Tofacitinib With Methotrexate in Third-Line Treatment of Patients With Active Rheumatoid Arthritis:...

Tofacitinib with Methotrexate in Third-Line Treatment of Patients with Active

Rheumatoid Arthritis: Patient-Reported Outcomes from a Phase 3 Trial

VIBEKE STRAND MD,1*

GERD R. BURMESTER MD,2*

CRISTIANO A.F. ZERBINI

MD,3 CHARLES A. MEBUS Ph.D.,

4 SAMUEL H. ZWILLICH MD,

4

DAVID GRUBEN Ph.D.,4 AND GENE V. WALLENSTEIN Ph.D.

4

*Both authors contributed equally to this work

1Biopharmaceutical Consultant, Portola Valley, CA, USA;

2Charité –

Universitätsmedizin Berlin, Berlin, Germany; 3Centro Paulista de Investigação Clinica,

São Paulo, Brazil; 4Pfizer Inc., Groton, CT, USA

Name and address for correspondence (and reprints):

Dr Gene Wallenstein

Pfizer Inc

445 Eastern Point Road

MS 8260-2515

Groton

CT 06340, USA

Tel: +1.860.441.5251

Fax: +1.860.686.7528

E-mail: [email protected]

Running head: Phase 3 study of tofacitinib plus methotrexate in TNF inhibitor-IR

population: patient-reported outcomes

Original Article Arthritis Care & ResearchDOI 10.1002/acr.22453

This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as an‘Accepted Article’, doi: 10.1002/acr.22453© 2014 American College of RheumatologyReceived: Mar 21, 2014; Revised: Jul 29, 2014; Accepted: Aug 26, 2014

2

Previous presentations:

Burmester G-R, van der Heijde D, Strand V, Zerbini CAF, Connell CA, Mebus CA,

Zwillich SH, Bradley JD, Gruben D, Wallenstein G. Effects of tofacitinib on patient-reported

outcomes in patients with active rheumatoid arthritis receiving stable-dose methotrexate:

results of two Phase 3 studies. Poster presented at the ACR/ARHP Annual Scientific

Meeting, Washington, DC, USA, November 9–14, 2012; poster number 1283.

Funding:

This study was sponsored by Pfizer Inc.

Author disclosures of conflicts of interest:

V Strand, GR Burmester and CAF Zerbini have received research grants and fees from

Pfizer Inc. C Mebus, S Zwillich, D Gruben and G Wallenstein are employees and

stockholders of Pfizer Inc.

Word count: 2390

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John Wiley & Sons, Inc.

Arthritis Care & Research

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ABSTRACT [247/250 WORDS]

Objective. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid

arthritis (RA). Patient-reported outcomes (PROs) in a 6-month, Phase 3, randomized

controlled trial (NCT00960440) are presented here.

Methods. Patients aged ≥18 years with active RA with an inadequate response to ≥1 tumor

necrosis factor inhibitor (TNFi) and on stable background methotrexate were randomized

2:2:1:1 to tofacitinib 5 mg or 10 mg twice daily (BID), or placebo advanced to 5 mg or 10 mg

BID at month 3. PROs measured at month 3 included: Patient Global Assessment of Disease

Activity (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI),

Medical Outcomes Study (MOS) Short-Form Health Survey Version 2 (acute; SF-36),

Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and MOS Sleep

Scale.

Results. Patients received tofacitinib 5 mg (n = 133) or 10 mg (n = 134), or placebo advanced

to tofacitinib 5 mg (n = 66) or 10 mg (n = 66). HAQ-DI (reported previously), PtGA

(P<0.0001), and SF-36 physical and mental component (P<0.05) scores were improved for

both tofacitinib doses versus placebo. Furthermore, improvements ≥minimum clinically

important difference were more frequently reported by tofacitinib-treated patients versus

placebo: PtGA (P<0.05), pain (P<0.0001), HAQ-DI (P<0.05), SF-36 physical and mental

component scores (P<0.05), and FACIT-F (P<0.001 for 5 mg BID). No statistical differences

were observed in the MOS Sleep Scale.

Conclusion. Tofacitinib treatment resulted in significant, clinically meaningful improvements

in multiple PROs versus placebo over 3 months’ treatment in patients with active RA and

previous inadequate response to TNFi.

