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XELJANZ / XELJANZ XR (tofacitinib) Clinical Studies

14 CLINICAL STUDIES

14.1 Rheumatoid Arthritis

The XELJANZ clinical development program included two dose-ranging trials and five confirmatory trials. Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily. XELJANZ 10 mg twice daily is not recommended for the treatment of rheumatoid arthritis [see Dosage and Administration (2.2)].

Dose-Ranging Trials

Dose selection for XELJANZ was based on two pivotal dose-ranging trials.

Dose-Ranging Study 1 was a 6-month monotherapy trial in 384 patients with active rheumatoid arthritis who had an inadequate response to a DMARD. Patients who previously received adalimumab therapy were excluded. Patients were randomized to 1 of 7 monotherapy treatments: XELJANZ 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by XELJANZ 5 mg twice daily for 3 months, or placebo.

Dose-Ranging Study 2 was a 6-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of XELJANZ (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.

The results of XELJANZ-treated patients achieving ACR20 responses in Studies 1 and 2 are shown in Figure 4. Although a dose-response relationship was observed in Study 1, the proportion of patients with an ACR20 response did not clearly differ between the 10 mg and 15 mg doses. In Study 2, a smaller proportion of patients achieved an ACR20 response in the placebo and XELJANZ 1 mg groups compared to patients treated with the other XELJANZ doses. However, there was no difference in the proportion of responders among patients treated with XELJANZ 3, 5, 10, 15 mg twice daily or 20 mg once daily doses.

Figure 4: Proportion of Patients with ACR20 Response at Month 3 in Dose-Ranging Studies 1 and 2

Figure 4

Study 1 was a dose-ranging monotherapy trial not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority to adalimumab.

Confirmatory Trials

Study RA-I (NCT00814307) was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced 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, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.

Study RA-II (NCT00856544) was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 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 advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined 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.

Study RA-III (NCT00853385) was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study 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.

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 rheumatoid arthritis who had an inadequate response to MTX received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study 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.

Study RA-V (NCT00960440) was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF blocking biologic agent received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced 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.

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 rheumatoid arthritis 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.

Clinical Response

The percentages of XELJANZ-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies RA-I, IV, and V are shown in Table 8. 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 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.

Table 8: Proportion of Patients with an ACR Response
Percent of Patients
Monotherapy in Nonbiologic or Biologic DMARD Inadequate Responders*MTX Inadequate RespondersTNF Blocker Inadequate Responders
Study IStudy IVStudy V
N§PBOXELJANZ
5 mg Twice Daily
PBO + MTXXELJANZ 5 mg Twice Daily + MTXPBO + MTXXELJANZ 5 mg Twice Daily + MTX
122243160321132133
*
Inadequate response to at least one DMARD (biologic or nonbiologic) due to lack of efficacy or toxicity.
Inadequate response to MTX defined as the presence of sufficient residual disease activity to meet the entry criteria.
Inadequate response to a least one TNF blocker due to lack of efficacy and/or intolerance.
§
N is number of randomized and treated patients.
NA Not applicable, as data for placebo treatment is not available beyond 3 months in Studies I and V due to placebo advancement.
ACR20
Month 326%59%27%55%24%41%
Month 6NA69%25%50%NA51%
ACR50
Month 312%31%8%29%8%26%
Month 6NA42%9%32%NA37%
ACR70
Month 36%15%3%11%2%14%
Month 6NA22%1%14%NA16%

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 9).

Table 9: Proportion of Patients with DAS28-4(ESR) Less Than 2.6 with Number of Residual Active Joints
Study IV
DAS28-4(ESR) Less Than 2.6Placebo + MTXXELJANZ 5 mg Twice Daily + MTX
160321
Proportion of responders at Month 6 (n)1% (2)6% (19)
Of responders, proportion with 0 active joints (n)50% (1)42% (8)
Of responders, proportion with 1 active joint (n)05% (1)
Of responders, proportion with 2 active joints (n)032% (6)
Of responders, proportion with 3 or more active joints (n)50% (1)21% (4)

The results of the components of the ACR response criteria for Study RA-IV are shown in Table 10. Similar results were observed for XELJANZ in Studies RA-I, II, III, V, and VI.

