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.

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 day^a over time up to week 48: (A) ASAS20 response^b 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 day^a over time up to week 48: (A) ∆ASDAS,^b (B) ∆hsCRP (mg/dL),^b (C) ∆BASMI^b 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.