# Improvement of Fatigue in Patients with Ankylosing Spondylitis Receiving Tofacitinib: Analyses of a Phase 3 Randomized Controlled Trial

Laure Gossec, Jessica Walsh, Raj Sengupta, Andrew Bushmakin, Joseph Cappelleri, Arne Yndestad, Oluwaseyi Dina, David Cella

<figure><img src="image_1.png" /></figure>

## To cite this version:

Laure Gossec, Jessica Walsh, Raj Sengupta, Andrew Bushmakin, Joseph Cappelleri, et al.. Improvement of Fatigue in Patients with Ankylosing Spondylitis Receiving Tofacitinib: Analyses of a Phase 3 Randomized Controlled Trial. Rheumatology and Therapy, 2024, 12 (1), pp.85-98. 10.1007/s40744-024-00727-5. [hal-05000747](https://hal.science/hal-05000747)

HAL Id: hal-05000747

https://hal.science/hal-05000747v1

Submitted on 21 Mar 2025

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Improvement of Fatigue in Patients with Ankylosing Spondylitis
## Receiving Tofacitinib: Analyses of a Phase 3 Randomized
Controlled Trial

Laure Gossec¹,²*, Jessica A. Walsh³, Raj Sengupta⁴, Andrew G. Bushmakin⁵,
Joseph C. Cappelleri⁵, Arne Yndestad⁶, Oluwaseyi Dina⁷ and David Cella⁸

¹ Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France

² Service de Rhumatologie, Hopital Pitie-Salpétrière, Paris, France

³ University of Utah Health and George E. Wahlen Department of Veterans Affairs Medical Health Center, Salt Lake City, Utah, USA

⁴ Royal National Hospital for Rheumatic Diseases, Bath, UK

⁵ Statistical Research and Data Science Center, Pfizer Inc, Groton, Connecticut, USA

⁶ Inflammation and Immunology, Pfizer Inc, Oslo, Norway

⁷ Inflammation and Immunology, Pfizer Inc, New York, New York, USA

⁸ Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

*Correspondence: Laure Gossec, Service de Rhumatologie, Hopital Pitie-Salpétrière, 47 Bd Hopital, 75013, Paris, France. Email: laure.gossec@aphp.fr. Telephone: +33 01 42 17 78 05.
**Word count manuscript (max for Original Research: 4,000):** 3,179

**Word count abstract (max: 300):** 258

**No. figures/tables (no max):** 2 figures/3 tables (Supplementary: 1 figure, 2 tables)

**References (no max):** 28

**Prior presentations**

Selected data in this manuscript were presented at the European Alliance of Associations for Rheumatology 2022 (June 01–04, 2022; Copenhagen, Denmark), and the Société Française de Rhumatologie 2022 (December 11–13, 2022; Paris, France).

**Target journal:** *Rheumatology and Therapy*
# 1 ABSTRACT

2 **Introduction:** Fatigue is a key symptom in patients with ankylosing spondylitis (AS).

3 The objective of this analysis was to estimate median time to initial and stable improvement
4 events in fatigue in patients with AS receiving tofacitinib.

5 **Methods:** This post hoc analysis used data from a phase 3 trial (NCT03502616) in patients
6 with active AS receiving tofacitinib 5 mg twice daily or placebo. Time to improvement in
7 fatigue was assessed using Functional Assessment of Chronic Illness Therapy–Fatigue
8 (FACIT-F) total score, experience domain score, and impact domain score. Rapidity of
9 improvement was assessed by time-to-event analyses (non-parametric Kaplan-Meier models);
10 initial improvement events (i.e., time to first week of FACIT-F improvement) and stable
11 improvement events (i.e., time to first week of FACIT-F improvement, sustained to
12 16 weeks) were examined.

13 **Results:** Overall, 269 patients were assessed (mean disease duration: 14.2 [standard deviation
14 (SD): 9.8] years; mean baseline FACIT-F total score: 27.2 [SD: 9.3]). Median times to initial
15 and stable improvement events in FACIT-F total and domain scores were significantly
16 shorter and occurred in more patients receiving tofacitinib than placebo. Median time to
17 initial and stable improvement events of 6 points in FACIT-F total score were 8 and 12 weeks
18 with tofacitinib, respectively (placebo: not reached). 70.0% versus 48.5% of patients
19 receiving tofacitinib versus placebo, respectively, experienced initial improvements of
20 6 points in FACIT-F total score within 16 weeks.

21 **Conclusions:** Improvements in fatigue occurred more rapidly with tofacitinib than placebo.
22 These results may be useful for healthcare providers when discussing tofacitinib treatment
23 expectations with patients.
24 **Trial registration**: ClinicalTrials.gov: NCT03502616 (June 7, 2018)

25 **Keywords**: Ankylosing spondylitis, Fatigue, Tofacitinib
26 **Key Summary Points**

27 **Why carry out this study?**

28 • Very brief background leading to the study (1–2 bullet points)

29 o Previous studies have demonstrated that improvements in fatigue in patients
30 with ankylosing spondylitis (AS) can be achieved with treatments such as
31 tumor necrosis factor inhibitors, interleukin-17 inhibitors, and Janus kinase
32 (JAK) inhibitors.

33 o However, there is a lack of data around the time frame for these
34 improvements.

35 • What did the study ask?/What was the hypothesis of the study? (1 bullet point)

36 o This post hoc analysis of a phase 3 trial aimed to estimate the median time
37 (i.e., the time at which 50% of patients were expected to experience an
38 improvement) to initial and stable improvements in patients with active AS
39 treated with the JAK inhibitor tofacitinib (dose: 5 mg twice daily) versus
40 placebo.

41 **What was learned from the study?**

42 • What were the study outcomes/conclusions? (data) (1 bullet point)

43 o Improvements in fatigue were observed with tofacitinib as early as week 2
44 (first post-baseline assessment); median time to initial and stable
45 improvements in the Functional Assessment of Chronic Illness
46 Therapy–Fatigue (FACIT-F) total score and experience and impact domain
47 scores was significantly shorter in patients receiving tofacitinib compared with
48 placebo.
49

* What has been learned from the study? (1–2 bullet points)

50

○ These findings help to clarify the time frame over which improvements in fatigue can be expected in patients with AS initiating tofacitinib, which may aid physicians in adjusting treatment strategies, goals, and expectations.

