14 CLINICAL STUDIES

14.1 Rheumatoid Arthritis

The efficacy and safety of RINVOQ 15 mg once daily were assessed in five Phase 3 randomized, double-blind, multicenter trials in patients with moderately to severely active rheumatoid arthritis and fulfilling the ACR/EULAR 2010 classification criteria. Patients 18 years of age and older were eligible to participate. The presence of at least 6 tender and 6 swollen joints and evidence of systemic inflammation based on elevation of hsCRP was required at baseline. Although other doses have been studied, the recommended dosage of RINVOQ is 15 mg once daily.

Trial RA-I (NCT02706873) was a 24-week monotherapy trial in 947 patients with moderately to severely active rheumatoid arthritis who were naïve to methotrexate (MTX). Patients received RINVOQ 15 mg or upadacitinib 30 mg orally once daily or MTX as monotherapy. At Week 26, non-responding patients on upadacitinib could be rescued with the addition of MTX, while patients on MTX could be rescued with the addition of blinded RINVOQ 15 mg or upadacitinib 30 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR50 response at Week 12. Key secondary endpoints included disease activity score (DAS28-CRP) ≤3.2 at Week 12, DAS28-CRP <2.6 at Week 24, change from baseline in HAQ-DI at Week 12, and change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Week 24.

Trial RA-II (NCT02706951) was a 14-week monotherapy trial in 648 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to MTX. Patients received RINVOQ 15 mg or upadacitinib 30 mg once daily monotherapy or continued their stable dose of MTX monotherapy. At Week 14, patients who were randomized to MTX were advanced to RINVOQ 15 mg or upadacitinib 30 mg once daily monotherapy in a blinded manner based on pre-determined assignment at baseline. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 14. Key secondary endpoints included DAS28-CRP ≤3.2, DAS28-CRP <2.6, and change from baseline in HAQ-DI at Week 14.

Trial RA-III (NCT02675426) was a 12-week trial in 661 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to conventional disease modifying anti-rheumatic drugs (cDMARDs). Patients received RINVOQ 15 mg or upadacitinib 30 mg once daily or placebo added to background cDMARD therapy. At Week 12, patients who were randomized to placebo were advanced to RINVOQ 15 mg or upadacitinib 30 mg once daily in a blinded manner based on pre-determined assignment at baseline. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12. Key secondary endpoints included DAS28-CRP ≤3.2, DAS28-CRP<2.6, and change from baseline in HAQ-DI at Week 12.

Trial RA-IV (NCT02629159) was a 48-week trial in 1629 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to MTX. Patients received RINVOQ 15 mg once daily, active comparator, or placebo added to background MTX. From Week 14, non-responding patients on RINVOQ 15 mg could be rescued to active comparator in a blinded manner, and non-responding patients on active comparator or placebo could be rescued to RINVOQ 15 mg in a blinded manner. At Week 26, all patients randomized to placebo were switched to RINVOQ 15 mg once daily in a blinded manner. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12 versus placebo. Key secondary endpoints versus placebo included DAS28-CRP ≤3.2, DAS28-CRP <2.6, change from baseline in HAQ-DI at Week 12, and change from baseline in mTSS at Week 26.

Trial RA-V (NCT02706847) was a 12-week trial in 499 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to biologic DMARDs. Patients received RINVOQ 15 mg or upadacitinib 30 mg once daily or placebo added to background cDMARD therapy. At Week 12, patients who were randomized to placebo were advanced to RINVOQ 15 mg or upadacitinib 30 mg once daily in a blinded manner based on pre-determined assignment at baseline. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12. Key secondary endpoints included DAS28-CRP ≤3.2 and change from baseline in HAQ-DI at Week 12.

Clinical Response

The percentages of RINVOQ-treated patients achieving ACR20, ACR50, and ACR70 responses, and DAS28(CRP) < 2.6 in all trials are shown in Table 13.

Patients treated with RINVOQ 15 mg, alone or in combination with cDMARDs, achieved higher ACR response rates compared to MTX monotherapy or placebo, respectively, at the primary efficacy timepoint (Table 13 ).

In Trial IV, the percent of patients achieving ACR20 response by visit is shown in Figure 1.

In Trials RA-III and RA-V, higher ACR20 response rates were observed at 1 week with RINVOQ 15 mg versus placebo.

Treatment with RINVOQ 15 mg, alone or in combination with cDMARDs, resulted in greater improvements in the ACR components compared to MTX or placebo at the primary efficacy timepoint (Table 14 ).

Table 13: Clinical Response in RA Patients in Trials RA-I, RA-II, RA-III, RA-IV and RA V
Trial RA-I MTX-Naïve		Trial RA-II MTX-IR		Trial RA-III cDMARD-IR		Trial RA-IV MTX-IR		Trial RA-V bDMARD-IR
Monotherapy		Monotherapy		Background cDMARDs		Background MTX		Background cDMARDs
MTX	RINVOQ 15 mg % Δ (95% CI)	MTX	RINVOQ 15 mg % Δ (95% CI)	PBO	RINVOQ 15 mg % Δ (95% CI)	PBO	RINVOQ 15 mg % Δ (95% CI)	PBO	RINVOQ 15 mg % Δ (95% CI)
N	314	317	216	217	221	221	651	651	169	164
Week
ACR20
12 ^a/14 ^b	54	76 22 (14, 29)	41	68 26 (17, 36)	36	64 28 (19, 37)	36	71 34 (29, 39)	28	65 36 (26, 46)
24 ^c/26 ^d	59	79 20 (13, 27)	36	67 32 (27, 37)
ACR50
12 ^a/14 ^b	28	52 24 (16, 31)	15	42 27 (18, 35)	15	38 23 (15, 31)	15	45 30 (26, 35)	12	34 22 (14, 31)
24 ^c/26 ^d	33	60 27 (19, 34)	21	54 33 (28, 38)
ACR70
12 ^a/14 ^b	14	32 18 (12, 25)	3	23 20 (14, 26)	6	21 15 (9, 21)	5	25 20 (16, 24)	7	12 5 (-1, 11)
24 ^c/26 ^d	18	44 26 (19, 33)	10	35 25 (21, 29)
DAS28-CRP <2.6
12 ^a/14 ^b	14	36 22 (15, 28)	8	28 20 (13, 27)	10	31 21 (14, 28)	6	29 23 (19, 27)	9	29 19 (11, 27)
24 ^c/26 ^d	18	48 30 (23, 37)	9	41 32 (27, 36)
Abbreviations: ACR20 (or 50 or 70) = American College of Rheumatology ≥20% (or ≥50% or ≥70%) improvement; bDMARD = biologic disease-modifying anti-rheumatic drug; CRP = c-reactive protein; DAS28 = Disease Activity Score 28 joints; cDMARDs = conventional disease-modifying anti-rheumatic drugs; MTX = methotrexate; PBO = placebo; IR = inadequate responder Patients who discontinued randomized treatment, or had cross-over between randomized treatments, or were missing data at week of evaluation were imputed as non-responders in the analyses. ^aTrial RA-I, Trial RA-III, Trial RA-IV, Trial RA-V ^bTrial RA-II ^cTrial RA-I ^dTrial RA-IV

