatment difference, associated CI, and P value for the test of difference between the upadacitinib group and the placebo group is constructed based on the MI inference. Risk difference and standard error is estimated using Cochran-Mantel-Haenszel test and screening high-sensitivity CRP status as stratification factor within each imputed “complete” dataset, after which Rubin’s rule is used to combine the results from 30 imputed “complete” datasets to produce an aggregated treatment difference, associated CI and P value.

Sources: Study 944, week 14 Clinical Study Report,¹⁴ Study 098 week 14 Clinical Study Report,¹⁵ and sponsor’s submission.¹⁶

Critical Appraisal

Randomization appeared sufficient and blinding appeared to be maintained throughout the study. Missing data were minimal and unlikely to affect study results. A multiplicity adjustment was conducted for the primary and main secondary outcomes at week 14; however, in Study 944, no multiplicity adjustment was performed for other secondary or exploratory outcomes, such as Assessment in SpondyloArthritis international Society 20% improvement in 5 of 6 domains (ASAS5/6), 5-Level EQ-5D (EQ-5D-5L), Short Form (36) Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), Work Productivity Activity Impairment–Spondyloarthritis (WPAI-SpA), and MRI SPARCC score (SIJ). In Study 098, no multiplicity adjustment was performed for symptom measurement scale (total back pain and nocturnal back pain), ID (ASDAS score < 1.3), LDA (ASDAS score < 2.1); HRQoL (EQ-5D-5L and SF-36), FACIT-F and MRI SPARCC score (SIJs). Given the large number of comparisons in the study, a statistically significant finding (P < 0.05) for the comparisons between upadacitinib and placebo for these outcomes without multiplicity adjustment may present a high risk of bias due to an inflated type I error rate. The statistical significance (P value) reported for those outcomes without a multiplicity adjustment therefore remains uncertain. One limitation was that both Study 944 and Study 098 were not designed to assess the comparative efficacy and safety between upadacitinib and the existing bDMARDs marketed in Canada (i.e., TNFi and IL-17i) for the treatment of AS. The direct comparative efficacy and safety of upadacitinib and other bDMARDs therefore remains unknown. In addition, extra-articular manifestations were not assessed as an efficacy in either of the studies, and the efficacy of upadacitinib on the extra-articular manifestations in the patients with AS remains to be investigated.

Regarding limitations for the long-term, the findings at week 52 for both studies and at 104 weeks for Study 098 in the extension phase were limited by the lack of any control group and the nature of the open-label study. Efficacy data beyond week 52 were not provided for the ongoing Study 944. The clinical expert CADTH consulted for this review indicated that, in clinical trials, the efficacy magnitude (particularly for those patient self-reported outcomes) is commonly overestimated due to the nature of the open-label protocol and the absence of a control group. Moreover, patients who enter into a long-term extension are generally responding to the medication, or are aware they will now receive the medication, and are relatively free of AEs, which further increases biases observed around efficacy and safety. The long-term outcome efficacy should therefore be interpreted with consideration of this limitation, although this would apply to all long-term extension studies. Finally, for the extension phase, the proportion of patients with TEAEs was not reported in either study. Instead, the numbers of TEAEs and TEAE person-years were provided.

The clinical expert CADTH consulted for this review indicated that exclusion of patients with total ankylosis of the spine and those who had inadequate response to 2 or more bDMARDs in the trials was a “clinical trial strategy” to exclude patients who were not likely to demonstrate changes in numerous outcome measures. However, this is consistent with previous AS clinical trials (e.g., secukinumab, ixekizumab, anti-TNFs). In real-world practice, it is possible that patients with total ankylosis who failed more than 2 bDMARDs may still demonstrate decreases in pain, stiffness, and fatigue and meaningful improvements in quality of life with the treatment. Overall, according to the clinical expert involved in the review, in both Study 944 and Study 098, the patients included in the trial were similar to those seen in Canadian clinical settings, except that those patients with total ankylosis of the spine who had failed more than 2 bDMARDs would also be considered eligible for therapy and be treated in a clinic. There is little concern about the generalizability in Canada of the findings from both Study 944 and Study 098.

Indirect Comparisons

Description of Studies

The sponsor submitted an indirect treatment comparison (ITC) of upadacitinib in adults with AS, and it is included in this review. || | |||||||| |||||||| ||| |||| |||||||| ||||||||||| |||||||| || |||||||||||| ||| |||||||| ||||||||||| || | |||||||| |||||||| ||| |||||||| |||| || ||||| |||||| |||||||||| |||||||||||||| ||| |||||||||| ||| |||||||| ||| ||||||||||| || |||||||||| |||||||| || ||||||| ||||||||||||

A focused literature search identified 2 published ITCs, which are also included in the review.^18,19

Efficacy Results

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The published ITCs had similar findings. One used a frequentist approach and did not specify prior bDMARD exposure.¹⁸ The number of included studies was larger than the sponsor-submitted ITC. Fewer efficacy outcomes were assessed, but it also included an assessment of SAEs. Upadacitinib was superior to placebo and did not differ from relevant comparators with respect to efficacy outcomes. The other published ITC used a Bayesian approach to estimate the comparative efficacy of JAKi drugs and secukinumab in patients with no prior exposure to bDMARDs.¹⁹ Secukinumab was the only relevant comparator for the Canadian context included in this ITC. Upadacitinib was superior to placebo and similar to secukinumab for efficacy outcomes.

Harms Results

|| |||||||||| || ||||| ||| |||||||| || ||| ||||||| ||||||||| |||| Both published ITCs included comparative estimates for SAEs. In the ITC that used a frequentist approach, upadacitinib was no different than placebo or other relevant comparators for SAEs.¹⁸ In the published ITC that used a Bayesian approach, upadacitinib was no different than placebo or secukinumab for SAEs.¹⁹

Critical Appraisal

A key limitation in the sponsor-submitted ITC is the evidence base for patients who had an inadequate response to a previous bDMARD, which appears to be the primary target population for this drug based on the Health Canada indication.¹⁰ The ITC provides comparative efficacy for only ixekizumab and secukinumab in patients with an inadequate response to a prior bDMARD. Although comparative efficacy is available for all relevant comparators in a bDMARD-naive population, it is uncertain if the comparative efficacy results for bDMARD-naive patients can be generalized to patients who had an inadequate response to a bDMARD. The clinical expert consulted by CADTH noted that bDMARD patients with an inadequate response would be expected to have a lower response compared to bDMARD-naive patients.

Another a key limitation of the sponsor-submitted study is the presence of heterogeneity in baseline patient characteristics among studies. Additional aspects of study design may also contribute to heterogeneity. Many of the baseline characteristics with heterogeneity have been identified in the literature as treatment-effect modifiers in AS. |||||| |||||||| ||| ||||||||||||| |||| ||||||||| ||| ||||||| |||| ||| ||||||||| |||||| |||||||| || ||| ||||||||| ||||| ||||| || ||||| ||| ||||||||||| ||||||| |||| |||||| |||||||| ||| ||||||||||||| |||| ||||||||| || | |||||||| || ||||||||| There is therefore increased uncertainty in the ITC findings.

One¹⁸ of the 2 published ITCs had similar limitations related to heterogeneity of baseline patient characteristics among the included studies, while heterogeneity in the other study¹⁹ could not be evaluated because no baseline patient characteristics were provided. One study had additional concerns about heterogeneity related to the time points used for efficacy assessment.¹⁸ Both ITCs also have limitations related to reporting of methods and results, as well as details about included studies.

Other Relevant Evidence

No other relevant evidence was identified.

Conclusions

Two double-blind RCTs of patients with active AS were included in this review. Study 944 was conducted in patients with inadequate response to or intolerance of 1 or 2 bDMARDs, and Study 098 was conducted in patients with inadequate response to at least 2 NSAIDs, but who were bDMARD-naive. The observed evidence indicated that, at week 14, once-daily, oral upadacitinib 15 mg showed a statistically significant and clinically meaningful (or useful) benefit as demonstrated by clinical response (e.g., ASAS40), AS symptom reduction (e.g., total back pain in Study 944), function and disability improvement (i.e., BASFI), HRQoL (ASQoL in Study 944), AS disease activity reduction (e.g., BASDAI50, ASDAS) and MRI-detected axial inflammation (i.e., MRI spine SPARCC change in Study 098) compared with placebo. Treatment with upadacitinib also demonstrated a statistically significantly greater improvement (in Study 944) in terms of ASAS HI, MRI spine SPARCC change, enthesitis (MASES) and spinal mobility (BASMI) compared with placebo at week 14. Treatment with upadacitinib also appeared to be favourable compared with placebo in terms of WPAI-SpA (in Study 944) and patient global assessment. The magnitude of clinical response (ASAS40) to upadacitinib appeared similar in bDMARD-experienced patients compared with bDMARD-naive patients, even though most clinical trials assessing efficacy in patients with an inadequate response to a bDMARD have demonstrated reduced treatment response. The efficacy achieved at week 14 appeared to be maintained at 52 weeks ||| |||| |||||||) and week 104 (for Study 098). The overall observed AEs aligned with the known safety profile of upadacitinib. No new safety signals were identified at week 14 and up to week 104. The evidence from 3 ITCs suggests that no treatment for AS is favoured over others for most efficacy outcomes in bDMARD-naive patients and patients who had an inadequate response to a bDMARD, although the evidence base is limited in the latter population. No treatment is favoured over others for the outcome of SAEs. The presence of heterogeneity in the included studies increases uncertainty in the findings.

Introduction

Disease Background

Ankylosing spondylitis, also referred to as radiographic axial SpA, is a chronic inflammatory disease primarily involving the spine and SIJs.^1,2 “Ankylosing” means fusing and “spondylitis” means inflammation of the spine. AS is considered an autoimmune disease²⁰ that usually begins in young adults (aged < 45 years), with a peak age of onset of between 20 and 30 years. AS is more common among men than among women.¹ Patients with AS exhibit radiographic abnormalities consistent with sacroiliitis. Patients experience back pain and progressive spinal stiffness and may also suffer from extra-articular manifestations such as uveitis, skin psoriasis, and IBD. AS symptoms and the rate of progression fluctuate with time and can vary substantially among patients. They result in functional impairment and subsequent potential socioeconomic consequences and disability; AS therefore negatively affects patients’ HRQoL.^1-3 A diagnosis of AS can be made based on the clinical features, biological testing, and imaging examinations of the disease.² The modified New York classification criteria for AS have often been applied as a diagnostic instrument.^4,5 The exact prevalence of AS is unknown and varies widely across countries, with Africa having the lowest prevalence (0.07%) and the US having the highest prevalence (0.32%).²¹ Studies have also suggested a difference in AS prevalence within the same country, which may be partly due to socioeconomic status and genetic variation.²¹ The worldwide prevalence of AS is reportedly 0.18%.²² A population-based study published by Haroon et al. showed that the prevalence of AS nearly tripled in Ontario from 1995 to 2010, the 2010 estimate being 0.2%. In the same study, the annual incidence of AS remained relatively stable, with a rate of 15 per 100,000 individuals.⁶ In 2019, AS was estimated to affect 300,000 patients in Canada.⁷ Population data from Alberta indicates similar provincial rates; however, there is a higher prevalence in First Nations populations (0.6%).²³ The American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations (2019),⁸ defines active AS as a disease causing symptoms at an unacceptably bothersome level to the patient and judged by the examining clinician to be due to inflammation. Stable AS was defined as asymptomatic or causing symptoms but at an acceptable level as reported by the patient. A minimum of 6 months was required to qualify as clinically stable.⁸