51

52
53 INTRODUCTION

54 Ankylosing spondylitis (AS) is a chronic, inflammatory arthritis that leads to structural
55 damage of the sacroiliac joints and the spine [1, 2]. It is commonly characterized by pain and
56 stiffness, as well as impairment of spinal mobility, physical function, and fatigue [1, 3, 4].
57 Indeed, fatigue is reported by 40-75% of patients with AS and is associated with higher
58 levels of pain and functional disability, resulting in a negative impact on several other
59 aspects of patients' health-related quality of life [4-7]. Therefore, fatigue is considered a
60 core outcome of disease assessment in randomized controlled trials (RCTs) of treatments for
61 AS [8].

62 Although previous studies have demonstrated that improvements in fatigue in patients
63 with AS can be achieved with treatments such as tumor necrosis factor inhibitors (TNFi)
64 [9-11], interleukin-17 inhibitors [12, 13], and Janus kinase (JAK) inhibitors [14, 15], there is
65 a lack of data around the time frame for these improvements. Improvements in fatigue are
66 typically assessed through mean changes in outcomes (such as Fatigue Numeric Rating Scale,
67 Bath AS Disease Activity Index Fatigue item, Chalder Fatigue Scale, and Functional
68 Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]) between a patient's baseline and
69 final visits [9-14]; however, such reporting does not provide information on the rapidity of
70 the improvements. Time-to-event analyses have been applied to investigate the time course of
71 improvements in fatigue and other patient-reported outcomes in psoriatic arthritis [16, 17],
72 but have been rarely applied in AS. Insights into the time frames for onset and sustainment of
73 fatigue improvement in patients receiving tofacitinib would be helpful for healthcare
74 providers and patients with AS when deciding on treatment strategies and setting
75 expectations regarding treatment benefit. Furthermore, evidence around the interpretation of
76 the FACIT-F experience and impact domains would allow for more targeted and
77 comprehensive assessments of fatigue, which would be useful to healthcare providers,
78 patients, researchers, and regulators.

79 Tofacitinib is an oral JAK inhibitor approved for the treatment of AS. The efficacy
80 and safety of tofacitinib in patients with active AS and an inadequate response or intolerance
81 to non-steroidal anti-inflammatory drugs (NSAIDs) have been demonstrated in a 16-week
82 phase 2 RCT (NCT01786668) [18] and a 48-week phase 3 RCT (NCT03502616) [19]. These
83 studies also showed greater improvements in fatigue for patients treated with tofacitinib over
84 12 (phase 2) and 16 weeks (phase 3) [18]. Improvements in fatigue were observed as early
85 as week 2 (first post-baseline assessment) in patients receiving tofacitinib versus placebo [14,
86 19]. In these trials, fatigue was assessed using the FACIT-F [20]. The FACIT-F is divided
87 into "experience" and "impact" domains that assess a patient's perceived fatigue and its
88 impact on their daily functioning, respectively [20]. Patients who received tofacitinib
89 demonstrated greater improvements in FACIT-F total score at week 16 [14, 19] compared
90 with placebo, which were maintained or further increased to week 48 [14, 19].

91 The aim of this post hoc analysis was to estimate the median time to initial and stable
92 improvements (an improvement sustained to study end) in FACIT-F total score, and
93 FACIT-F experience and impact domains, using non-parametric Kaplan-Meier models, in
94 patients with active AS treated with tofacitinib versus placebo.
95

# METHODS

96

## Data and Patients

97

This post hoc analysis used data from the double-blind phase (weeks 0–16) of the 48-week,

98

phase 3, placebo-controlled study of tofacitinib in patients with active AS (NCT03502616).

99

Full details have been reported previously [19].

100

Briefly, eligible patients were aged ≥ 18 years, had a diagnosis of AS (with active disease at screening and baseline) and fulfilled the modified New York AS criteria

101

(documented with central reading of the radiograph of the sacroiliac joints) [21].

102

Approximately 80% of the study population were required to be biologic disease-modifying

103

antirheumatic drug (bDMARD)-naïve and approximately 20% were required to have an inadequate response to ≤ 2 TNFi or to have had prior bDMARD (TNFi or non-TNFi) use

104

without an inadequate response. In the double-blind phase (weeks 0–16), patients were randomized 1:1 to receive tofacitinib 5 mg twice daily or placebo. In the open-label phase

105

(weeks 16–48), all patients received open-label tofacitinib 5 mg twice daily until week 48.

106

Some stable background therapies could be continued throughout the study, including NSAIDs, methotrexate (≤ 25 mg/week), sulfasalazine (≤ 3 g/day), and oral corticosteroids

109

(≤ 10 mg/day of prednisone or equivalent).

110

111

The trial was conducted in accordance with the International Council for

112

Harmonisation Good Clinical Practice guidelines, local regulatory requirements, and the ethical principles of the Declaration of Helsinki. Patients provided written, informed consent,

113

and the study protocol was approved by an Institutional Review Board or Independent Ethics Committee at each study site.

115

116
## 117 Assessments

Fatigue was assessed using the FACIT-F, a validated measure of fatigue, consisting of a 118 13-item questionnaire that evaluates self-reported fatigue during daily activities over the past 119 week [20]. The total (13-item) score is most frequently reported and is scored from 0–52, 120 with higher scores reflecting less fatigue. Furthermore, FACIT-F items can be classified into 121 two components of fatigue: an “experience” domain (5 items that evaluate patients’ 122 perceptions of tiredness, energy level, weakness, fatigue, and listlessness) and an “impact” 123 domain (8 items that evaluate how fatigue affects an individual’s daily functioning, including 124 performing usual activities, social activities, sleeping, and eating) [20]. “Experience” and 125 “impact” domain scores range between 0 and 20, and 0 and 32, respectively; higher scores 126 reflect less experience/impact of fatigue [14, 22]. 127

## 128 Statistical Analyses

A series of time-to-event analyses were performed on data from the double-blind phase using 129 non-parametric Kaplan-Meier models [23]. Improvements in fatigue were assessed based on 130 absolute and percentage changes from baseline in FACIT-F total score and domain scores. 131 The time to an initial improvement event was defined as time to first post-baseline week with 132 an improvement in FACIT-F total score or a domain score of ≥ 1, 2, 3, etc. points (up to 133 10 points), or by 5%, 10%, 15%, etc. (up to 100%). The time to a stable improvement event 134 was defined as the week at which an improvement in FACIT-F total score or a domain score 135 of ≥ 1, 2, 3, etc. points (up to 10 points), or by 5%, 10%, 15%, etc. (up to 100%) was reached 136 and then sustained on average at that threshold up to week 16 (with ≥ 2 observations present). 137 For example, if an improvement in a FACIT-F score of ≥ 3 points was reached at week 4, and 138 the average improvement from week 4 until the end of the study was also ≥ 3 points, then this 139
140 was considered a stable improvement event of 3 points at week 4. Improvements of
141 ≥ 6 points for total score, ≥ 3 points for the “experience” domain, and ≥ 4 points for the
142 “impact” domain were considered clinically meaningful (i.e., meaningful within-patient
143 change) [24].