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SIGNIFICANCE & INNOVATIONS

• In this refractory, difficult-to-treat population with inadequate response to tumor

necrosis factor inhibitors (TNFi), tofacitinib in combination with methotrexate (MTX)

significantly improved patient-reported outcomes, including HRQoL, versus placebo

(on background MTX).

• These findings demonstrate, from the perspective of patients with inadequate response

to TNFi, clinically meaningful and relevant benefits of tofacitinib added to

background MTX. These patient-perceived benefits contribute importantly to overall

clinical efficacy.

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INTRODUCTION

Rheumatoid arthritis (RA) is a chronic, inflammatory disease characterized by progressive

joint destruction, and impairment in physical function and health-related quality of life

(HRQoL) (1–4). From a patient perspective, improvements in pain, physical function, fatigue,

and HRQoL are more important and meaningful than improvements in joint swelling,

tenderness, or inhibition of structural damage, when therapies for RA are evaluated (5).

Accordingly, the Outcomes Measures in Rheumatology (OMERACT) international

consensus effort, American College of Rheumatology (ACR), and European League Against

Rheumatism (EULAR) have recognized the importance of including a variety of

patient-reported outcomes (PROs) in randomized controlled trials (RCTs) (6–9). PROs

complement physician and laboratory measures in providing scientific evidence to support

decisions regarding clinical therapy (10).

Disease-modifying anti-rheumatic drugs (DMARDs), most prominently methotrexate

(MTX), represent the cornerstone of RA therapy. Patients with an inadequate response to

MTX frequently progress to receive biologic DMARDs, including tumor necrosis factor

inhibitors (TNFi). However, many patients do not respond well, lose their clinical response,

or experience adverse events with TNFi (11–14). Although patients with an inadequate

response to one TNFi may be switched to a second TNFi, patients may experience

progressive loss of efficacy with a subsequent TNFi (15). In addition, response to treatment,

physical function and other PROs decreases with more failed therapies and longer disease

duration (16). Patients with previously inadequate responses to TNFi, therefore, continue to

represent a challenging population to treat.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. Six Phase 3 RCTs have

demonstrated significant improvements in signs and symptoms of active RA compared with

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placebo (17–21) or MTX (22). PROs have been reported from all six Phase 3 trials; they have

demonstrated significant improvements with tofacitinib treatment versus placebo, with and

without background MTX across a range of patient populations (23–28).

In the Phase 3 ORAL Step trial (A3921032; clinicaltrials.gov identifier NCT00960440),

399 patients with active RA, with inadequate response to at least one TNFi and receiving

stable, background MTX were randomized to receive tofacitinib 5 mg, 10 mg, or placebo

twice daily (BID). Patients randomized to receive placebo advanced to tofacitinib 5 mg or

10 mg BID at month 3 (17). Co-primary endpoints – ACR20 response, mean change from

baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) and Disease

Activity Score-defined remission (DAS28-4, erythrocyte sedimentation rate [ESR] <2.6), all

measured at month 3 – were met for both doses of tofacitinib (17). Here, we report

improvements in additional PROs with tofacitinib (versus placebo) from this Phase 3 RCT.

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METHODS

Patients

Inclusion and exclusion criteria have been reported previously (17). Briefly, patients were

aged ≥18 years with moderate to severe active RA, defined as tender joint count ≥6 and

swollen joint count ≥6 (68/66-joint count) and either an ESR (Westergren method) >28 mm/h

or C-reactive protein >7 mg/L. Patients were required to have had previous inadequate

responses or intolerance to at least one approved TNFi. Patients had been receiving oral or

parenteral MTX with folate supplementation continuously for ≥4 months and had been

receiving stable doses, 7.5–25 mg weekly, for ≥6 weeks prior to the first dose of study

medication.

Study design and treatment

This 6-month, Phase 3 RCT was conducted at 82 centers in 13 countries worldwide. Patients

were randomized 2:2:1:1 to receive tofacitinib 5 mg or 10 mg BID, placebo advanced to

tofacitinib 5 mg BID, or placebo advanced to tofacitinib 10 mg BID. All patients receiving

placebo were blindly advanced to tofacitinib at month 3. Permitted concomitant medications,

wash-out schedules for prior DMARDS, and planned primary efficacy and safety analyses,

are described elsewhere (17).