Table 14: Components of ACR Response at Primary Efficacy Timepoint ^a
Trial RA-I MTX-Naïve		Trial RA-II ^b MTX-IR		Trial RA-III cDMARD-IR		Trial RA-IV MTX-IR		Trial RA-V bDMARD-IR
Monotherapy		Monotherapy		Background cDMARDs		Background MTX		Background cDMARDs
MTX	RINVOQ 15 mg	MTX	RINVOQ 15 mg	PBO	RINVOQ 15 mg	PBO	RINVOQ 15 mg	PBO	RINVOQ 15 mg
N	314	317	216	217	221	221	651	651	169	164
Number of tender joints (0-68)
Baseline	26 (16)	25 (14)	25 (16)	24 (15)	25 (15)	25 (14)	26 (14)	26 (15)	28 (15)	28 (16)
Week 12/14	13 (15)	9 (12)	15 (16)	10 (13)	16 (17)	12 (14)	16 (15)	10 (13)	18 (17)	11 (14)
Number of swollen joints (0-66)
Baseline	17 (11)	17 (10)	17 (12)	16 (11)	15 (9)	16 (10)	16 (9)	17 (10)	16 (10)	17 (11)
Week 12/14	6 (8)	5 (7)	9 (11)	6 (9)	9 (10)	7 (10)	9 (9)	5 (7)	9 (10)	6 (8)
Pain ^c
Baseline	66 (21)	68 (21)	63 (21)	62 (23)	62 (21)	64 (19)	65 (21)	66 (21)	69 (21)	68 (20)
Week 12/14	41 (25)	31 (25)	49 (25)	36 (27)	51 (26)	33 (24)	49 (25)	33 (24)	55 (28)	41 (28)
Patient global assessment ^c
Baseline	66 (21)	67 (22)	60 (22)	62 (22)	60 (20)	63 (22)	64 (21)	64 (22)	66 (23)	67 (20)
Week 12/14	42 (25)	31 (24)	48 (26)	37 (27)	50 (26)	32 (24)	48 (24)	33 (24)	54 (28)	40 (26)
Disability Index (HAQ-DI) ^d
Baseline	1.60 (0.67)	1.60 (0.67)	1.47 (0.66)	1.47 (0.66)	1.42 (0.63)	1.48 (0.61)	1.61 (0.61)	1.63 (0.64)	1.56 (0.60)	1.67 (0.64)
Week 12/14	1.08 (0.72)	0.76 (0.69)	1.19 (0.69)	0.86 (0.67)	1.13 (0.70)	0.85 (0.66)	1.28 (0.67)	0.98 (0.68)	1.33 (0.66)	1.24 (0.77)
Physician global assessment ^c
Baseline	69 (16)	67 (17)	62 (17)	66 (18)	64 (18)	64 (16)	66 (18)	66 (17)	67 (17)	69 (17)
Week 12/14	32 (22)	22 (19)	37 (24)	26 (21)	41 (24)	26 (21)	41 (25)	27 (21)	39 (25)	29 (22)
CRP (mg/L)
Baseline	21.2 (22.1)	23.0 (27.4)	14.5 (17.3)	14.0 (16.5)	12.6 (14.0)	16.6 (19.2)	18.0 (21.5)	17.9 (22.5)	16.3 (21.1)	16.3 (18.6)
Week 12/14	10.9 (14.9)	4.2 (8.8)	12.8 (21.4)	3.7 (7.8)	13.1 (15.5)	4.6 (9.6)	16.2 (19.8)	5.5 (10.9)	13.9 (17.3)	5.0 (14.0)
Abbreviations: ACR = American College of Rheumatology; bDMARD = biologic disease-modifying anti-rheumatic drug; CRP = c-reactive protein; cDMARDs = conventional disease-modifying anti-rheumatic drugs; HAQ-DI = Health Assessment Questionnaire Disability Index; IR = inadequate responder; MTX = methotrexate; PBO = placebo ^aData shown are mean (standard deviation). ^bPrimary efficacy timepoint is at Week 14. ^cVisual analog scale: 0 = best, 100 = worst. ^dHealth Assessment Questionnaire-Disability Index: 0=best, 3=worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

Figure 1. Percent of Patients Achieving ACR20 in Trial RA-IV

Referenced Image

Abbreviations: ACR20 = American College of Rheumatology ≥20% improvement; MTX = methotrexate
Patients who discontinued randomized treatment, or were missing ACR20 results, or were lost-to-follow-up or withdrawn from the trial were imputed as non-responders.

In RA-I and RA-IV, a higher proportion of patients treated with RINVOQ 15 mg alone or in combination with MTX, achieved DAS28-CRP < 2.6 compared to MTX or placebo at the primary efficacy timepoint (Table 15 ).

Table 15: Proportion of Patients with DAS28-CRP Less Than 2.6 with Number of Residual Active Joints at Primary Efficacy Timepoint
Trial RA-I MTX- naïve
Monotherapy
DAS28-CRP Less Than 2.6	MTX N = 314	RINVOQ 15 mg N = 317
Proportion of responders at Week 12 (n)	14% (43)	36% (113)
Of responders, proportion with 0 active joints (n)	51% (22)	45% (51)
Of responders, proportion with 1 active joint (n)	35% (15)	23% (26)
Of responders, proportion with 2 active joints (n)	9% (4)	17% (19)
Of responders, proportion with 3 or more active joints (n)	5% (2)	15% (17)
Trial RA-IV MTX-IR
Background MTX
DAS28-CRP Less Than 2.6	PBO N = 651	RINVOQ 15 mg N = 651
Proportion of responders at Week 12 (n)	6% (40)	29% (187)
Of responders, proportion with 0 active joints (n)	60% (24)	48% (89)
Of responders, proportion with 1 active joint (n)	20% (8)	23% (43)
Of responders, proportion with 2 active joints (n)	15% (6)	13% (25)
Of responders, proportion with 3 or more active joints (n)	5% (2)	16% (30)
Abbreviations: CRP = c-reactive protein; DAS28 = Disease Activity Score 28 joints; MTX = methotrexate; PBO = placebo; IR = inadequate responder

Radiographic R esponse

Inhibition of progression of structural joint damage was assessed using the modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score, at Week 26 in Trial RA-IV and Week 24 in Trial RA-I. The proportion of patients with no radiographic progression (mTSS change from baseline ≤ 0) was also assessed.

In Trial RA-IV, treatment with RINVOQ 15 mg inhibited the progression of structural joint damage compared to placebo in combination with cDMARDs at Week 26 (Table 16 ). Analyses of erosion and joint space narrowing scores were consistent with overall results.

In the placebo plus MTX group, 76% of the patients experienced no radiographic progression at Week 26 compared to 83% of the patients treated with RINVOQ 15 mg.

In Trial RA-I, treatment with RINVOQ 15 mg monotherapy inhibited the progression of structural joint damage compared to MTX monotherapy at Week 24 (Table 16 ). Analyses of erosion and joint space narrowing scores were consistent with overall results.

In the MTX monotherapy group, 78% of the patients experienced no radiographic progression at Week 24 compared to 87% of the patients treated with RINVOQ 15 mg monotherapy.

Table 16: Radiographic Changes
Trial RA-IV MTX-IR
Background MTX
mTSS	PBO (N=651) Mean (SD)	RINVOQ 15 mg (N=651) Mean (SD)	Estimated Difference vs PBO at Week 26 (95% CI) ^a
Baseline	35.9 (52)	34.0 (50)
Week 26 ^b	0.78 (0.1)	0.15 (0.1)	-0.63 (-0.92, -0.34)
Trial RA-I MTX-naïve
Monotherapy
MTX (N=309) Mean (SD)	RINVOQ 15 mg (N=309) Mean (SD)	Estimated Difference vs MTX at Week 24 (95% CI) ^c
Baseline	13.3 (31)	18.1 (38)
Week 24 ^d	0.67 (2.8)	0.14 (1.4)	-0.53 (-0.85, -0.20)
Abbreviations: mTSS = modified Total Sharp Score, MTX = methotrexate; PBO = placebo; SD = standard deviation; IR = inadequate responders; bDMARDs = biologic disease modifying anti-rheumatic drugs; LS = least squares; CI = confidence intervals ^aLS means and 95% CI based on a random coefficient model fit to the mTSS value adjusting for time, treatment group, prior bDMARDs use, treatment group-by-time interaction, with random slopes and random intercept. ^bEstimated linear rate of structural progression by Week 26 and standard errors are presented. ^cLS means and 95% CI based on a linear regression model fit to change from baseline in mTSS adjusting for treatment group, baseline mTSS, and geographic region. ^dMean change from baseline and standard deviation are presented.

Physical Function Response

Treatment with RINVOQ 15 mg, alone or in combination with cDMARDs, resulted in a greater improvement in physical function at Week 12/14 compared to all comparators as measured by HAQ-DI.

Other Health-Related Outcomes

In all trials except for Trial RA-V, patients receiving RINVOQ 15 mg had greater improvement from baseline in physical component summary (PCS) score, mental component summary (MCS) scores, and in all 8 domains of the Short Form Health Survey (SF-36) compared to placebo in combination with cDMARDs or MTX monotherapy at Week 12/14.

Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F) in Trials RA-I, RA-III, and RA-IV. Improvement in fatigue at Week 12 was observed in patients treated with RINVOQ 15 mg compared to patients on placebo in combination with cDMARDs or MTX monotherapy.

14.2 Psoriatic Arthritis

The efficacy and safety of RINVOQ 15 mg once daily were assessed in two Phase 3 randomized, double-blind, multicenter, placebo-controlled trials in patients 18 years of age or older with moderately to severely active psoriatic arthritis. All patients had active psoriatic arthritis for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender joints and at least 3 swollen joints, and active plaque psoriasis or history of plaque psoriasis. Although another dose has been studied, the recommended dose of RINVOQ is 15 mg once daily for psoriatic arthritis.

Trial PsA-I (NCT03104400) was a 24-week trial in 1705 patients with moderately to severely active psoriatic arthritis who had an inadequate response or intolerance to at least one non-biologic DMARD. Patients received RINVOQ 15 mg or upadacitinib 30 mg once daily, adalimumab, or placebo, alone or in combination with background non-biologic DMARDs. At Week 24, all patients randomized to placebo were switched to RINVOQ 15 mg or upadacitinib 30 mg once daily in a blinded manner. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.

Trial PsA-II (NCT03104374) was a 24-week trial in 642 patients with moderately to severely active psoriatic arthritis who had an inadequate response or intolerance to at least one biologic DMARD. Patients received RINVOQ 15 mg or upadacitinib 30 mg once daily or placebo, alone or in combination with background non-biologic DMARDs. At Week 24, all patients randomized to placebo were switched to RINVOQ 15 mg or upadacitinib 30 mg once daily in a blinded manner. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.