144 Median times (i.e., the time at which 50% of patients were expected to experience an
145 improvement) from baseline to initial and stable improvement events in FACIT-F total and
146 domain scores for the treatment groups were estimated. Results represent median values for
147 the time to improvement event in the total study population; timing of improvements in
148 fatigue vary for individual patients. Patients whose FACIT-F scores did not improve were
149 censored at the last observation at which data were available for them. The test of equality
150 over strata log-rank test was used to compare the time-to-event curves across treatment
151 groups [23]. There was no imputation for missing data.

## 152 RESULTS

### 153 Patients

154 Data from 269 patients (receiving tofacitinib: *n* = 133 or placebo: *n* = 136) were included in
155 this post hoc analysis. Patient demographics and baseline disease characteristics have been
156 reported previously [19]; they were generally similar across treatment groups. Briefly, in
157 patients receiving tofacitinib or placebo, most patients were male (87.2% and 79.4%,
158 respectively), were receiving NSAIDs (79.7% and 79.4%), and were bDMARD-naïve
159 (76.7% and 77.2%). Of patients receiving tofacitinib or placebo who reported their race,
160 18.8% and 22.1% were Asian, respectively, and 80.5% and 77.9% were White, respectively.
161 Mean disease duration since symptom onset was 14.2 (standard deviation [SD]: 9.8) years
162 (tofacitinib-treated patients) and 12.9 (SD: 9.5) years (placebo) [19]. For tofacitinib-treated
patients, mean FACIT-F total score was 27.2 (maximum score: 52; SD: 10.7); experience domain score was 8.9 (maximum score: 20; SD: 4.3), impact domain score was 18.3 (maximum score: 32; SD: 6.9), and Bath AS Disease Activity Index (Fatigue) (Question 1, numeric rating scale 0–10) score was 6.8 (SD: 1.5). Corresponding mean (SD) values for patients who received placebo were 27.4 (9.3), 8.7 (4.0), 18.8 (5.9), and 6.8 (1.7), respectively [14, 19].

## 169 Initial Improvement Events in Fatigue

In general, the median time to initial improvement events in the FACIT-F total score was shorter in patients receiving tofacitinib versus placebo (Fig. 1a and d; *p* < 0.05); a “lower” median time for a particular treatment group indicates that fatigue improved more rapidly). Median time to an initial improvement event of 6 points in the FACIT-F total score was 8 weeks with tofacitinib; however, with placebo, median time to an initial improvement event of 6 points was not reached within 16 weeks (Fig. 1a and d). Similarly, median time to an initial improvement event of 20% and 40% change in FACIT-F total score was 6 weeks and not reached, respectively, with tofacitinib (placebo: 16 weeks for 20% and not reached for 40% change).

A greater number of patients receiving tofacitinib versus placebo experienced initial improvement events in FACIT-F total score within 16 weeks (Table 1). For example, 70.0% of patients receiving tofacitinib experienced initial improvement events of 6 points in FACIT-F total score within 16 weeks versus 48.5% receiving placebo (Table 1). Initial improvement events of 20% and 40% in the FACIT-F total score were experienced by 66.2% and 43.6% of patients receiving tofacitinib (placebo: 50.7% and 25.7%), respectively (see Table S1 in the electronic supplementary material).
186

Similar trends were observed for the FACIT-F experience and impact domains

187

(Fig. 1b, c, e, and f).

188

More patients receiving tofacitinib versus placebo experienced initial improvement

189

events for the FACIT-F experience and impact domains within 16 weeks (Table 1). For

190

example, 66.2% and 66.2% of patients receiving tofacitinib experienced clinically

191

meaningful initial improvement events of 3 and 4 points in the FACIT-F experience and

192

impact domains, respectively, within 16 weeks, compared with 52.2% and 45.6% of patients

193

receiving placebo (Table 1).
194

<caption>**Table 1** Proportions of patients experiencing initial improvement events within 16 weeks</caption>

195

(absolute change)

<table><thead><tr><th rowspan="2">Fatigue improvement event threshold</th><th colspan="2">FACIT-F<br>total score</th><th colspan="2">FACIT-F<br>experience domain</th><th colspan="2">FACIT-F<br>impact domain</th></tr><tr><th>n (%)</th><th>p value*</th><th>n (%)</th><th>p value*</th><th>n (%)</th><th>p value*</th></tr></thead><tbody><tr><td>3 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>109 (82.0)</td><td>0.0002</td><td>88 (66.2)</td><td>0.0050</td><td>100 (75.2)</td><td>0.0001</td></tr><tr><td>Placebo</td><td>88 (64.7)</td><td></td><td>71 (52.2)</td><td></td><td>75 (55.1)</td><td></td></tr><tr><td>4 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>103 (77.4)</td><td>0.0001</td><td>74 (55.6)</td><td>0.0032</td><td>88 (66.2)</td><td>0.0005</td></tr><tr><td>Placebo</td><td>80 (58.8)</td><td></td><td>54 (39.7)</td><td></td><td>62 (45.6)</td><td></td></tr><tr><td>5 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>97 (72.9)</td><td>0.0003</td><td>63 (47.4)</td><td>0.0046</td><td>70 (52.6)</td><td>0.0130</td></tr><tr><td>Placebo</td><td>74 (54.4)</td><td></td><td>44 (32.4)</td><td></td><td>52 (38.2)</td><td></td></tr><tr><td>6 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>93 (70.0)</td><td>&lt; 0.0001</td><td>53 (39.8)</td><td>0.0004</td><td>60 (45.1)</td><td>0.0079</td></tr><tr><td>Placebo</td><td>66 (48.5)</td><td></td><td>28 (20.6)</td><td></td><td>40 (29.4)</td><td></td></tr><tr><td>7 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>86 (64.7)</td><td>0.0002</td><td>39 (29.3)</td><td>0.0077</td><td>54 (40.6)</td><td>0.0008</td></tr><tr><td>Placebo</td><td>60 (44.1)</td><td></td><td>22 (16.2)</td><td></td><td>30 (22.1)</td><td></td></tr><tr><td>10 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>61 (45.9)</td><td>0.0005</td><td>13 (9.8)</td><td>0.2484</td><td>28 (21.1)</td><td>0.0211</td></tr><tr><td>Placebo</td><td>36 (26.5)</td><td></td><td>8 (5.9)</td><td></td><td>15 (11.0)</td><td></td></tr></tbody></table>