Assessment of patient-reported outcomes

Patient Global Assessment of Disease Activity (PtGA) was recorded using a 100 mm visual

analog scale (VAS), higher scores indicating worse disease activity. Patient assessment of

arthritis pain was also recorded utilizing a 100 mm VAS. HAQ-DI, the co-primary endpoint

(17,29), assessed performance of activities of daily living, scored from 0 (able to perform

without difficulty) to 3 (unable to perform). HRQoL was evaluated using the Medical

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Outcomes Study (MOS) Short-Form (36-item) Health Survey (SF-36) Version 2 (acute) (30),

including eight domains scored from 0–100 and summarized into physical (PCS) and mental

(MCS) component scores. Visualizations of SF-36 data were generated from domain scores,

as previously described (31). The EuroQol 5-Dimensions (EQ-5D) Health State Profile was

also assessed. Fatigue was assessed by the Functional Assessment of Chronic Illness

Therapy-Fatigue (FACIT-F) scale (range 0–52), where higher scores represent less fatigue

(32). The MOS Sleep Scale (MOS-SS) assessed nine items of sleep disturbance to construct

an overall sleep problems score.

PtGA, pain, and HAQ-DI were assessed at baseline, week 2, months 1, 3, 4.5, and 6, or early

treatment discontinuation. SF-36, FACIT-F, and MOS-SS were assessed at baseline, week 2,

months 1, 3, and 6, or early treatment discontinuation. EQ-5D was assessed at baseline,

months 1, 3, and 6, or early treatment discontinuation.

Here, results in PROs are reported at month 3, before patients randomized to placebo

advanced to tofacitinib treatment. Data from the two placebo groups were pooled into a

single treatment group at month 3. At month 6, data were analyzed for each group in which

patients received placebo and then advanced to tofacitinib.

Statistical analysis

Determination of sample size is described elsewhere (17). With the exception of HAQ-DI,

which was a co-primary endpoint, PROs were pre-specified secondary endpoints.

Significance was declared at P ≤ 0.05, and there was no attempt to control for Type-1 error.

A longitudinal mixed-effect repeated-measures model was utilized to calculate mean changes

from baseline in the full analysis set (all patients who received ≥1 dose of study drug with

baseline and ≥1 post-baseline measures) without explicit imputation for missing values.

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Treatment, week, and treatment-by-week interactions were included as fixed effects in the

model, with patients as a random effect. Estimates of least squares (LS) mean changes from

baseline and mean differences from placebo were derived from the model with 95%

confidence intervals (LS means from a model are means that are adjusted for other terms in

the model and, as such, provide more accurate estimates of changes from baseline for each

treatment group than do simple arithmetic means, and also are less sensitive to missing data).

SF-36 derived data were compared with values from healthy individuals in the US, which

were selected to match the specific age and gender distribution of this protocol population

(referred to as age- and gender-matched norms) (30).

RESULTS

Patients

Baseline demographics and disease characteristics were similar between treatment groups

(17). Three hundred and ninety-nine (399) patients were randomized to tofacitinib 5 mg

(n = 133), tofacitinib 10 mg (n = 134), placebo advanced to tofacitinib 5 mg (n = 66) or

tofacitinib 10 mg (n = 66) at month 3. The majority of patients in each group (81% – 91%)

were from North America and Europe and, as previously reported, over 80% were white (17).

Mean age ranged from 54.4 to 55.4 years, and mean duration of RA from 11.3 to 13.0 years.

The mean number of previous TNFi treatments was 1.4 to 1.5: 257 patients (64%) had

previously received one TNFi, 104 (26%) two, and 32 (8%) three or more. Forty-six patients

(12%) had also received biologic DMARDs other than TNFi (17).

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Patient-reported outcomes

At baseline, PROs were similar across treatment groups (Table 1). Significant improvements

versus placebo in HAQ-DI, pain score, and FACIT-F observed at month 3 with tofacitinib

5 mg and 10 mg BID were reported previously (17), and here we note that PtGA (Table1 and

Figure 1) and SF-36, PCS and MCS (Table 1 and Figure 2), significantly improved from

baseline in both tofacitinib groups versus placebo at month 3. In addition, all SF-36 domains

and EQ-5D scores improved significantly at month 3 with tofacitinib treatment versus

placebo (Table 1). There were no significant improvements (versus placebo) in MOS-SS

overall sleep problems score in any of the tofacitinib treatment groups (Table 1). Significant

improvements from baseline in PtGA, pain and SF-36 component scores were evident as

early as week 2 and continued to month 6 (Figures 1 and 2). Improvements from baseline in

FACIT-F, which was measured at month 3 and month 6, remained significant (versus

placebo) at month 6 (Figure 1). Improvements in PROs were similar in both tofacitinib

treatment groups, although frequently numerically higher with tofacitinib 10 mg BID (Table

1; Figures 1 and 2).

