14 CLINICAL STUDIES

14.1 Rheumatoid Arthritis

The efficacy and safety of SIMPONI ARIA were evaluated in one multicenter, randomized, double-blind, controlled trial (Trial RA, NCT00973479) in 592 patients ≥ 18 years of age with moderately to severely active RA despite concurrent MTX therapy and had not previously been treated with a biologic TNF-blocker. Patients were diagnosed according to the American College of Rheumatology (ACR) criteria, at least 3 months prior to administration of study agent and were required to have at least 6 swollen and 6 tender joints. Patients were randomized to receive either SIMPONI ARIA 2 mg/kg (N=395) or placebo (N=197) over a 30-minute intravenous infusion at Weeks 0, 4 and every 8 weeks thereafter in addition to their weekly maintenance MTX dose (15–25 mg). All patients receiving placebo + MTX received SIMPONI ARIA + MTX after Week 24, but the trial remained blinded until all patients had completed 108 weeks of treatment. Efficacy data were collected and analyzed through Week 52. Patients were allowed to continue stable doses of concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs. The use of other DMARDs including cytotoxic agents or other biologics was prohibited.

The primary endpoint in Trial RA was the percentage of patients achieving an ACR 20 response at Week 14. In Trial RA, the majority of subjects were women (82%) and were Caucasian (80%) with a median age of 52 years and a median weight of 70 kg. Median disease duration was 4.7 years, and 50% of the patients used at least one DMARD other than MTX in the past. At baseline, 81% of patients received concomitant NSAIDs and 81% of patients received low-dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day). The median baseline DAS28-CRP was 5.9 and the median van der Heijde-Sharp score at baseline was 28.5.

Clinical Response

A greater percentage of patients treated with the combination of SIMPONI ARIA + MTX achieved ACR 20 at Week 14 and ACR 50 at Week 24 versus patients treated with the placebo + MTX as shown in Table 2. The percent of patients achieving ACR 20 responses by visit for Trial RA is shown in Figure 1.

Table 2: Trial RA – Proportion of Patients with an ACR Response
Trial RA Active RA, despite MTX
	Placebo + MTX	SIMPONI ARIA + MTX	95% CI *
* For difference in proportions. † N reflects randomized patients.
N †	197	395
ACR 20
Week 14	25%	59%	25.9, 41.4
Week 24	32%	63%	23.3, 39.4
ACR 50
Week 14	9%	30%	15.3, 27.2
Week 24	13%	35%	15.1, 28.4
ACR 70
Week 14	3%	12%	5.3, 13.4
Week 24	4%	18%	8.8, 18.1

Figure 1: Trial RA – Percent of Patients Achieving ACR 20 Response Over Time: Randomized Patients

	The analysis is based on the intent-to-treat population. Last observation carried forward was performed for missing data. Patients who discontinued treatment due to lack of efficacy were counted as non-responders, as were patients who started prohibited medication or failed to achieve at least a 10% improvement in joint counts at Week 16.

The improvement in all components of the ACR response criteria for the SIMPONI ARIA + MTX group was greater compared to the placebo + MTX group in Trial RA as shown in Table 3.

Table 3: Trial RA ─ Components of ACR Response at Week 14
Trial RA Active RA, despite MTX
	Placebo + MTX	SIMPONI ARIA + MTX
Note: All values are means.
* N reflects randomized patients; actual number of patients evaluable for each endpoint may vary.
N *	197	395
Number of swollen joints (0–66)
Baseline	15	15
Week 14	11	6
Number of tender joints (0–68)
Baseline	26	26
Week 14	20	13
Patient's assessment of pain (0–10)
Baseline	6.5	6.5
Week 14	5.6	3.9
Patient's global assessment of disease activity (0–10)
Baseline	6.5	6.5
Week 14	5.5	4.0
Physician's global assessment of disease activity (0–10)
Baseline	6.3	6.2
Week 14	4.9	3.1
HAQ score (0–3)
Baseline	1.6	1.6
Week 14	1.4	1.1
CRP (mg/dL) (0–1)
Baseline	2.2	2.8
Week 14	1.8	0.9

At Week 14, a greater proportion of patients treated with SIMPONI ARIA + MTX achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 compared with the placebo + MTX group (15% compared to 5%; 95% CI for difference [6.3%, 15.5%]).