Table 10: Components of ACR Response at Month 3
Study IV
XELJANZ 5 mg Twice Daily + MTXPlacebo + MTX
N=321N=160
Component (mean) *BaselineMonth 3*BaselineMonth 3*
*
Data shown is mean (Standard Deviation) at Month 3.
Visual analog scale: 0 = best, 100 = worst.
Health Assessment Questionnaire Disability Index: 0 = best, 3 = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Number of tender joints
(0–68)
24
(14)
13
(14)
23
(13)
18
(14)
Number of swollen joints
(0–66)
14
(8)
6
(8)
14
(9)
10
(9)
Pain58
(23)
34
(23)
55
(24)
47
(24)
Patient global assessment58
(24)
35
(23)
54
(23)
47
(24)
Disability index
(HAQ-DI)
1.41
(0.68)
0.99
(0.65)
1.32
(0.67)
1.19
(0.68)
Physician global assessment59
(16)
30
(19)
56
(18)
43
(22)
CRP (mg/L)15.3
(19.0)
7.1
(19.1)
13.7
(14.9)
14.6
(18.7)

The percent of ACR20 responders by visit for Study RA-IV is shown in Figure 5. Similar responses were observed for XELJANZ in Studies RA-I, II, III, V, and VI.

Figure 5: Percentage of ACR20 Responders by Visit for Study RA-IV

Figure 5

Radiographic Response

Two studies were conducted to evaluate the effect of XELJANZ on structural joint damage. In Study RA-IV and Study RA-VI, progression of structural joint damage was assessed radiographically and expressed as change from baseline in mTSS and its components, the erosion score and joint space narrowing score, at Months 6 and 12. The proportion of patients with no radiographic progression (mTSS change less than or equal to 0) was also assessed.

In Study RA-IV, XELJANZ 5 mg twice daily reduced the mean progression of structural damage (not statistically significant) as shown in Table 10. Analyses of erosion and joint space narrowing scores were consistent with the overall results.

In the placebo plus MTX group, 74% of patients experienced no radiographic progression at Month 6 compared to 84% of patients treated with XELJANZ plus MTX 5 mg twice daily.

In Study RA-VI, XELJANZ monotherapy inhibited the progression of structural damage compared to MTX at Months 6 and 12 as shown in Table 10. Analyses of erosion and joint space narrowing scores were consistent with the overall results.

In the MTX group, 55% of patients experienced no radiographic progression at Month 6 compared to 73% of patients treated with XELJANZ 5 mg twice daily.

Table 11: Radiographic Changes at Months 6 and 12
*
SD = Standard Deviation
Difference between least squares means XELJANZ minus placebo or MTX (95% CI = 95% confidence interval)
Month 6 and Month 12 data are mean change from baseline.
Study IV
Placebo
N=139
Mean (SD)*
XELJANZ 5 mg Twice Daily
N=277
Mean (SD) *
XELJANZ 5 mg Twice Daily
Mean Difference from Placebo (CI)
mTSS
Baseline33 (42)31 (48)-
Month 60.5 (2.0)0.1 (1.7)-0.3 (-0.7, 0.0)
Study VI
MTX
N=166
Mean (SD)*
XELJANZ 5 mg Twice Daily
N=346
Mean (SD) *
XELJANZ 5 mg Twice Daily
Mean Difference from MTX (CI)
mTSS
Baseline17 (29)20 (40)-
Month 60.8 (2.7)0.2 (2.3)-0.7 (-1.0, -0.3)
Month 121.3 (3.7)0.4 (3.0)-0.9 (-1.4, -0.4)

Physical Function Response

Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ 5 mg twice daily demonstrated greater improvement from baseline in physical functioning compared to placebo at Month 3.

The mean (95% CI) difference from placebo in HAQ-DI improvement from baseline at Month 3 in Study RA-III was -0.22 (-0.35, -0.10) in patients receiving 5 mg XELJANZ twice daily. Similar results were obtained in Studies RA-I, II, IV and V. In the 12-month trials, HAQ-DI results in XELJANZ-treated patients were consistent at 6 and 12 months.

Other Health-Related Outcomes

General health status was assessed by the Short Form health survey (SF-36). In Studies RA-I, IV, and V, patients receiving XELJANZ 5 mg twice daily demonstrated greater improvement from baseline compared to placebo in physical component summary (PCS), mental component summary (MCS) scores and in all 8 domains of the SF-36 at Month 3.

