14.1 Clinical Studies in Rheumatoid Arthritis

The rheumatoid arthritis (RA) clinical development program with XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) included six randomized controlled trials in adults with moderate to severe active RA.

Trial Design

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Study RA-I (NCT00814307) was a 6-month monotherapy trial in which 610 patients with moderate to severe active RA who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 mg or 10 mg twice daily or placebo added to their background DMARD. At the Month 3 visit, all patients randomized to placebo treatment were switched in a blinded fashion to a second predetermined treatment of XELJANZ 5 mg or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.

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Study RA-II (NCT00856544) was a 12-month trial in which 792 patients with moderate to severe active RA who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 mg or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were switched in a blinded fashion to a second predetermined treatment of XELJANZ 5 mg or 10 mg twice daily. At the end of Month 6, all patients treated with placebo were switched to their second predetermined XELJANZ treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.

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Study RA-III (NCT00853385) was a 12-month trial in 717 patients with moderate to severe active RA who had an inadequate response to methotrexate (MTX). Patients received XELJANZ 5 mg or 10 mg orally twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Patients treated with placebo were switched as in Study RA-II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.

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Study RA-IV (NCT00847613) was a 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active RA who had an inadequate response to MTX received XELJANZ 5 mg or 10 mg twice daily or placebo added to background MTX. Patients treated with placebo were switched as in Study RA-II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.

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Study RA-V (NCT00960440) was a 6-month trial in which 399 patients with moderate to severe active RA who had an inadequate response to at least one approved TNF blocking biological product received XELJANZ 5 mg or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were switched in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.

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Study RA-VI (NCT01039688) was a 2-year monotherapy trial with a planned analysis at 1 year in which 952 MTX-naïve patients with moderate to severe active RA received XELJANZ 5 or 10 mg twice daily or MTX dose-titrated over 8 weeks to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Month 6 and the proportion of patients who achieved an ACR70 response at Month 6.

Although other dosages have been studied, the recommended dosage of XELJANZ is 5 mg twice daily. XELJANZ 10 mg twice daily is not recommended for the treatment of RA [see Dosage and Administration (2.3)].

Clinical Response

The percentages of XELJANZ-treated patients who achieved ACR20, ACR50, and ACR70 responses in Studies RA-I, IV, and V are shown in Table 10. Similar results were observed with Studies RA-II and III. In trials RA-I through V, patients treated with 5 mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus patients treated with placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at 6 and 12 months.

In Study RA-IV, a greater proportion of patients treated with XELJANZ 5 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone (Table 11).

The results of the components of the ACR response criteria for Study RA-IV are shown in Table 12. Similar results were observed for XELJANZ in Studies RA-I, II, III, V, and VI.

The percent of ACR20 responders by visit for Study RA-IV is shown in Figure 4. Similar responses were observed for XELJANZ in Studies RA-I, II, III, V, and VI.

Figure 4: Percentage of ACR20 Responders by Visit Through Month 6 in Study RA-IV

14.2 Clinical Studies in Psoriatic Arthritis

The psoriatic arthritis (PsA) clinical development program with XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) included 2 multicenter, randomized, double-blind, placebo-controlled trials in 816 adults with active PsA (Studies PsA-I and PsA-II).

Trial Designs and Population

All patients had active PsA for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender/painful joints and at least 3 swollen joints, and active plaque psoriasis. Patients randomized and treated across the 2 clinical trials represented different PsA subtypes at screening, including <5 joints or asymmetric involvement (21%), ≥5 joints involved (90%), distal interphalangeal (DIP) joint involvement (61%), arthritis mutilans (8%), and spondylitis (19%). Patients in these clinical trials had a diagnosis of PsA for a mean (SD) of 7.7 (7.2) years. At baseline, 80% and 53% of patients had enthesitis and dactylitis, respectively. At baseline, all patients were required to receive treatment with a stable dose of a nonbiologic DMARD (79% received methotrexate, 13% received sulfasalazine, 7% received leflunomide, 1% received other nonbiologic DMARDs). In both clinical trials, the primary endpoints were the ACR20 response and the change from baseline in HAQ-DI at Month 3.