Standards of Therapy

According to the update of ASAS–European Alliance of Associations for Rheumatology Recommendations on the management of axial spondyloarthritis (2022)⁹ and the practice guidelines developed by the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network in 2019,⁸ the goals of treatment for patients with AS are to maximize long-term HRQoL, control symptoms and inflammation, maintain spinal flexibility and normal posture, reduce functional limitations, maintain work ability, decrease disease complications, and prevent progressive structural damage.^8,9 Treatment decisions are based on the degree of disease activity, functional disability, and HRQoL.⁸ There are no internationally accepted remission criteria for AS. Remission has been defined as the persistent absence of clinical and radiologic signs of disease activity without treatment over a specific period of time. The only criterion that has been formally derived is the ASAS PR criteria, which evaluates symptomatic improvement and represents a state of low-level disease activity rather than remission. Patients who achieve PR are clinically equivalent to those with no symptoms or significant damage, consistent with a BASDAI score of 0 to 1, a BASFI score of 0 to 1, and an ASDAS of 0 to 1. However, this set of criteria is used primarily in clinical trials.^16,24 Although no treatment has currently proven to result in complete remission of AS, measuring remission is important as it should be the aim of therapy, where a treatment that results in remission represents the optimal therapeutic approach.²⁴

Several drug classes are used in the pharmacologic therapy of AS. NSAIDs, including nonselective and selective cyclooxygenase-2 inhibitors, are the first choice of treatment for adult patients with active AS. Should NSAIDs fail or if there are contraindications, the next line of treatment is a bDMARD, including a TNFi, IL-17i, or a JAKi. Current practice is to start with a TNFi or IL-17i. TNFis marketed in Canada for the treatment of AS include adalimumab, certolizumab, etanercept, golimumab, and infliximab. IL-17is marketed in Canada for the treatment of AS include ixekizumab and secukinumab (Table 3). Clinical evidence has shown that these drugs are associated with significant improvements in disease activity and function, and a higher proportion of patients meeting the ASAS response criteria, compared to placebo. After failure of the first TNFi, switching to another bDMARD (TNFi or IL-17i) or a JAKi should be considered^1,8,9,25 In addition, csDMARDs such as sulfasalazine can be used in patients with AS and peripheral arthritis when they have contraindications to or decline treatment with a TNFi.^8,25 In adults with active AS, systemic glucocorticoids are not recommended; however, locally administered parenteral glucocorticoids can be used in adults with AS with stable axial disease and active enthesitis or active peripheral arthritis.^8,25 The treatment recommendations for AS and nonradiographic axial SpA are similar.⁸

Drug

Upadacitinib is an oral, selective JAKi.¹⁰ These inhibitors are also classified as tsDMARDs. JAKs are intracellular enzymes that transduce signals from cell surface receptors for cytokines or growth factors involved in a broad range of cellular processes, including inflammatory responses, hematopoiesis, and immune surveillance.¹⁰ Upadacitinib has greater inhibitory potency for the JAK1 protein relative to the JAK2, JAK3, and TYK2 proteins. Upadacitinib is available as 15 mg or 30 mg extended-release tablets.¹⁰ Indications previously approved by Health Canada for upadacitinib include the treatment of adults with moderately to severely active RA who have had an inadequate response or are intolerant to methotrexate; treatment of adults with active PsA who have had an inadequate response or are intolerant to methotrexate or other DMARDs; and treatment of adults and adolescents aged 12 years and older with refractory moderate-to-severe AD who are not adequately controlled with a systemic treatment (e.g., steroid or biologic) or when use of those therapies is inadvisable.¹⁰ Upadacitinib was previously reviewed by CADTH in February 2020 for the indication of adults with moderately to severely active RA, and a final recommendation for reimbursement with conditions was issued.¹¹ It was also reviewed by CADTH in June 2021 for the indication of adult patients with active PsA who have had an inadequate response or are intolerant to methotrexate or other DMARDs, with a final recommendation of reimbursement if certain conditions are met.¹² Recently, it has been reviewed by CADTH (October 2022) for the treatment of adults and adolescents aged 12 years and older with refractory moderate-to-severe AD who are not adequately controlled with a systemic treatment (e.g., a steroid or biologic) or when use of those therapies is inadvisable. A final recommendation of reimbursement if certain conditions are met was issued.¹³

The Health Canada–approved indication of interest for this review is for the treatment of adults with active AS who have had an inadequate response to a biologic DMARD or when use of those therapies is inadvisable. The recommended dose regimen is 15 mg, administered orally, once daily. Upadacitinib may be used as monotherapy or in combination with NSAIDs (Table 3). The sponsor’s reimbursement request is identical to the Health Canada–approved indication.

The characteristics of upadacitinib and its most common comparators for the purpose of this review are presented in Table 3.

Table 3: Key Characteristics of Upadacitinib, Ixekizumab, Secukinumab, Adalimumab, Certolizumab Pegol, Etanercept, Golimumab, and Infliximab

AS = ankylosing spondylitis; SpA = spondyloarthritis; CD = Crohn disease; DMARD = disease-modifying antirheumatic drug; HS = hidradenitis suppurativa; IgG4 = immunoglobin G4; IgG1 = immunoglobin G1; IgG1k = immunoglobin G1 kappa; IL-17A = interleukin-17A; JIA = juvenile idiopathic arthritis; NSAID = nonsteroidal anti-inflammatory drug; PP = plaque psoriasis; PsA = psoriatic arthritis; q.4.w. = every 4 weeks; RA = rheumatoid arthritis; SC = subcutaneous; TB = tuberculosis; TNF = tumour necrosis factor; TNFi = tumour necrosis factor inhibitor; UC = ulcerative colitis.

^aHealth Canada indication.

Sources: Health Canada product monographs for upadacitinib,¹⁰ ixekizumab,²⁶ secukinumab,²⁷ adalimumab,²⁸ certolizumab pegol,²⁹ etanercept,³⁰ golimumab,³¹ and infliximab.³²

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

Two responses to CADTH’s call for patient input for this review were received from ACE and through a joint submission from CAPA, Arthritis Society Canada, the CSA, and Creaky Joints Canada. ACE, CAPA, Arthritis Society Canada, the CSA, and Creaky Joints Canada serve individuals living with arthritis, including AS, and their caregivers, health care providers, and community members.

Patient perspectives from the joint input were obtained from a survey shared via email, social media, and the 4 organizations’ websites from October 12, 2022, to October 30, 2022. Patient perspectives from the ACE input were obtained from an ACE Survey Monkey platform.

Among the 264 joint survey participants living with AS, 9 had direct experience with upadacitinib and close to 90% indicated they live with back pain, while 72% have back pain, 86% have joint stiffness, and 51% experienced sore heels and feet. Patient respondents were also faced with other symptoms of AS, such as anxiety and depression (52% of respondents), bowel inflammation (49%), psoriasis (35%), migraine (32%), uveitis (31%), osteoporosis (23%), and heart problems (11%). Most survey participants rated their disease severity as 59 out of 100. In addition, patients indicated having trouble managing symptoms, including fatigue, difficulty concentrating, stress, mobility issues, and loss of appetite. Similarly, patient respondents from the ACE patient input reported experiencing fatigue, mobility issues, weight gain, and constant pain, and indicated that the disease affects their quality of life, daily activities, and their mood. Caregivers of patient respondents from the ACE input also stated that the disease affected their quality of life as they must pay attention to their time management.

The joint patient input stated that, during an AS flare, which is a period of worsening symptoms, patients may have difficulties performing day-to-day activities. Patient respondents with AS reported that the disease severely affects all aspects of their lives, from their physical and mental health to their family life, self-esteem, work, intimacy, and participation in social and leisure activities.

According to the joint patient input, many treatments are available to manage AS, including NSAIDs, corticosteroids, csDMARDs, and bDMARDs. The joint patient input stated that the effectiveness and tolerance of these treatments vary significantly among patients, with more than 40% of respondents indicating that they had an inadequate response to currently available treatments. The joint patient input indicated that some patients had to change their medication after a short period of time; others did not respond adequately to the currently available treatments. In addition, the joint patient input stated that side effects of current AS medications were another major concern for people living with AS. Fatigue, nausea and vomiting, increased risk of infections, liver toxicity, and weight gain affect patient adherence to medication and daily activities.

According to the patient respondents from the ACE patient input, currently available treatments can effectively manage their disease symptoms. However, concerns were raised regarding the cost of the medications, side effects, and the need to change medications due to decreased effectiveness within a short period of time.

The joint patient input highlighted that other treatment options, such as medical cannabis and/or nonpharmacological approaches to managing AS symptoms, are difficult to access because they are not reimbursed, not offered, or because these options require lengthy waits. According to the joint patient input, many factors, such as side effects, mode of administration, time required for treatment, travel, patient preferences, and cost, need to be considered by health care providers to determine the most effective treatment.

Nine respondents from the joint input reported having experience with upadacitinib. Positive aspects of treatment with upadacitinib reported by patient respondents included the simple route of administration, improved disease symptoms, mobility, and better quality of life with more energy. Few patient respondents experienced more frequent infections and headaches from treatment with upadacitinib.

Patient respondents from the joint patient input stated that managing AS can be improved by having access to affordable treatments that have a simple administration route (e.g., pills) and fewer adverse effects and infection rates, and are also able to reduce disease-related symptoms, improve their quality of life, and enable them to pursue their daily activities. The ACE patient input highlighted that patient respondents value additional treatment options with fewer AEs and improved pain control and remission rates.

Clinician Input

Input From Clinical Expert Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of AS.

Unmet Needs

The clinical expert indicated that not all patients respond to available treatments. ASAS40 is a common primary end point in clinical trials, which corresponds to a 40% improvement in 3 out of 4 domains (patient global assessment, total back pain, BASFI, and morning stiffness) with an absolute improvement of at least 2 and no worsening of the remaining domain. Roughly 40% of patients are able to achieve this response in clinical trials. Response rates to more stringent measures, such as ASAS PR and ID, are much lower.

The clinical expert indicated that roughly 10% of patients with AS also have IBD. While TNFis can effectively treat both, many patients with severe IBD do not respond to a TNFi even at high doses (e.g., ixekizumab 10 mg/kg every 4 weeks) or they initially respond but experience a loss of efficacy or have to stop due to side effects (drug-induced psoriasis). An IL-17i would be contraindicated in these patients, leaving few options available to patients.

The clinical expert indicated that the efficacy of the first biologic is lost within 3 to 5 years in roughly half of patients. When patients fail a biologic due to inadequate efficacy, clinicians often consider switching to a different mechanism of action. If they have a secondary loss of effect, the clinician can consider switching within class.

The clinical expert also indicated that some patients may have a contraindication to available therapies. With a TNFi, clinicians are cautious in patients with a personal or family history of multiple sclerosis, lupus, or drug-induced psoriasis. Clinicians would try to avoid prescribing IL-17is to patients with a history of IBD.

The clinical expert indicated that no oral bDMARD options are available, and many patients are young, may enjoy travelling, or have an aversion to needles.

Place in Therapy

The clinical expert indicated that treatment data from the upadacitinib trials in axial SpA show treatment response rates that appear to be comparable to those of other biologic drugs, such as TNF and IL-17 inhibitors. Because JAKi drugs do not appear to work through a TNF or IL-17 pathway, an alternative mechanism of action would be ideal for these patients.

The clinical expert indicated that upadacitinib has been shown to reduce objective markers of inflammation such as CRP and bone marrow edema in the SIJs and spine on MRI. Bone marrow edema has been shown to be a strong predictor of future syndesmophyte formation. Clinicians can also extrapolate from the PsA data, which indicate that upadacitinib can inhibit radiographic progression in peripheral joint disease.

The clinical expert indicated that if a patient requires an escalation in therapy, a clinician would decide whether a TNFi, IL-17i, or JAKi would be the most appropriate, and start the patient on that therapy in that situation. In rare circumstances, the clinician may have to combine biologics. For example, if a patient has severe Crohn disease and is not responsive to a TNFi, as well as in cases of axial disease, a clinician will often consider combining vedolizumab (Entyvio) with a TNFi. A drug such as upadacitinib would be an ideal candidate as it has been shown in a network meta-analysis (NMA) to be extremely effective for the treatment of IBD, as well as axial and peripheral disease.

