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- Three Janssen-sponsored phase 3, multicenter, randomized, double-blind, placebocontrolled studies evaluating the efficacy and safety of STELARA in patients with active axial spondyloarthritis (SpA; radiographic or nonradiographic) were discontinued due to STELARA not achieving the primary and major secondary endpoints in study 1.1
- Through week 24, the proportions of patients experiencing adverse events (AEs) in the STELARA treatment groups were consistent across all treatment groups in all 3 studies. There were no new safety signals identified during these studies.
- The TOPAS (UsTekinumab for the Treatment Of Patients with Active Ankylosing Spondylitis) trial evaluated the efficacy and safety of STELARA in patients with active ankylosing spondylitis (AS) despite nonsteroidal antiinflammatory drug (NSAID) treatment. In this prospective, open-label, single-arm, proof-of-concept study, 65% of patients achieved the primary endpoint, improvement of ≥40% and ≥2 units in at least 3 domains according to the Assessment of SpondyloArthritis International Society 40 (ASAS40) criteria at week 24. A total of 92 AEs of mild-moderate severity occurred in the study. No AEs led to discontinuation.2
Deodhar et al (2019)1 evaluated the efficacy and safety of STELARA in patients with axial spondyloarthritis (SpA; radiographic or nonradiographic) in 3 Janssen-sponsored, phase 3, multicenter, randomized, double-blind, placebo-controlled studies.
- Study 1 included patients with radiographic axial SpA who had an inadequate response to or were intolerant of NSAIDs and who were naive to anti-tumor necrosis factor (TNF) treatment. A week 24 analysis of study 1 was planned to determine continuation of studies 2 and 3.
- Study 2 included patients with radiographic axial sPA who were refractory (defined as having an inadequate response or intolerance) to a single anti-TNF agent.
- Study 3 included patients with nonradiographic axial SpA who had an inadequate response to or were intolerant of NSAIDs and who could have been exposed to a single anti-TNF agent.
- In all 3 studies, patients were randomized 1:1:1 to receive subcutaneous (SC) STELARA 45 mg or 90 mg at weeks 0, 4, and 16 and then every 12 weeks or to receive placebo at weeks 0, 4, and 16. Patients in the placebo treatment group were then rerandomized at week 24 to receive either STELARA 45 mg or 90 mg at weeks 24 and 28 and then every 12 weeks.
- In studies 1 and 2, patients in the 3 treatment groups who qualified for early escape (<10% improvement from baseline in both total back pain and morning stiffness measures at both week 12 and week 16) received open-label SC golimumab 50 mg at week 16 and every 4 weeks thereafter through week 52. Safety evaluations were assessed at week 64 (in study 2) and at week 112 (in study 1).
- In study 3, patients in the placebo treatment group that met the early escape criteria were to be rerandomized blindly at week 16 to receive either SC STELARA 45 mg or 90 mg at weeks 16, 20, 28, and every 12 weeks thereafter through week 52. At week 24, all the remaining placebo-treated patients crossed over to receive either STELARA 45 mg or 90 mg at weeks 24 and 28, then every 12 weeks. All patients with inactive disease at both weeks 40 and 52 were to be rerandomized at week 52 to keep receiving STELARA or switch to placebo. The study was to continue to week 100.
- The primary endpoint in studies 1 and 2 was the proportion of patients that achieved an Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (ASAS40) response at week 24 and in study 3, the primary endpoint was the proportion of patients who achieved an Assessment of SpondyloArthritis international Society criteria for 20% improvement in disease activity (ASAS20) response at week 24.
- The major secondary endpoints included the proportions of patients that achieved an ASAS20 response in studies 1 and 2 and an ASAS40 response in study 3, the proportion of patients with 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) response, change from baseline in the Bath Ankylosing Spondylitis Functional Index (BASFI), and the proportion of patients with inactive disease according to the Ankylosing Spondylitis Disease Activity Score using the CRP level (an ASDAS-CRP, score <1.3).
- Of the 2062 patients that were screened, 1018 patients were randomized, and 1017 patients were treated.
- In studies 1 and 2, most of the patients were male (85% and 83%, respectively) and Caucasian (73% and 79%, respectively).