Clinical Response

In both trials, patients treated with RINVOQ 15 mg achieved significantly higher ACR20 responses compared to placebo at Week 12 (Table 17 , Figure 2 ). A higher proportion of patients treated with RINVOQ 15 mg achieved ACR50 and ACR70 responses at Week 12 compared to placebo.

Treatment with RINVOQ 15 mg resulted in improvements in the ACR components compared to placebo at the primary efficacy timepoint (Table 18 ).

Table 17: Clinical Response
Trial	Trial PsA-I non-biologic DMARD-IR		Trial PsA-II bDMARD-IR
Treatment Group	PBO %	RINVOQ 15 mg % Δ (95% CI)	PBO %	RINVOQ 15 mg % Δ (95% CI)
N	423	429	212	211
ACR20
Week 12	36	71 35 (28, 41)	24	57 33 (24, 42)
ACR50
Week 12	13	38 24 (19, 30)	5	32 27 (20, 34)
ACR70
Week 12	2	16 13 (10, 17)	1	9 8 (4, 12)
Abbreviations: ACR20 (or 50 or 70) = American College of Rheumatology ≥20% (or ≥50% or ≥70%) improvement, bDMARD = biologic disease-modifying anti-rheumatic drug; IR = inadequate responder; PBO = placebo Patients who discontinued randomized treatment or were missing data at week of evaluation were imputed as non-responders in the analyses.

Table 18: Components of ACR Response ^a
Trial	Trial PsA-I non-biologic DMARD-IR		Trial PsA-II bDMARD-IR
Treatment Group	PBO (N=423)	RINVOQ 15 mg (N=429)	PBO (N=212)	RINVOQ 15 mg (N=211)
Number of tender/painful joints (0-68)
Baseline	20.0 (14.3)	20.4 (14.7)	25.3 (17.6)	24.9 (17.3)
Week 12	12.5 (13.3)	8.8 (12.5)	19.3 (18.5)	12.6 (15.6)
Number of swollen joints (0-66)
Baseline	11.0 (8.2)	11.6 (9.3)	12.0 (8.9)	11.3 (8.2)
Week 12	5.6 (7.2)	3.5 (6.0)	7.3 (9.4)	4.4 (5.7)
Patient assessment of pain ^b
Baseline	6.1 (2.1)	6.2 (2.1)	6.6 (2.1)	6.4 (2.1)
Week 12	5.1 (2.3)	3.8 (2.4)	5.9 (2.3)	4.4 (2.5)
Patient global assessment ^b
Baseline	6.3 (2.0)	6.6 (2.0)	6.8 (2.0)	6.8 (1.9)
Week 12	5.2 (2.2)	3.8 (2.3)	6.1 (2.3)	4.5 (2.5)
Disability index (HAQ-DI) ^c
Baseline	1.1 (0.6)	1.2 (0.7)	1.2 (0.7)	1.1 (0.6)
Week 12	1.0 (0.7)	0.7 (0.6)	1.1 (0.6)	0.8 (0.7)
Physician global assessment ^b
Baseline	6.5 (1.6)	6.7 (1.6)	6.5 (1.8)	6.5 (1.8)
Week 12	4.3 (2.2)	3.1 (2.0)	5.0 (2.2)	3.4 (2.1)
hsCRP (mg/L)
Baseline	11.5 (15.8)	11.0 (14.9)	10.4 (18.5)	11.2 (18.6)
Week 12	10.1 (15.2)	4.2 (9.9)	9.4 (13.4)	4.3 (7.9)
Abbreviations: ACR = American College of Rheumatology; hsCRP = high sensitivity c-reactive protein; HAQ-DI = Health Assessment Questionnaire-Disability Index; IR = inadequate responder; PBO = placebo ^aData shown are mean (standard deviation). ^bNumeric rating scale (NRS): 0 = best, 10 = worst ^cHealth Assessment Questionnaire-Disability Index: 0=best, 3=worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

The percentage of patients achieving ACR20 response by visit is shown in Figure 2.

Figure 2. Percent of Patients Achieving ACR20 in Trial PsA-II

Referenced Image

Abbreviations: ACR20 = American College of Rheumatology ≥20% improvement Patients who discontinued randomized treatment, or were missing ACR20 results, or were lost-to-follow-up or withdrawn from the trial were imputed as non-responders.

Treatment with RINVOQ 15 mg resulted in improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis.

Treatment with RINVOQ 15 mg resulted in improvement in skin manifestations in patients with PsA. However, RINVOQ has not been studied in and is not indicated for the treatment of plaque psoriasis.

Physical Function Response

In both trials, patients treated with RINVOQ 15 mg showed significant improvement in physical function from baseline compared to placebo as assessed by HAQ-DI at Week 12 (Table 17 ). The mean difference (95% CI) from placebo in HAQ-DI change from baseline at Week 12 was -0.28 (-0.35, -0.22) in Trial PsA-I and -0.21 (-0.30, -0.12) in Trial PsA-II.

The proportion of HAQ-DI responders (≥ 0.35 improvement from baseline in HAQ-DI score) at Week 12 in Trial PsA-I and Trial PsA-II was 58% and 45%, respectively, in patients receiving RINVOQ 15 mg and 33% and 27%, respectively, in patients receiving placebo.

Radiographic Response

In Trial PsA-I, inhibition of progression of structural damage was assessed radiographically and expressed as the change from baseline in modified Total Sharp Score (mTSS) and its components, the erosion score and the joint space narrowing score, at Week 24.

Treatment with RINVOQ 15 mg inhibited progression of structural joint damage compared to placebo at Week 24 (Table 19 ). Analyses of erosion and joint space narrowing scores were consistent with overall results. The proportion of patients with no radiographic progression (mTSS change ≤ 0) at Week 24 was 93% in patients receiving RINVOQ 15 mg and 89% in patients receiving placebo.

Table 19: Radiographic Changes in Trial PsA-I
PBO (N=392) Mean (SD)	RINVOQ 15 mg (N=407) Mean (SD)	Estimated Difference vs PBO at Week 24 (95% CI) ^a
mTSS
Baseline	13.32 (31.2)	13.14 (42.4)
Week 24 ^b	0.23 (0.07)	-0.02 (0.04)	-0.25 (-0.41, -0.09)
Abbreviations: CI = confidence intervals; LS = least squares; mTSS = modified Total Sharp Score; PBO = placebo; SD = standard deviation ^aLS means and 95% CI based on a random coefficient model fit to the mTSS value adjusting for time, treatment group, current DMARD use (yes/no), treatment group-by-time interaction, with random slopes and random intercept. ^bEstimated linear rate of structural progression by Week 24 and standard errors are presented.

Other Health-Related Outcomes

Health-related quality of life was assessed by SF-36. In both trials, patients receiving RINVOQ 15 mg experienced significantly greater improvement from baseline in the Physical Component Summary score compared to placebo at Week 12. Greater improvement was also observed in the Mental Component Summary score and all 8 domains of SF-36 compared to placebo.

Patients receiving RINVOQ 15 mg showed greater improvement from baseline in fatigue, as measured by FACIT-F score, at Week 12 compared to placebo in both trials.

14.3 Atopic Dermatitis

The efficacy of RINVOQ 15 mg and 30 mg once daily, was assessed in three Phase 3 randomized, double-blind, multicenter trials (AD-1, AD-2, AD-3; NCT03569293, NCT03607422, and NCT03568318, respectively) in a total of 2584 patients (12 years of age and older). RINVOQ was evaluated in 344 pediatric patients and 2240 adult patients with moderate to severe atopic dermatitis (AD) not adequately controlled by topical medication(s).

Disease severity at baseline was defined by a validated Investigator's Global Assessment (vIGA-AD) score ≥3 in the overall assessment of AD on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16, a minimum body surface area (BSA) involvement of ≥10%, and weekly average Worst Pruritus Numerical Rating Scale (NRS) score ≥4. Overall, 57% of the patients were male and 69% were white. The mean age at baseline was 34 years (ranged from 12 to 75 years) and 13% of the patients were 12 to less than 18 years. At baseline, 49% of patients had a vIGA-AD score of 3 (moderate AD), and 51% of patients had a vIGA-AD score of 4 (severe AD). The baseline mean EASI score was 29 and the baseline weekly average Worst Pruritus NRS score was 7. Approximately 52% of the patients had prior exposure to systemic AD treatment.

In all three trials, patients received RINVOQ once daily oral doses of 15 mg, 30 mg, or matching placebo for 16 weeks. In Trial AD-3, patients also received RINVOQ or placebo with concomitant topical corticosteroids (TCS) for 16 weeks.

All three trials assessed the co-primary endpoints of the proportion of patients with a vIGA-AD score of 0 (clear) or 1 (almost clear) with at least a 2-point improvement and the proportion of patients with EASI-75 (improvement of at least 75% in EASI score from baseline) at Week 16. Secondary endpoints included EASI-90 and EASI-100 at Week 16, and the proportion of patients with reduction in itch (≥4-point improvement from baseline in the Worst Pruritus NRS) at Weeks 1, 4, and 16. In Trials AD-1 and AD-2, the proportion of patients with reduction in pain (≥4-point improvement in the Atopic Dermatitis Symptom Scale [ADerm-SS] Skin Pain NRS) from baseline to Week 16 was a secondary endpoint.