The clinical expert indicated that the approved Health Canada label is to use these drugs if a previous biologic has failed or if other biologics are unsuitable. Most rheumatologists were disappointed with that decision and were hoping to use upadacitinib as a first-time DMARD in appropriate patients. In a recent study with a sufficient sample size, upadacitinib was shown to be effective for nonradiographic axial SpA, and the sponsor is expected to request Health Canada approval for use as a first-line drug under this indication.

The clinical expert indicated that the drug under review would provide further options to treat patients, either due to contraindications to TNFis and IL-17is, previous failures to these drugs, convenience to patients in the form of an oral option, and efficacy in patients with both IBD and axial SpA.

The clinical expert indicated that patients should first try 2 NSAIDs for 2 to 4 weeks unless there is a contraindication. If they still have high disease activity, this should be a first-line option available to patients, along with a TNF and IL-17 inhibitor. With the current Health Canada indication as a second-line drug, this could be used if patients who have previously failed a biologic or who have a contraindication. From a safety perspective, most rheumatologists are comfortable with using this drug as a first-line biologic drug because it has been approved to treat RA.

Patient Population

The clinical expert indicated that any patient with active AS without a contraindication to a JAKi would likely benefit from treatment with upadacitinib. Patients who also have active IBD, prefer an oral option, or have failed or have a contraindication to a TNFi or IL-17i may also benefit.

The clinical expert indicated that patients with high disease activity are most in need of an intervention. Elevated CRP and bone marrow edema on MRI may be predictive of a higher response but many patients with neither of these symptoms will also respond very well. In these patients, the degree of structural damage should be comparable to that seen in the SIJ on MRI or CT.

The clinical expert indicated that patients with longstanding disease tend to have a reduced response to all therapies, but even patients with total fusion of the spine have been demonstrated a benefit versus placebo in RCTs.

The clinical expert indicated that patients would need to see a rheumatologist to confirm the diagnosis and determine the level of activity (ruling out other possible causes of symptoms).

The clinical expert indicated that the diagnosis of AS involves characteristic clinical findings in conjunction with identifying sacroiliitis in a pelvic X-ray. There can be considerable inter-reader reliability issues, particularly with early disease. Many rheumatologists typically confirm a diagnosis with an SIJ MRI before proceeding with a bDMARD. This is a major challenge in parts of the country where access to MRI is limited.

The clinical expert indicated that, in addition to a description of back pain, features such as uveitis, psoriasis, IBD, peripheral inflammatory arthritis, enthesitis, HLA-B27, CRP, and MRI are all helpful clues to make a diagnosis.

The clinical expert indicated that the probability of under or overdiagnosis is largely related to the experience of the clinician. Most cases are straightforward, and convincing imaging, clinical features, and possibly a positive HLA-B27 can help a rheumatologist make a definitive diagnosis. However, as with all diseases in rheumatology, these are clinical syndromes and there are often patients whose presentation is not as clear. The experience of the radiologist reading the X-ray, CT, or MRI is also important.

The clinical expert indicated that predictors of treatment response would be early onset of symptoms, male gender, CRP elevation, and degree of bone marrow edema seen on MRI.

Assessing Response to Treatment

The clinical expert indicated that clinicians typically follow up with a patient after 3 months of therapy. If there is absolutely no response, clinician would consider switching to a different drug. If there is partial remission, the clinician may give up to 6 months to determine benefit.

The clinical expert indicated that, in daily practice, treatment response is measured by improvement in the BASDAI or ASDAS. Typically, a BASDAI50 reduction is a reasonable response. Control of uveitis, psoriasis, and IBD as well as resolution of inflammatory arthritis and enthesitis are also taken into consideration. If the CRP was elevated at baseline, this may be followed; however, many individuals may have an elevated CRP for reasons other than AS. Additionally, most patients with active AS do not have an elevated CRP.

The clinical expert indicated that clinicians would see patients every 3 to 6 months to ensure stability of their disease.

The clinical expert indicated that, in clinical trials, clinicians would want to see an ASAS40 response and statistically significant improvement in other measures such as ASDAS, CRP, MRI, ASAS HI, ASQoL, and BASFI.

Discontinuing Treatment

The clinical expert indicated that a clinician would discontinue the medication if the patient was developing side effects such as infections. Given the possible association of JAK molecules increasing the risk of venous thrombosis, cardiovascular disease, and malignancy, clinicians may avoid this class in high-risk individuals. If these were to occur, a clinician would strongly consider discontinuing the medication.

The clinical expert indicated that, if a patient’s symptoms were to recur, the clinician may consider switching to another medication if they were convinced that this was due to active disease.

The clinical expert indicated that, if the patient were to develop other manifestations such as severe uveitis, the clinician would either try to treat the uveitis alone with topical therapy or methotrexate or consider switching to a monoclonal TNFi.

The clinical expert indicated that some studies of TNFi drugs show that it may be possible to consider decreasing the dose in patients who are stable; however, complete discontinuation of medication almost always results in a flare (80% within 1 year).

Prescribing Conditions

The clinical expert indicated that a rheumatologist would be needed to confirm a diagnosis, treat, and monitor patients with AS. If other manifestations are involved, they may be co-followed by ophthalmology, gastroenterology, and dermatology. In some rural areas of Canada, patients may be followed by a general internist with a special interest in rheumatology.

Clinician Group Input

The CRA provided this input. Two clinicians who are members of the SPARCC executive committee and were involved in the 2014 CRA/SPARCC treatment recommendations contributed to these submissions.

Clinician group indicated that there is an unmet need for the treatment of patients with AS for the following reasons: not all patients respond to currently available treatments; medications become less effective more frequently, which requires a switch to another medication; various adverse effects of the current therapies; persistence of constant spinal pain and active extra-articular manifestations. The lack of orally administrated options also affects compliance and adherence to treatment plans.

Overall, the views of the clinician group were consistent with those of the clinical expert consulted by CADTH. The clinician group indicated that the most essential treatment goals are reducing pain and improving function.

The group advocated for the use of NSAIDs as first-line pharmacologic therapy for AS and for biologic options (a TNFi- or IL-17i) as first-line biologic therapies when NSAIDs are insufficient. Other classes of biologic treatments, such as a tsDMARD (JAKi), could be used if initial treatments fail.

Clinician input suggested that patients would benefit more from upadacitinib, a selective JAKi for axial SpA, given its unique mechanism of action and oral administration, which are considered ideal options for many patients, particularly those who have failed treatment with continuous NSAIDs and continue to have high measures of disease activity. However, people with severe active infections, acute or chronic, and people with severe hepatic disorders might not be suitable for upadacitinib use.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical expert consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

ACR20 = American College of Rheumatology 20% response; ACR50 = American College of Rheumatology 50% response; AS = ankylosing spondylitis; ASAS = Assessment of SpondyloArthritis international Society; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; bDMARD = biologic disease-modifying antirheumatic drug; CDEC = CADTH Canadian Drug Expert Committee; CRP = C-reactive protein; csDMARD = conventional synthetic disease-modifying antirheumatic drug; EULAR = European Alliance of Associations for Rheumatology; HAQ = Health Assessment Questionnaire; IBD = inflammatory bowel disease; IL-17 = interleukin-17; IL-17i = interleukin-17 inhibitor; IL-23 = interleukin-23; JAKi = Janus kinase inhibitor; NOC = Notice of compliance; NSAID = nonsteroidal anti-inflammatory drug; pCPA = pan-Canadian Pharmaceutical Alliance; QALY = quality-adjusted life-year; RA = rheumatoid arthritis; RCT = randomized controlled trial; tsDMARD = targeted synthetic disease-modifying antirheumatic drug; TNF = tumour necrosis factor; TNFi = tumour necrosis factor inhibitor; UC = ulcerative colitis; VAS = visual analogue scale; vs. = versus.

Clinical Evidence

The clinical evidence included in the review of upadacitinib is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes additional relevant studies (If available) that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of upadacitinib (extended-release tablets,15 mg and 30 mg), 15 mg once daily, administered orally, for the treatment of adult patients with active AS who have had an inadequate response to a biologic DMARD or when use of those therapies is inadvisable. Upadacitinib may be used as monotherapy or in combination with NSAIDs.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; AS = ankylosing spondylitis; ASAS40 = Assessment of SpondyloArthritis international Society 40% improvement; ASAS HI = ASAS Health Index; ASDAS = Ankylosing Spondylitis Disease Activity Score; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMIlin = Linear Bath Ankylosing Spondylitis Metrology Index; bDMARD = biologic disease-modifying antirheumatic drug; CPK = creatine phosphokinase; EQ-5D-5L = 5-Level EQ-5D; MACE = major adverse cardiovascular event; MASES = Maastricht Ankylosing Spondylitis Enthesitis Score; NSAID = nonsteroidal anti-inflammatory drug; SAE = serious adverse event; SF-36 = Short Form (36) Health Survey; SPARCC = Spondyloarthritis Research Consortium of Canada; vs. = versus; WDAE = withdrawal due to adverse event; WPAI-SpA = Work Productivity Activity Impairment–Spondyloarthritis.

Note: The sponsor indicated that 30 mg was not submitted for review.

^aOutcomes that were considered important by the patient groups.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.³⁴

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in EndNote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Rinvoq (upadacitinib). Clinical trials registries searched included the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Appendix 1 provides detailed search strategies.

The initial search was completed on November 11, 2022. Regular alerts updated the search until the meeting of CDEC on March 22, 2023.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.³⁵ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Appendix 1 provides more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included, and differences were resolved through discussion.

Findings From the Literature

Two studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Studies

AS = ankylosing spondylitis; ASAS = Assessment in SpondyloArthritis international Society; ASAS5/6 = Assessment in SpondyloArthritis international Society 20% improvement in 5 of 6 domains; ASAS20 = Assessment of SpondyloArthritis international Society 20% improvement; ASAS40 = Assessment of SpondyloArthritis international Society 40% improvement; ASAS HI = Assessment of SpondyloArthritis international Society Health Index; ASDAS = Ankylosing Spondylitis Disease Activity Score; ASQoL = Ankylosing Spondylitis Quality of Life; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; BASDAI50 = Bath Ankylosing Spondylitis Disease Activity Index 50% improvement; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMIlin = Linear Bath Ankylosing Spondylitis Metrology Index; bDMARD = biologic disease-modifying antirheumatic drug; CRP = C-reactive protein; csDMARD = conventional synthetic disease-modifying antirheumatic drug; DMARD = disease-modifying antirheumatic drug; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; IBD = inflammatory bowel disease; JAKi = Janus kinase inhibitor; LDA = low disease activity; MASES = Maastricht Ankylosing Spondylitis Enthesitis Score; mSASSS = Modified Stoke Ankylosing Spondylitis Spine Score; NA = not applicable; NRS = numerical rating scale; NSAID = nonsteroidal anti-inflammatory drug; PGA = Physician’s Global Assessment; PR = partial remission; PsA = psoriatic arthritis; PtGA = Patient’s Global Assessment of Disease Activity; RA = rheumatoid arthritis; RCT = randomized controlled trial; SF-36 = Short Form (36) Health Survey; SIJ = sacroiliac joint; SJC = swollen joint count; SpA = spondyloarthritis; SPARCC = Spondyloarthritis Research Consortium of Canada; TJC = tender joint count; WPAI-SpA = Work Productivity Activity Impairment–Spondyloarthritis.

