A Phase 3 Randomized, Placebo-Controlled, Double-Blind Program to Evaluate Efficacy and Safety of Upadacitinib in Adult Subjects With Axial Spondyloarthritis Followed by a Remission-Withdrawal Period
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Enrollment
- 734
- Locations
- 212
- Primary Endpoint
- Study 1: Percentage of Participants Achieving Assessment of SpondyloArthritis International Society 40 (ASAS40) Response at Week 14
Study Overview
Brief Summary
This protocol includes 2 standalone studies with randomization, data collection, analysis and reporting conducted independently.
The main objectives of this protocol are:
- To evaluate the efficacy of upadacitinib compared with placebo on reduction of signs and symptoms in adults with active axial spondyloarthritis (axSpA) including biologic disease-modifying antirheumatic drug inadequate responders (bDMARD-IR) ankylosing spondylitis (AS) (Study 1) and non-radiographic axial spondyloarthritis (nr-axSpA) (Study 2).
- To assess the safety and tolerability of upadacitinib in adults with active axSpA including bDMARD-IR AS (Study 1) and nr-axSpA (Study 2).
- To evaluate the safety and tolerability of upadacitinib in extended treatment in adult participants with active axSpA including bDMARD-IR AS who have completed the Double-Blind Period (Study 1) and nr-axSpA who have completed the Double-Blind Period (Study 2).
- To evaluate the maintenance of disease control after withdrawal of upadacitinib.
Detailed Description
Study 1 (bDMARD-IR AS) is comprised of a 14-week randomized, double-blind, parallel-group, placebo-controlled period (the Double-Blind Period); a 90-week open-label, long-term extension period (the Open-Label Extension Period); and a 30-day Follow-Up Visit (F/U Visit).
Study 2 (nr-axSpA) is comprised of a 52-week randomized, double-blind, parallel-group, placebo-controlled period (the Double-Blind Period); a 52-week open-label, long-term extension period (the Open-Label Extension Period); and a 30-day F/U Visit.
In the Double-Blind Period for both studies, participants are randomized in a 1:1 ratio to receive either upadacitinib or placebo once daily (QD).
Participants in the placebo group switch to upadacitinib 15 mg QD at Week 14 in the Open-Label Extension Period for Study 1 (bDMARD-IR AS) and Week 52 in the Open-Label Extension Period for Study 2 (nr-axSpA).
Participants in remission at Week 104 have the option to enroll in a remission-withdrawal period.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Must have a clinical diagnosis of ankylosing spondylitis (AS) and meet the modified New York Criteria for AS,
- •Must not have total spinal ankylosis
- •Must have been previously exposed to 1 or 2 bDMARDs (at least 1 tumor necrosis factor [TNF] inhibitor or 1 interleukin [IL]-17 inhibitor [IL-17i]), and must have discontinued the bDMARD therapy due to either lack of efficacy (after at least 12 weeks of treatment with a bDMARD at an adequate dose) or intolerance (irrespective of treatment duration). Prior exposure to two bDMARDs was allowed for no more than 30% of patients; among patients with prior exposure to two bDMARDs, a lack of efficacy to one bDMARD and intolerance to another was permitted, but a patient could not have a lack of efficacy to two bDMARDs
- •Must have a clinical diagnosis of nr-axSpA fulfilling the 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA but not meeting the radiologic criterion of the modified New York criteria for AS
- •Must have objective signs of active inflammation consistent with axSpA on magnetic resonance imaging (MRI) of sacroiliac (SI) joints or based on high sensitivity C-reactive protein (hsCRP) > the upper limit of normal (ULN).
- •Prior treatment with at most one bDMARD (either TNF inhibitor or IL-17i) is allowed for at least 20% but no more than 35% of enrolled patients who had to discontinue the prior bDMARD due to either lack of efficacy (after ≥ 12 weeks at an adequate dose) or intolerance (regardless of treatment duration).
- •Must have a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 at the Screening and Baseline Visits.