Clinical Response

Monotherapy Trials (AD-1 and AD-2)

The results of RINVOQ monotherapy trials (AD-1 and AD-2) are presented in Table 20. Figure 3 presents the proportion of patients with ≥ 4-point improvement in Worst Pruritus NRS at Weeks 1, 4, and 16 for Trials AD-1 and AD-2.

Table 20: Efficacy Results of Monotherapy Trials at Week 16 in Patients with Moderate to Severe AD
Trial AD-1			Trial AD-2
PBO	RINVOQ 15 mg	RINVOQ 30 mg	PBO	RINVOQ 15 mg	RINVOQ 30 mg
Number of patients randomized	281	281	285	278	276	282
vIGA-AD 0/1 ^a^,^b	8%	48%	62%	5%	39%	52%
Difference from PBO (95% CI)	40% (33%, 46%)	54% (47%, 60%)	34% (28%, 40%)	47% (41%, 54%)
EASI-75 ^a	16%	70%	80%	13%	60%	73%
Difference from PBO (95% CI)	53% (46%, 60%)	63% (57%, 70%)	47% (40%, 54%)	60% (53%, 66%)
EASI-90 ^a	8%	53%	66%	5%	42%	58%
Difference from PBO (95% CI)	45% (39%, 52%)	58% (51%, 64%)	37% (31%, 43%)	53% (47%, 59%)
EASI-100 ^a	2%	17%	27%	1%	14%	19%
Difference from PBO (95% CI)	15% (10%, 20%)	25% (20%, 31%)	13% (9%, 18%)	18% (13%, 23%)
Number of patients with baseline Worst Pruritus NRS score ≥ 4	272	274	280	274	270	280
≥ 4-point improvement in Worst Pruritus NRS ^c	12%	52%	60%	9%	42%	60%
Difference from PBO (95% CI)	40% (33%, 48%)	48% (41%, 55%)	33% (26%, 39%)	50% (44%, 57%)
Number of patients with baseline ADerm-SS Skin Pain NRS score ≥ 4	233	237	249	247	237	238
≥ 4-point improvement in ADerm-SS Skin Pain NRS ^d	15%	54%	63%	13%	49%	65%
Difference from PBO (95% CI)	39% (31%, 47%)	49% (41%, 56%)	36% (28%, 43%)	52% (44%, 59%)
Abbreviations: ADerm-SS = Atopic Dermatitis Symptom Scale; PBO = placebo ^aBased on number of patients randomized ^bResponder was defined as a patient with vIGA-AD 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on a 0-4 ordinal scale ^cBased on number of patients whose baseline Worst Pruritus NRS is ≥ 4 ^dBased on number of patients whose baseline ADerm-SS Skin Pain NRS is ≥ 4

Figure 3 . Proportion of Patients with Moderate to Severe AD with ≥4-point Improvement in the Worst Pruritus NRS in M onotherapy Trials

Referenced Image

Examination of age, gender, race, weight, and prior systemic treatment with immunosuppressants did not identify differences in response to RINVOQ among these subgroups in Trials AD-1 and AD-2.

Concomitant TCS Trial (AD-3)

The results of the RINVOQ with concomitant TCS trial (AD-3) are presented in Table 21. Figure 4 presents the proportion of patients with ≥ 4-point improvement in Worst Pruritus NRS at Weeks 1, 4, and 16 for Trial AD-3.

Table 21: Efficacy Results with Concomitant TCS at Week 16 in Patients with Moderate to Severe AD
Trial AD-3
PBO + TCS	RINVOQ 15 mg + TCS	RINVOQ 30 mg + TCS
Number of patients randomized	304	300	297
vIGA-AD 0/1 ^a,^b	11%	40%	59%
Difference from PBO (95% CI)	29% (22%, 35%)	48% (41%, 54%)
EASI-75 ^a^,	26%	65%	77%
Difference from PBO (95% CI)	38% (31%, 45%)	51% (44%, 57%)
EASI-90 ^a	13%	43%	63%
Difference from PBO (95% CI)	30% (23%, 36%)	50% (43%, 56%)
EASI-100 ^a	1%	12%	23%
Difference from PBO (95% CI)	11% (7%, 14%)	21% (16%, 26%)
Number of patients with baseline Worst Pruritus NRS score ≥ 4	294	288	291
≥ 4-point improvement in Worst Pruritus NRS ^c	15%	52%	64%
Difference from PBO (95% CI)	37% (30%, 44%)	49% (42%, 56%)
Abbreviations: PBO = placebo ^aBased on number of patients randomized ^bResponder was defined as a patient with vIGA-AD 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on a 0-4 ordinal scale ^cBased on number of patients whose baseline Worst Pruritus NRS is ≥ 4

Figure 4 . Proportion of Patients with Moderate to Severe AD with ≥4-point Improvement in the Worst Pruritus NRS in Concomitant TCS Trial

Referenced Image

Examination of age, gender, race, weight, and prior systemic treatment with immunosuppressants did not identify differences in response to RINVOQ among these subgroups in Trial AD-3.

Pediatric Patient Population

The efficacy results of the RINVOQ monotherapy trials (AD-1 and AD-2) and the RINVOQ with concomitant TCS trial (AD-3) at Week 16 for pediatric patients 12 years of age and older are presented in Table 22 and Table 23, respectively.

Table 22: Efficacy Results of Monotherapy Trials for Pediatric Patients 12 Years of Age and Older with Moderate to Severe AD at Week 16
Trial AD-1			Trial AD-2
PBO	RINVOQ 15 mg	RINVOQ 30 mg	PBO	RINVOQ 15 mg	RINVOQ 30 mg
Number of pediatric patients randomized	40	42	42	36	33	35
vIGA-AD 0/1 ^a^,^b	8%	38%	69%	3%	42%	62%
Difference from PBO (95% CI)	31% (14%, 47%)	62% (45%, 78%)	40% (22%, 57%)	60% (42%, 77%)
EASI-75 ^a	8%	71%	83%	14%	67%	74%
Difference from PBO (95% CI)	63% (47%, 79%)	75% (61%, 89%)	53% (33%, 72%)	61% (42%, 79%)
Number of pediatric patients with baseline Worst Pruritus NRS score ≥ 4	39	40	42	36	30	34
≥ 4-point improvement in Worst Pruritus NRS ^c	15%	45%	55%	3%	33%	50%
Difference from PBO (95% CI)	30% (10%, 49%)	39% (21%, 58%)	31% (13%, 48%)	47% (30%, 65%)
Abbreviations: PBO = placebo ^aBased on number of pediatric patients randomized ^bResponder was defined as a patient with vIGA-AD 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on a 0-4 ordinal scale ^cBased on number of pediatric patients whose baseline Worst Pruritus NRS is ≥ 4

Table 23: Efficacy Results with Concomitant TCS for Pediatric Patients 12 Years of Age and Older with Moderate to Severe AD at Week 16
Trial AD-3
PBO + TCS	RINVOQ 15 mg + TCS	RINVOQ 30 mg + TCS
Number of pediatric patients randomized	40	39	37
vIGA-AD 0/1 ^a,^b	8%	31%	65%
Difference from PBO (95% CI)	23% (7%, 40%)	57% (40%, 75%)
EASI-75 ^a	30%	56%	76%
Difference from PBO (95% CI)	26% (5%, 47%)	46% (26%, 65%)
Number of pediatric patients with baseline Worst Pruritus NRS score ≥ 4	38	36	33
≥ 4-point improvement in Worst Pruritus NRS ^c	13%	42%	55%
Difference from PBO (95% CI)	29% (9%, 48%)	41% (21%, 61%)
Abbreviations: PBO = placebo ^aBased on number of pediatric patients randomized ^bResponder was defined as a patient with vIGA-AD 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on a 0-4 ordinal scale ^cBased on number of pediatric patients whose baseline Worst Pruritus NRS is ≥ 4

14.4 Ulcerative Colitis

Induction Trials (Study UC-1 and Study UC-2)

In two identical induction trials (UC-1; NCT02819635 and UC-2; NCT03653026), patients were randomized 2:1 to receive either RINVOQ 45 mg once daily or placebo for 8 weeks. A total of 988 patients were analyzed across the two trials. These trials included adult patients with moderately to severely active ulcerative colitis who had an inadequate response, loss of response, or intolerance to oral aminosalicylates, corticosteroids, immunosuppressants, and/or biologic therapy. Enrolled patients were permitted to use stable doses of oral aminosalicylates, methotrexate, ulcerative colitis-related antibiotics, and/or oral corticosteroids (up to 30 mg/day prednisone or equivalent). At baseline, 38% of patients were receiving corticosteroids, and 68% of patients were receiving aminosalicylates. Concomitant biologic therapies, azathioprine, 6-mercaptopurine, intravenous or rectal corticosteroids were prohibited. A total of 51% of patients had previously failed treatment with or were intolerant to at least one biologic therapy. RINVOQ is indicated for patients who have an inadequate response or intolerance to one or more TNF blockers [see Indications and Usage (1.4 )].