Notes: Study 944 included study 1 and study 2. In this review, Study 944 specifically indicates Study 944 – study 1. For this review, only study 1 (for bDMARD–inadequate response AS) in Study 944 was relevant. Study 2 in Study 944 (for nonradiological axial SpA) was not relevant and not included in this review.¹⁶ The final Clinical Study Report for week 104 for Study 098 was not available at the time of the submission. The sponsor indicated that, regarding the availability of the final analysis (104 weeks, February 23, 2022), the Clinical Study Report for M16 to 098, the Clinical Study Report is expected to be finalized in the first quarter of 2023. No major impact on the efficacy and safety conclusions is expected. (November 10, 2022 in response to CADTH request).¹⁶ Two additional report was included (2 Health Canada reviewer reports).^42,43

Sources: Clinical Study Reports,^14,15,36,37 sponsor’s submission,¹⁶ and Health Canada reviewers’ report.^42,43

Description of Studies

Two trials (STUDY 944^15,36 and STUDY 098^14,37) were included for this review. Study 944 (i.e., Study 1 of Study M19 to 944, SELECT -AXIS 2, N = 420) was a phase II multicentre, randomized, double-blind, placebo-controlled trial of the efficacy and safety of upadacitinib 15 mg administered orally once daily compared to placebo in patients with active AS who were intolerant or had an inadequate response to a bDMARD. Study 944 examined the efficacy and safety of upadacitinib 15 mg administered orally once daily against placebo. Study 944 included a 14-week double-blind period (period 1) and a 90-week, open-label, single-arm extension period (period 2) (Figure 2). The study consisted of 5 phases; the first was a screening period (lasting up to 35 days before period 1, determining patient eligibility); the second was period 1, a double-blinded treatment period from week 0 (baseline) to week 14 inclusive evaluating the efficacy and safety of upadacitinib compared to placebo in which patients who completed the double-blinded 14-week study were eligible to enter into the extension phase; the third was an extended treatment period after week 14 to week 104 inclusive assessing the long-term efficacy and safety of upadacitinib; the fourth was a remission withdrawal period, which will last up to 152 weeks; and the fifth was a follow-up phase lasting 30 days. For this review, results of the 52-week extension phase are included at the time of the submission. The results of the 104-week extension and the remission withdrawal period are not available. Study 944 was conducted in 119 sites in 22 countries including Canada, the US, Mexico, Australia, New Zealand, and European, South American, and Asian countries.

Study 098 (i.e., Study M16 to 098, SELECT-AXIS 1, N = 187) was a phase II and III, randomized, double-blind, placebo-controlled trial in adult patients with active AS who had an inadequate response or are intolerant to 2 or more NSAIDS, but bDMARD-naive. The objective of Study 098 was to examine the efficacy and safety of upadacitinib 15 mg administered orally once daily with placebo. Study 098 study included 4 phases (Figure 3); the first was a screening period (lasting up to 35 days before period 1, determining patient eligibility); the second was period 1, a double-blinded treatment period from week 0 (baseline) to week 14 inclusive, evaluating the efficacy and safety of upadacitinib compared to placebo, in which patients who completed the double-blinded 14-week study were eligible to enter the extension phase; the third was an extended treatment period after week 14 to week 104 inclusive, assessing the long-term efficacy and safety of upadacitinib; and the fourth was a follow-up phase lasting 30 days. Study 098 was conducted in 62 sites in 20 countries: Canada, the US, Australia, New Zealand, and European and Asian countries.

In Study 944, at least 1 protocol deviation was reported in ||||| patients in the upadacitinib group and ||||| patients in placebo group. Eligibility criteria violation was the most frequent deviation (upadacitinib versus placebo) |||| ||| |||||| | ||| |||||||| |||||||||| ||||||||| ||||||| |||||||||| ||| ||| |||||||||| ||||||| || |||||||| |||| |||||||| ||| |||||||| ||| ||||| |||||| || ||||||||| |||| |||||||||| |||||| ||||||| ||||||| The totality of the protocol deviations incurred during the study did not affect the study outcomes, interpretation of study results, and/or conclusions. In Study 098, at least 1 protocol deviation was reported in ||||| |||||||| || ||| ||||| ||| |||| |||||||| || ||||||| |||||| ||| |||||||| ||||||||| |||| ||||||| || ||||||||||| |||||||| ||||||||| (Table 28).

Figure 2: Study 944 — Study Schematic

AS = ankylosing spondylitis; ASAS = Assessment of SpondyloArthritis international Society; DB = double-blind; bDMARD-IR = biologic disease-modifying antirheumatic drug–inadequate responder; nr-axSpA = nonradiographic axial spondyloarthritis; PBO = placebo; QD = once daily; SI = sacroiliac; UPA = upadacitinib; Wk = week.

Source: Clinical Study Report and Study 0944^15,36

Figure 3: Study 098 — Study Design Schematic

ABT-494 = upadacitinib; AS = ankylosing spondylitis; ASAS = Assessment of SpondyloArthritis international Society; ASAS20 = Assessment of SpondyloArthritis international Society 20% improvement; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; bDMARD = biologic disease-modifying antirheumatic drugs; hsCRP = high-sensitivity C-reactive protein; NRS = numerical rating scale; NSAID = nonsteroidal anti-inflammatory drug; QD = once daily; ULN = upper limit of normal; W = week.

^a Clinical diagnosis of AS and meeting the modified New York criteria for AS. Patient must have baseline disease activity as defined by having BASDAI score of 4 or higher and a patient assessment of total back pain score of 4 or higher based on a 0-to-10 NRS at the screening and baseline visit.

^b Stratified by geographic region (US and Canada, Japan, and rest of the world) and hsCRP (≤ ULN versus > ULN).

^c The X-rays of the spine and pelvis will not be required during the screening period if the patient had a previous anteroposterior pelvis X-ray and lateral spine X-rays within 90 days of the screening period, provided that the X-rays are confirmed to be adequate for the required evaluations and are deemed acceptable by the central imaging vendor.

^d For patients at select sites who consented to participation in the low-dose CT scan substudy.

^e Starting at week 16, patients who do not achieve at least an ASAS20 response at 2 consecutive visits will have the option to add or modify doses of NSAIDs, acetaminophen and/or paracetamol, low-potency opioid medications (tramadol or a combination of acetaminophen and codeine or hydrocodone), and/or modify the dose of methotrexate or sulfasalazine at week 20 or thereafter.

^f Starting at week 24, patients who still do not achieve at least ASAS20 at 2 consecutive visits were discontinued from study drug treatment.

Source: Study 098 Clinical Study Report.^14,37

Populations

Inclusion and Exclusion Criteria

In Study 944, the main selection criteria were adult patients (aged ≥ 18 years) who had an AS diagnosis (fulfillment of modified New York criteria based on a central reading of SIJ radiographs). Patients had active disease at screening and baseline defined as a BASDAI score and a patient assessment of total back pain score of 4 or higher on a 0-to-10 numerical rating scale (NRS), an inadequate response to 2 or more NSAIDs or intolerance to or contraindication for NSAIDs, and an inadequate response to bDMARD therapy. An inadequate response to bDMARD therapy was defined as discontinuing bDMARD therapy (TNFi or IL-17i) due to lack of efficacy (after ≥ 12 weeks of treatment at an adequate dose) based on the investigators’ assessment of intolerance (irrespective of treatment duration). Prior exposure to 2 bDMARDs was allowed for no more than 30% of patients; among patients with prior exposure to 2 bDMARDs, a lack of efficacy to a single bDMARD and intolerance to another was permitted. Patients receiving concomitant oral corticosteroids or NSAIDs must have been on a stable dose for at least 14 days before baseline, while those receiving concomitant csDMARDs were required to be on a stable dose for at least 28 days before baseline. The key exclusion criteria were patients with total spinal ankylosis; lack of efficacy to 2 bDMARDs, previous exposure to any JAKi, and patients with extra-articular manifestations (i.e., psoriasis, uveitis, or IBD) who were not clinically stable for at least 30 days before study entry.

In Study 098, eligible adult patients (aged ≥ 18 years) met the modified New York criteria for AS based on a central reading of radiographs of the SIJs, had active disease at baseline defined as a score of 4 or more and a patient assessment of back pain score of 4 or higher (on an NRS of 0 to 10) at screening and baseline visits. The key characteristic differentiating the patients from those in Study 944 was an inadequate response to at least 2 NSAIDS or intolerance to or contraindication for NSAIDs, but without experience with bDMARDs. Patients receiving concomitant csDMARDs, i.e., methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine, at a stable dose for ≥ 28 days before baseline) or oral glucocorticoids, NSAIDs, and analgesics (a stable dose for ≥ 14 days before baseline) were eligible. The key exclusion criteria were patients with total spinal ankylosis, previous exposure to any JAKi, prior exposure to any biologic therapy with a potential therapeutic impact on SpA, and extra-articular manifestations (i.e., psoriasis, uveitis, or IBD) that were not clinically stable for at least 30 days before study entry.

Baseline Characteristics

The demographics and baseline characteristics in the full analysis set (FAS) population (equivalent to the intention-to-treat [ITT] populations) for Study 944 and Study 098 are presented in Table 7, Table 8, and Table 9.

In Study 944, overall, the baseline characteristics were balanced between treatment groups. The mean age of patients ranged from 42.2 to 42.6 years between the treatment groups; the majority of patients were male (72.5% to 75.6%) and white (79.6% to 80.9%). The mean duration of AS symptoms was 12.6 to 12.9 years. The mean time since AS diagnosis was 7.5 to 7.9 years. The mean total BASDAI score was 6.8 in both treatment groups. The baseline ASDAS score was 3.9 in both treatment groups. The mean total back pain score was 7.4 to 7.5. The mean MRI of spine SPARCC score ranged from 8.8 to 10.7. The proportion of patients positive for HLA-B27 ranged from 81.2% to 85.3%. In addition, 73.0% patients in the upadacitinib group and 75.6% patients in the placebo group had a prior inadequate response to a TNFi and 13.5% patients in the upadacitinib group and 11.5% patients in the placebo group had a prior inadequate response to an IL-17i. A total of 21.3% patients in the upadacitinib group and 23.4% patients in the placebo group had prior intolerance to a TNFi or an IL-17 inhibitor.

In Study 098, overall, the baseline characteristics were balanced between treatment groups. The mean age of patients ranged from 43.7 to 47.0 years between the treatment groups; the majority of patients were male (68.0% to 73.0%) and white (81.0% to 85.0%). The mean duration of AS symptoms was 14.0 to 14.8 years. The mean time since AS diagnosis was 6.0 to 7.8 years. The mean total BASDAI score ranged from 6.3 to 6.5 between treatment groups. The baseline ASDAS score ranged from 3.5 to 3.7 between treatment groups. The mean total back pain score was 6.7 to 6.8. The mean MRI of spine SPARCC score ranged from 10.4 to 11.9. The proportion of patients positive for HLA-B27 ranged from 75.0% to 78.0%. || ||||||||| ||| |||||||||| || |||||||| |||| |||||||| ||| || ||||||||||| ||||||| ||| |||||| ||| || ||| |||||| ||||||||| ||||||.

Table 7: Summary of Baseline Characteristics

q.d. = once daily; SD = standard deviation.

Notes: Percentages calculated on nonmissing values. A patient was counted in the category closest to user.

Sources: Study 0944 Clinical Study Reports^15,36 and Study 098 Clinical Study Reports.^14,37

Table 8: Baseline Disease Characteristics — General

AS = ankylosing spondylitis; bDMARD = biologic disease-modifying antirheumatic drug; HLA-B27 = human leukocyte antigen-B27; IL-17i = interleukin-17 inhibitor; NSAID = nonsteroidal anti-inflammatory drug; q.d. = once daily; SD = standard deviation; TNFi = tumour necrosis factor inhibitor.