- In studies 1 and 2, the mean age was 39.0 and 41.2 years, and the mean duration of inflammatory back pain (IBP) was 10.8 and 14.3 years, respectively.
- In study 3, 51% of patients were male, 85% were Caucasian, the mean age was 34.3 years, and the mean duration of IBP was 4.5 years.
- The primary and major secondary endpoints were not achieved in study 1 and the study was discontinued. As a result, studies 2 and 3 were prematurely discontinued prior to being fully enrolled.
- In study 1, the proportion of patients that achieved an ASAS40 response in the STELARA 45 mg, STELARA 90 mg, and in the placebo groups were 31%, 28%, and 28%, respectively.
- Neither STELARA dose demonstrated an improvement compared to placebo in achieving an ASAS20 response, a BASDAI50 response, and inactive disease according to the ASDAS-CRP, score <1.3, or mean change from baseline in the BASFI.
- In study 2, the proportion of patients that achieved an ASAS40 response in the STELARA 45 mg and 90 mg treatment groups were 19% and 27%, respectively, compared to 12% in the placebo group. Early study discontinuation prohibited valid statistical testing.
- In study 3, the proportion of patients that achieved an ASAS20 response in the STELARA 45 mg and 90 mg groups were 55% and 49%, respectively, versus 48% in the placebo group.
- In all 3 studies, <2.0% of STELARA-treated patients had an injection site reaction; all were considered mild in severity.
- Through week 24 in study 1, 40% of patients in the combined STELARA treatment group and 43% of patients in the placebo group had ≥1 AE.
- Through week 24, no patient in study 1 discontinued due to AEs.
- In the combined STELARA group, 3 patients reported serious AEs (SAE), subdural hematoma, osteoarthritis, and facial paralysis. In the placebo group, 2 patients reported SAEs, ischemic stroke and vertebrobasilar insufficiency.
- The proportion of patients reporting AEs through week 24 in the combined STELARA groups, in studies 2 and 3 were similar to the proportion of patients in study 1.
- In study 2, discontinuation due to an AE through week 24 occurred in 3 STELARA treated patients reporting worsening of AS, arthralgia, and back pain and in 1 patient in the placebo group reporting back and musculoskeletal pain. Ten serious AEs, which included upper abdominal pain, nausea, vomiting, obesity, uterine polyp, gastrointestinal hemorrhage, cholelithiasis, worsening of AS, rotator cuff syndrome, and cerebrovascular accident, were reported in 7 patients in the combined STELARA group. Three serious AEs, which included uterine prolapse, back pain, and myocardial ischemia, were reported in 3 patients in the placebo group.
- Through week 24 in study 3, 1 STELARA treated patient discontinued due to pustular psoriasis. During this period, serious AEs were reported in 3 STELARA treated patients (inguinal hernia, chronic sinusitis, and ankle fracture) and 2 patients in the placebo group (uveitis and worsening of axial SpA).
- In all 3 studies, no patient died, experienced a serious or opportunistic infection, or presented with malignancy or active tuberculosis.
Poddubnyy et al (2014)2 evaluated the efficacy and safety of STELARA in adult patients with active AS, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥4, despite NSAID treatment (without NSAID if there was intolerance/contraindication).
- In this prospective, open-label, single-arm, proof-of-concept, 28-week study, patients received subcutaneous STELARA 90 mg at baseline, week 4, and week 16, with a followup period of 12 weeks.
- The primary study endpoint was the proportion of patients who achieved ASAS40 response at week 24.
- Secondary endpoints included Assessment of SpondyloArthritis International Society 20 (ASAS20) response, improvement of ≥20% in at least 5 out of 6 domains (ASAS5/6 response), a value not above 2 units in each of the 4 domains (Assessment of SpondyloArthritis International Society [ASAS] partial remission), 50% improvement of the BASDAI (BASDAI50), clinically important improvement (change in score ≥1.1) and major improvement (change score ≥2.0) of the C-reactive protein (CRP) based ASAS endorsed AS Disease Activity Score (ASDAS), ASDAS inactive disease state (status score <1.3), the mean improvement in ASDAS, BASDAI, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), patient global assessment, physician global assessment, general and nocturnal pain on the numeric rating scale, CRP level, erythrocyte sedimentation rate (ESR), and achievement of the patient acceptable symptom state and of the physician acceptable symptoms state at week 24.