- •Must have a Total Back Pain score ≥ 4 based on a 0 - 10 numerical rating scale at the Screening and Baseline Visits.
- •Has had an inadequate response to at least 2 nonsteroidal anti-inflammatory drugs (NSAIDs) over an at least 4-week period in total at maximum recommended or tolerated doses, or has an intolerance to or contraindication for NSAIDs as defined by the Investigator.
Exclusion Criteria
- •Must not have been exposed to any Janus kinase (JAK) inhibitor (including but not limited to upadacitinib [Rinvoq®], tofacitinib [Xeljanz®], baricitinib [Olumiant®], filgotinib, ruxolitinib [Jakafi®], abrocitinib [PF-04965842], and peficitinib [Smyraf®]).
- •Prior bDMARD therapy must be washed out.
- •Participant must not have a history of an allergic reaction or significant sensitivity to constituents of the study drug.
Arms & Interventions
Study 1: Placebo
Participants receive matching placebo for 14 weeks and then switch to receive 15 mg upadacitinib orally once a day for 90 weeks. Participants who flare after 104 weeks will receive open-label upadacitinib once daily from the time of flare for 24 weeks (re-treatment).
Intervention: Upadacitinib (Drug)
Study 1: Upadacitinib 15 mg
Participants receive 15 mg upadacitinib orally once a day for 104 weeks. Participants who flare after 104 weeks will receive open-label upadacitinib once daily from the time of flare for 24 weeks (re-treatment).
Intervention: Upadacitinib (Drug)
Study 1: Placebo
Participants receive matching placebo for 14 weeks and then switch to receive 15 mg upadacitinib orally once a day for 90 weeks. Participants who flare after 104 weeks will receive open-label upadacitinib once daily from the time of flare for 24 weeks (re-treatment).
Intervention: Placebo (Drug)
Study 2: Upadacitinib 15 mg
Participants receive 15 mg upadacitinib orally once a day for 104 weeks. Participants who flare after 104 weeks will receive open-label upadacitinib once daily from the time of flare for 24 weeks (re-treatment).
Intervention: Upadacitinib (Drug)
Study 2: Placebo
Participants receive matching placebo for 52 weeks and then switch to receive 15 mg upadacitinib orally once a day for 52 weeks. Participants who flare after 104 weeks will receive open-label upadacitinib once daily from the time of flare for 24 weeks (re-treatment).
Intervention: Upadacitinib (Drug)
Study 2: Placebo
Participants receive matching placebo for 52 weeks and then switch to receive 15 mg upadacitinib orally once a day for 52 weeks. Participants who flare after 104 weeks will receive open-label upadacitinib once daily from the time of flare for 24 weeks (re-treatment).
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Study 1: Percentage of Participants Achieving Assessment of SpondyloArthritis International Society 40 (ASAS40) Response at Week 14
Time Frame: Baseline and Week 14
ASAS40 response was defined as improvement of ≥ 40% relative to Baseline and absolute improvement of ≥ 2 units (on a scale from 0 to 10) in ≥ 3 of the following 4 domains with no deterioration (defined as a net worsening of \> 0 units) in the potential remaining domain: * Patient's global assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (no activity) to 10 (severe activity); * Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe pain); * Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which consists of 10 items assessing participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible); * Inflammation, measured by the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 \[level of stiffness\] and 6 \[duration of stiffness\]) each on a scale from 0 (none/0 hours) to 10 (very severe/2 hours or more duration).
Study 2: Percentage of Participants Achieving an ASAS40 Response at Week 14
Time Frame: Baseline and Week 14
ASAS40 response was defined as improvement of ≥ 40% relative to Baseline and absolute improvement of ≥ 2 units (on a scale from 0 to 10) in ≥ 3 of the following 4 domains with no deterioration (defined as a net worsening of \> 0 units) in the potential remaining domain: * Patient's global assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (no activity) to 10 (severe activity); * Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe pain); * Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which consists of 10 items assessing participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible); * Inflammation, measured by the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 \[level of stiffness\] and 6 \[duration of stiffness\]) each on a scale from 0 (none/0 hours) to 10 (very severe/2 hours or more duration).