Sources: Study 0944 Clinical Study Reports^15,36 and Study 098 Clinical Study Reports.^14,37

Table 9: Baseline Disease Characteristics — Outcome-Related

ASAS HI = Assessment of SpondyloArthritis international Society Health Index; ASDAS = Ankylosing Spondylitis Disease Activity Score; ASQoL = ankylosing spondylitis quality of life; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMI = Bath Ankylosing Spondylitis Metrology Index; CRP = C-reactive protein; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; hsCRP = high-sensitivity C-reactive protein; MASES = Maastricht Ankylosing Spondylitis Enthesitis Score; NR = not reported; NRS = numerical rating scale; q.d. = once daily; SD = standard deviation; SF-36 = Short Form (36) Health Survey; SPARCC = Spondyloarthritis Research Consortium of Canada.

^aBased on MASES > 0 at baseline.

^bUpper limit of normal = 2.87 mg/L.

Sources: Study 0944 Clinical Study Reports^15,36 and Study 098 Clinical Study Reports.^14,37

Interventions

In both Study 944 and Study 098, patients were allocated to randomized and blinded treatment based on a unique identification number generated by interactive response technology (IRT) at the screening visit. For patients who re-screened, the number assigned by the IRT at the initial screening visit was used. The IRT assigned a randomization number that would encode the patient’s treatment-group assignment according to a randomization schedule set by the AbbVie statistics department. In the double-blind period, patients were randomized in a 1:1 ratio to the upadacitinib (15 mg oral, once-daily) or placebo group (placebos were presented as orally administered tablets that were identical in appearance). At week 14, patients entered an open-label extended treatment period (weeks 14 to 104). During the open-label period, all patients received 15 mg upadacitinib orally once daily.

In Study 944, randomization was stratified by screening high-sensitivity C-reactive protein (hsCRP ≤ or > an upper limit of normal of 2.87 mg/L), class of prior bDMARD use (a TNFi, an IL-17i, or 2 bDMARDs), and geographical region. The sponsor, investigators, study-site personnel, and the patients were blinded to the treatment assignments. In Study 098, randomization was stratified by screening hsCRP (≤ or > an upper limit of normal of 2.87 mg/L) and geographical region. The sponsor, investigators, study-site personnel, and the patients were blinded to the treatment assignments.

Use of Concomitant NSAIDs and csDMARDs

In Study 944, slightly more patients in the upadacitinib group received 1 or more concomitant csDMARDs than in the placebo group (upadacitinib versus placebo) ||||| ||| ||||||| ||||| |||||||| |||| |||||||| || |||||||||||| ||||| |||||||| ||| || |||| ||||||||||| |||| |||||||||||||| |||| |||| || ||||||| ||||| ||||||||||||| ||| |||||||| ||||| ||| ||||||| According to the clinical expert consulted for this review, this imbalance was unlikely to have affected the study results. || |||| ||| ||| || ||||||||||| ||||| ||| |||||||| |||| ||| |||||||| || |||||

In the double-blind period of Study 098, 76.3% of patients in the upadacitinib group and 86.2% of patients in the placebo group took 1 or more concomitant NSAIDs. Similar proportions in the 2 groups received concomitant csDMARD therapy (upadacitinib versus placebo: 14.0% versus 18.1%, respectively); ||| ||||||||||| ||| |||| ||| || |||| ||||||||||| |||| |||||||||||||| |||| |||| ||| ||||| || |||||||||||| ||| ||||||| ||||| ||||||||||||| || |||| || ||| |||| |||| ||| || ||||||||||| |||||| ||| |||||||| |||| ||| |||||||| || |||||

Rescue Therapy

In Study 944, at week 24, patients who do not achieve an ASAS20 response at both week 18 and week 24 were allowed to add or modify any of the background axial SpA medications (such as NSAIDs, csDMARDs, or a corticosteroid). After week 24 (e.g., at week 32 through week 104 visits), addition or modification of the background axial SpA medications could be made according to the investigator’s judgment regardless of the disease activity status. In Study 098, with rescue therapy starting at week 16, patients who do not achieve at least an ASAS20 response at 2 consecutive visits had the option to add or modify doses of NSAIDs, and/or modify the dose of methotrexate or sulfasalazine at week 20. Change in dose or addition of DMARDs other than methotrexate or sulfasalazine is not permitted for rescue. Starting at week 24, patients who did not achieve at least an ASAS20 response at 2 consecutive visits discontinued from study drug treatment.

No detailed information on rescue medication use was reported in either of the 2 studies.

Outcomes

A list of efficacy end points identified in the CADTH review protocol (Table 5) that were assessed in the clinical trials included in this review is provided in Table 10. These end points are further summarized in the following section. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Assessment of SpondyloArthritis international Society Criteria

ASAS40 and ASAS20

The primary efficacy outcome in Study 944 and Study 098 was the proportion of patients who met ASAS40 response criteria at week 14. An ASAS40 response is defined as an improvement of 40% or greater and an absolute improvement from baseline of 2 or more units (range = 0 to 10) in at least 3 of 4 main domains (i.e., patient global assessment, spinal pain, function, and inflammation), without any worsening in the remaining domain. ASAS20 was assessed as a main secondary outcome (i.e., it was analyzed with multiplicity adjustment) in both Study 944 and Study 098. ASAS20 response is defined as an improvement of 20% or greater and an absolute improvement from baseline of 1 or more units (range = 0 to 10) in at least 3 of 4 main domains, without any worsening of 20% or greater and 1 or more units (range = 0 to 10) in the remaining domain.

ASAS40 and ASAS20 are composite measures containing 4 main domains: Patient’s Global Assessment of Disease Activity (PtGA) on an NRS, with a score ranging from 0 (not active) to 10 (very active); assessment of back pain intensity with an NRS from 0 (not active) to 10 (very active); function represented by the BASFI as measured by an NRS ranging from 0 (not active) to 10 (very active); and inflammation represented by mean duration and severity of morning stiffness (measured by the average scores from the last 2 questions on the BASDAI, using a scale of 0 to 10). Two additional domains were included: spinal mobility represented by the BASMI lateral spinal flexion assessment and CRP.

ASAS Partial Remission

ASAS PR was assessed as a main secondary outcome (i.e., it was analyzed with multiplicity adjustment) in both Study 944 and Study 098. An ASAS PR response is defined as a value not above 2 units (range = 0 to 10 on an NRS) in each of the following 4 main domains: patient global assessment, spinal pain, function, and inflammation.

Assessment in SpondyloArthritis international Society 20% Improvement in 5 of 6 Domains

The Assessment in SpondyloArthritis international Society 20% improvement in 5 of 6 domains (ASAS5/6) was as additional outcome (i.e., exploratory outcome, without multiplicity adjustment) in Study 098. The ASAS5/6 was not assessed in Study 944. The ASAS5/6 includes assessments of all 6 individual ASAS domains and represents improvement of 20% or greater in at least 5 domains.

Symptom Measurement

In both Study 944 and Study 098, The AS symptom measures included the total back pain, total nocturnal back pain, and fatigue (FACIT-F). Both the total back pain and total nocturnal back pain were assessed as main secondary outcomes in Study 944 but were exploratory outcomes in Study 098. Both the total back pain and total nocturnal back pain were assessed with an NRS (0 to 10). A higher score indicates more severe pain.

Functional Assessment of Chronic Illness Therapy–Fatigue

The FACIT-F is a patient self-completed questionnaire to assess the intensity of fatigue (and its impact on daily life) during usual daily activities over the past week. It consists of a 13-item questionnaire that assesses self-reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. The level of fatigue is measured on a 4-point Likert scale (4 = not at all fatigued; 0 = very much fatigued). The instrument scoring yields a range from 0 to 52, with higher scores representing better overall health status (i.e., less fatigue). A meaningful within-patient change for the FACIT-F total score is estimated to be 3.1 to 6.3 points in patients with AS.

Bath Ankylosing Spondylitis Functional Index

The BASFI is 1 of the 4 main components of ASAS criteria. The BASFI is a validated, patient self-administered, composite instrument widely used in AS to assess physical function. The BASFI consists of 8 specific questions regarding function in AS and 2 questions reflecting the patient’s ability to cope with everyday life. Each question is answered on a 10 cm horizontal visual analogue scale (VAS) or an NRS (0 to 10), the mean of which gives the BASFI score (on a scale of 0 to 10). The higher the BASFI score, the greater the degree of functional impairment with reductions from baseline indicating improvement. The minimal clinically important difference (MCID) was 0.6 units on a 10-unit scale. In both studies, the BASFI was assessed as a main secondary outcome.

Health-Related Quality of Life

Ankylosing Spondylitis Quality of Life

Patient-reported impacts of AS on HRQoL included the impact of disease on sleep, mood, motivation, coping, activities of daily living, independence, relationships, and social life. ASQoL was assessed with a NRS of 0 to 10. A higher score indicates poorer quality of life. It was reported that increase of 1 point indicated “worsening” and a decrease of −2 indicated “improvement.”⁴⁴ In both studies, ASQoL was assessed as a main secondary outcome.

Assessment of SpondyloArthritis international Society Health Index

The ASAS HI is an axial SpA–specific, 17-item, patient-reported instrument designed to assess functioning, disability, and health. The ASAS HI has scores ranging from 0 (good health) to 17 (poor health). Each item consists of 1 question to which the patient needed to respond with either “I agree” (score of 1) or “I do not agree” (score of 0). A score of 1 is given when the item is affirmed, indicating adverse health. A higher score indicates a poor health quality. All item scores are summed to give a total score or index.

A minimal important difference (MID) for the ASAS HI was not identified in the literature. In both Study 944 and Study 098, the ASAS HI was assessed as a main secondary outcome.

5-Level EQ-5D

The EQ-5D-5L scale is a generic quality-of-life instrument that may be applied to a wide range of health conditions and treatments. The first of 2 parts of the EQ-5L-5D is a descriptive system that classifies respondents (aged ≥ 12 years) into 1 of 243 distinct health states. The descriptive system consists of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 possible levels of response (no problems, slight problems, moderate problems, severe problems, or extreme problems). Respondents are asked to choose the level that reflects their health state for each of the 5 dimensions. A scoring function can be used to assign a value (EQ-5D index score) to self-reported health states from a set of population-based preference weights. The second part is a 20 cm VAS (EQ VAS) that has end points labelled 0 and 100, with respective anchors of “worst imaginable health state” and “best imaginable health state.” Respondents are asked to rate their health by drawing a line from an anchor box to the point on the EQ VAS that best represents their health on that day. The EQ-5D index score is generated by applying a multiattribute utility function to the descriptive system. Different utility functions are available that reflect the preferences of specific populations (e.g., US or UK). The lowest possible overall score (corresponding to severe problems on all 5 attributes) varies depending on the utility function that is applied to the descriptive system (e.g., to −0.59 for the UK algorithm and −0.109 for the US algorithm). Scores of less than 0 represent health states that are valued by society as being worse than dead, while scores of 0 and 1 are assigned to the health states “dead” and “perfect health,” respectively. Reported MCIDs for this scale have ranged from 0.033 to 0.074. But an MID has not been specifically identified in AS patients. The EQ-5D was assessed as another secondary outcome in Study 944, but it was not assessed in Study 098.

Short Form (36) Health Survey

The SF-36 is a 36-item, general health status instrument that has been used extensively in clinical trials in many disease areas. The SF-36 consists of 8 health domains: physical functioning, pain, vitality, social functioning, psychological functioning, general health perceptions, and role limitations due to physical and emotional problems. For each of the 8 categories, a subscale score can be calculated. The SF-36 also provides 2 component summaries, the physical component summary (PCS) and the mental component summary (MCS). PCS and MCS scores range from 0 to 100, with higher scores indicating a better health status. The summary scales are scored using norm-based methods, with regression weights and constants derived from the general US population. Both the PCS and MCS scales are transformed to have a mean of 50 and a standard deviation of 10 in the general US population. All scores above or below 50 are therefore considered above or below average, respectively, for the general US population. Changes of between 2.5 to 5.0 points in the PCS and MCS of the SF-36 are considered clinically relevant, as are changes of 5 to 10 points in the domain scores. However, an MID for the SF-36 has not been specifically measured in AS patients. In Study 944, the SF-36 was assessed as an exploratory outcome. However, the SF-36 was not assessed in Study 098.