14.2 Psoriatic Arthritis

The XELJANZ clinical development program to assess efficacy and safety included 2 multicenter, randomized, double-blind, placebo-controlled confirmatory trials in 816 patients 18 years of age and older (PsA-I and PsA-II). Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily. XELJANZ 10 mg twice daily is not recommended for the treatment of psoriatic arthritis [see Dosage and Administration (2.2)]. All patients had active psoriatic arthritis 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 psoriatic arthritis 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 psoriatic arthritis 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.

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. 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 advanced in a blinded fashion to a predetermined XELJANZ dose of 5 mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate noninferiority or superiority to adalimumab.

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 advanced in a blinded fashion to a predetermined XELJANZ dose of 5 mg or 10 mg twice daily as in Study PsA-I.

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 12 and 13).

Table 12: Proportion of Patients with an ACR Response in Study PsA-I* [Nonbiologic DMARD Inadequate Responders (TNF Blocker-Naïve)]
Treatment GroupPlaceboXELJANZ
5 mg
Twice Daily
N105107
Response RateResponse RateDifference (%)
95% CI from Placebo
Subjects with missing data were treated as non-responders.
*
Subjects received one concomitant nonbiologic DMARD.
N is number of randomized and treated patients.
Month 3
  ACR2033%50%17.1 (4.1, 30.2)
  ACR5010%28%18.5 (8.3, 28.7)
  ACR705%17%12.1 (3.9, 20.2)
Table 13: Proportion of Patients with an ACR Response in Study PsA-II* (TNF Blocker Inadequate Responders)
Treatment GroupPlaceboXELJANZ
5 mg
Twice Daily
N131131
Response RateResponse RateDifference (%)
95% CI from Placebo
Subjects with missing data were treated as non-responders.
*
Subjects received one concomitant nonbiologic DMARD.
N is number of randomized and treated patients.
Month 3
  ACR2024%50%26.0 (14.7, 37.2)
  ACR5015%30%15.3 (5.4, 25.2)
  ACR7010%17%6.9 (-1.3, 15.1)

Improvements from baseline in the ACR response criteria components for both studies are shown in Table 14.

Table 14: Components of ACR Response 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*
Treatment GroupPlaceboXELJANZ
5 mg
Twice Daily
PlaceboXELJANZ
5 mg
Twice Daily
N at Baseline105107131131
*
Subjects received one concomitant nonbiologic DMARD.
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.
ACR Component
Number of tender/painful joints (0–68)
  Baseline20.620.519.820.5
  Month 314.612.215.111.5
Number of swollen joints (0–66)
  Baseline11.512.910.512.1
  Month 37.16.37.74.8
Patient assessment of arthritis pain
  Baseline53.255.754.956.4
  Month 344.734.748.036.1
Patient global assessment of arthritis
  Baseline53.954.755.857.4
  Month 344.435.549.236.9
HAQ-DI§
  Baseline1.111.161.251.26
  Month 30.950.811.090.88
Physician's Global Assessment of Arthritis
  Baseline53.854.653.753.5
  Month 335.429.536.427.0
CRP (mg/L)
  Baseline10.410.512.113.8
  Month 38.64.011.47.7

The percentage of ACR20 responders by visit for Study PsA-I is shown in Figure 6. 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).

BID=twice daily; SE=standard error.
Subjects with missing data were treated as non-responders.
*
Subjects received one concomitant nonbiologic DMARD.
Figure 6: Percentage of ACR20 Responders by Visit Through Month 3 in Study PsA-I*

Figure 6

In patients with active psoriatic arthritis evidence of benefit in enthesitis and dactylitis was observed with XELJANZ treatment.

Physical Function

Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ 5 mg twice daily demonstrated significantly greater improvement (p ≤0.05) from baseline in physical functioning compared to placebo at Month 3 (Table 15).