Radiographic Response

In Trial RA, structural joint damage was assessed radiographically and expressed as a change in van der Heijde-Modified Sharp Score (vdH-S) and its components, the erosion score and Joint Space Narrowing (JSN) score, at Week 24 compared to baseline. The SIMPONI ARIA + MTX treatment group inhibited the progression of structural damage compared with placebo + MTX, as assessed by total vdH-S score as shown in Table 4.

Table 4: Trial RA – Radiographic Change From Baseline at Week 24
	Placebo + MTX (N=197) *	SIMPONI ARIA + MTX (N=395) *,†
	Mean	Mean
* N reflects randomized patients. † p-value is displayed only for the major secondary endpoint. ‡ p≤0.001.
Change Total vdH-S Score	1.1	0.03 ‡
Change Erosion Score	0.5	-0.1
Change JSN Score	0.6	0.1

At Week 24, a greater proportion of patients in the SIMPONI ARIA + MTX group (71%) had no progression of structural damage (change in the total vdH-S score ≤ 0), compared to 57% of patients in the placebo + MTX group. At Week 52, the mean change from baseline in total vdH-S score was 1.2 in patients originally randomized to placebo + MTX who crossed over to SIMPONI ARIA + MTX at Week 16 or Week 24, and 0.1 in patients originally randomized to SIMPONI ARIA + MTX who remained on active treatment.

Physical Function Response in Patients with RA

Physical function was assessed by the disability index of the Health Assessment Questionnaire (HAQ-DI). At Week 14, the SIMPONI ARIA + MTX group showed greater mean improvement in the HAQ-DI compared with placebo + MTX (0.5 compared to 0.2; 95% CI for difference [0.2, 0.4]).

Other Health-Related Outcomes

General health status was assessed by the 36-item Short Form Health Survey (SF-36). In Trial RA, patients receiving SIMPONI ARIA + MTX demonstrated greater improvement from baseline compared with placebo + MTX in physical component summary (PCS), mental component summary (MCS) scores and in all 8 domains of the SF-36.

Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F) in Trial RA. Treatment with SIMPONI ARIA resulted in improvement in fatigue as measured by FACIT-F.

14.2 Psoriatic Arthritis

The efficacy and safety of SIMPONI ARIA were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial in 480 patients ≥ 18 years of age with active psoriatic arthritis despite NSAID or DMARD therapy (Trial PsA, NCT02181673). Previous treatment with a biologic was not allowed. Patients in this trial had a diagnosis of PsA for at least six months and had symptoms of active disease [≥5 swollen joints and ≥5 tender joints and a CRP level of ≥ 0.6 mg/dL]. Patients were randomized to either receive SIMPONI ARIA 2 mg/kg (N=241) or placebo (N=239) as a 30-minute intravenous infusion at Weeks 0, 4, 12 and 20. All patients on placebo received SIMPONI ARIA at Week 24, Week 28 and every 8 weeks thereafter through Week 52. Patients in the SIMPONI ARIA treatment group continued to receive SIMPONI ARIA infusions at Week 28 and every 8 weeks through Week 52.

Patients were allowed to continue stable doses of MTX, NSAIDs, and low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone per day) during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited.

The primary endpoint was the percentage of patients achieving an ACR 20 response at Week 14.

Patients with each subtype of PsA were enrolled, including polyarticular arthritis with absence of rheumatoid nodules (44%), asymmetric peripheral arthritis (19%), distal interphalangeal joint involvement (8.1%), spondylitis with peripheral arthritis (25%), and arthritis mutilans (4.8%). The median duration of PsA disease was 3.5 years, 86% of patients had previously used MTX, and 35% of patients received at least one other DMARD in the past. At baseline, 76% and 54% of the patients had enthesitis and dactylitis, respectively. The median total modified vdH-S score at baseline was 15.5. During the trial, concomitant medications used included MTX (70%), oral corticosteroids (28%), and NSAIDs (71%).