At month 3, LS mean changes from baseline exceeded minimal clinically important

differences (MCID) in PtGA (≥10 points (33)), pain (≥10 points (33)), HAQ-DI (≥0.22 points

(34)), SF-36 PCS and MCS (≥2.5 points (35)), and FACIT-F (≥4 points (36)) for both

tofacitinib doses. LS mean changes in SF-36 domain scores also exceeded MCID

(≥5.0 points (35)) in two domains (bodily pain [BP] and vitality [VT]) with tofacitinib 5 mg,

and five domains (physical functioning [PF], role physical [RP], social functioning [SF], BP,

and VT) with tofacitinib 10 mg. LS mean changes in PROs for patients receiving placebo did

not meet MCID (Table 1).

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The proportion of patients reporting improvements ≥MCID in PROs at month 3 were

significantly higher in both tofacitinib groups versus placebo in PtGA, pain, HAQ-DI, SF-36

PCS and MCS, and in three (BP, VT, and general health [GH]) and five (PF, RP, BP, VT,

and SF) SF-36 domain scores with 5 mg and 10 mg respectively (Table 2). The proportion of

patients reporting improvements ≥MCID was also significantly higher for FACIT-F (Table 2)

in the tofacitinib 5 mg treatment group versus placebo.

When the proportion of patients reporting changes ≥MCID in PROs and the number needed

to treat (NNT) were compared between treatment groups, associations were observed

between particular PROs, although no formal statistical assessment was performed (Table 2).

The proportion of patients reporting improvements ≥MCID and NNTs was similar between

pain and SF-36 BP domain for both tofacitinib doses; between FACIT-F and SF-36 VT

domain in the tofacitinib 5 mg group; between HAQ-DI and SF-36 PF domain in the

tofacitinib 10 mg group; and between SF-36 RP and role emotional [RE] domains in the

tofacitinib 10 mg group, despite LS mean changes from baseline in SF-36 RE not being

statistically significant.

HRQoL: study and normative populations

SF-36 scores at baseline and month 3 are presented with SF-36 values from age-and gender-

matched norms to provide a benchmark comparison (Figure 3). SF-36 PCS and MCS at

baseline were approximately 2 and 1 standard deviations, respectively, below normative

scores of 50. At baseline, domain scores across all treatment groups were up to half of the

normative values (Figure 3 (30)). At month 3, VT domain scores in tofacitinib-treated

patients approached normative scores (Figure 3).

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DISCUSSION

In this Phase 3 RCT, treatment with tofacitinib 5 mg or 10 mg BID resulted in statistically

significant and clinically meaningful improvements versus placebo in HAQ-DI (month 3 data

reported previously (17)), PtGA, pain, physical function, HRQoL, and fatigue in patients with

RA and inadequate response to TNFi (TNFi-IR) receiving background MTX. These

improvements are of particular interest, as the central importance of these outcomes to

patients with active RA has been highlighted in previous RCTs (2,3,37).

Improvements in PROs were similar for both tofacitinib doses, but often numerically higher

with tofacitinib 10 mg BID. Significant improvements were observed after as little as two

weeks and maintained for the duration of tofacitinib treatment. Mean improvements from

baseline with tofacitinib were clinically meaningful, exceeding MCID and statistically

significant versus placebo, in PtGA, pain, HAQ-DI, SF-36 PCS and MCS, and in three and

five domains of SF-36 (with tofacitinib 5 mg and 10 mg BID, respectively). More patients in

both tofacitinib treatment groups reported clinically meaningful improvements in PROs than

did placebo-treated patients, with small NNTs. Together, these findings reflect a broad

beneficial effect of tofacitinib treatment on physical function, pain, fatigue, HRQoL,

including SF-36 domains of bodily pain and vitality, by not only reducing fatigue but

increasing patients’ energy levels. These improvements in PROs are consistent with the

primary efficacy data from the study, where ACR20/50/70 responses and DAS28-defined

remission and low disease activity rates were significantly improved in both tofacitinib

treatment groups versus placebo (17). No significant improvement in MOS-SS overall sleep

problems score was observed in any group, which remains unexplained. In other Phase 3

studies of tofacitinib, improvements from baseline in MOS-SS have been observed at

month 3 with tofacitinib 5 mg BID (26,27) and 10 mg BID (26–28) versus placebo.