Table 15: Change from Baseline in HAQ-DI in Studies PsA-I and PsA-II
Least Squares Mean Change from Baseline In HAQ-DI at Month 3
Nonbiologic DMARD Inadequate Responders* (TNF Blocker-Naïve)TNF Blocker Inadequate Responders
Study PsA-IStudy PsA-II
Treatment GroupPlaceboXELJANZ 5 mg
Twice Daily
PlaceboXELJANZ 5 mg
Twice Daily
N§104107131129
*
Inadequate response to at least one nonbiologic DMARD due to lack of efficacy and/or intolerability.
Inadequate response to at least one TNF blocker due to lack of efficacy and/or intolerability.
Subjects received one concomitant nonbiologic DMARD.
§
N is the total number of subjects in the statistical analysis.
LSM Change from Baseline-0.18-0.35-0.14-0.39
Difference from Placebo (95% CI)--0.17
(-0.29, -0.05)
--0.25
(-0.38, -0.13)

In Study PsA-I, the HAQ-DI responder rate (response defined as having improvement from baseline of ≥0.35) at Month 3 was 53% in patients receiving XELJANZ 5 mg twice daily and 31% in patients receiving placebo. Similar responses were observed in Study PsA-II.

Other Health-Related Outcomes

General health status was assessed by the Short Form health survey (SF-36). In Studies PsA-I and PsA-II, patients receiving XELJANZ 5 mg twice daily had greater improvement from baseline compared to placebo in Physical Component Summary (PCS) score, but not in Mental Component Summary (MCS) score at Month 3. Patients receiving XELJANZ 5 mg twice daily reported consistently greater improvement relative to placebo in the domains of Physical Functioning, Bodily Pain, Vitality, and Social Functioning, but not in Role Physical, General Health, Role Emotional, or Mental Health.

Radiographic Response

Treatment effect on inhibition of radiographic progression in psoriatic arthritis could not be established from the results of Study PsA-I.

14.3 Ulcerative Colitis

Induction Trials (Study UC-I [NCT01465763] and Study UC-II [NCT01458951])

In two identical induction trials (UC-I and UC-II), 1139 patients were randomized (598 and 541 patients, respectively) to XELJANZ 10 mg twice daily or placebo with a 4:1 treatment allocation ratio. These trials included adult patients with moderately to severely active UC (total Mayo score of 6 to 12, with an endoscopy subscore of at least 2, and rectal bleeding subscore of at least 1) and who had failed or were intolerant to at least 1 of the following treatments: oral or intravenous corticosteroids, azathioprine, 6-MP or TNF blocker. XELJANZ is indicated for patients who have an inadequate response or who are intolerant to TNF blockers [see Indications and Usage (1)].

The disease activity was assessed by Mayo scoring index (0 to 12) which consists of four subscores (0 to 3 for each subscore): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of 2 was defined by marked erythema, absent vascular pattern, any friability, and erosions; an endoscopy subscore of 3 was defined by spontaneous bleeding and ulceration.

Patients were permitted to use stable doses of oral aminosalicylates and corticosteroids (prednisone daily dose up to 25 mg equivalent). Concomitant immunosuppressants (oral immunomodulators or biologic therapies) were not permitted for UC patients during these studies.

A total of 52%, 73% and 72% of patients had previously failed or were intolerant to TNF blockers (51% in Study UC-1 and 52% in Study UC-II), corticosteroids (75% in Study UC-I and 71% in Study UC-II), and/or immunosuppressants (74% in Study UC-I and 70% in Study UC-II), respectively.

Oral corticosteroids were received as concomitant treatment for UC by 47% of patients (45% in Study UC-I and 48% in Study UC-II) and 71% were receiving concomitant aminosalicylates as treatment for UC (71% in Study UC-I, and 72% in Study UC-II). The baseline clinical characteristics were generally similar between the XELJANZ treated patients and patients receiving placebo.

The primary endpoint of Study UC-I and Study UC-II was the proportion of patients in remission at Week 8, and the key secondary endpoint was the proportion of patients with improvement of endoscopic appearance of the mucosa at Week 8.

The efficacy results of Study UC-I and Study UC-II based on the centrally read endoscopy results are shown in Table 16.