Clinical Response

In Trial PsA, SIMPONI ARIA treatment, compared with placebo, resulted in a significant improvement in signs and symptoms as demonstrated by the percentage of patients with an ACR 20 response at Week 14 (see Table 5). Similar ACR 20 responses at Week 24 were observed in patients with different PsA subtypes. ACR 20 responses observed in the SIMPONI ARIA-treated groups were similar in patients who were or were not receiving concomitant MTX.

Table 5: Trial PsA –Percentage of Patients with ACR Responses at Weeks 14 and 24
	Placebo	SIMPONI ARIA	Difference from placebo (95% CI)
	(N *=239)	(N *=241)
Note: The analysis is based on the intent-to-treat population. Last observation carried forward was performed for partial missing data and non-responder imputation for completely missing data. Patients who discontinued treatment due to lack of efficacy were imputed as non-responders, as were patients who started prohibited medication, increased corticosteroids or MTX, or failed to achieve at least a 5% improvement in joint counts at Week 16 and received a concomitant medication intervention (corticosteroids, MTX or NSAIDs).
* N reflects randomized patients. Bold text indicates primary endpoint. † p<0.001
ACR 20 response
Week 14	22%	75%	53% † (46, 61)
Week 24	24%	77%	53% (45, 60)
ACR 50 response
Week 14	6.3%	44%	37% (30, 44)
Week 24	6.3%	54%	47% (40, 54)
ACR 70 response
Week 14	2.1%	25%	22% (17, 28)
Week 24	3.3%	33%	29% (23, 36)

The percentage of patients achieving ACR20 responses by visit through Week 24 for Trial PsA is shown in Figure 2.

Figure 2: Trial PsA - Percentage of Patients Achieving ACR20 Response Through Week 24

	The analysis is based on the intent-to-treat population. Last observation carried forward was performed for partial missing data and non-responder imputation for completely missing data. Patients who discontinued treatment due to lack of efficacy were imputed as non-responders, as were patients who started prohibited medication, increased corticosteroids or MTX, or failed to achieve at least a 5% improvement in joint counts at Week 16 and received a concomitant medication intervention (corticosteroids, MTX or NSAIDs).

Table 6 shows the improvement in the individual components of the ACR response criteria for the SIMPONI ARIA and placebo groups in Trial PsA.

Table 6: Trial PsA – Mean Changes in ACR Components at Week 14
	Placebo N *=239		SIMPONI ARIA N *=241
	Baseline	Week 14 change from baseline	Baseline	Week 14 change from baseline
Note: All values are means.
* N reflects randomized patients; actual number of patients evaluable for each endpoint may vary. † Health Assessment Questionnaire-Disability Index.
ACR Components
No. of Swollen Joints (0–66)	14	-2.9	14	-11
Number of Tender Joints (0–68)	26	-4.2	25	-15
Patient's assessment of Pain (0–100 mm)	64	-11	63	-31
Patient Global Assessment (0–100 mm)	63	-11	65	-32
Physician Global Assessment (0–100 mm)	64	-13	62	-39
Disability Index (HAQ) (0–3) †	1.3	-0.13	1.3	-0.60
hsCRP (mg/L)	20	-2.9	19	-16

Patients with enthesitis at baseline were evaluated for mean improvement using the Leeds Enthesitis Index (LEI) on a scale of 0–6. SIMPONI ARIA-treated patients showed a significantly greater improvement in enthesitis, with a mean reduction of 1.8 as compared with a mean reduction in placebo-treated patients of 0.8 at Week 14. Patients with dactylitis at baseline were evaluated for mean improvement on a scale of 0–60. SIMPONI ARIA-treated patients showed a significantly greater improvement, with a mean reduction of 7.8 compared with a mean reduction of 2.8 in placebo-treated patients at Week 14.