196

FACIT-F Functional Assessment of Chronic Illness Therapy–Fatigue, *n* number of patients achieving an initial

197

improvement event, *N* total number of patients in each treatment group

198

* Test of equality over strata log-rank test, *p* < 0.05 (tofacitinib 5 mg twice daily versus placebo)

199

Tofacitinib 5 mg twice daily: *N* = 133; placebo: *N* = 136
200 **Stable Improvement Events in Fatigue**

201 In general, median time to stable improvement events in FACIT-F total score (i.e., sustained
202 on average at threshold up to week 16) was shorter in patients receiving tofacitinib versus
203 placebo (Fig. 2a and d; *p* < 0.05]). Median time to a stable improvement event of 6 points in
204 FACIT-F total score (considered clinically meaningful) was 12 weeks with tofacitinib and
205 was not reached within 16 weeks with placebo (Fig. 2a and d). With placebo, only a median
206 time to a stable improvement event of 2 points in FACIT-F total score was reached within
207 16 weeks (Fig. 2d). Median time to a stable improvement event of 20% and 40% change in
208 FACIT-F total score was 8 weeks and not reached, respectively, with tofacitinib (placebo: not
209 reached for both).

210 More patients receiving tofacitinib versus placebo experienced stable improvement
211 events in the FACIT-F total score within 16 weeks (Table 2). For example, 54.1% of patients
212 receiving tofacitinib experienced stable improvement events of 6 points in FACIT-F total
213 score (placebo: 25.7%; Table 2). Stable improvement events of 20% and 40% in the
214 FACIT-F total score were experienced by 57.1% and 32.3% of patients receiving tofacitinib
215 (placebo: 27.9% and 14.0%), respectively (see Table S2 in the electronic supplementary
216 material).

217 Similar trends were observed for the FACIT-F experience and impact domains
218 (Fig. 2b, c, e, and f).

219 Similar to FACIT-F total score, significantly more patients receiving tofacitinib
220 versus placebo experienced stable improvement events in FACIT-F experience and impact
221 domains within 16 weeks (except for the 10-point threshold in the experience domain
222 [Table 2]). Median time to stable improvement events of 20% in the FACIT-F experience and
223

impact domains was 4 and 12 weeks, respectively, with tofacitinib (placebo: not reached);

224

median time to a 40% improvement event was not reached in either treatment group for both

225

domains.
226

<caption>**Table 2** Proportions of patients experiencing stable improvement events within 16 weeks</caption>

227

(absolute change)

<table><thead><tr><th rowspan="2">Fatigue improvement event threshold</th><th colspan="2">FACIT-F<br>total score</th><th colspan="2">FACIT-F<br>experience domain</th><th colspan="2">FACIT-F<br>impact domain</th></tr><tr><th>n (%)</th><th>p value*</th><th>n (%)</th><th>p value*</th><th>n (%)</th><th>p value*</th></tr></thead><tbody><tr><td>3 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>96 (72.2)</td><td>&lt; 0.0001</td><td>73 (54.9)</td><td>&lt; 0.0001</td><td>75 (56.4)</td><td>&lt; 0.0001</td></tr><tr><td>Placebo</td><td>65 (47.8)</td><td></td><td>41 (30.1)</td><td></td><td>43 (31.6)</td><td></td></tr><tr><td>4 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>88 (66.2)</td><td>&lt; 0.0001</td><td>58 (43.6)</td><td>0.0004</td><td>59 (44.4)</td><td>0.0002</td></tr><tr><td>Placebo</td><td>49 (36.0)</td><td></td><td>33 (24.3)</td><td></td><td>32 (23.5)</td><td></td></tr><tr><td>5 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>80 (60.2)</td><td>&lt; 0.0001</td><td>38 (28.6)</td><td>0.0002</td><td>46 (34.6)</td><td>0.0005</td></tr><tr><td>Placebo</td><td>39 (28.7)</td><td></td><td>15 (11.0)</td><td></td><td>23 (16.9)</td><td></td></tr><tr><td>6 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>72 (54.1)</td><td>&lt; 0.0001</td><td>32 (24.1)</td><td>0.0003</td><td>40 (30.1)</td><td>0.0017</td></tr><tr><td>Placebo</td><td>35 (25.7)</td><td></td><td>11 (8.1)</td><td></td><td>20 (14.7)</td><td></td></tr><tr><td>7 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>63 (47.4)</td><td>&lt; 0.0001</td><td>18 (13.5)</td><td>0.0189</td><td>32 (24.1)</td><td>0.0038</td></tr><tr><td>Placebo</td><td>28 (20.6)</td><td></td><td>7 (5.1)</td><td></td><td>15 (11.0)</td><td></td></tr><tr><td>10 points</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>37 (27.8)</td><td>0.0012</td><td>6 (4.5)</td><td>0.5080</td><td>19 (14.3)</td><td>0.0115</td></tr><tr><td>Placebo</td><td>17 (12.5)</td><td></td><td>4 (2.9)</td><td></td><td>7 (5.1)</td><td></td></tr></tbody></table>

228

FACIT-F Functional Assessment of Chronic Illness Therapy–Fatigue, *n* number of patients achieving a stable improvement event, *N* total number of patients in each treatment group

229

230

* Test of equality over strata log-rank test, *p* < 0.05 (tofacitinib 5 mg twice daily versus placebo)

231

Tofacitinib 5 mg twice daily: *N* = 133; placebo: *N* = 136
In patients receiving tofacitinib, stable improvement events in FACIT-F total score occurred either simultaneously or shortly after initial improvement events (within 4 weeks); the same trend was observed for FACIT-F domains (see Fig. S1a in the electronic supplementary material). The time between achieving initial and stable improvement events in FACIT-F total score and domain scores was generally longer in patients receiving placebo (see Fig. S1b in the electronic supplementary material).