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Study PsA-I was a 12-month clinical trial in 422 patients who had an inadequate response to a nonbiologic DMARD (67% and 33% were inadequate responders to 1 nonbiologic DMARD and ≥2 nonbiologic DMARDs, respectively) and who were naïve to treatment with a TNF blocker. Although Study PsA-1 included patients who are TNF blocker-naïve, XELJANZ and XELJANZ XR are not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.2)]. Patients were randomized in a 2:2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, all patients randomized to placebo treatment were switched in a blinded fashion to a predetermined XELJANZ dosage of 5 mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate noninferiority or superiority to adalimumab.

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Study PsA-II was a 6-month clinical trial in 394 patients who had an inadequate response to at least 1 approved TNF blocker (66%, 19%, and 15% were inadequate responders to 1 TNF blocker, 2 TNF blockers and ≥3 TNF blockers, respectively). Patients were randomized in a 2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, placebo patients were switched in a blinded fashion to a predetermined XELJANZ dosage of 5 mg or 10 mg twice daily as in Study PsA-I.

Although other dosages have been studied, the recommended dosage of XELJANZ is 5 mg twice daily. XELJANZ 10 mg twice daily is not recommended for treatment of PsA [see Dosage and Administration (2.3)].

Clinical Response

At Month 3, patients treated with XELJANZ 5 mg twice daily had higher (p≤0.05) response rates versus placebo for ACR20, ACR50, and ACR70 in Study PsA-I and for ACR20 and ACR50 in Study PsA-II; ACR70 response rates were also higher for XELJANZ 5 mg twice daily versus placebo in Study PsA-II, although the differences versus placebo were not statistically significant (p>0.05) (Tables 14 and 15).

Table 14: Proportion of Adults with Active PsA with an ACR Response at Month 3 in Study PsA-I* [Nonbiologic DMARD Inadequate Responders (TNF Blocker-Naïve)]†

Treatment Group	Placebo	XELJANZ 5 mg Twice Daily + Background Nonbiologic DMARD
Patients with missing data were treated as non-responders.
* Patients received one concomitant nonbiologic DMARD. † XELJANZ and XELJANZ XR are not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.2)]. ‡ N is number of randomized and treated patients.
N‡	105	107
	Response Rate	Response Rate	Difference (%) 95% CI from Placebo
Month 3
ACR20	33%	50%	17.1 (4.1, 30.2)
ACR50	10%	28%	18.5 (8.3, 28.7)
ACR70	5%	17%	12.1 (3.9, 20.2)

Table 15: Proportion of Adults with Active PsA with an ACR Response at Month 3 in Study PsA-II* (TNF Blocker Inadequate Responders)

Treatment Group	Placebo	XELJANZ 5 mg Twice Daily
Patients with missing data were treated as non-responders.
* Patients received one concomitant nonbiologic DMARD. † N is number of randomized and treated patients.
N†	131	131
	Response Rate	Response Rate	Difference (%) 95% CI from Placebo
Month 3
ACR20	24%	50%	26.0 (14.7, 37.2)
ACR50	15%	30%	15.3 (5.4, 25.2)
ACR70	10%	17%	6.9 (-1.3, 15.1)

Improvements from baseline in the ACR response criteria components for both studies are shown in Table 16.

Table 16: Components of ACR Response in Adults with Active PsA at Baseline and Month 3 in Studies PsA-I and PsA-II