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Changes in PROs with tofacitinib 5 mg and 10 mg BID appeared similar, although frequently

numerically higher with tofacitinib 10 mg BID, reflected in lower NNTs. Not surprisingly,

associations were observed between the number of patients reporting clinically meaningful

improvements in HAQ-DI and SF-36 PF domain, pain and SF-36 BP domain, and FACIT-F

and SF-36 VT domain, indicating that these PROs measure comparable aspects of HRQoL.

Baseline SF-36 domain scores were much lower than for age- and gender-matched norms,

indicating a substantial burden of disease in this population with incomplete response to

TNFi and long duration of disease (mean 11.3–13.0 years) . The broad range of

improvements in PROs observed in this treatment-refractory population, compared with those

in other Phase 3 tofacitinib RA trials, is encouraging.

Our findings are consistent with reported changes in PROs in other TNFi-IR populations

subsequently treated with established biologic agents. The proportion of patients reporting

improvements ≥MCID in FACIT-F and HAQ-DI after treatment with rituximab plus MTX

for 6 months were similar to those reported here (38). Again, similar proportions of patients

reported clinically meaningful changes in PtGA, pain, HAQ-DI, SF-36 PCS and MCS, and

FACIT-F, with 24 weeks’ tocilizumab + MTX (39). HAQ-DI responses ≥MCID (≥0.3 points)

were reported in 47% of TNFi-IR patients receiving abatacept + DMARD for 6 months (40).

In contrast to this study, improvements in sleep quality with abatacept were observed in

TNFi-IR patients (36).

This study focused on the first 3 months of this RCT to allow for comparison with the

placebo-treated population before advancement to tofacitinib. As RA is a chronic condition

requiring long-term treatment, ongoing extension studies are seeking to address whether

benefits observed in the short-term are maintained in the long term (41,42).

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In conclusion, tofacitinib therapy with background MTX improved HRQoL and reduced the

broad burden of active RA over 3 months’ treatment in TNFi-IR patients, compared with

placebo. These findings demonstrate both statistically and clinically meaningful benefits of

tofacitinib from the patient’s perspective, in addition to physician-reported outcomes.

ACKNOWLEDGMENTS

The authors would like to thank the patients who were involved in this study, and the

A3921032 investigators and study team. Medical writing support was provided by Kate

Silverthorne, PhD, and Claire Cridland at Complete Medical Communications and was

funded by Pfizer Inc.

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41. Burmester G-R, Blanco R, Rubbert-Roth A, Hendrikx T, Kwok K, Bradley J, et al.

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Treatment of Patients with Rheumatoid Arthritis and an Inadequate Response to TNF

Inhibitors: Analyses of Pooled Phase 2, Phase 3, and Long-term Extension Studies.

Arthritis and Rheumatism 2012;64:4172 (L12).

42. Wollenhaupt J, Silverfield J, Lee EB, Curtis JR, Wood SP, Soma K, et al. Safety and

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Table 1. Mean baseline values and LS mean changes from baseline at month 3 for

patient-reported outcomes

Baseline mean (SD) Month 3 LS mean change from baseline (SE)†

Placebo

+ MTX

Tofacitinib

5 mg BID

+ MTX

Tofacitinib

10 mg BID

+ MTX

Placebo

+ MTX

Tofacitinib

5 mg BID

+ MTX

Tofacitinib

10 mg BID +

MTX

n 131 127 128 117 114 120

PtGA (VAS) 61.87

(22.92)

64.69

(23.22)

58.79

(23.59)

–9.19

(2.42)

–23.39***

(2.43)

–25.05***

(2.48)

n 131 127 128 115 114 119

Pain (VAS) ‡ 60.74

(23.50)

65.73

(22.79)

60.10

(23.16)

–8.26

(2.41)

–27.16***

(2.43)

–24.95***

(2.48)

n 132 132 134 118 117 125

HAQ-DI‡ 1.63

(0.66)

1.60

(0.66)

1.50

(0.61)

–0.18

(0.04)

–0.43***

(0.04)

–0.46***

(0.04)

n 129 132 134 114 117 125

FACIT-F‡ 26.98

(11.52)

27.84

(11.12)

29.48

(11.39)

1.11

(1.04)

6.27***

(1.01)

4.57*

(1.03)

n 129 133 132 115 117 123

MOS-SS§ 46.08

(20.73)