Patients receiving tofacitinib who experienced initial improvement events in FACIT-F total score within 16 weeks were more likely to also experience stable improvement events in the FACIT-F total score, compared with placebo (Table 3). More than 80% of patients receiving tofacitinib who experienced initial improvement events of 3–5 points in the FACIT-F total score then sustained this improvement on average to week 16 (Table 3).
243

<caption>**Table 3** Proportion of patients experiencing initial improvement events who went on to experience stable improvement events<sup>a</sup></caption>

244

<table><thead><tr><th>Fatigue improvement event threshold</th><th>FACIT-F<br>total score<br>n1/n2 (%)</th><th>FACIT-F<br>experience domain<br>n1/n2 (%)</th><th>FACIT-F<br>impact domain<br>n1/n2 (%)</th></tr></thead><tbody><tr><td>3 points</td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>96/109 (88.1)</td><td>73/88 (83.0)</td><td>75/100 (75.0)</td></tr><tr><td>Placebo</td><td>65/88 (73.9)</td><td>41/71 (57.7)</td><td>43/75 (57.3)</td></tr><tr><td>4 points</td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>88/103 (85.4)</td><td>58/74 (78.4)</td><td>59/88 (67.0)</td></tr><tr><td>Placebo</td><td>49/80 (61.3)</td><td>33/54 (61.1)</td><td>32/62 (51.6)</td></tr><tr><td>5 points</td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>80/97 (82.5)</td><td>38/63 (60.3)</td><td>46/70 (65.7)</td></tr><tr><td>Placebo</td><td>39/74 (52.7)</td><td>15/44 (34.1)</td><td>23/52 (44.2)</td></tr><tr><td>6 points</td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>72/93 (77.4)</td><td>32/53 (60.4)</td><td>40/60 (66.7)</td></tr><tr><td>Placebo</td><td>35/66 (53.0)</td><td>11/28 (39.3)</td><td>20/40 (50.0)</td></tr><tr><td>7 points</td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>63/86 (73.3)</td><td>18/39 (46.2)</td><td>32/54 (59.3)</td></tr><tr><td>Placebo</td><td>28/60 (46.7)</td><td>7/22 (31.8)</td><td>15/30 (50.0)</td></tr><tr><td>10 points</td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>37/61 (60.7)</td><td>6/13 (46.2)</td><td>19/28 (67.9)</td></tr><tr><td>Placebo</td><td>17/36 (47.2)</td><td>4/8 (50.0)</td><td>7/15 (46.7)</td></tr></tbody></table>

245

FACIT-F Functional Assessment of Chronic Illness Therapy–Fatigue, n1 number of patients achieving a stable improvement event, n2 number of patients achieving an initial improvement, N total number of patients in each treatment group

246

247

248

Tofacitinib 5 mg twice daily: N = 133; placebo: N = 136

249

<sup>a</sup>Calculated by dividing *n* with stable improvements by *n* with initial improvement events at each improvement event threshold in each treatment group

250
251 DISCUSSION

252 This post hoc analysis of data from a phase 3 RCT provides information regarding the time
253 frames for initial and stable improvements in fatigue using FACIT-F, over the course of
254 16 weeks, in patients with AS treated with tofacitinib 5 mg twice daily or placebo. Across
255 FACIT-F total and domain scores, initial and stable improvements in fatigue occurred more
256 rapidly and in greater numbers for patients receiving tofacitinib, compared with placebo.
257 Our results showed that 70.0% of patients receiving tofacitinib experienced a clinically
258 meaningful initial improvement event in FACIT-F total score (6 points), compared with
259 48.5% of patients receiving placebo.

260 In this analysis, we used conservative estimates of clinically meaningful
261 improvements (≥ 6 points for FACIT-F total score, ≥ 3 points for the experience domain,
262 and ≥ 4 points for the impact domain [24]). Median time (i.e., the time at which 50% of
263 patients were expected to experience an improvement) to a clinically meaningful initial
264 improvement in FACIT-F scores was only reached in the tofacitinib group within 16 weeks,
265 except for a clinically meaningful initial improvement in experience domain scores which
266 was reached in both treatment groups. Median time to a clinically meaningful stable
267 improvement was only reached in the tofacitinib group within 16 weeks, except for a
268 clinically meaningful stable improvement in impact domain scores which was not reached in
269 either treatment group. In the placebo group, the median times to stable improvement events
270 of only 1 or 2 points were reached within 16 weeks, suggesting that initial improvements due
271 to placebo effects are not sustainable over time. Across other studies in patients with AS,
272 rheumatoid arthritis, and psoriatic arthritis, there is mixed evidence of sustained improvement
273 in FACIT-F with placebo [12, 25, 26].
274 When examining the median time to initial versus stable improvement events in 275 fatigue, median time to stable improvement events in fatigue were reached simultaneously or 276 shortly after median times to initial improvement events in patients treated with tofacitinib, 277 suggesting that sustained benefits in fatigue may be expected early in the tofacitinib treatment 278 course. Moreover, in the subset of patients who achieved sustained improvement, this took 279 longer with placebo than with tofacitinib, demonstrated by the wider separation in the curves 280 for initial and stable improvements in the placebo versus tofacitinib group.

281 In the tofacitinib group, median times to improvement events were similar for the 282 FACIT-F experience domain and impact domain, which assess perceptions/severity of feeling 283 states (tiredness, energy level, weakness, fatigue, and listlessness), and daily functioning, 284 respectively [20]. A cohort study of patients with AS in the UK found that routine assessment 285 of both frequency and severity of fatigue is important for understanding the impact of fatigue 286 and its change over time when identifying patients at risk of fatigue-related impairment [6]. 287 Further evidence around the interpretation of the FACIT-F experience and impact domains 288 will allow for more targeted and comprehensive assessments of fatigue, which will be useful 289 to healthcare providers, patients, researchers, and regulators.