	Nonbiologic DMARD Inadequate Responders (TNF Blocker-Naïve)		TNF Blocker Inadequate Responders
	Study PsA-I*,†		Study PsA-II*
* Patients received one concomitant nonbiologic DMARD. † XELJANZ and XELJANZ XR are not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.2)]. ‡ Data shown are mean value at baseline and at Month 3. § Visual analog scale (VAS): 0 = best, 100 = worst. ¶ HAQ-DI = Health Assessment Questionnaire – Disability Index: 0 = best, 3 = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Treatment Group	Placebo	XELJANZ 5 mg Twice Daily	Placebo	XELJANZ 5 mg Twice Daily
N at Baseline	105	107	131	131
ACR Component‡
Number of tender/painful joints (0–68)
Baseline	20.6	20.5	19.8	20.5
Month 3	14.6	12.2	15.1	11.5
Number of swollen joints (0–66)
Baseline	11.5	12.9	10.5	12.1
Month 3	7.1	6.3	7.7	4.8
Patient assessment of arthritis pain§
Baseline	53.2	55.7	54.9	56.4
Month 3	44.7	34.7	48.0	36.1
Patient global assessment of arthritis§
Baseline	53.9	54.7	55.8	57.4
Month 3	44.4	35.5	49.2	36.9
HAQ-DI¶
Baseline	1.11	1.16	1.25	1.26
Month 3	0.95	0.81	1.09	0.88
Physician's Global Assessment of Arthritis§
Baseline	53.8	54.6	53.7	53.5
Month 3	35.4	29.5	36.4	27.0
CRP (mg/L)
Baseline	10.4	10.5	12.1	13.8
Month 3	8.6	4.0	11.4	7.7

The percentage of ACR20 responders by visit for Study PsA-I is shown in Figure 5. Similar responses were observed in Study PsA-II. In both studies, improvement in ACR20 response on XELJANZ was observed at the first visit after baseline (Week 2).

Figure 5: Percentage of ACR20 Responders by Visit Through Month 3 in Study PsA-I*†

BID = twice daily; SE = standard error.

Patients with missing data were treated as non-responders.

* Subjects received one concomitant nonbiologic DMARD. † XELJANZ and XELJANZ XR are not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.2)].

14.3 Clinical Studies in Ankylosing Spondylitis

The ankylosing spondylitis (AS) clinical development program with XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) included one placebo-controlled trial (Study AS-I) in adults with active AS. Patients had active disease as defined by both Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and back pain score (BASDAI question 2) of greater or equal to 4 despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease modifying anti-rheumatic drug (DMARD) therapy.

Clinical Response

Patients treated with XELJANZ 5 mg twice daily achieved greater improvements in ASAS20 and ASAS40 responses compared to patients treated with placebo at Week 16 (Table 18). Consistent results were observed in the subgroup of patients who had an inadequate response to TNF blockers for both the ASAS20 (primary endpoint) and ASAS40 (secondary endpoint) at Week 16 (Table 18).

Table 18: ASAS20 and ASAS40 Responses in Adults with Active AS at Week 16 in Study AS-I

	Placebo	XELJANZ 5 mg Twice Daily	Difference from Placebo (95% CI)
Abbreviations: CI = confidence interval; TNFi-IR = tumor necrosis factor inhibitor inadequate response.
* type I error-controlled. † p-value <0.0001.
All patients (N)	N=136	N=133
ASAS20 response*, %	29	56	27 (16, 38)†
ASAS40 response*, %	13	41	28 (18, 38)†
TNFi-IR patients (N)	N=30	N=29
ASAS20 response, %	17	41	25 (2, 47)
ASAS40 response, %	7	28	21 (2, 39)

The improvements in the components of the ASAS response and other measures of disease activity were greater in the XELJANZ 5 mg twice daily group compared to the placebo group as shown in Table 19.

Table 19: ASAS Components and Other Measures of Disease Activity in Adults with Active AS at Week 16 in Study AS-I