Disease activity was assessed on the modified Mayo score (mMS), a 3-component Mayo score (0-9) which consists of the following subscores (0 to 3 for each subscore): stool frequency (SFS), rectal bleeding (RBS), and findings on centrally read endoscopy score (ES). An ES of 2 was defined by marked erythema, lack of vascular pattern, any friability, and/or erosions, and a score of 3 was defined by spontaneous bleeding and ulceration. Enrolled patients had a mMS between 5 to 9 with an ES of 2 or 3; at baseline the median mMS was 7, with 61% of patients having a baseline mMS of 5 to 7 and 39% having a mMS of 8 to 9.

At baseline, 39% and 37% of patients received corticosteroids, 1% and 1% of patients received methotrexate, and 68% and 69% of patients received aminosalicylates in UC-1 and UC-2, respectively. Patient disease activity was moderate (mMS ≤7) in 61% and 60% of patients and severe (mMS >7) in 39% and 40% of patients in UC-1 and UC-2, respectively.

The primary endpoint was clinical remission defined using the mMS at Week 8. Secondary endpoints included clinical response, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 24 and Table 25 ).

Table 24: Proportion of Patients Meeting Primary and Key Secondary Efficacy Endpoints at Week 8 - Study UC-1
Study UC-1
Endpoint	Placebo	RINVOQ 45 mg Once Daily	Treatment Difference vs Placebo (95% CI)
Clinical Remission ^a
Total Population	N=154 5%	N=319 26%	22% ^b (16, 27)
Prior biologic failure ^c	N=78 < 1%	N=168 18%
Without prior biologic failure	N=76 9%	N=151 35%
Clinical Response ^d
Total Population	N=154 27%	N=319 73%	46% ^b (38, 54)
Prior biologic failure ^c	N=78 13%	N=168 64%
Without prior biologic failure	N=76 42%	N=151 82%
Endoscopic Improvement ^e
Total Population	N=154 7%	N=319 36%	29% ^b (23, 36)
Prior biologic failure ^c	N=78 2%	N=168 27%
Without prior biologic failure	N=76 13%	N=151 47%
Histologic Endoscopic Mucosal Improvement ^f
Total Population	N=154 7%	N=319 30%	24% ^b (17, 30)
Prior biologic failure ^c	N=78 1%	N=168 23%
Without prior biologic failure	N=76 12%	N=151 38%
^aPer mMS: SFS ≤1 and not greater than baseline, RBS = 0, ES of ≤ 1 without friability ^bp <0.001, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomization stratification factors ^cPrior biologic failure includes inadequate response, loss of response, or intolerance to one or more biologic treatments for ulcerative colitis. ^dPer mMS: decrease ≥ 2 points and ≥ 30% from baseline and a decrease in RBS ≥ 1 from baseline or an absolute RBS ≤1 ^eES ≤ 1 without friability ^fES ≤1 without friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in <5% of crypts, no crypt destruction and no erosions, ulcerations or granulation tissue)

Table 25: Proportion of Patients Meeting Primary and Key Secondary Efficacy Endpoints at Week 8 - Study UC-2
Study UC-2
Endpoint	Placebo	RINVOQ 45 mg Once Daily	Treatment Difference vs Placebo (95% CI)
Clinical Remission ^a
Total Population	N=174 4%	N=341 33%	29% ^b (23, 35)
Prior biologic failure ^c	N=89 2%	N=173 30%
Without prior biologic failure	N=85 6%	N=168 38%
Clinical Response ^d
Total Population	N=174 25%	N=341 74%	49% ^b (42, 57)
Prior biologic failure ^c	N=89 19%	N=173 69%
Without prior biologic failure	N=85 32%	N=168 80%
Endoscopic Improvement ^e
Total Population	N=174 8%	N=341 44%	35% ^b (29, 42)
Prior biologic failure ^c	N=89 5%	N=173 37%
Without prior biologic failure	N=85 12%	N=168 51%
Histologic Endoscopic Mucosal Improvement ^f
Total Population	N=174 6%	N=341 37%	30% ^b (24, 36)
Prior biologic failure ^c	N=89 5%	N=173 31%
Without prior biologic failure	N=85 7%	N=168 43%
^aPer mMS: SFS ≤ 1 and not greater than baseline, RBS = 0, ES of ≤ 1 without friability ^bp <0.001, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomization stratification factors ^cPrior biologic failure includes inadequate response, loss of response, or intolerance to one or more biologic treatments for ulcerative colitis. ^dPer mMS: decrease ≥ 2 points and ≥ 30% from baseline and a decrease in RBS ≥ 1 from baseline or an absolute RBS ≤1 ^eES ≤ 1 without friability ^fES ≤1 without friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in <5% of crypts, no crypt destruction and no erosions, ulcerations or granulation tissue)

Studies UC-1 and UC-2 were not designed to evaluate the relationship of histologic endoscopic mucosal improvement at Week 8 to disease progression and long-term outcomes.

Rectal Bleeding and Stool Frequency Subscores

Onset of clinical response was assessed using the SFS and RBS (partial modified Mayo Score [pmMS]). Initial response was defined as a decrease of ≥1 point and ≥30% from baseline in pmMS and a decrease in RBS ≥1 or an absolute RBS≤1. Onset of response occurred as early as Week 2 in a greater proportion of patients treated with RINVOQ 45 mg once daily compared to placebo.

Endoscopic and Histologic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. At Week 8, a greater proportion of patients treated with RINVOQ 45 mg once daily compared to placebo achieved endoscopic remission (UC-1: 14% vs 1%, UC-2: 18% vs 2%). Endoscopic remission with Geboes histologic score < 2.0 (indicating no neutrophils in crypts or lamina propria and no increase in eosinophil, no crypt destruction, and no erosions, ulcerations, or granulation tissue) was achieved by a greater proportion of patients treated with RINVOQ 45 mg once daily compared to placebo at Week 8 (UC-1: 11% vs 1%, UC-2: 13% vs 2%).

Abdominal Pain and Bowel Urgency

A greater proportion of patients treated with RINVOQ 45 mg once daily compared to placebo had no abdominal pain (UC-1: 47% vs 23%, UC-2: 54% vs 24%) and no bowel urgency (UC-1: 48% vs 21%, UC-2: 54% vs 26%) at Week 8.

Fatigue

In Studies UC-1 and UC-2, patients treated with RINVOQ experienced a clinically meaningful improvement in fatigue, as assessed by change from baseline in FACIT-F score, at Week 8, compared to placebo-treated patients. The effect of RINVOQ to improve fatigue after 8 weeks of induction has not been established.

Maintenance Study UC-3

In UC-3 (NCT02819635), a total of 451 patients who received RINVOQ 45 mg once daily in either UC-1, UC-2 or UC-4 and achieved clinical response were re-randomized to receive RINVOQ 15 mg, 30 mg or placebo once daily for up to 52 weeks.

The primary endpoint was clinical remission defined using mMS at Week 52. Secondary endpoints included corticosteroid-free clinical remission, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 26 ).

Table 26: Proportion of Patients Meeting Primary and Key Secondary Efficacy Endpoints at Week 52 in Maintenance Study UC-3
Endpoint	Placebo	RINVOQ 15 mg Once Daily	Treatment Difference 15 mg vs Placebo (95% CI)	RINVOQ 30 mg Once Daily	Treatment Difference 30 mg vs Placebo (95% CI)
Clinical remission ^a
Total Population	N=149 12%	N=148 42%	31% ^b (22, 40)	N=154 52%	39% ^b (30, 48)
Prior biologic failure ^c	N=81 7%	N=71 41%	N=73 49%
Without prior biologic failure	N=68 18%	N=77 44%	N=81 54%
Corticosteroid-free clinical remission ^d
Total Population	N=54 22%	N=47 57%	35% ^b (18, 53)	N=58 68%	45% ^b (29, 62)
Prior biologic failure ^c	N=22 14%	N=17 71%	N=20 73%
Without prior biologic failure	N=32 28%	N=30 49%	N=38 65%
Endoscopic Improvement ^e
Total Population	N=149 14%	N=148 49%	34% ^b (25, 44)	N=154 62%	46% ^b (37, 56)
Prior biologic failure ^c	N=81 8%	N=71 43%	N=73 56%
Without prior biologic failure	N=68 22%	N=77 54%	N=81 67%
Histologic Endoscopic Mucosal Improvement ^f
Total Population	N=149 12%	N=148 35%	24% ^b (15, 33)	N=154 50%	37% ^b (28, 47)
Prior biologic failure ^c	N=81 5%	N=71 33%	N=73 48%
Without prior biologic failure	N=68 20%	N=77 37%	N=81 52%
^aPer mMS: SFS ≤1 and not greater than baseline, RBS = 0, ES ≤1 without friability ^bp <0.001, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomization stratification factors ^cPrior biologic failure includes inadequate response, loss of response, or intolerance to one or more biologic treatments for ulcerative colitis. ^dClinical remission per mMS at Week 52 and corticosteroid free for ≥90 days immediately preceding Week 52 among patients who achieved clinical remission at the end of the induction treatment ^eES ≤ 1 without friability ^fES ≤1 without friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in <5% of crypts, no crypt destruction and no erosions, ulcerations or granulation tissue)

The relationship between histologic endoscopic mucosal improvement at Week 52 and disease progression and longer-term outcomes after Week 52 was not evaluated in Study UC-3.