290 Greater improvements in fatigue with tofacitinib versus placebo have been previously 291 demonstrated in the 16-week phase 2 [18] and 48-week phase 3 [19] RCTs investigating 292 efficacy and safety of tofacitinib in patients with active AS and an inadequate response or 293 intolerance to NSAIDs. However, to our knowledge, this is the first analysis to assess time to 294 initial and stable improvements in fatigue in patients with AS treated with tofacitinib. The 295 current results, which demonstrate that initial and stable improvements in fatigue occurred 296 faster with tofacitinib versus placebo within 16 weeks, align with other studies that have 297 assessed fatigue in AS [27]. In a phase 3 trial of patients with AS treated with the JAK
inhibitor upadacitinib (15 or 30 mg once daily), improvements in FACIT-F could be distinguished from placebo by week 2, although they were small and unlikely to be clinically relevant at this time point. FACIT-F improvements continued to week 24 and remained greater than placebo [26]. Moreover, patients with AS receiving secukinumab, an interleukin-17 inhibitor, have shown a greater improvement in fatigue versus placebo in two phase 3 studies [27, 28]. In the phase 3 MEASURE 1 RCT, patients with AS reported improved fatigue (according to FACIT-F) with secukinumab (150 or 75 mg every 4 weeks) versus placebo at week 16 [28]. Similarly, patients with AS receiving secukinumab in the phase 3 MEASURE 2 RCT experienced improvements in fatigue at week 4, which were sustained until week 104, and were better than placebo [27].

The current results also align with those of a recent study that examined time to initial improvements in fatigue in patients with PsA receiving tofacitinib 5 or 10 mg twice daily, which demonstrated median time to initial FACIT-F total score response ≥ 4 was quicker for tofacitinib 5 mg twice daily (within approximately 1 month of treatment initiation), versus patients who received adalimumab, tofacitinib 10 mg twice daily, or placebo, switching to tofacitinib 5 or 10 mg twice daily (within approximate 3 months of treatment initiation) [16].

The current analysis has some limitations that should be acknowledged. These include the post hoc nature of this exploratory analysis; the primary phase 3 RCT was not designed to compare median times in the two treatment arms, as patients were assessed according to a protocol-determined fixed schedule of regular clinic visits. In addition, the analysis was limited by the short time frame of the placebo-controlled period of the original study. Since the study population represents patients with high disease activity at baseline, results may not be generalizable to patients with milder disease. Strengths of this analysis include the ability to detect treatment differences across the 16-week duration of the double-blind phase of the
phase 3 RCT, as well as the inclusion of data that represent clinically meaningful

improvements, rather than only statistical differences.

## 324 CONCLUSIONS

Initial and subsequent stable improvements in fatigue in patients with AS (as determined by

FACIT-F total score, experience, and impact domains) occurred more rapidly and in greater

numbers with tofacitinib versus placebo. These findings help to clarify the time frame over

which improvements in fatigue can be expected in patients with AS initiating tofacitinib.

The time-to-event outcomes are unique within the AS fatigue literature and may help

healthcare providers and patients to adjust treatment strategies, expectations, and goals.
331 ACKNOWLEDGMENTS

332 Medical writing support, under the direction of the authors, was provided by Lauren Hogarth,
333 MSc, CMC Connect, a division of IPG Health Medical Communications, and was funded by
334 Pfizer, New York, NY, USA, in accordance with Good Publication Practice (GPP 2022)
335 guidelines (Ann Intern Med. 2022;175:1298-304).

336 Declarations

337 Ethics Approval and Consent to Participate

338 The trial was conducted in accordance with the International Council for Harmonisation
339 Good Clinical Practice guidelines, local regulatory requirements, and the ethical principles of
340 the Declaration of Helsinki. Patients provided written, informed consent, and the study
341 protocol was approved by an Institutional Review Board or Independent Ethics Committee at
342 each study site.

343 Consent for Publication

344 Not applicable.

345 Availability of Data and Materials

346 Upon request, and subject to review, Pfizer will provide the data that support the findings of
347 this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide
348 access to the related individual de-identified participant data.

349 See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.
350 **Competing Interests**

351 LG has received grants or contracts from Pfizer Inc, Sandoz, and UCB, consulting fees from
352 AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Janssen, Novartis, Pfizer Inc, and UCB,
353 honoraria for lectures from AbbVie, Amgen, Eli Lilly, Galapagos, Gilead Sciences, Janssen,
354 MSD, Pfizer Inc, Sandoz, and UCB, support for attending meetings and/or travel from
355 AbbVie, Janssen, Novartis, Pfizer Inc, and UCB, and medical writing support from Janssen,
356 Pfizer Inc, and UCB. JAW has received grant support from AbbVie, Merck, and Pfizer Inc,
357 and consulting fees from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer Inc, and UCB. RS has
358 received grant support from AbbVie, Celgene, Novartis, and UCB, and speaker honoraria
359 from AbbVie, Biogen, Celgene, Eli Lilly, Novartis, and UCB. AGB, JCC, AY, and OD are
360 employees of, and stockholders in, Pfizer Inc. DC has received consulting fees from AbbVie,
361 Alexion Pharmaceuticals, Astellas Pharma, Bayer, Bristol Myers Squibb, Clovis Oncology,
362 Evidera, Exelixis, Horizon Therapeutics, Janssen, Merck/Schering-Plough, National
363 Academy of Sciences, Novartis Pharma K.K. (Japan), Pfizer Inc, PledPharma, and
364 Regeneron, and has an ownership interest as President in FACIT.org.

365 **Funding**

366 This study was sponsored by Pfizer Inc.

367 **Author Contributions**

368 All authors were involved in drafting the article or revising it critically for important
369 intellectual content, and all authors approved the final version to be submitted for publication.
370 AGB, JCC, and OD were responsible for study conception and design and acquired the data.
371 LG, JAW, AGB, JCC, OD, and DC analyzed the data. All authors were responsible for
372 interpreting the data.
373 REFERENCES

374 1. Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ.
375 Global prevalence of ankylosing spondylitis. Rheumatology (Oxford). 2014;53:650-7.