	Placebo (N=136)		XELJANZ 5 mg Twice Daily (N=133)
	Baseline (mean)	Week 16 (LSM change from Baseline)*	Baseline (mean)	Week 16 (LSM change from Baseline)*	Difference from Placebo (95% CI)*
LSM = least squares mean.
* Estimates are generated based on a mixed model for repeated measures using both on-treatment and off-treatment data. † Measured on a numerical rating scale with 0 = not active or no pain, 10 = very active or most severe pain. ‡ type I error-controlled. § p < 0.0001. ¶ Bath Ankylosing Spondylitis Functional Index measured on a numerical rating scale with 0 = easy and 10 = impossible. # Inflammation is the mean of two patient-reported stiffness self-assessments in BASDAI. Þ BASDAI total score. ß Bath Ankylosing Spondylitis Metrology Index. à High sensitivity C-reactive protein.
ASAS Components
- Patient Global Assessment of Disease Activity (0–10)†,‡	7.0	-1.0	6.9	-2.5	-1.5 (-2.00, -0.97)§
- Total spinal pain (0–10)†,‡	6.9	-1.1	6.9	-2.6	-1.5 (-2.00, -1.03)§
- BASFI (0–10)¶,‡	5.9	-0.8	5.8	-2.0	-1.2 (-1.64, -0.79)§
- Inflammation (0–10)#,‡	6.8	-1.1	6.6	-2.8	-1.7 (-2.13, -1.18)§
BASDAI ScoreÞ	6.5	-1.2	6.4	-2.6	-1.4 (-1.86, -0.98)§
BASMIß,‡	4.4	-0.1	4.5	-0.6	-0.5 (-0.66, -0.36)§
hsCRPà,‡ (mg/dL)	1.8	-0.1	1.6	-1.1	-0.9 (-1.17, -0.69)§

The percentage of patients with active AS who achieved ASAS20 response by visit is shown in Figure 6.

Figure 6: Percentage of ASAS20 Responders Over Time Up to Week 16 in Patients with Active AS in Study AS-I

SE = standard error.
Patients with missing data were treated as non-responders.

14.4 Clinical Studies in Polyarticular Course Juvenile Idiopathic Arthritis

The efficacy of XELJANZ (tablets and oral solution) for pcJIA was assessed in Study pcJIA-I (NCT02592434). This was a 44-week, two-part study (that consisted of an 18-week, open-label, run-in phase, followed by a 26-week double-blind, placebo-controlled, randomized withdrawal phase) in pediatric patients 2 years to 17 years of age with active rheumatoid factor (RF) negative polyarthritis, RF positive polyarthritis, extended oligoarthritis, and systemic JIA without systemic manifestations who had an inadequate response or intolerance to at least one DMARD which could have included MTX or biologic agents. This study also included patients ages 2 years to 17 years of age with active juvenile psoriatic arthritis (jPsA) and enthesitis-related arthritis (ERA) who had an inadequate response to NSAIDs. Although the clinical studies included some patients who are TNF blocker-naïve, XELJANZ is not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.4)].

Patients received XELJANZ (dosed at 5 mg twice daily or body weight-based equivalent twice daily) for 18 weeks (run-in phase) followed by randomization to either XELJANZ (dosed at 5 mg twice daily or body weight-based equivalent twice daily) or placebo for 26 weeks (double blind phase). Only patients who achieved at least a JIA ACR30 response at the end of the run-in phase were randomized (1:1) to the double-blind phase. Treatment with a stable dose of MTX was permitted but was not required during the study. Concurrent use of biologics or DMARDs other than MTX was not permitted in the study.

Baseline Disease Characteristics

A total of 225 pediatric patients with JIA (56 male and 169 female) with active polyarthritis were enrolled in the run-in phase including RF negative (104), RF positive (39), extended oligoarthritis (28), systemic JIA without systemic manifestations (13), jPsA (20), and ERA (21). Patients had a mean (SD) disease duration of 3.8 ± 3.5 years, and a mean (SD) number of active joints of 12.2 ± 8.1.

Efficacy Results

Of the 225 patients, 173 (77%) patients achieved JIA ACR30 response at Week 18 and were randomized into the double-blind phase to either XELJANZ (n=88) or placebo (n=85). At the conclusion of the 18-week, open-label, run-in phase, pediatric ACR 30/50/70 responses were 77%, 70%, and 49%, respectively.

In both the run-in and double-blind phases, approximately one-third of the patients were taking concomitant oral corticosteroids, and approximately two-thirds were taking concomitant MTX.

The primary endpoint was the occurrence of disease flare at Week 44 relative to the double-blind phase baseline at Week 18. Disease flare was defined (according to Pediatric Rheumatology Collaborative Study Group (PRCSG)/Pediatric Rheumatology International Trials Organization (PRINTO) Disease Flare criteria) as worsening of ≥30% in 3 or more of the 6 JIA core response variables with no more than 1 of the remaining JIA core response variables improving by ≥30%.