Endoscopic and Histologic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. In UC-3, a greater proportion of patients treated with RINVOQ 15 mg and 30 mg once daily compared to placebo achieved endoscopic remission at Week 52 (24% and 26% vs 6%). Endoscopic remission with Geboes histologic score < 2.0 was achieved by a greater proportion of patients treated with RINVOQ 15 mg and 30 mg once daily compared to placebo at Week 52 (18% and 19% vs 5%).

Abdominal Pain and Bowel Urgency

At Week 52, a greater proportion of patients treated with RINVOQ 15 mg and 30 mg once daily compared to placebo had no abdominal pain (46%, 55% and 21%, respectively) and no bowel urgency (56%, 64% and 17%, respectively).

14.5 Crohn’s Disease

Induction Trials (Studies CD-1 and CD-2)

In two induction trials, CD-1 (NCT03345836) and CD-2 (NCT03345849), patients were randomized 2:1 to receive RINVOQ 45 mg or placebo once daily for 12 weeks. Efficacy was assessed in a population of 857 patients (419 patients in CD-1 and 438 patients in CD-2) with moderately to severely active Crohn’s disease (CD), with baseline Crohn’s Disease Activity Index (CDAI) score of at least 220 and centrally-reviewed Simple Endoscopic Score for Crohn’s Disease (SES-CD) of ≥ 6, or ≥ 4 for isolated ileal disease, excluding the narrowing component. In CD-1, all patients had inadequate response or were intolerant to treatment with one or more biological therapies (prior biologic failure). In CD-2, 45% (197/438) of patients had inadequate response or were intolerant to treatment with one or more biological therapies (prior biologic failure). Enrolled patients in both studies were permitted to use stable doses of CD-related antibiotics, aminosalicylates, or methotrexate. Concomitant corticosteroids (up to 30 mg/day prednisone or equivalent) were permitted at enrollment; tapering was initiated at Week 4.

In CD-1, patients had a mean age of 37 years (range 18 to 74 years); 46% were female; and 72% identified as White, 21% as Asian, 6% as Black or African American, 0.5% as American Indian or Alaska Native, and 0.5% as multiple racial groups. In CD-2, patients had a mean age of 40 years (range of 18 to 74 years); 45% were female; 74% identified as White, 20% as Asian, 4% as Black or African American, and 2% as multiple racial groups.

At baseline, 36% and 37% of patients received corticosteroids, 7% and 3% of patients received methotrexate, 15% and 24% of patients received aminosalicylates, and 2% and 1% of patients received CD-related antibiotics in CD-1 and CD-2, respectively.

The co-primary endpoints were the proportion of patients achieving clinical remission (by CDAI) at Week 12, and the proportion of patients achieving endoscopic response (by SES-CD) at Week 12. Secondary efficacy endpoints included clinical response, corticosteroid-free remission, and endoscopic remission (see Table 27 and Table 28 ).

Table 27: Proportion of Patients Meeting Primary and Additional Efficacy Endpoints in Induction Study CD-1
CD-1
Endpoint	Placebo	RINVOQ 45 mg Once Daily	Treatment Difference vs Placebo (95% CI)
Co-Primary Endpoints at Week 12
Clinical remission ^a	N=146 18%	N=273 36%	17% (9, 25) ^•
Endoscopic response ^b	N=146 3%	N=273 34%	30% (24, 36) ^•
Additional Endpoints at Week 12
Clinical response (CR-100) ^c	N=146 31%	N=273 54%	22% (13, 31) ^•
Corticosteroid-free clinical remission in patients on corticosteroids at baseline ^a,d	N=53 11%	N=96 30%	17% (5, 29) ^••
Endoscopic remission ^e	N=146 3%	N=273 19%	15% (10, 21) ^•
^•p < 0.001, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomization stratification factors ^••p < 0.01, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomization stratification factors ^aCDAI < 150 ^bDecrease in SES-CD > 50% from baseline of the induction study (or for patients with an SES-CD of 4 at baseline of the induction study, at least a 2-point reduction from baseline of the induction study) ^cDecrease of at least 100 points in CDAI from baseline ^dDiscontinuation of corticosteroid and achievement of clinical remission among patients on corticosteroid at baseline ^eSES-CD ≤ 4 and no individual subscore >1 in any individual variable

Table 28: Proportion of Patients Meeting Primary and Additional Efficacy Endpoints in Induction Study CD-2
CD-2
Endpoint	Placebo	RINVOQ 45 mg Once Daily	Treatment Difference vs Placebo (95% CI)
Co-Primary Endpoints at Week 12
Clinical remission ^a
Total population	N=143 23%	N=295 46%	24% (15, 32) ^•
Prior biologic failure	N=62 7%	N=135 42%
Without prior biologic failure	N=81 35%	N=160 50%
Endoscopic response ^b
Total population	N=143 13%	N=295 46%	33% (26, 41) ^•
Prior biologic failure	N=62 10%	N=135 39%
Without prior biologic failure	N=81 15%	N=160 51%
Additional Endpoints at Week 12
Clinical response (CR-100) ^c
Total population	N=143 40%	N=295 64%	24% (15, 33) ^•
Prior biologic failure	N=62 25%	N=135 66%
Without prior biologic failure	N=81 52%	N=160 62%
Corticosteroid-free clinical remission in patients on CS at baseline ^a,d
Total population	N=54 13%	N=108 40%	27% (14, 39) ^•
Prior biologic failure	N=29 7%	N=60 35%
Without prior biologic failure	N=25 20%	N=48 46%
Endoscopic remission ^e
Total population	N=143 8%	N=295 30%	22% (16, 29) ^•
Prior biologic failure	N=62 3%	N=135 22%
Without prior biologic failure	N=81 11%	N=160 37%
^•p < 0.001, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomization stratification factors ^aCDAI < 150 ^bDecrease in SES-CD > 50% from baseline of the induction study (or for patients with an SES-CD of 4 at baseline of the induction study, at least a 2-point reduction from baseline of the induction study) ^cDecrease of at least 100 points in CDAI from baseline ^dDiscontinuation of corticosteroid and achievement of clinical remission among patients on corticosteroid at baseline ^eSES-CD ≤ 4 and no individual subscore >1 in any individual variable

Onset of clinical response based on CDAI was observed as early as two weeks in Studies CD-1 and CD-2, with a greater proportion of patients achieving clinical response at Week 2 in RINVOQ-treated patients compared with placebo.

In Studies CD-1 and CD-2, reductions in stool frequency and abdominal pain were observed in a greater proportion of patients treated with RINVOQ 45 mg induction regimen compared to placebo at Week 12.

In Studies CD-1 and CD-2, patients treated with RINVOQ experienced a clinically meaningful improvement in fatigue, assessed by change from baseline in FACIT-F score, at Week 12, compared to placebo-treated patients. The effect of RINVOQ to improve fatigue after 12 weeks of induction has not been established.

Maintenance Study (CD-3)

The efficacy analysis for CD-3 (NCT03345823) evaluated 343 patients who responded to 12 weeks of RINVOQ 45 mg once daily induction treatment. Patients were re-randomized to receive a maintenance regimen of either RINVOQ 15 mg or 30 mg once daily or placebo for 52 weeks, representing a total of at least 64 weeks of therapy.

The co-primary endpoints of clinical remission (by CDAI) and endoscopic response (by SES-CD) were assessed at Week 52. Secondary efficacy endpoints included corticosteroid-free clinical remission, maintenance of clinical remission, endoscopic remission, and achieving both clinical and endoscopic remission, at Week 52 (see Table 29 ).