376 2. Poddubnyy D, Sieper J. Treatment of axial spondyloarthritis: what does the future
377 hold? Curr Rheumatol Rep. 2020;22:47.

378 3. Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A. Ankylosing spondylitis: an
379 overview. Ann Rheum Dis. 2002;61:iii8-iii18.

380 4. Turan Y, Duruöz MT, Bal S, Guvenc A, Cerrahoglu L, Gurgan A. Assessment of
381 fatigue in patients with ankylosing spondylitis. Rheumatol Int. 2007;27:847-52.

382 5. van Tubergen A, Coenen J, Landewé R, et al. Assessment of fatigue in patients with
383 ankylosing spondylitis: a psychometric analysis. Arthritis Rheum. 2002;47:8-16.

384 6. Haywood KL, Packham JC, Jordan KP. Assessing fatigue in ankylosing spondylitis:
385 the importance of frequency and severity. Rheumatology (Oxford). 2014;53:552-6.

386 7. Strand V, Deodhar A, Alten R, et al. Pain and fatigue in patients with ankylosing
387 spondylitis treated with tumor necrosis factor inhibitors: multinational real-world findings. J
388 Clin Rheumatol. 2021;27:e446-e55.

389 8. Navarro-Compán V, Boel A, Boonen A, et al. The ASAS-OMERACT core domain
390 set for axial spondyloarthritis. Semin Arthritis Rheum. 2021;51:1342-9.

391 9. Shim J, Dean LE, Karabayas M, Jones GT, Macfarlane GJ, Basu N. Quantifying and
392 predicting the effect of anti-TNF therapy on axSpA-related fatigue: results from the BSRBR-
393 AS registry and meta-analysis. Rheumatology (Oxford). 2020;59:3408-14.

394 10. Sieper J, Kivitz A, van Tubergen A, et al. Impact of certolizumab pegol on patient-
395 reported outcomes in patients with axial spondyloarthritis. Arthritis Care Res (Hoboken).
396 2015;67:1475-80.
397 11. Hammoudeh M, Zack DJ, Li W, Stewart VM, Koenig AS. Associations between inflammation, nocturnal back pain and fatigue in ankylosing spondylitis and improvements with etanercept therapy. J Int Med Res. 2013;41:1150-9.

400 12. Kvien TK, Conaghan PG, Gossec L, et al. Secukinumab and sustained reduction in fatigue in patients with ankylosing spondylitis: long-term results of two phase III randomized controlled trials. Arthritis Care Res (Hoboken). 2022;74:759-67.

403 13. Deodhar AA, Mease PJ, Rahman P, et al. Ixekizumab improves spinal pain, function, fatigue, stiffness, and sleep in radiographic axial spondyloarthritis: COAST-V/W 52-week results. BMC Rheumatol. 2021;5:35.

406 14. Navarro-Compán V, Wei JCC, Van den Bosch F, et al. Effect of tofacitinib on pain, fatigue, health-related quality of life and work productivity in patients with active ankylosing spondylitis: results from a phase III, randomised, double-blind, placebo-controlled trial. RMD Open. 2022;8:e002253.

410 15. Lee YH, Song GG. Janus kinase inhibitors for treating active ankylosing spondylitis: a meta-analysis of randomized controlled trials. Z Rheumatol. 2022;81:71-6.

412 16. Gladman DD, Coates LC, Wu J, et al. Time to response for clinical and patient-reported outcomes in patients with psoriatic arthritis treated with tofacitinib, adalimumab, or placebo. Arthritis Res Ther. 2022;24:40.

415 17. de Vlam K, Ogdie A, Bushmakin AG, et al. Median time to pain improvement and the impact of baseline pain severity on pain response in patients with psoriatic arthritis treated with tofacitinib. RMD Open. 2021;7:e001609.

418 18. van der Heijde D, Deodhar A, Wei JC, et al. Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis. 2017;76:1340-7.
19. Deodhar A, Sliwinska-Stanczyk P, Xu H, et al. Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2021;80:1004–13.

20. Cella D, Lai JS, Stone A. Self-reported fatigue: one dimension or more? Lessons from the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) questionnaire. Support Care Cancer. 2011;19:1441–150.

21. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27:361–8.

22. Chandran V, Bhella S, Schentag C, Gladman DD. Functional assessment of chronic illness therapy-fatigue scale is valid in patients with psoriatic arthritis. Annals of the Rheumatic Diseases. 2007;66:936–9.

23. van Belle G, Fisher LD, Heagerty PJ, Lumley T. Biostatistics: a methodology for the health sciences. 2nd ed. New York: John Wiley & Sons; 2004.

24. Cella D, Lenderking W, Chongpinitchai P, et al. Psychometric evaluation of Functional Assessment of Chronic Illness Therapy-Fatigue in patients with active ankylosing spondylitis [abstract]. Ann Rheum Dis. 2021;80(Suppl 1):146.

25. Bartlett SJ, Bingham CO, van Vollenhoven R, et al. The impact of tofacitinib on fatigue, sleep, and health-related quality of life in patients with rheumatoid arthritis: a post hoc analysis of data from Phase 3 trials. Arthritis Res Ther. 2022;24:83.

26. Strand V, Mease PJ, Soriano ER, et al. Improvement in patient-reported outcomes in patients with psoriatic arthritis treated with upadacitinib versus placebo or adalimumab: results from SELECT-PsA 1. Rheumatol Ther. 2021;8:1789–808.

27. Deodhar A, Conaghan PG, Kvien TK, et al. Secukinumab provides rapid and persistent relief in pain and fatigue symptoms in patients with ankylosing spondylitis
irrespective of baseline C-reactive protein levels or prior tumour necrosis factor inhibitor

therapy: 2-year data from the MEASURE 2 study. Clin Exp Rheumatol. 2019;37:260-9.

28. Deodhar AA, Dougados M, Baeten DL, et al. Effect of secukinumab on patient-

reported outcomes in patients with active ankylosing spondylitis: a phase III randomized trial

(MEASURE 1). Arthritis Rheumatol. 2016;68:2901-10.