XELJANZ-treated patients experienced significantly fewer disease flares at Week 44 compared to placebo-treated patients (31% [27/88] vs. 55% [47/85]; difference in proportions -25% [95% CI: -39%, -10%]; p=0.0007). The occurrence of disease flare by visit in Study pcJIA-I is shown in Figure 7.

Figure 7: Occurrence of Disease Flare in Pediatric Patients 2 Years of Age and Older with JIA by Visit from Week 18 to Week 44 in the Double-Blind Phase in Study pcJIA-I

BID = twice daily; SE = standard error; N = total number of patients.

The 26-week double-blind phase is from Week 18 through Week 44 on and after randomization day.

14.5 Clinical Studies in Ulcerative Colitis

14.6 Safety Study in Adults with Rheumatoid Arthritis (XELJANZ Versus TNF-blocker)

A randomized open-label trial (RA Safety Study 1; NCT02092467) was conducted to evaluate safety with XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) at two doses, 5 mg twice daily (N=1455) and 10 mg twice daily (N=1456), versus the TNF-blocker control (N=1451) in RA patients 50 years of age and older with at least one cardiovascular risk factor. The co-primary endpoints were adjudicated MACE (defined as cardiovascular death, non-fatal MI, and non-fatal stroke) and adjudicated malignancy (excluding non-melanoma skin cancer). The study was designed to exclude a prespecified risk margin of 1.8 for the hazard ratio of combined XELJANZ regimens versus the TNF-blocker control for each co-primary endpoint. An independent committee conducted a blinded evaluation of the co-primary endpoints according to predefined criteria (adjudication). The study was event-driven and patients were followed until a sufficient number of primary outcome events accrued. Other endpoints included mortality, serious infections, and thromboembolic events. The median on-study follow-up time was 4 years.

The mean age of the population was 61 years (range: 50 to 88 years). Most patients were female (78%) and Caucasian (77%). Patients had a diagnosis of RA for a mean of 10 years, and a median swollen and tender joint count of 11 and 15 respectively. Cardiovascular risk factors included cigarette smoking (current or past) (48%), hypertension (66%), high density lipoprotein <40 mg/dL (12%), diabetes mellitus (17%), family history of premature coronary heart disease (15%), extra-articular disease associated with RA (37%), and history of coronary artery disease (11%).

The non-inferiority criterion was not met for the primary comparison of the combined XELJANZ dosages to TNF blockers since the upper limit of the 95% CI exceeded the pre-specified non-inferiority criterion of 1.8 (for MACE, the upper limit of the 95% CI was 1.94; for malignancies excluding NMSC, the upper limit of the 95% CI was 2.09).

Table 22 shows the study results for each of the co-primary endpoints, and other endpoints. There was an increased risk of death, MACE, malignancies, serious infections, and thromboembolic events associated with both dosages of XELJANZ.

Lymphomas and lung cancers, which are a subset of all malignancies in RA Safety Study 1, were observed at a higher rate in patients treated with XELJANZ 5 mg twice a day and XELJANZ 10 mg twice a day compared to those treated with TNF blockers. Lymphoma was reported for 4 patients who received XELJANZ 5 mg twice a day, 6 patients who received XELJANZ 10 mg twice a day, and 1 patient who received TNF blockers (Incidence Rate [IR] of 0.07, 0.11, and 0.02 per 100 patient-years, respectively). Among current and past smokers, lung cancer was reported for 13 patients who received XELJANZ 5 mg twice a day, 15 patients who received XELJANZ 10 mg twice a day, and 7 patients who received TNF blockers (IR of 0.48, 0.59, and 0.27 per 100 patient-years, respectively).

Given these increased risks, XELJANZ (tablets and oral solution) 10 mg twice daily (or XELJANZ XR (extended-release tablets) 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS or pcJIA [see Dosage and Administration (2.3, 2.4)].