Table 16: Proportion of Patients Meeting Primary and Key Secondary Efficacy Endpoints at Week 8 (Induction Study UC-I and Study UC-II, Central Endoscopy Read)
CI = Confidence interval; N = number of patients in the analysis set; TNF = tumor necrosis factor
*
Remission was defined as clinical remission (a Mayo score ≤2 with no individual subscore >1) and rectal bleeding subscore of 0.
p-value <0.01,
Prior TNF blocker failure was defined in this program as inadequate response, loss of response, or intolerance to TNF blocker therapy.
§
Patients in this group had failed one or more conventional therapies (corticosteroid, azathioprine, 6-mercaptopurine) but did not have history of prior failure of TNF blocker therapy.
Improvement of endoscopic appearance of the mucosa was defined as Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern).
#
p-value <0.001.
Study UC-I
EndpointPlaceboXELJANZ
10 mg
Twice Daily
Treatment Difference versus Placebo
(95% CI)
Remission at Week 8*
Total PopulationN=122N=47610%
(4.3, 16.3)
8%18%
  With Prior TNF Blocker FailureN=64N=243
2%11%
  Without Prior TNF Blocker Failure§N=58N=233
16%26%
Improvement of endoscopic appearance of the mucosa at Week 8
Total PopulationN=122N=47616%#
(8.1, 23.4)
16%31%
  With Prior TNF Blocker FailureN=64N=243
6%23%
  Without Prior TNF Blocker Failure§N=58N=233
26%40%
Study UC-II
EndpointPlaceboXELJANZ
10 mg
Twice Daily
Treatment Difference
(95% CI)
Remission at Week 8*
Total PopulationN=112N=42913%#
(8.1, 17.9)
4%17%
  With Prior TNF Blocker FailureN=60N=222
0%12%
  Without Prior TNF Blocker Failure§N=52N=207
8%22%
Improvement of endoscopic appearance of the mucosa at Week 8
Total PopulationN=112N-42917%#
(9.5, 24.1)
12%28%
  With Prior TNF Blocker FailureN=60N=222
7%22%
  Without Prior TNF Blocker Failure§N=52N=207
17%36%

Clinical Response at Week 8

Clinical response was defined as a decrease from baseline in Mayo score of ≥3 points and ≥30%, with an accompanying decrease in the subscore for rectal bleeding of ≥1 point or absolute subscore for rectal bleeding of 0 or 1.

Clinical response was observed in 60% of patients treated with XELJANZ 10 mg twice daily compared to 33% of placebo patients in Study UC-I and 55% compared to 29% in Study UC-II.

Normalization of the Endoscopic Appearance of the Mucosa at Week 8

Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0 and was observed in 7% of patients treated with XELJANZ 10 mg twice daily compared to 2% of placebo patients in both Studies UC-I and UC-II.

Rectal Bleeding and Stool Frequency

Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in patients treated with XELJANZ.

Maintenance Trial (Study UC-III [NCT01458574])

A total of 593 patients who completed the induction trials (UC-I or UC-II) and achieved clinical response were re-randomized with 1:1:1 treatment allocation ratio to XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, or placebo for 52 weeks in Study UC-III. XELJANZ 5 mg twice daily is the recommended dosage for maintenance therapy; limit use of XELJANZ 10 mg twice daily beyond induction to those with loss of response and should be used for the shortest duration [see Dosage and Administration (2.3)]. As in the induction trials, patients were permitted to use stable doses of oral aminosalicylates; however, corticosteroid tapering was required upon entrance into this study for patients who were receiving corticosteroids at baseline. Concomitant immunosuppressants (oral immunomodulators or biologic therapies) were not permitted.

At baseline of Study UC-III:

  • 179 (30%) patients were in remission
  • 289 (49%) patients were receiving oral corticosteroids
  • 265 (45%), 445 (75%), and 413 (70%) patients had previously failed or were intolerant to TNF blocker therapy, corticosteroids, and immunosuppressants, respectively.

The primary endpoint was the proportion of patients in remission at Week 52. There were 2 key secondary endpoints: the proportion of patients with improvement of endoscopic appearance at Week 52, and the proportion of patients with sustained corticosteroid-free remission at both Week 24 and Week 52 among patients in remission at baseline of Study UC-III.

The efficacy results of Study UC-III based on the centrally read endoscopy results are summarized in Table 17.