Secondary Outcomes
- Study 1: Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 14(Baseline and Week 14)
- Study 1: Percentage of Participants With Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Response at Week 14(Baseline and Week 14)
- Study 1: Percentage of Participants With ASDAS Inactive Disease at Week 14(Week 14)
- Study 1: Change From Baseline in Patient's Assessment of Nocturnal Back Pain at Week 14(Baseline and Week 14)
- Study 1: Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) Score at Week 14(Baseline and Week 14)
- Study 2: Percentage of Participants With ASDAS Inactive Disease at Week 52(Week 52)
- Study 1: Change From Baseline in Magnetic Resonance Imaging (MRI) Spondyloarthritis Research Consortium of Canada (SPARCC) Score for the Spine at Week 14(Baseline and Week 14)
- Study 1: Change From Baseline in Linear Bath Ankylosing Spondylitis Metrology Index (BASMI[Lin]) at Week 14(Baseline and Week 14)
- Study 1: Percentage of Participants With an ASAS20 Response at Week 14(Baseline and Week 14)
- Study 1: Percentage of Participants With ASDAS Low Disease Activity at Week 14(Week 14)
- Study 1: Change From Baseline in Patient's Assessment of Total Back Pain at Week 14(Baseline and Week 14)
- Study 1: Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 14(Baseline and Week 14)
- Study 1: Percentage of Participants With ASAS Partial Remission at Week 14(Week 14)
- Study 1: Change From Baseline in ASAS Health Index at Week 14(Baseline and Week 14)
- Study 1: Change From Baseline in MRI SPARCC Score for Sacroiliac Joints at Week 14(Baseline and Week 14)
- Study 2: Change From Baseline in MRI SPARCC Score for the Spine at Week 14(Baseline and Week 14)
- Study 2: Percentage of Participants With ASDAS Low Disease Activity at Week 52(Week 52)
- Study 1: Change From Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at Week 14(Baseline and Week 14)
- Study 2: Change From Baseline in MRI SPARCC Score for SI Joints at Week 14(Baseline and Week 14)
- Study 2: Percentage of Participants With BASDAI 50 Response at Week 14(Baseline and Week 14)
- Study 2: Change From Baseline in Patient's Assessment of Total Back Pain at Week 14(Baseline and Week 14)
- Study 2: Change From Baseline in ASDAS at Week 14(Baseline and Week 14)
- Study 2: Percentage of Participants With ASDAS Inactive Disease at Week 14(Week 14)
- Study 2: Percentage of Participants With ASDAS Low Disease Activity at Week 14(Week 14)
- Study 2: Percentage of Participants With ASAS Partial Remission at Week 14(Week 14)
- Study 2: Change From Baseline in Patient's Assessment of Nocturnal Back Pain at Week 14(Baseline and Week 14)
- Study 2: Change From Baseline in BASFI at Week 14(Baseline and Week 14)
- Study 2: Change From Baseline in ASQoL at Week 14(Baseline and Week 14)
- Study 2: Change From Baseline in ASAS Health Index at Week 14(Baseline and Week 14)
- Study 2: Percentage of Participants Achieving an ASAS20 Response at Week 14(Baseline and Week 14)
- Study 2: Change From Baseline in BASMI(Lin) at Week 14(Baseline and Week 14)
- Study 2: Change From Baseline in MASES at Week 14(Baseline and Week 14)
- Study 2: Percentage of Participants Achieving an ASAS40 Response at Week 52(Baseline and Week 52)
- Study 2: Percentage of Participants Who Initiated Rescue Treatment Between Week 24 and Week 52(Week 24, Week 32, Week 40, and Week 52)
- Study 2: Percentage of Participants With ASDAS Major Improvement at Week 52(Baseline and Week 52)