Work Productivity Activity Impairment–Spondyloarthritis

The WPAI-SpA is a 6-item, patient-reported instrument designed to assess the impact of SpA on work productivity and activity impairment. Four scores are derived: percentage of absenteeism, percentage of presenteeism, an overall work impairment score that combines absenteeism and presenteeism, and percentage of impairment in activities performed outside of work. Greater scores indicate greater impairment. No MID was identified in the literature. WPAI-SpA was assessed as an exploratory outcome in Study 944 and as a main secondary outcome in Study 098.

Bath Ankylosing Spondylitis Disease Activity Index

The BASDAI is the most common and widely used validated measure of inflammatory activity of AS. The BASDAI is a self-administered patient questionnaire that generates a composite index of patient responses to major symptoms of AS. It includes 6 questions addressing 5 major symptoms: fatigue, axial (spinal) and peripheral joint pain, localized tenderness, and morning stiffness (both the degree of stiffness and the length of time for which stiffness persists). Patient responses are recorded on a 10-unit horizontal NRS or 10 cm VAS or a numeric response scale (1 to 10). The scores for questions 5 and 6 (severity and duration of morning stiffness) are averaged to produce a result that is then averaged with the scores from the remaining 4 questions. The final BASDAI score has a range of 0 to 10: the higher the score, the greater the measured degree of disease activity. A reduction in the BASDAI score is considered improvement. The definition of treatment response (i.e., MCID) includes a change in the BASDAI value defined as 2 units (on a 0-to-10 scale) of the BASDAI. BASDAI50, which reflects an improvement of 50%, was assessed as a main secondary outcome in both Study 944 and Study 098. But the change from baseline of the BASDAI was assessed as an exploratory outcome in both studies.

Ankylosing Spondylitis Disease Activity Score

The ASDAS is a composite index to assess disease activity in AS. The parameters used for the ASDAS (with CRP as an acute-phase reactant) are total back pain (BASDAI question 2); patient global assessment (individual ASAS domain); peripheral pain and/or swelling (BASDAI question 3); duration of morning stiffness (BASDAI question 6); and CRP (mg/L). The ASDAS CRP score is calculated with the following equation: 0.121 × total back pain + 0.110 × patient global + 0.073 × peripheral pain/swelling + 0.058 × duration of morning stiffness + 0.579 × ln (CRP + 1). Four disease activity states have been defined by ASAS consensus:

• an ASDAS less than 1.3 defines ID

• an ASDAS greater than or equal to 1.3 and less than 2.1 defines LDA

• an ASDAS greater than or equal to 2.1 and no more than 3.5 defines high disease activity

• an ASDAS greater than 3.5 defines very high disease activity.

A clinically important improvement is defined as a change of 1.1 or more units, and major improvement is defined as a change of 2.0 or more units. At the 2018 ASAS annual meeting, the nomenclature for a cut-off of an ASDAS greater than or equal to 1.3 and less than 2.1 was updated. “Moderate disease activity” was replaced by “low disease activity” to better reflect what ASDAS values greater than or equal to 1.3 and less than 2.1 represent, in the opinion of patients and physicians.

Inactive AS (an ASDAS score of < 1.3) and ASDAS LDA (an ASDAS score of < 2.1) were assessed as a main secondary outcome in Study 944. But they were assessed as an exploratory outcome in Study 098. A clinically important improvement, defined as change of 1.1 or more units, was assessed as an exploratory outcomes in both studies.

Patient Global Assessment

The PtGA relates to a single specific ASAS domain based on an NRS. For this assessment, the patient was asked to respond to the following question: “How active was your spondylitis on average during the last week?” The answer was recorded on an NRS and was rated between 0 (not active) and 10 (very active). Additionally, an international validation study on the ASAS HI assessed PtGA using cut-off values of less than 3 and greater than 6 on an NRS to distinguish between a “good” and a “poor” health status, respectively. While an MID for PtGA was not identified in the literature, the minimum change that should be considered detectable would be approximately 2 to 3 units on a scale of 0 to 10. The PtGA was assessed as an exploratory outcome in both studies.

MRI Spine SPARCC Index

The SPARCC MRI Index for the spine is an MRI-based scoring system that assesses the presence, 3-dimensional extent, and signal intensity of active inflammatory lesions represented by bone marrow edema, in the spine of affected patients. In the spine, the scoring system measures edema in the bone marrow of discovertebral units (DVUs), each unit representing the region between 2 imaginary lines drawn through the middle of adjacent vertebrae. All 23 DVUs of the spine (from C2 to S1) were scored for bone marrow edema. A single DVU has a scoring range of 0 to 18, bringing the maximum total score to 414, with higher scores reflecting worse disease. An MID of 5.0 units for the SPARCC MRI score for the spine has been identified. The MRI Spine SPARCC Index was assessed as a main secondary outcome (multiplicity was adjusted in the analysis) in both Study 944 and Study 098.

MRI SIJ SPARCC Index

The MRI SPARCC score for the SIJ is a scoring method based on the assessment of an increased signal denoting bone marrow edema on T2‐weighted short-T1 inversion recovery (STIR) sequences. All signal changes within the iliac bone and sacrum up to the sacral foramina are scored on 6 consecutive slices through the SIJ. Each SIJ is divided into 4 quadrants: upper iliac, lower iliac, upper sacral, and lower sacral. The presence of an increased signal on STIR in each of these 4 quadrants was scored on a dichotomous basis, where 1 indicates an increased signal and 0 a normal signal. Total SIJ SPARCC scores can range from 0 to 72, with higher scores reflecting worse disease. An MID of 2.5 units for the SPARCC MRI score for SIJ has been identified. The MRI SIJ SPARCC Index was assessed as an exploratory outcome in both studies.

Linear Bath Ankylosing Spondylitis Metrology Index

The BASMIlin was assessed as a main secondary outcome in both studies. It was assessed with an NRS of 0 to 10. A higher score indicates poorer mobility. No MID information was identified.

Maastricht Ankylosing Spondylitis Enthesitis Score

The MASES was assessed as a main secondary outcome in both studies using an NRS of 0 to 10. A higher score indicates poorer mobility. No MID information was identified.

Safety Outcomes

In both trials, safety data are presented as AEs, SAEs, death, WDAEs, and notable AEs. All AE data presented in this review report are for TEAEs, defined as an AE with an onset date that was after the first dose of the study drug, and no more than 30 days after the last dose of the study drug.

Table 10: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

ASAS5/6 = Assessment in SpondyloArthritis international Society 20% improvement in 5 of 6 domains; ASAS20 = Assessment of SpondyloArthritis international Society 20% improvement; ASAS40 = Assessment of SpondyloArthritis international Society 40% improvement; ASAS HI = Assessment of SpondyloArthritis international Society Health Index; ASDAS = Ankylosing Spondylitis Disease Activity Score; ASQoL = Ankylosing Spondylitis Quality of Life; BASDAI50 = Bath Ankylosing Spondylitis Disease Activity Index 50% improvement; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMIlin = Linear Bath Ankylosing Spondylitis Metrology Index; MASES = Maastricht Ankylosing Spondylitis Enthesitis Score; NR = not reported; SPARCC = Spondyloarthritis Research Consortium of Canada; WPAI-SpA = Work Productivity Activity Impairment–Spondyloarthritis

Note: Main secondary means the multiplicity-controlled secondary end points at week 14.

Sources: Study 0944 Clinical Study Reports^15,36 and Study 098 Clinical Study Reports.^14,37

Statistical Analysis

Primary Outcome of the Studies

Power Calculation

In Study 944, the planned total sample size of 386 patients for this study (with a 1:1 randomization ratio for placebo and upadacitinib 15 mg) provides at least 90% power for the primary end point of an ASAS40 response of upadacitinib 15 mg versus placebo using a 2-sided chi-square test at the 0.05 level. For ASAS40, the assumed response rates for upadacitinib and placebo are 24% and 6%, respectively. |||| |||||| |||| |||| |||||||| ||| ||||| ||| ||||||| |||| ||||||| |||||||| ||||| ||| |||||||||||| ||| ||||||| || ||| ||| |||| ||||||||||||. || ||||||||| |||| |||||| |||| |||||||| || ||||| ||| ||||| ||| ||||||| || ||| |||||||||||| |||||||||| ||||||||| ||||||||| ||||||||| |||||| |||| |||||||| || |||||| |||||| |||| |||||||| || ||| |||||| ||||| || |||||| |||||| || ||||||||| ||||| ||| |||||| |||| |||||||| || ||||| |||| ||||| |||||| |||| |||||||| || ||||||||| |||| ||||| ||||| |||| |||||| |||| |||||||| || |||||| ||| |||| ||| These assumptions were based on a review of historical bDMARD clinical studies of AS patients.^45-47

In Study 098, the planned sample size of 170 for this study (with a 1:1 randomization ratio) provides at least 90% power for a 26% difference in ASAS40 response rate (assuming a placebo ASAS40 response rate of 20%). Power and sample-size calculations are performed at a 2-sided significance level of 0.05 and accounting for a 10% dropout rate.¹⁴

In both Study 944 and Study 098, all efficacy analyses were conducted in the FAS. In addition, per-protocol analysis for the primary end point was performed. All tests were 2-sided at an alpha level of 0.05. “Baseline” refers to the last nonmissing observation before the first administration of the study drug or randomization if no study drug was given. Two sets of efficacy analysis were planned: for the double-blind period and the long-term (extension phase).

The primary analysis was performed after all patients had completed the double-blind period or discontinued the study in the double-blind period and the database had been locked. This was the only and final analysis for the primary and secondary efficacy end points as well as all other efficacy end points in the double-blind period. Analyses were performed for the protocol-defined primary time point by randomized treatment groups (upadacitinib 15 mg once daily and placebo). No protocol-defined treatment switching occurred in the double-blind period. Formal statistical inference was generated, and results from this set of analyses were used as the key efficacy findings of this study.

Statistical Test or Model

Unless otherwise specified, binary variables were analyzed using a Cochran-Mantel-Haenszel test, stratified by screening hsCRP level status (hsCRP > upper limit of normal, hsCRP ≤ upper limit of normal). Continuous variables were analyzed using a mixed-effect model for repeated measures (MMRM) or analysis of covariance method adjusting for screening hsCRP level status. Unless otherwise specified, any patient who was randomized based on an incorrect stratum was analyzed according to the actual stratum the patient belongs to. In both Study 944 and Study 098, the primary analyses for continuous efficacy outcomes were made using the MMRM. The primary analyses for MRI SPARCC scores was based on the observed case using analysis of covariance.

A long-term efficacy analysis was conducted at week 52 for both Study 944 and Study 098 or week 104 (Study 098 only). There was no statistical testing for long-term efficacy analysis up to week 52 or week 104; descriptive statistics were provided by randomized treatment-group sequences: placebo group → upadacitinib 15 mg once-daily group; and upadacitinib 15 mg once daily group → upadacitinib 15 mg once-daily group.

Analysis Populations

The following analysis populations were used for the analyses in both Study 944 and Study 098. The FAS includes all randomized patients who received at least 1 dose of the study drug. Patients were included in the analysis based on the treatment group as randomized. The FAS was used for all efficacy and baseline analyses. The per-protocol analysis set represents a subset of the FAS consisting of all FAS patients who did not have any major protocol violations that affected the primary efficacy analysis. The primary end point was also analyzed in the per-protocol analysis set. The final criteria and the exclusion of patients from the per-protocol analysis set was finalized before unblinding for the primary analysis. The safety analysis set consists of all patients who received at least 1 dose of the study drug. For the safety analysis set, patients were assigned to a treatment group based on the treatment actually received, regardless of the treatment randomized. Unless otherwise specified, efficacy and health outcomes analyses were conducted on the FAS (equivalent to the ITT population).