Radiographic Response

In Trial PsA, structural joint damage was assessed radiographically and expressed as a change from baseline at Week 24 in total modified vdH-S score and its components, the erosion score and JSN score. SIMPONI ARIA inhibited the progression of structural damage compared with placebo, as assessed by total modified vdH-S score as shown in Table 7.

Table 7: Trial PsA – Radiographic Change From Baseline at Week 24
	Placebo N *=237	SIMPONI ARIA N *=237	Difference from placebo (95% CI)
	Mean	Mean
Note: All values are means.
* N reflects randomized patients evaluable for radiographic assessment.
Change Total Modified vdH-S Score	2.0	-0.4	-2.3 (-2.9, -1.7)

At Week 24, a greater proportion of patients in the SIMPONI ARIA group (72%) had no progression of structural damage (change in the total modified vdH-S score ≤ 0), compared to 43% of patients in the placebo group.

Physical Function and Responses

Improvement in physical function as assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI) demonstrated that the proportion of patients who achieved clinically meaningful improvement of ≥ 0.3 in HAQ-DI score from baseline was greater in the SIMPONI ARIA-treated group compared to placebo at Week 14 (69% compared to 32%).

Other Health Related Outcomes

General health status was assessed by the 36-item Short Form Health Survey (SF-36). In Trial PsA, patients receiving SIMPONI ARIA demonstrated greater improvement from baseline compared with placebo in physical component summary, mental component summary scores and in all 8 domains of the SF-36.

Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F) in Trial PsA. Treatment with SIMPONI ARIA resulted in improvement in fatigue as measured by FACIT-F.

Treatment of Pediatric Patients

The efficacy of SIMPONI ARIA in pediatric patients with PsA is based on the pharmacokinetic exposure and extrapolation of the established efficacy of SIMPONI ARIA in adult PsA patients in Trial PsA [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

14.3 Ankylosing Spondylitis

The efficacy and safety of SIMPONI ARIA were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial (Trial AS, NCT02186873) in 208 patients ≥ 18 years of age with active ankylosing spondylitis (AS) and inadequate response or intolerance to NSAIDs. Patients had a diagnosis of definite AS for at least 3 months according to modified New York criteria. Patients had symptoms of active disease [Bath AS Disease Activity Index (BASDAI) ≥ 4, VAS for total back pain of ≥ 4, on scales of 0 to 10 cm (0 to 100 mm), and a hsCRP level of ≥ 0.3 mg/dL (3 mg/L)]. Patients were randomized to receive either SIMPONI ARIA 2 mg/kg (N=105) or placebo (N=103) as a 30-minute intravenous infusion at Weeks 0, 4 and 12. All patients on placebo received SIMPONI ARIA at Week 16, Week 20 and every 8 weeks thereafter through Week 52. Patients in the SIMPONI ARIA treatment group continued to receive SIMPONI ARIA infusions at Week 20 and every 8 weeks through Week 52. Patients were allowed to continue stable doses of concomitant MTX, SSZ, hydroxychloroquine (HCQ), low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone per day), and/or NSAIDs during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited.

The primary endpoint was the percentage of patients achieving an Assessment in Ankylosing Spondylitis (ASAS) 20 response at Week 16.

In Trial AS, the median duration of AS disease was 2.8 years, median duration of inflammatory back pain was 8 years, 90% were HLA-B27 positive, 8.2% had prior joint surgery or procedure, 5.8% had complete ankylosis of the spine, 14% had received prior therapy with one biologic TNF blocker (other than golimumab) and discontinued for reasons other than lack of efficacy within the first 16 weeks of treatment (primary failure), and 76% received at least one DMARD in the past. During the trial, the use of concomitant medications was NSAIDs (88%), SSZ (38%), corticosteroids (26%), MTX (18%), and HCQ (0.5%).

Clinical Response

In Trial AS, SIMPONI ARIA treatment, compared with placebo, resulted in a significant improvement in signs and symptoms as demonstrated by the percentage of patients with an ASAS 20 response at Week 16 (see Table 8).