Table 29: Proportion of Patients Meeting Primary and Additional Efficacy Endpoints at Week 52 in Maintenance Study CD-3
Endpoint	Placebo ⁺	RINVOQ 15 mg Once Daily	RINVOQ 30 mg Once Daily	Treatment Difference 15 mg vs Placebo (95% CI)	Treatment Difference 30 mg vs Placebo (95% CI)
Co-Primary Endpoints
Clinical remission ^a
Total population	N=111 14%	N=113 42%	N=119 55%	29% (18, 39) ^•	40% (29, 51) ^•
Prior biologic failure	N=87 13%	N=85 35%	N=90 54%
Without prior biologic failure	N=24 21%	N=28 61%	N=29 55%
Endoscopic response ^b
Total population	N=111 7%	N=113 28%	N=119 41%	22% (13, 32) ^•	34% (25, 44) ^•
Prior biologic failure	N=87 5%	N=85 22%	N=90 42%
Without prior biologic failure	N=24 17%	N=28 45%	N=29 38%
Additional Endpoints
Corticosteroid-free clinical remission ^c
Total population	N=111 14%	N=113 42%	N=119 53%	29% (18, 39) ^•	38% (27, 49) ^•
Prior biologic failure	N=87 13%	N=85 35%	N=90 52%
Without prior biologic failure	N=24 21%	N=28 61%	N=29 55%
Maintenance of clinical remission ^d
Total population	N=73 22%	N=72 51%	N=79 67%	32% (18, 46) ^•	43% (29, 57) ^•
Prior biologic failure	N=56 20%	N=50 46%	N=55 69%
Without prior biologic failure	N=17 29%	N=22 64%	N=24 63%
Endoscopic remission ^e
Total population	N=111 5%	N=113 19%	N=119 30%	14% (6, 22) ^•	25% (15, 34) ^•
Prior biologic failure	N=87 3%	N=85 14%	N=90 30%
Without prior biologic failure	N=24 13%	N=28 32%	N=29 31%
Clinical and endoscopic remission
Total population	N=111 4%	N=113 16%	N=119 26%	13% (6, 21) ^•	22% (14, 31) ^•
Prior biologic failure	N=87 2%	N=85 13%	N=90 26%
Without prior biologic failure	N=24 8%	N=28 25%	N=29 28%
⁺The placebo group consisted of patients who achieved clinical response per CDAI with RINVOQ 45 mg at the end of the induction study and were randomized to receive placebo at the start of maintenance therapy. ^•p < 0.001, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomization stratification factors ^aCDAI < 150 ^bDecrease in SES-CD > 50% from baseline of the induction study (or for patients with an SES-CD of 4 at baseline of the induction study, at least a 2-point reduction from baseline of the induction study) ^cCorticosteroid-free for 90 days prior to Week 52 and achievement of clinical remission. Among the subset of patients who were on corticosteroids at induction baseline, 48% (N=44) in RINVOQ 15 mg group, 44% (N=45) in RINVOQ 30 mg group, and 7% (N=46) in placebo were corticosteroid-free for 90 days prior to Week 52 and in clinical remission. ^dDefined as achievement of clinical remission at Week 52 in patients who achieved clinical remission at the entry of the maintenance study. ^eSES-CD ≤ 4 and no subscore > 1 in any individual variable

At Week 52, reductions in stool frequency and abdominal pain were observed in a greater proportion of patients treated with RINVOQ 15 mg and 30 mg compared to placebo.

1.400000000000000e+01 6 Ankylosing Spondylitis

The efficacy and safety of RINVOQ 15 mg once daily were assessed in two randomized, double-blind, multicenter, placebo-controlled trials in patients 18 years of age or older with active ankylosing spondylitis based upon the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 and Patient’s Assessment of Total Back Pain score ≥4.

Trial AS-I (NCT03178487) was a 14-week trial in 187 ankylosing spondylitis patients with an inadequate response to at least two nonsteroidal anti-inflammatory drugs (NSAIDs) or intolerance to or contraindication for NSAIDs and had no previous exposure to biologic DMARDs. At baseline, patients had symptoms of ankylosing spondylitis for an average of 14.4 years and approximately 16% of the patients were on a concomitant cDMARD. Patients received RINVOQ 15 mg once daily or placebo. At Week 14, all patients randomized to placebo were switched to RINVOQ 15 mg once daily. The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at Week 14.

Trial AS-II (NCT 04169373) was a 14-week trial in 420 ankylosing spondylitis patients with an inadequate response to 1 or 2 biologic DMARDs. At baseline, patients had symptoms of ankylosing spondylitis for an average of 12.8 years and approximately 31% of the patients were on a concomitant cDMARD. Patients received RINVOQ 15 mg once daily or placebo. At Week 14, all patients randomized to placebo were switched to RINVOQ 15 mg once daily. The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at Week 14.

Clinical Response

In both trials, a significantly greater proportion of patients treated with RINVOQ 15 mg achieved an ASAS40 response compared to placebo at Week 14 (Table 30 , Figure 5 ).

Examination of gender, baseline body mass index (BMI), and baseline hsCRP did not identify differences in response to RINVOQ among these subgroups at Week 14.

Table 30: Clinical Response at Week 14
Trial AS-I bDMARD-naïve			Trial AS-II bDMARD-IR
PBO (N=94)	RINVOQ 15 mg (N=93)	Difference from PBO (95% CI)	PBO (N=209)	RINVOQ 15 mg (N= 211 )	Difference from PBO (95% CI)
ASAS40 ^a (%)	25.5	50.5	25 (12, 38)	18.2	44.5	26 (18, 35)
ASAS20 ^a (%)	39.4	63.4	24 (10, 38)	38.3	65.4	27 (18, 36)
Abbreviations: ASAS20 (or 40) = Assessment of SpondyloArthritis international Society ≥20% (or ≥40%) improvement; bDMARD = biologic disease modifying anti-rheumatic drug; IR = inadequate responders; PBO = placebo ^aAn ASAS20 (ASAS40) response is defined as a ≥20% (≥40%) improvement and an absolute improvement from baseline of ≥1 (≥2) unit(s) (range 0 to 10) in ≥3 of 4 domains (Patient Global, Total Back Pain, Function, and Inflammation), and no worsening in the potential remaining domain (defined as worsening ≥20% and ≥1 unit for ASAS20 or defined as worsening of > 0 units for ASAS40). For binary endpoints, Week 14 results are based on non-responder imputation (Trial AS-I) and on non-responder imputation in conjunction with multiple imputation (Trial AS-II).

Treatment with RINVOQ 15 mg resulted in improvements in the individual components of the ASAS40 response criteria compared to placebo (Table 31 ).

Table 31: ASAS Components and Other Measures of Disease Activity ^a
Trial AS-I bDMARD-naïve		Trial AS-II bDMARD-IR
Treatment Group	PBO	RINVOQ 15 mg	PBO	RINVOQ 15 mg
N	94	93	209	211
Patient Global Assessment of Disease Activity ^b
Baseline	6.8 (1.66)	6.6 (1.81)	7.2 (1.40)	7.4 (1.48)
Week 14	5.4 (1.97)	3.8 (2.44)	5.9 (2.13)	4.3 (2.36)
Total Back Pain ^b
Baseline	6.7 (1.78)	6.8 (1.77)	7.4 (1.43)	7.5 (1.48)
Week 14	5.0 (2.27)	3.7 (2.39)	5.9 (2.09)	4.4 (2.48)
BASFI ^b
Baseline	5.54 (2.17)	5.35 (2.36)	6.18 (1.87)	6.28 (2.03)
Week 14	4.21 (2.26)	3.14 (2.37)	5.09 (2.21)	3.98 (2.45)
Inflammation ^c
Baseline	6.66 (1.90)	6.51 (1.99)	6.75 (1.55)	6.88 (1.84)
Week 14	4.61 (2.13)	3.40 (2.16)	5.11 (2.30)	3.87 (2.50)
hsCRP (mg/L)
Baseline	11.02 (10.85)	8.90 (12.42)	14.71 (17.54)	15.30 (20.53)
Week 14	11.72 (15.93)	2.23 (3.56)	15.31 (17.55)	3.82 (8.26)
Abbreviations: ASAS = Assessment of SpondyloArthritis international Society; BASFI = Bath Ankylosing Spondylitis Functional Index; bDMARD = biologic disease modifying anti-rheumatic drug; hsCRP = high sensitivity C-reactive protein; IR = inadequate responder; PBO = placebo; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index Results are based on as-observed data from patients who have baseline observation. ^aData shown are mean (standard deviation). ^bNumeric rating scale (NRS): 0 = best, 10 = worst ^cmean of BASDAI questions 5 and 6 assessing morning stiffness severity and duration: 0 = best, 10 = worst

Figure 5. Percent of Patients Achieving ASAS40 in Trial AS-II•

Referenced Image

•Results are based on non-responder imputation in conjunction with multiple imputation.

Other Health-Related Outcomes

In Trial AS-II, patients treated with RINVOQ 15 mg showed significant improvements in health-related quality of life as measured by Ankylosing Spondylitis Quality of Life (ASQoL) compared to placebo at Week 14. In Trial AS-I, improvement in ASQoL compared to placebo was also observed.

Enthesitis

In Trial AS-II, patients with pre-existing enthesitis treated with RINVOQ 15 mg showed significant improvement in enthesitis compared to placebo as measured by change from baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at Week 14. In Trial AS-I, improvement in MASES compared to placebo was also observed.

Spinal mobility

In Trial AS-II, patients treated with RINVOQ 15 mg showed significant improvement in spinal mobility compared to placebo as measured by change from baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 14. In Trial AS-I, improvement in BASMI compared to placebo was also observed.