Data Imputation Methods

For missing data, it was assumed that they were missing at random. The following methods for imputation of missing data were used for analyses for the double-blind phase:

• Nonresponder imputation (NRI): Analyses of categorical efficacy outcomes were assessed using an NRI method. Patients were considered nonresponders for the NRI analysis if they did not meet the clinical response criteria, without at least 1 postbaseline observation, had missing clinical response data at the week 14 or discontinued study drug at any time before week 14 for any reason.

• Multiplicity adjustment: a multiple testing procedure (i.e., the Hochberg procedure) was used to control the family-wise type I error rate at a 2-sided alpha level of 0.05. The multiplicity-controlled secondary end points (also known as key or main secondary outcomes) at week 14 are presented Table 28 for Study 944 and Table 29 in Study 098 in Appendix 3.

Subgroup Analyses

In Study 944, key subgroup analysis (subgroups of interest for this review) for the primary outcome (ASAS40) were based on patients’ prior experience with bDMARDs (i.e., TNFi and IL-17i drugs).

Sensitivity Analyses

In both Study 944 and Study 098, sensitivity analysis (i.e., analysis as observed [AO], AO with nonresponder imputation [AO-NRI] and AO with multiple imputation [AO-MI]) for ASAS40 were conducted.

Table 11: Statistical Analysis of Efficacy End Points in Study 944 and Study 098

ANCOVA = analysis of covariance; AO = as observed; hsCRP = high-sensitivity C-reactive protein; MI = multiple imputation; MMRM = mixed-effect model for repeated measures; NRI = nonresponder imputation; ULN = upper limit of normal; vs. = versus.

Sources: Study Clinical Study Reports^15,36 and Study 098 Clinical Study Reports.^14,37

Results

Patient Disposition

Patient disposition for Study 944 and Study 098 are presented in Table 12. In the Study 944, 1,352 patients were screened. A total of 420 were randomized. Of the 420 randomized patients, 211 received upadacitinib (i.e., 15 mg orally once daily) and 209 received placebo (i.e., FAS population); all patients received at least 1 dose of the treatment (i.e., the FAS population is equivalent to the ITT population). Of the FAS population, 97.6% of the patients in the upadacitinib group and 97.1% of patients in the placebo group completed the study. The proportions of patients who discontinued from the study were 2.4% in the upadacitinib group and 2.9% in the placebo group. Discontinuations were due to AEs (upadacitinib versus placebo: 0% versus 1.4%, respectively); withdrawal by patient (upadacitinib versus placebo: 0.9% versus 0.5%); lost to follow-up (upadacitinib versus placebo: 0.5% versus 0.5%); lack of efficacy (upadacitinib versus placebo: 0.5% versus 0.5%); COVID-19 logistical restrictions (upadacitinib versus placebo: 0.5% versus 0.0%), and other (upadacitinib versus placebo: 1.4% versus 0.5%).

In the Study 098, a total of 395 patients were screened and 187 were randomized. Of the 187 randomized patients, 93 received upadacitinib (i.e., 15 mg orally once daily) and 94 received placebo (i.e., the FAS population); All patients received at least 1 dose of the treatment. Of the FAS population, 95.7% of the patients in the upadacitinib group and 94.7% of the patients in the placebo group completed the study. The proportions of patients who discontinued from the study were 4.3% in the upadacitinib group and 5.3% in the placebo group. Discontinuations were due to AEs (upadacitinib versus placebo: 2.2% versus 3.2%, respectively); withdrawal by patient (upadacitinib versus placebo: 2.2% versus 1.1%); lost to follow-up (upadacitinib versus placebo: 0.0% versus 1.1%), and other upadacitinib versus placebo: 1.1% versus 1.15%).

In Study 944, ||||| |||||||| || |||| |||||||||||| ||| ||||||| ||||| |||||||| ||| |||| ||||| ||||||||| |||||| | ||||| || ||||| |||||||| || |||||||||||| ||||| ||| ||||| || ||||||| ||||| ||||||||| ||| ||||| |||| || |||| ||| ||| |||||||| |||| ||| |||| ||| ||| ||| ||||||||| || ||| |||| || |||| ||||||| In Study 098, 95.7% patients in the upadacitinib group and 94.7% of the placebo group entered the open-label extension phase. A total of 83.9% of the upadacitinib group and 87.2% of the placebo group completed the study drug at week 64 (no information was provided for week 52). In addition, 76.3% of patients in the upadacitinib group and 77.7% of patients in the placebo group completed the study drug at week 104 (Table 12).

Exposure to Study Treatments

At week 14, in Study 944, the mean treatment durations were |||| |||| ||||||| |||| || || |||| in the upadacitinib group and |||| |||| ||||||| |||| | || ||| ||||| in the placebo group. In Study 098, the mean treatment durations ||| |||| |||| ||||||| |||| | || |||| in the upadacitinib group and |||| |||| ||||||| |||| || || ||| ||||| in the placebo group. In both studies, ||| |||||| || |||||||| ||| ||||||| |||||| ||| ||||||||| ||||||| ||||||||| |||||||| |||||| ||| ||||||||| ||||| |||| ||||| |||| || |||| || || ||||| |||| ||||| ||||| ||| ||||| |||| ||| ||||| ||| || |||| || ||| |||| ||| |||||||||||| (Table 13 and Table 14).

Table 12: Patient Disposition

NR = not reported; q.d. = once daily.

^a.Patients who discontinued the study drug are counted under each reason given for discontinuation; the sum of the counts given for the reasons therefore may be greater than the overall number of discontinuations.

Sources: Study 0944 Clinical Study Reports^15,36 and Study 098 Clinical Study Reports.^14,37

Table 13: Extent of Exposure (Safety Analysis Set)

DB = double-blind; PBO = placebo; q.d. = once daily; SD = standard deviation; UPA = upadacitinib.

Sources: Study 0944 Clinical Study Reports^15,36 and Study 098 Clinical Study Reports.^14,37

Table 14: Extent of Exposure (Long-term, period 2, Safety Analysis Set)

DB = double-blind; PBO = placebo; q.d. = once daily; SD = standard deviation; UPA = upadacitinib.

Sources: Study 0944 Clinical Study Reports^15,36 and Study 098 Clinical Study Reports.^14,37

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported here. Appendix 3 provides detailed efficacy data.

Clinical Response

Primary Analysis

The primary outcome in both Study 944 and Study 098 was ASAS40 at week 14. The results of ASAS40 are presented in Table 15, Figure 4, and Figure 5.

In Study 944, in the primary analysis (i.e., the FAS), the proportions of patients achieving ASAS40 were 44.5% and 18.2% in the upadacitinib (15 mg, oral, once daily) and placebo groups, respectively. The mean between-groups difference (upadacitinib versus placebo) was 26.4% (95% CI, 17.9% to 34.9%; P < 0.0001). || ||| |||||||| ||||||||| ||| |||| || |||| ||||||| ||||| |||||||||| ||||| |||| ||| |||||| |||||| ||||| || |||||| |||||||||| ||||| ||| |||||||||| |||| ||| ||||||| || ||| ||||||| |||||||| |||| ||| ||| |||||||||| |||| ||||| |||| The subgroup analysis showed that the proportion of patients achieving ASAS40 |||| ||||| ||| ||||| || |||||||||||| |||| ||| ||| ||||||| |||||||||||| || |||||||| ||||||||||| ||| ||| ||||||||| |||||| ||| ||||| ||| |||| || |||||||||||| |||| ||| ||| ||||||| |||||||||||| || |||||||| ||||||||||| ||| ||||| ||||||||| |||||. Other sensitivity analysis (i.e., AO, AO-NRI, and AO-MI) for ASAS40 were also reportedly |||||||||| |||| ||| ||||||| || ||| ||||||| |||||||| |||||| |||| |||| ||||| Table 15 and Figure 4).

In Study 098, in the primary analysis (i.e., the FAS), the proportions of patients achieving ASAS40 were 51.6% and 25.5% in the upadacitinib (15 mg, oral, once daily) and placebo groups, respectively. The mean between-groups difference (upadacitinib versus placebo) was 26.1% (95% CI, 12.6% to 39.5%; P < 0.001). || ||| |||||||| ||||||||| ||| |||| || |||| ||||||| ||||| |||||||||| ||||| |||| ||| |||||| |||||| |||| || |||||| ||||||||| ||||| ||| |||||||||| |||| ||| ||||||| || ||| ||||||| |||||||| |||| ||| ||| |||||||||| (Table 15). Other sensitivity analysis (i.e., AO, AO-NRI, and AO-MI for ASAS40 |||| |||| |||||||||| |||||||||| |||| ||||||| || ||| ||||||| |||||||| |||||| |||| |||| |||| (Table 15 and Figure 5).

Table 15: ASAS40 Response at Week 14

AO = as observed; ASAS40 = Assessment of SpondyloArthritis international Society 40% improvement; CI = confidence interval; FAS = full analysis set; IL-17 = interleukin-17; MI = multiple imputation; NA = not applicable; NR = not reported; NRI = nonresponder imputation; PBO = Placebo; q.d. = once daily; TNF = tumour necrosis factor; UPA = upadacitinib; vs. = versus.

Note: NRI-MI is nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19.

^an is calculated by N and MI-aggregated response rate (%).

^bTreatment difference, associated CI, and P values for tests of differences between the UPA and PBO groups were constructed based on the MI inference. Risk difference and standard error were estimated using a Cochran-Mantel-Haenszel test and screening high-sensitivity C-reactive protein status as a stratification factor within each imputed “complete” dataset, after which Rubin’s rule was used to combine the results from 30 imputed “complete” datasets to produce an aggregated treatment difference, associated CI, and P value.

Sources: Study 944, week 14 Clinical Study Report^14,36 and Study 098 week 14 Clinical Study Report.^15,37

Figure 4: ASAS40 Response at Week 14 — Study 944 (NRI-MI, Full Analysis Set)

ASAS40 = Assessment of SpondyloArthritis international Society 40% improvement; MI = multiple imputation; NRI = nonresponder imputation; QD = once daily.

Note: Nominal P ≤ 0.05 at weeks 4 to 12 and P < 0.0001 at week 14.

Sources: Study 944, week 14 Clinical Study Report.¹⁴

Figure 5: ASAS40 Response at Week 14 — Study 098 (NRI, Full Analysis Set) — Redacted

ASAS40 = Assessment of SpondyloArthritis international Society 40% improvement; NRI = nonresponder imputation.

Notes: Nominal P < 0.001 at each time point.

This figure has been removed at the request of the sponsor.

Source: Study 098 week 14 Clinical Study Report.¹⁵

ASAS40 Subgroup Analysis

In Study 944, the subgroup analysis showed that the proportions of patients achieving ASAS40 at week 14 |||| ||||| ||| ||||| in the upadacitinib and placebo groups, respectively, among patients with experienced with 1 TNFi; and ||||| ||| |||| in the upadacitinib and placebo groups, respectively, among patients with experienced with 1 IL-17i (refer to Table 15).

No subgroup analysis of the interest in this review was reported in Study 098.

Sensitivity Analysis

In both study 944 and Study 098, sensitivity analysis (i.e., AO, AO-NRI, and AO-MI) for ASAS40 |||| |||| |||||||||| |||||||||| |||| ||||||| || ||| ||||||| |||||||| |||||| |||| |||| (Table 15).

Extension Period at Week 52

In Study 944, the proportions of patients who achieved ASAS40 were ||||| || ||| ||||| ||| ||||| || ||||||| to the upadacitinib group, respectively. In Study 098, the proportions of patients who achieved ASAS40 were 69.9% in the upadacitinib group and 69.1% in the placebo-to- upadacitinib group (refer to Table 15 and Table 30).