43.10

(21.00)

41.57

(17.88)

–3.80

(1.45)

–6.80

(1.42)

–5.82

(1.46)

SF-36 component scores

n 132 133 134 116 118 125

PCS 29.98

(7.99)

30.72

(9.29)

32.13

(7.58)

2.03

(0.69)

5.65***

(0.68)

6.57***

(0.69)

MCS 41.34

(13.25)

42.82

(12.69)

43.24

(12.81)

0.37

(0.94)

3.52*

(0.92)

3.96*

(0.93)

SF-36 domain scores

n 132 133 134 117 118 125

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PF 28.32

(9.30)

30.54

(10.76)

31.61

(8.58)

1.55

(0.81)

4.61*

(0.79)

5.77***

(0.81)

RP 32.53

(9.66)

33.66

(10.21)

34.08

(9.67)

1.70

(0.85)

4.60*

(0.83)

6.24***

(0.85)

BP 31.95

(7.70)

31.09

(8.13)

32.55

(7.45)

2.49

(0.78)

8.05***

(0.77)

8.77***

(0.78)

GH 34.82

(8.67)

35.84

(9.50)

37.73

(9.18)

0.66

(0.64)

3.68**

(0.63)

3.52**

(0.64)

VT 38.41

(10.77)

39.71

(9.87)

40.11

(10.26)

2.20

(0.90)

6.40**

(0.89)

6.71***

(0.91)

SF 35.95

(12.39)

37.40

(13.10)

39.47

(12.11)

0.76

(0.93)

4.20*

(0.91)

5.27***

(0.92)

RE 35.52

(14.22)

37.58

(14.08)

36.75

(13.58)

–0.82

(1.12)a

3.00*

(1.10)

4.02**

(1.11)

MH 39.69

(12.66)

40.66

(11.63)

41.91

(11.99)

1.43

(0.89)

4.22*

(0.87)

4.47*

(0.88)

n 129 131 134 115 115 123

EQ-5D 0.38

(0.33)

0.38

(0.34)

0.47

(0.32)

0.03

(0.03)

0.15**

(0.03)

0.18***

(0.03)

*P < 0.05; **P < 0.001; ***P < 0.0001 versus placebo.

†Full analysis set, longitudinal model.

‡ LS mean change from baseline in HAQ-DI, pain score, and FACIT-F at month 3, and significance vs placebo

were reported previously (17) and are presented here for comparison

§Overall sleep problems score.

aN = 116.

BID = twice daily; BP = bodily pain; EQ-5D = EuroQol 5-Dimensions questionnaire; GH = general health;

LS = least squares; MCS = mental component score; MH = mental health; MOS-SS = Medical Outcomes Study-

Sleep Scale; MTX = methotrexate; PCS = physical component score; PF = physical functioning; PtGA = patient

global assessment of arthritis; RE = role emotional; RP = role physical; SD = standard deviation; SE = standard

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error; SF = social functioning; SF-36 = Medical Outcomes Study Short-Form (36-item) Health Survey Version

2 (acute); VAS = visual analog scale; VT = vitality.

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Table 2. Proportion of patients reporting improvements ≥MCID at month 3, and NNTs

(full analysis set, no imputation)

Tofacitinib

PRO MCID (threshold value)

Placebo

+ MTX

5 mg BID

+ MTX

10 mg BID

+ MTX

PtGA (VAS) Patients reporting change ≥MCID (–10), % 41.88 64.91** 59.17*

NNT 4.3 5.8

Pain (VAS) Patients reporting change ≥MCID (–10), % 39.13 69.30*** 65.55***

NNT 3.3 3.8

Physical function

(HAQ-DI)

Patients reporting change ≥MCID (0.22), % 46.61 60.68* 64.80*

NNT 7.1 5.5

Fatigue

(FACIT-F)

Patients reporting change ≥MCID (4), % 38.60 61.54** 48.00

NNT 4.4 10.6

Health-related quality of life (SF-36)

PCS Patients reporting change ≥MCID (2.5), % 49.14 67.80* 66.40*

NNT 5.4 5.8

MCS Patients reporting change ≥MCID (2.5), % 37.07 54.24* 49.60*

NNT 5.8 8.0

PF Patients reporting change ≥MCID (5), % 34.19 39.83 48.00*

NNT 17.7 7.2

RP Patients reporting change ≥MCID (5), % 30.77 38.98 47.20*

NNT 12.2 6.1

BP Patients reporting change ≥MCID (5), % 26.50 57.63*** 57.60***

NNT 3.2 3.2

GH Patients reporting change ≥MCID (5), % 22.22 35.59* 27.20

NNT 7.5 20.1

VT Patients reporting change ≥MCID (5), % 33.33 52.54* 54.40**

NNT 5.2 4.7

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SF Patients reporting change ≥MCID (5), % 42.74 51.69 56.00*