1.400000000000000e+01 7 Non-radiographic Axial Spondyloarthritis

The efficacy and safety of RINVOQ 15 mg once daily were assessed in a randomized, double-blind, multicenter, placebo-controlled trial in patients 18 years of age or older with active non-radiographic axial spondyloarthritis. Trial nr-axSpA (NCT04169373) was a 52-week placebo-controlled trial in 314 patients (of which 313 patients received study treatment) with active non-radiographic axial spondyloarthritis with an inadequate response to at least two nonsteroidal anti-inflammatory drugs (NSAIDs) or intolerance to or contraindication for NSAIDs. Patients must have had objective signs of inflammation indicated by elevated C-reactive protein (CRP) (defined as > upper limit of normal), and/or sacroiliitis on magnetic resonance imaging (MRI), and no definitive radiographic evidence of structural damage on sacroiliac joints. Patients had active disease as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4, and a Patient's Assessment of Total Back Pain score ≥ 4 based on a 0 – 10 numerical rating scale (NRS) at the Screening and baseline Visits. At baseline, approximately 29.1% of the patients were on a concomitant cDMARD. 32.9% of the patients had an inadequate response or intolerance to bDMARD therapy. Patients received RINVOQ 15 mg once daily or placebo. The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at Week 14.

Clinical Response

In Trial nr-axSpA, a significantly greater proportion of patients treated with RINVOQ 15 mg achieved an ASAS40 response compared to placebo at Week 14 (Table 32 , Figure 6 ).

Examination of gender, baseline BMI, symptom duration of non-radiographic axial spondyloarthritis, baseline hsCRP, MRI sacroiliitis, and prior use of bDMARDs did not identify differences in response to RINVOQ among these subgroups at Week 14.

Table 32: Clinical Response at Week 14
PBO (N=15 7 )	RINVOQ 15 mg (N=15 6 )	Difference from PBO (95% CI)
ASAS40 ^a (%)	22.3	44.9	22.5 (12.4, 32.5)
ASAS20 ^a (%)	43.3	66.7	23.2 (12.6, 33.8)
Abbreviations: ASAS20 (or 40) = Assessment of SpondyloArthritis international Society ≥20% (or ≥40%) improvement; PBO = placebo ^aAn ASAS20 (ASAS40) response is defined as a ≥20% (≥40%) improvement and an absolute improvement from baseline of ≥1 (≥2) unit(s) (range 0 to 10) in ≥3 of 4 domains (Patient Global, Total Back Pain, Function, and Inflammation), and no worsening in the potential remaining domain (defined as worsening ≥20% and ≥1 unit for ASAS20 or defined as worsening of > 0 units for ASAS40). For binary endpoints, results are based on non-responder imputation in conjunction with multiple imputation.

Treatment with RINVOQ 15 mg resulted in improvements in the individual components of the ASAS40 response criteria compared to placebo (Table 33 ).

Table 33: ASAS Components and Other Measures of Disease Activity ^a
Treatment Group	PBO (N= 157 )	RINVOQ 15 mg (N= 156 )
Patient Global Assessment of Disease Activity ^b
Baseline	7.30 (1.38)	6.99 (1.62)
Week 14	5.35 (2.31)	4.16 (2.38)
Total Back Pain ^b
Baseline	7.29 (1.39)	7.23 (1.55)
Week 14	5.27 (2.36)	4.29 (2.49)
BASFI ^b
Baseline	5.99 (2.14)	5.89 (2.08)
Week 14	4.47 (2.42)	3.33 (2.39)
Inflammation ^c
Baseline	6.68 (1.67)	6.60 (1.83)
Week 14	4.69 (2.36)	3.48 (2.51)
hsCRP (mg/L)
Baseline	8.75 (12.91)	9.93 (16.17)
Week 14	7.25 (10.61)	2.84 (4.90)
Abbreviations: ASAS = Assessment of SpondyloArthritis international Society; BASFI = Bath Ankylosing Spondylitis Functional Index; hsCRP = high sensitivity C-Reactive Protein; PBO = placebo ^aData shown are mean (standard deviation). ^bNumeric rating scale (NRS): 0 = best, 10 = worst ^cmean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) questions 5 and 6 assessing morning stiffness severity and duration: 0 = best, 10 = worst

Figure 6. Percent of Patients Achieving ASAS40•

Referenced Image

•Results are based on non-responder imputation in conjunction with multiple imputation.

Other Health-Related Outcomes

Patients treated with RINVOQ 15 mg showed significant improvements in health-related quality of life as measured by Ankylosing Spondylitis Quality of Life (ASQoL) compared to placebo at Week 14.

14.8 Polyarticular Juvenile Idiopathic Arthritis

The efficacy of RINVOQ/RINVOQ LQ in pediatric patients with JIA with active polyarthritis is based on exposure-matched extrapolation of the established efficacy of RINVOQ in rheumatoid arthritis patients. Safety and efficacy of RINVOQ/RINVOQ LQ were also assessed in a multicenter, open-label, single-arm study in 83 children (2 to < 18 years of age) with JIA with active polyarthritis (NCT03725007). The pJIA patient subtypes at study entry included rheumatoid factor negative polyarticular (68.7%), rheumatoid factor positive polyarticular (15.7%), extended oligoarticular (13.3%), and systemic JIA without systemic manifestations (2.4%). All patients received RINVOQ LQ or RINVOQ tablet dosages based on weight for up to 156 weeks. Patients treated with a stable dose of MTX were permitted to enter the study; changes in MTX dose were permitted during the study. Efficacy was assessed as supportive endpoints through Week 48. The efficacy was generally consistent with responses in patients with rheumatoid arthritis.

14.9 Giant Cell Arteritis

The efficacy and safety of RINVOQ 15 mg once daily were assessed in Trial GCA (NCT03725202), a Phase 3 randomized, double-blind, multicenter, placebo-controlled study in patients 50 years of age and older (81.8% were 65 years of age and older, 73.1% were female, 93.7% white) with new-onset or relapsing giant cell arteritis. Trial GCA was a 52-week trial in which 428 patients were randomized in a 2:1:1 ratio and dosed once daily with RINVOQ 15 mg, upadacitinib 7.5 mg, or placebo. All patients received background corticosteroid therapy. The RINVOQ and upadacitinib-treated groups followed a pre-specified corticosteroid taper regimen with the aim to reach 0 mg by 26 weeks, while the placebo-treated group followed a pre-specified corticosteroid taper regimen with the aim to reach 0 mg by 52 weeks. The primary endpoint was the proportion of patients achieving sustained remission at Week 52 as defined by the absence of giant cell arteritis signs and symptoms from Week 12 through Week 52 and adherence to the protocol-defined corticosteroid taper regimen. A key secondary endpoint was the proportion of patients achieving sustained complete remission at Week 52 as defined by the absence of giant cell arteritis signs and symptoms from Week 12 through Week 52, normalization of erythrocyte sedimentation rate and hsCRP from Week 12 through Week 52, and adherence to the protocol-defined corticosteroid taper regimen. The study included a 52-week extension for a total study duration of up to 2 years.

Clinical R esponse

RINVOQ 15 mg and a 26-week corticosteroid taper showed superiority in achieving corticosteroid-free sustained remission at Week 52 compared to placebo and a 52-week corticosteroid taper (Table 34 ).

Table 34. Clinical Response in Trial GCA
Treatment Group	PBO + 52-week corticosteroid taper N =112	RINVOQ 15 mg + 26-week corticosteroid taper N =209	Treatment Difference vs PBO (95% CI)
Sustained remission at Week 52	33 29.0%	97 46.4%	17.1% (6.3, 27.8) ^a
Sustained complete remission at Week 52	18 16.1%	78 37.1%	20.7% (11.3, 30.2) ^b
Components of sustained complete remission at Week 52
Absence of GCA signs and symptoms ^c	33 29.8%	97 46.3%
Normalization of ESR ^d	27 23.8%	98 47.0%
Normalization of hsCRP ^e	28 25.0%	110 52.6%
Adherence to protocol-defined corticosteroid taper regimen	44 39.3%	122 58.4%
Abbreviations: ESR = erythrocyte sedimentation rate; GCA = giant cell arteritis; hsCRP = high sensitivity C-reactive protein; PBO = placebo ^ap≤0.01 ^bp≤0.001 ^cPatients who did not have any signs or symptoms of GCA recorded from Week 12 through Week 52 ^dESR to ≤ 30 mm/hr (if ESR > 30 mm/hr and elevation is not attributable to GCA, this criterion can still be met) from Week 12 through Week 52 ^ehsCRP to < 1 mg/dL, without elevation to ≥ 1 mg/dL (on 2 consecutive visits) from Week 12 through Week 52

Treatment with RINVOQ 15 mg and a 26-week corticosteroid taper resulted in improvements in the components of corticosteroid-free sustained complete remission at Week 52 compared to placebo and a 52-week corticosteroid taper (Table 34 ).

Cumulative C orticosteroid D ose

The total actual cumulative corticosteroid dose was lower in the RINVOQ 15 mg and a 26-week corticosteroid taper arm (mean [SD] 2283.9 [1840.0] mg and median 1615 mg) relative to the placebo and a 52-week corticosteroid taper arm (mean [SD] 3388.3 [1463.1] mg and median 2882 mg).

Rinvoq |