Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study

Abstract

Objective: To assess the efficacy/safety of tofacitinib in adult patients with active ankylosing spondylitis (AS).

Methods: This phase III, randomised, double-blind, placebo-controlled study enrolled patients aged ≥18 years diagnosed with active AS, meeting the modified New York criteria, with centrally read radiographs, and an inadequate response or intolerance to ≥2 non-steroidal anti-inflammatory drugs. Patients were randomised 1:1 to receive tofacitinib 5 mg two times per day or placebo for 16 weeks. After week 16, all patients received open-label tofacitinib until week 48. The primary and key secondary endpoints were Assessment of SpondyloArthritis international Society ≥20% improvement (ASAS20) and ≥40% improvement (ASAS40) responses, respectively, at week 16. Safety was assessed throughout.

Results: 269 patients were randomised and treated: tofacitinib, n=133; placebo, n=136. At week 16, the ASAS20 response rate was significantly (p<0.0001) greater with tofacitinib (56.4%, 75 of 133) versus placebo (29.4%, 40 of 136), and the ASAS40 response rate was significantly (p<0.0001) greater with tofacitinib (40.6%, 54 of 133) versus placebo (12.5%, 17 of 136). Up to week 16, with tofacitinib and placebo, respectively, 73 of 133 (54.9%) and 70 of 136 (51.5%) patients had adverse events; 2 of 133 (1.5%) and 1 of 136 (0.7%) had serious adverse events. Up to week 48, with tofacitinib, 3 of 133 (2.3%) patients had adjudicated hepatic events, 3 of 133 (2.3%) had non-serious herpes zoster, and 1 of 133 (0.8%) had a serious infection; with placebo→tofacitinib, 2 (1.5%) patients had non-serious herpes zoster. There were no deaths, malignancies, major adverse cardiovascular events, thromboembolic events or opportunistic infections.

Conclusions: In adults with active AS, tofacitinib demonstrated significantly greater efficacy versus placebo. No new potential safety risks were identified.

Trial registration number: NCT03502616.

Keywords: ankylosing; antirheumatic agents; spondylitis; therapeutics.

Conflict of interest statement

Competing interests: AD has received grant/research support from AbbVie, Boehringer Ingelheim, Eli Lilly, GSK, Novartis, Pfizer Inc and UCB, and is a consultant for AbbVie, Amgen, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Galapagos, Gilead Sciences, GSK, Janssen, Novartis, Pfizer Inc and UCB. PS-S and HX have no competing interests to declare. XB is a consultant for AbbVie, Amgen, BMS, Celgene, Eli Lilly, Gilead Sciences, Janssen, MSD, Novartis, Pfizer Inc and UCB. LSG has received grant/research support from Pfizer Inc and UCB, and is a consultant for AbbVie, Eli Lilly, Gilead Sciences, GSK, Novartis and UCB. DF, LW, JW, SM, CW, OD, LF and KSK are employees and shareholders of Pfizer Inc. DvdH is a consultant for AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eli Lilly, Galapagos, Gilead Sciences, GSK, Janssen, Merck, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi, Takeda and UCB, and is Director of Imaging Rheumatology BV.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Patient disposition. Data are from the week 48 final analysis. Patients receiving placebo in the double-blind phase advanced at week 16 to tofacitinib 5 mg two times per day for the open-label phase. aOne additional patient was screened and was considered to be not eligible; this patient did not provide any demographic data and is therefore not included in the formal patient disposition. bDMARD, biologic disease-modifying antirheumatic drug; BID, two times per day.

Figure 2

Efficacy of tofacitinib 5 mg two times per day versus placebo→tofacitinib 5 mg two times per daya over time up to week 48: (A) ASAS20 responseb and (B) ASAS40 response.b Data up to week 16 are from the week 16 analysis: data cut-off 19 December 2019; data snapshot 29 January 2020. Data for weeks 24–48 are from the week 48 final analysis. ***p<0.001 for comparing tofacitinib 5 mg two times per day versus placebo. †p≤0.05 for comparing tofacitinib 5 mg two times per day versus placebo, according to the prespecified step-down testing procedure for global type I error control. ‡p≤0.05 for comparing tofacitinib 5 mg two times per day versus placebo, according to the prespecified step-down testing procedure for type I error control of ASAS response over time. aPatients receiving placebo advanced to tofacitinib 5 mg two times per day at week 16 (dashed line). bUp to week 16, response rate was tested in hierarchical sequence to control for type I error: weeks 16, 12, 8, 4 and 2. Statistical significance could be declared only if the prior time points in the sequence met the requirements for significance (p≤0.05). After week 16, there was no type I error control. Normal approximation adjusting for the stratification factor (bDMARD treatment history: bDMARD-naïve vs TNFi-IR or prior bDMARD use without IR) derived from the clinical database via the Cochran-Mantel-Haenszel approach was used. Missing response was considered as non-response. ASAS, Assessment of SpondyloArthritis international Society; ASAS20, ASAS ≥20% improvement; ASAS40, ≥40% improvement; bDMARD, biologic disease-modifying antirheumatic drug; BID, two times per day; IR, inadequate response or intolerance; N, number of patients in full analysis set; TNFi, tumour necrosis factor inhibitor.

Figure 3

Efficacy of tofacitinib 5 mg two times per day versus placebo→tofacitinib 5 mg two times per daya over time up to week 48: (A) ∆ASDAS,b (B) ∆hsCRP (mg/dL),b (C) ∆BASMIb and (D) ∆FACIT-F total score.b Data up to week 16 are from the week 16 analysis: data cut-off 19 December 2019; data snapshot 29 January 2020. Data for weeks 24–48 are from the week 48 final analysis. ***p<0.001 for comparing tofacitinib 5 mg two times per day versus placebo. †p≤0.05 for comparing tofacitinib 5 mg two times per day versus placebo, according to the prespecified step-down testing procedure for global type I error control. aPatients receiving placebo advanced to tofacitinib 5 mg two times per day at week 16 (dashed line). bMixed model for repeated measures included fixed effects of treatment group, visit, treatment group by visit interaction, stratification factor (bDMARD treatment history: bDMARD-naïve vs TNFi-IR or prior bDMARD use without IR) derived from the clinical database, stratification factor by visit interaction, baseline value, and baseline value by visit interaction. The model used a common unstructured variance–covariance matrix, without imputation for missing values. Two separate models were used. In the analyses of results through the first 16 weeks, the data cut-off of 19 December 2019 was used; the results through week 16 are from this model. In the analyses of the results through week 48 (including all post-baseline data through week 48), the week 48 final data were used; the results from week 24 through week 48 are from this model. ∆, change from baseline; ASDAS, Ankylosing Spondylitis Disease Activity Score using hsCRP; BASMI, Bath Ankylosing Spondylitis Metrology Index; bDMARD, biologic disease-modifying antirheumatic drug; BID, two times per day; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; hsCRP, high-sensitivity C-reactive protein; IR, inadequate response or intolerance; LSM, least squares mean; N, number of patients in full analysis set; N1, number of patients with observation at visit; TNFi, tumour necrosis factor inhibitor.