451
452 **Figures**

453 **Fig. 1** Probability estimates for initial improvements (a–c). Median times to initial improvement events (d–f)

<figure><img src="image_3.png" /></figure>

454

455 Panels a, b, and c: Median times to initial improvement events in fatigue were evaluated from baseline and were the first post-baseline week

456 where patients experienced an improvement event in FACIT-F total score (6 points) or a domain score (3 and 4 points in experience and impact
457 domains, respectively). Improvements at these thresholds were considered clinically meaningful (i.e., meaningful within-patient change) [24].

458 Panels **d**, **e**, and **f**: * Test of equality over strata log-rank test, *p* < 0.05 (tofacitinib 5 mg twice daily versus placebo). Median times to initial

459 improvement events in FACIT-F total score or domain scores as a function of the improvement event threshold (1–10 points; x axis). Median

460 time to initial improvement events (y axis) was based on absolute changes in FACIT-F scores, according to the specified thresholds of

461 improvement events (x axis). The vertical dotted line represents the threshold for a clinically meaningful improvement event (≥ 6 points for total

462 score, ≥ 3 points for experience domain score, and ≥ 4 points for impact domain score) [24]. *FACIT-F* Functional Assessment of Chronic Illness

463 Therapy–Fatigue
<figure><img src="image_4.png" /><figcaption>464 **Fig. 2** Probability estimates for stable improvements (a–c). Median times to stable improvement events (d–f).</figcaption></figure>

465

466 Panels a, b, and c: Median times to stable improvement events in fatigue were evaluated from baseline and were the first post-baseline week
467 where patients experienced an improvement event in FACIT-F total score (6 points) or a domain score (3 and 4 points in experience and impact
468 domains, respectively) and then sustained on average at that threshold (based on at least two time points) up to week 16. Improvements at these
469 thresholds were considered clinically meaningful (i.e., meaningful within-patient change) [24]. Panels d, e, and f: \* Test of equality over strata
470 log-rank test, *p* < 0.05 (tofacitinib 5 mg twice daily versus placebo). Times to stable improvement in fatigue were evaluated based on the week at

471 which an improvement event in FACIT-F total score or a domain score of 1–10 points was reached and then sustained on average at that

472 threshold (based on at least two time points) up to week 16. Median time to a stable improvement event (y axis) was based on absolute changes

473 in FACIT-F scores, according to specified thresholds of improvement event (x axis). The vertical dotted line represents a conservative threshold

474 for a clinically meaningful improvement event (≥ 6 points for total score, ≥ 3 points for experience domain score, and ≥ 4 points for impact

475 domain score). FACIT-F Functional Assessment of Chronic Illness Therapy–Fatigue
Supplementary Material

<table><caption>**Table S1** Proportions of patients experiencing initial improvement events within 16 weeks (percentage change)</caption><thead><tr><th rowspan="2">Fatigue improvement event threshold</th><th colspan="2">FACIT-F total score</th><th colspan="2">FACIT-F experience domain</th><th colspan="2">FACIT-F impact domain</th></tr><tr><th>n (%)</th><th>p value*</th><th>n (%)</th><th>p value*</th><th>n (%)</th><th>p value*</th></tr></thead><tbody><tr><td>20%</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>88 (66.2)</td><td>0.0034</td><td>92 (69.2)</td><td>0.0311</td><td>80 (60.2)</td><td>0.0059</td></tr><tr><td>Placebo</td><td>69 (50.7)</td><td></td><td>79 (58.1)</td><td></td><td>61 (44.9)</td><td></td></tr><tr><td>40%</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>58 (43.6)</td><td>0.0081</td><td>73 (54.9)</td><td>0.0179</td><td>53 (39.8)</td><td>0.0005</td></tr><tr><td>Placebo</td><td>35 (25.7)</td><td></td><td>58 (42.6)</td><td></td><td>28 (20.6)</td><td></td></tr></tbody></table>

FACIT-F Functional Assessment of Chronic Illness Therapy–Fatigue, *n* number of patients achieving an initial improvement event, *N* total number of patients in each treatment group

* Test of equality over strata log-rank test, *p* < 0.05 (tofacitinib 5 mg twice daily versus placebo)

Tofacitinib 5 mg twice daily: *N* = 133; placebo: *N* = 136
<table><caption>**Table S2** Proportions of patients experiencing stable improvement events within 16 weeks (percentage change)</caption><thead><tr><th rowspan="2">Fatigue improvement event threshold</th><th colspan="2">FACIT-F total score</th><th colspan="2">FACIT-F experience domain</th><th colspan="2">FACIT-F impact domain</th></tr><tr><th>n (%)</th><th>p value*</th><th>n (%)</th><th>p value*</th><th>n (%)</th><th>p value*</th></tr></thead><tbody><tr><td>20%</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>76 (57.1)</td><td>&lt; 0.0001</td><td>78 (58.6)</td><td>0.0009</td><td>67 (50.4)</td><td>&lt; 0.0001</td></tr><tr><td>Placebo</td><td>38 (27.9)</td><td></td><td>54 (39.7)</td><td></td><td>34 (25)</td><td></td></tr><tr><td>40%</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tofacitinib 5 mg twice daily</td><td>43 (32.3)</td><td>0.0003</td><td>61 (45.9)</td><td>0.0001</td><td>39 (29.3)</td><td>0.0019</td></tr><tr><td>Placebo</td><td>19 (14)</td><td></td><td>34 (25)</td><td></td><td>19 (14)</td><td></td></tr></tbody></table>

FACIT-F Functional Assessment of Chronic Illness Therapy–Fatigue, *n* number of patients achieving a stable improvement event, *N* total number of patients in each treatment group

* Test of equality over strata log-rank test, *p* < 0.05 (tofacitinib 5 mg twice daily versus placebo)

Tofacitinib 5 mg twice daily: *N* = 133; placebo: *N* = 136
<figure><img src="image_5.png" /><figcaption>**Fig. S1** Median times to initial versus stable improvement events with a tofacitinib and b placebo.</figcaption></figure>

* Test of equality over strata log-rank test, *p* < 0.05 (tofacitinib 5 mg twice daily versus placebo). Median time to initial improvement event (y axis) was based on absolute changes in FACIT-F scores, according to the specified thresholds of improvement event (x axis). The vertical
dotted line represents a conservative threshold for clinically meaningful improvement event (≥ 6 points for total score, ≥ 3 points for experience domain score, and ≥ 4 points for impact domain score). *FACIT-F* Functional Assessment of Chronic Illness Therapy–Fatigue