NNT 11.2 7.5

RE Patients reporting change ≥MCID (5), % 28.45 33.05 40.00

NNT 21.7 8.7

MH Patients reporting change ≥MCID (5), % 39.32 51.69 41.60

NNT 8.1 43.8

*P < 0.05, **P < 0.001, ***P < 0.0001 versus placebo.

BID = twice daily; BP = bodily pain; FACIT-F = Functional Assessment of Chronic Illness Therapy-Fatigue;

GH = general health; HAQ-DI = Health Assessment Questionnaire-Disability Index; MCS = mental component

score; MCID = minimal clinically important difference; MH = mental health; MTX = methotrexate;

NNT = number needed to treat; PCS = physical component score; PF = physical functioning;

PRO = patient-reported outcome; PtGA = patient global assessment of arthritis; RE = role emotional; RP = role

physical; SF = social functioning; SF-36 = Medical Outcomes Study Short-Form (36-item) Health Survey

Version 2 (acute); VAS = visual analog scale; VT = vitality.

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Figure legends

Figure 1. Least squares mean change (± standard error) from baseline in patient-reported

outcome scores (full analysis set, longitudinal model). Black dotted line represents the point

at which patients receiving placebo advanced to tofacitinib. Gray dotted line indicates

minimal clinically important difference. (A) PtGA; (B) Pain; (C) FACIT-F. BID = twice

daily; FACIT-F = Functional Assessment of Chronic Illness Therapy-Fatigue; LS = least

squares; MTX = methotrexate; PtGA = patient global assessment of arthritis; SE = standard

error.

Figure 2. Least squares mean change (± standard error) from baseline in SF-36 scores (full

analysis set, longitudinal model). Dotted line represents the point at which patients receiving

placebo advanced to tofacitinib. (A) SF-36 PCS; (B) SF-36 MCS. BID = twice daily;

LS = least squares; MCS = mental component score; MTX = methotrexate; PCS = physical

component score; SE = standard error; SF-36 = Medical Outcomes Study Short-Form

(36-item) Health Survey Version 2 (acute).

Figure 3. Visualization of mean overall SF-36 domain scores: (A) age- and gender-matched

norms versus weighted, combined baseline scores; (B) tofacitinib 5 mg BID, tofacitinib

10 mg BID and placebo at month 3; (C) tofacitinib 5 mg BID, tofacitinib 10 mg BID and

placebo at month 3 versus age- and gender-matched norms, and weighted, combined

baseline. Age- and gender-matched norms consist of SF-36 derived data from healthy

individuals in the US, which were selected to match the age and gender distribution of this

specific protocol population. Each spoke represents a domain, and the score for each group is

plotted along the spoke. BID, twice daily; BP = bodily pain; GH = general health;

MH = mental health; PF = physical functioning; RE = role emotional; RP = role physical;

SF = social functioning; SF-36 = Medical Outcomes Study Short-Form (36-item) Health

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Survey Version 2 (acute); US, United States; VT = vitality.

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Figures

Figure 1. Least squares mean change (± standard error) from baseline in patient-reported

outcome scores (full analysis set, longitudinal model). Black dotted line represents the point

at which patients receiving placebo advanced to tofacitinib. Gray dotted line indicates

minimal clinically important difference. (A) PtGA; (B) Pain; (C) FACIT-F.

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Figure 2. Least squares mean change (± standard error) from baseline in SF-36 scores (full

analysis set, longitudinal model). Dotted line represents the point at which patients receiving

placebo advanced to tofacitinib. (A) SF-36 PCS; (B) SF-36 MCS.

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Figure 3. Visualization of mean overall SF-36 domain scores: (A) age- and gender-matched

norms versus weighted, combined baseline scores; (B) tofacitinib 5 mg BID, tofacitinib

10 mg BID and placebo at month 3; (C) tofacitinib 5 mg BID, tofacitinib 10 mg BID and

placebo at month 3 versus age- and gender-matched norms, and weighted, combined

baseline.

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