- Additional secondary outcomes analyzed in patients with peripheral manifestations were swollen joint count and improvement of enthesitis (assessed by Maastricht Ankylosing Spondylitis Enthesitis Score [MASES] and Spondyloarthritis Research Consortium of Canada [SPARCC] enthesitis index).
- The mean age of enrolled patients was 37.5 years and those who were enrolled had a mean AS duration of 13.3 years.
- Of the 22 patients screened for the study, 20 patients were eligible and received STELARA.
- Among the 20 patients that received STELARA, 3 patients discontinued due to lack of efficacy.
Selected Secondary Outcomes at Week 242
|ASAS20 response, n (%)||15 (75)||53-90|
|ASAS5/6 response, n (%)||10 (50)||29-71|
|ASAS partial remission, n (%)||6 (30)||14-53|
|BASDAI50, n (%)||11 (55)||32-77|
|ASDAS clinically important improvementa, %||50||29-71|
|ASDAS major improvementb, %||20||7-41|
|ASDAS inactive disease statec, %||35||15-59|
|Abbreviations: ASAS, Assessment of SpondyloArthritis International Society; ASAS20, Assessment of SpondyloArthritis International Society 20; ASAS5/6, improvement of ≥20% in at least 5 out of 6 domains; ASDAS, ankylosing spondylitis disease activity score; BASDAI50, 50% improvement of the Bath Ankylosing Spondylitis Disease Activity Index; CI, confidence interval.|
aASDAS absolute improvement by ≥1.1 as compared with baseline.
bASDAS absolute improvement ≥2.0.
Changes in the Clinical, Laboratory, and Imaging Parameters Over 24 Weeks in Patients with Active ASa2
|BASDAI, points NRS (mean±SD)||5.3±1.5||3.0±1.8||<0.001|
|BASFI, points NRS (mean±SD)||5.3±1.9||3.0±2.3||<0.001|
|Chest expansion, cm||3.7±1.9||4.4±2.1||0.032|
|MASES enthesitis score (mean±SD)||3.1±3.5||2.5±3.9||0.326|
|SPARCC enthesitis index (mean±SD)||2.9±3.4||2.6±3.0||0.195|
|ASAS NSAIDs intake score (mean±SD)||68.7±37.9||33.3±33.6||0.008|
|Sacroiliac joints osteitis score (mean±SD)b||5.4±4.9||3.2±3.4||0.026|
|Spine osteitis score (mean±SD)||4.1±3.6||2.8±3.0||0.041|
|Abbreviations: AS, ankylosing spondylitis; ASAS, Assessment of SpondyloArthritis International Society; ASDAS, Ankylosing Spondylitis Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BASMI, Bath Ankylosing Spondylitis Metrology Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MASES, Maastricht Ankylosing Spondylitis Enthesitis Score; NRS, numeric rating scale; NSAIDs, nonsteroidal antiinflammatory drugs; SD, standard deviation; SPARCC, Spondyloarthritis Research Consortium of Canada.|
bBerlin magnetic resonance imaging scores, calculated for n=17 patients with complete sets of images.
- Ninety-two AEs of mild-moderate severity occurred in the study. No AEs led to discontinuation.
- Worsening of AS-related back pain which resulted in hospitalization was the only serious AE reported.
- The most common AEs were upper respiratory tract infection (15%), rhinitis (8%), abdominal pain/discomfort (8%), headache (8%), and diarrhea (4%).
- No injection site reactions, serious infections, opportunistic infections, cases of tuberculosis, cases of malignancies, or deaths were reported.
A literature search of Ovid MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 31 October 2022. Summarized in this response are data from phase 3 clinical trials and a prospective proof-of-concept study.
|1|| Deodhar A, Gensler LS, Sieper J. Three multicenter, randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of ustekinumab in axial spondyloarthritis. Arthritis Rheumatol. 2019;71(2):258-270.|
|2|| Poddubnyy D, Hermann K-GA, Callhoff J, et al. Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann Rheum Dis. 2014;73(5):817-823.|