Extension Period at Week 104

In Study 098, the proportions of patients who achieved ASAS40 were 65.6% in upadacitinib group and 63.8% in the placebo-to- upadacitinib group (refer to Table 15 and Table 31).

Secondary Outcomes

ASAS20 at Week 14

ASAS20 response was reported as a main secondary outcome (i.e., it was multiplicity-controlled) in both Study 944 and Study 098. The results of ASAS40 at week 14 are presented in Table 16, Figure 6, and Figure 7.

In the FAS analysis of Study 944, the proportions of patients who achieved ASAS20 at week 14 were 65.4% and 38.3% in the upadacitinib (15 mg, oral, once daily) and placebo groups, respectively. The mean between-groups difference (upadacitinib versus placebo) was 27.1% (95% CI, 17.9% to 36.3; P < 0.0001).

In the FAS analysis of Study 098, the proportions of patients who achieved ASAS20 at week 14 were 65.4% and 44.4% in the upadacitinib (15 mg, oral, once daily) and placebo groups, respectively. The mean between-groups difference (upadacitinib versus placebo) was 24.1% (95% CI, 10.2% to 38.0%; P < 0.001).

The multiplicity-adjusted statistical significance results of the main secondary outcomes at week 14 are presented in Table 29 and Table 30 in Appendix 3 for Study 944 and Study 098, respectively.

ASAS 20 — Extension Period at Week 52

In Study 944, the proportion patients who achieved ASAS20 |||| ||||| || |||||||||||| ||||| ||| ||||| || ||||||| || |||||||||||| ||||| |||||||||||||

In Study 098, the proportions of patients who achieved ASAS20 were 76.3% in the upadacitinib group and 84.0% in the placebo-to-upadacitinib group (refer to Table 31).

Extension Period at Week 104

In Study 098, the proportions of patients who achieved ASAS20 were 67.1% in the upadacitinib group and 69.1% in the placebo-to-upadacitinib group (refer to Table 31).

Table 16: Primary and Multiplicity-Controlled Secondary Outcomes at Week 14 (FAS)

AO = as observed; AS = ankylosing spondylitis; ASAS = Assessment of SpondyloArthritis international Society; ASAS5/6 = Assessment in SpondyloArthritis international Society 20% improvement in 5 of 6 domains; ASAS20 = Assessment of SpondyloArthritis international Society 20% improvement; ASAS40 = Assessment of SpondyloArthritis international Society 40% improvement; ASDAS = Ankylosing Spondylitis Disease Activity Score; ASQoL = ankylosing spondylitis quality of life; BASDAI50 = Bath Ankylosing Spondylitis Disease Activity Index 50% improvement; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMI = Bath Ankylosing Spondylitis Metrology Index; CFB = change from baseline; CI = confidence interval; CRP = C-reactive protein; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; FAS = full analysis set;; MASES = Maastricht Ankylosing Spondylitis Enthesitis Score NR = not reported; PBO = placebo; q.d. = once daily; SF-36 = Short Form (36) Health Survey; SIJ = sacroiliac joint; SPARCC = Spondyloarthritis Research Consortium of Canada; UPA = upadacitinib; vs. = versus; WPAI = Work Productivity Activity Impairment.

Note: For Study 098, the ASAS Health Index between-groups difference was not statistically significant because the chain was broken before the ASAS Health Index, and therefore it was not evaluated. Data are percent or mean change from baseline unless noted otherwise. ASDAS low disease activity was defined as ASDAS (CRP) of less than 2.1 and ASDAS inactive disease as ASDAS (CRP) of less than 1.3. Standard deviations of the mean for baseline and week 14 were not available from the sponsor.

^aFor categorical end points, a Cochran-Mantel-Haenszel test was used with nonresponder imputation incorporating multiple imputations to handle missing data due to COVID-19. For continuous end points, a mixed model for repeated measures was used, and N is number of unique patients contributing to model estimates.

^bP value is unadjusted.

^cResults are obtained via the sequential multiple testing procedure controlling the overall type I error rate of all primary and multiplicity-controlled secondary end points at the significance level of 0.05 (2-sided).

Sources: Study 944, week 14 Clinical Study Report,¹⁴ Study 098 week 14 Clinical Study Report,¹⁵ and sponsor’s submission.¹⁶

Figure 6: ASAS20 Response at Week 14 — Study 944 (NRI-MI, Full Analysis Set) — Redacted

ASAS20 = Assessment of SpondyloArthritis international Society 20% improvement; MI = multiple imputation; NRI = nonresponder imputation.

Notes: Nominal P ≤ 0.05 at weeks 1 through 12 and P < 0.0001 at week 14.

This figure has been removed at the request of the sponsor.

Source: Study 944, week 14 Clinical Study Report.¹⁴

Figure 7: ASAS20 Response at Week 14 — Study 098 (NRI, Full Analysis set) — Redacted

ASAS20 = Assessment of SpondyloArthritis international Society 20% improvement; NRI = nonresponder imputation.

Note: This figure has been removed at the request of the sponsor.

Source: Study 098 week 14 Clinical Study Report.¹⁵

ASAS PR Responses at Week 14

ASAS PR response was reported as a main secondary outcome (i.e., it was multiplicity-controlled) in both Study 944 and Study 098. The results of ASAS PR at week 14 are presented in Table 16.

In the FAS analysis of Study 944, the proportions of patients who achieved ASAS PR at week 14 were 17.5% and 4.3% in the 15 upadacitinib mg, oral, once-daily and placebo groups, respectively. The mean between-groups difference (upadacitinib versus placebo) was 13.2% (95% CI, 7.4% to 19.0%; P < 0.0001).

In the FAS analysis of Study 098, the proportions of patients who achieved ASAS PR at week 14 were 19.4% and 1.1% in the upadacitinib 15 mg, oral, once-daily and placebo groups, respectively. The mean between-groups difference (upadacitinib versus placebo) was 18.3% (95% CI, 10.0% to 26.6%, P < 0.001).

ASAS PR — Extension Period at Week 52

|| ||||| |||| ||| |||||||||| |||||||| ||| |||||||| |||| || |||| ||||| || ||| ||||| ||| ||||| || ||||||| || |||||||||||| ||||| |||||||||||||

In Study 098, the proportions of patients achieving ASAS PR were 50.6% in the upadacitinib group and 45.2% in the placebo-to-upadacitinib group (refer to Table 30).

ASAS PR — Extension Period at Week 104

In Study 098, the proportions of patients who achieved ASAS PR were 51.4% in the upadacitinib group and 43.7% in the placebo-to-upadacitinib group (refer to Table 31).

ASAS5/6 at Week 14

ASAS5/6 response was not reported in Study 944.

In Study 098, ASAS5/6 was reported as an exploratory secondary outcome (i.e., it was not multiplicity-controlled). The results of ASAS5/6 at week 14 are presented in Table 16. || ||| |||| ||| |||||||||| || |||||||| |||||||| |||| ||| |||| |||||||| || ||||| ||| ||||| || ||| |||||||||||| || ||| ||||| || ||| ||||||| ||||| ||||||||||||| ||| |||| ||||||| ||||| |||||||||| ||||| |||| ||| |||||| |||||| ||||| || |||||| ||||||||

ASAS5/6 — Extension Period at Week 52

In Study 944, the proportions of patients who achieved ASAS5/6 were not reported.

In Study 098, the proportions of patients who achieved ASAS5/| |||| ||||| || ||| ||||| ||| ||||| || ||||||| || ||| groups, respectively (refer to Table 30).

ASAS5/6 — Extension Period at Week 104

In Study 098, the proportions of patients who achieved ASAS5/6 were |||| | || ||| ||||| ||| ||||| || ||||||| to the upadacitinib group, respectively (refer to Table 31).

Measures of Ankylosing Spondylitis Symptoms

The results of the AS symptom measures at week 14 (i.e., total back pain, nocturnal back pan, and fatigue) are presented in Table 16.

Total Back Pain at Week 14

Total back pain is 1 of the 6 ASAS criteria components. It was assessed as a main secondary outcome in Study 944 and an exploratory outcome in Study 098.

In Study 944, at week 14, the means of changes from baseline for total back pain were −3.00 (95% CI, −3.30 to −2.70) and −1.47 (95% CI, −1.77 to −1.16) in the upadacitinib (15 mg, oral, once daily) and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −1.53 (95% CI, −1.96 to −1.11; P < 0.0001).

In Study 098, at week 14, the means of changes from baseline for total back pain were ||||| ||||||| |||||| and ||||| ||||||| |||||| in the upadacitinib (15 mg, oral, once daily) and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was |||||| |||||| ||||| || |||||| ||||||||

Total Back Pain Change From Baseline — Extension Period at Week 52

|| ||||| |||| ||| ||||| |||| |||| ||| |||| ||||||| |||| ||||| |||||| || | |||| || ||| ||||| ||| ||||| |||||| || |||||| || ||||||| || ||| ||||| |||||||||||||

In Study 098, the total back pain CFB means were −4.48 |||||| || |||||| in the upadacitinib group and −4.52 |||||| || |||||| in the placebo-to-upadacitinib group (refer to Table 31).

Total Back Pain Change From Baseline — Extension Period at Week 104

In Study 098, the total back pain CFB means were −4.40 |||||| || |||||| in the upadacitinib group and −4.30 |||||| || |||||| in the placebo-to-upadacitinib group (refer to Table 31).

Nocturnal Back Pain at Week 14

Nocturnal back pain was assessed as a main secondary outcome in Study 944 and an exploratory outcome in Study 098.

In Study 944, at week 14, the means of changes from baseline for nocturnal back pain were −3.21 (95% CI, −3.52 to −2.89) and −1.52 (95% CI, −1.84 to −1.20) in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was −1.69 (95% CI, −2.14 to −1.24; P < 0.0001).

In Study 098, at week 14, the means of changes from baseline for nocturnal back pain were |||||||||||| |||||| ||| ||||| ||||||| |||||| in the upadacitinib and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was ||||| |||||| || ||||||| |||||| ||||| || |||||| ||||||||

Nocturnal Back Pain Change From Baseline — Extension Period at Week 52

|| ||||| |||| ||| ||||||||| |||| |||| ||| |||| ||||||| |||| ||||| |||||| || |||||| || ||| ||||| ||| ||||||||||| || |||||| || ||||||| || |||||||||||| ||||| |||||||||||||

In Study 098, the nocturnal back pain change from baseline means (95% CI) were −4.47 |||||| || |||||| in the upadacitinib group and −4.64 |||||| || | |||| in the placebo-to-upadacitinib group (refer to Table 31).

Nocturnal Back Pain Change From Baseline — Extension Period at Week 104

In Study 098, the total nocturnal Back Pain change from baseline means (95% CI) were −4.32 |||||| || | ||||| in the upadacitinib group and −4.59 |||||| || |||||| in the placebo-to-upadacitinib group (refer to Table 31).

Fatigue at Week 14

Fatigue was assessed with FACIT-F as an exploratory outcome in both Study 944 and Study 098.

In Study 944, at week 14, the means of changes from baseline for FACIT-F were |||| |||||| ||||| ||| |||| |||||| ||||) in the upadacitinib 15 mg, oral, once-daily and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) was ||||| |||||| |||| || ||||| |||||||||

In Study 098, at week 14, the means of changes from baseline for FACIT-F were |||| | ||||| ||||| and |||| |||||| ||||| in the upadacitinib 15 mg, oral, once-daily and placebo groups, respectively. The mean between-groups difference in change from baseline (upadacitinib versus placebo) ||| ||||| |||||| |||| || ||||| ||||||.

FACIT-F Change From Baseline — Extension Period at Week 52