Table 17: Proportion of Patients Meeting Primary and Key Secondary Efficacy Endpoints in Maintenance Study UC-III (Central Endoscopy Read)
Treatment Difference versus Placebo
(95% CI)
EndpointPlaceboXELJANZ
5 mg
Twice Daily
XELJANZ
10 mg
Twice Daily
XELJANZ
5 mg
Twice Daily
XELJANZ
10 mg
Twice Daily
CI = Confidence interval; N = number of patients in the analysis set; TNF = tumor necrosis factor.
*
Remission was defined as clinical remission (a Mayo score ≤2 with no individual subscore >1) and rectal bleeding subscore of 0.
p-value <0.0001.
Prior TNF blocker failure was defined in this program as inadequate response, loss of response, or intolerance to TNF blocker therapy.
§
Patients in this group had failed one or more conventional therapies (corticosteroid, azathioprine, 6-mercaptopurine) but did not have history of prior failure of TNF blocker therapy.
Improvement of endoscopic appearance of the mucosa was defined as Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern).
#
Sustained corticosteroid-free remission was defined as being in remission and not taking corticosteroids for at least 4 weeks prior to the visit at both Week 24 and Week 52.
Remission at Week 52*
Total PopulationN=198N=198N=19723%
(15.3, 31.2)
30%
(21.4, 37.6)
11%34%41%
  With Prior TNF Blocker FailureN=89N=83N=93
11%24%37%
  Without Prior TNF Blocker Failure§N=109N=115N=104
11%42%44%
Improvement of endoscopic appearance of the mucosa at Week 52
Total PopulationN=198N=198N=19724%
(16.0, 32.5)
33%
(24.2, 41.0)
13%37%46%
  With Prior TNF Blocker FailureN=89N=83N=93
12%30%40%
  Without Prior TNF Blocker Failure§N=109N=115N=104
14%43%51%
Sustained corticosteroid-free remission at both Week 24 and Week 52 among patients in remission at baseline#
Total PopulationN=59N=65N=5530%
(17.4, 43.2)
42%
(27.9, 56.5)
5%35%47%
  With Prior TNF Blocker FailureN=21N=18N=18
5%22%39%
  Without Prior TNF Blocker Failure§N=38N=47N=37
5%40%51%

Maintenance of Clinical Response

Maintenance of clinical response was defined as the proportion of patients who met the definition of clinical response (defined as a decrease from the induction study (UC-I, UC-II) baseline Mayo score of ≥3 points and ≥30%, with an accompanying decrease in the rectal bleeding subscore of ≥1 point or rectal bleeding subscore of 0 or 1) at both Baseline and Week 52 of Study UC-III.

Maintenance of clinical response was observed in 52% in the XELJANZ 5 mg twice daily group and 62% in the XELJANZ 10 mg twice daily group compared to 20% of placebo patients.

Maintenance of Remission (Among Patients in Remission at Baseline)

In the 179 patients who were in remission at baseline of Study UC-III (N = 59 for placebo, N = 65 for XELJANZ 5 mg twice daily, N = 55 for XELJANZ 10 mg twice daily), 46% in the XELJANZ 5 mg twice daily group and 56% in the XELJANZ 10 mg twice daily group maintained remission at Week 52 compared to 10% of placebo patients.

Normalization of the Endoscopic Appearance of the Mucosa

Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0 and was observed at Week 52 in 15% of patients in the XELJANZ 5 mg twice daily group and 17% of patients in the XELJANZ 10 mg twice daily group compared to 4% of placebo patients.

Open-label Extension Study (Study UC-IV [NCT01470612])

In Study UC-IV, 914 patients were treated of which 156 received 5 mg twice daily and 758 received 10 mg twice daily.

Of the 905 patients who were assigned to XELJANZ 10 mg twice daily in the 8-week induction studies (Study UC-I or Study UC-II), 322 patients completed the induction studies but did not achieve clinical response. Of these 322 patients, 291 continued to receive XELJANZ 10 mg twice daily (unblinded) and had available data after an additional 8 weeks in Study UC-IV. After 8 additional weeks (a total of 16 weeks treatment), 148 patients achieved clinical response, and 25 patients achieved remission (based on central endoscopy read). Among those 143 patients who achieved clinical response by 16 weeks and had available data at Week 52, 66 patients achieved remission (based on local endoscopy read) after continued treatment with XELJANZ 10 mg twice daily for 52 weeks.

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