Table 8: Trial AS – Percentage of ASAS Responders at Weeks 16
	Placebo N *=103	SIMPONI ARIA N *=105	Treatment Difference (95% CI)
Note: The analysis is based on the intent-to-treat population. Last observation carried forward was performed for partial missing data and non-responder imputation for completely missing data.
* N reflects randomized patients. Bold text indicates primary endpoint. † p<0.001
Responders
ASAS 20	26%	73%	47% † (35, 59)
ASAS 40	8.7%	48%	39% (28, 50)

The percentage of patients achieving ASAS 20 responses by visit through Week 16 for Trial AS is shown in Figure 3.

Figure 3: Trial AS – Percentage of Patients Achieving an ASAS 20 Response Through Week 16

	The analysis is based on the intent-to-treat population. Last observation carried forward was performed for partial missing data and non-responder imputation for completely missing data.

Table 9 shows the improvement in the components of the ASAS response criteria and other measures of disease activity for the SIMPONI ARIA and placebo groups in Trial AS.

Table 9: Trial AS – Mean Changes in ASAS 20 Components and Other Measures of Disease Activity at Week 16 *
	Placebo N *=103		SIMPONI ARIA N *=105
	Baseline	Week 16 change from baseline	Baseline	Week 16 change from baseline
Note: All values are means.
* N reflects randomized patients; actual number of patients evaluable for each endpoint may vary. † Measured on a Visual Analog Scale (VAS) with 0= very well, 100=very poor ‡ Measured on a Visual Analog Scale (VAS) with 0= no pain, 100=most severe pain § BASFI is Bath Ankylosing Spondylitis Functional Index. ¶ Inflammation is the mean of 2 morning stiffness self-assessments in the BASDAI. # Bath Ankylosing Spondylitis Metrology Index.
ASAS 20 Response criteria
Patient Global Assessment of Disease Activity (0–100 mm) †	71	-8.3	73	-34
Total back pain (0–100 mm) ‡	73	-12	72	-32
BASFI (0–10) §	6.1	-0.5	6.3	-2.4
Inflammation (0–10) ¶	7.4	-1.1	7.3	-3.6
BASDAI Score	7.1	-1.1	7.1	-3.1
BASMI #	5.0	-0.1	5.0	-0.4
hsCRP (mg/L)	19	-2.3	20	-17

At Week 16, a greater percentage of patients treated with SIMPONI ARIA achieved a low level of disease activity (<2 [on a scale of 0 to 10 cm] in all four ASAS domains) compared with patients treated with placebo (16.2% vs. 3.9%).

Other Health-Related Outcomes

General health status was assessed by the 36-item Short Form Health Survey (SF-36). In Trial AS, patients receiving SIMPONI ARIA demonstrated greater improvement from baseline compared with placebo in physical component summary and mental component summary scores and in all 8 domains of the SF-36.

SIMPONI ARIA-treated patients showed significant improvement compared with placebo-treated patients in health related quality of life as assessed by the Ankylosing Spondylitis Quality of Life questionnaire (ASQoL).

14.4 Polyarticular Juvenile Idiopathic Arthritis (pJIA)

The efficacy of SIMPONI ARIA in pediatric patients with pJIA is based on the pharmacokinetic exposure and extrapolation of the established efficacy of SIMPONI ARIA in RA patients. Efficacy of SIMPONI ARIA was also assessed in a multicenter, open-label, single-arm study in 127 children (2 to < 18 years of age) with JIA with active polyarthritis despite treatment with MTX for at least 2 months (Trial pJIA, NCT02277444). The polyarticular JIA patient subtypes at study entry included: rheumatoid factor negative (43%), rheumatoid factor positive (35%), enthesitis-related arthritis (9%), oligoarticular extended (6%), juvenile psoriatic arthritis (4%), and systemic JIA without systemic manifestations (3%). All patients received SIMPONI ARIA 80 mg/m 2as an intravenous infusion at Week 0, 4, and every 8 weeks through Week 52. Patients continued stable doses of MTX weekly through Week 28; after Week 28, changes in MTX dose were permitted. Efficacy was assessed as supportive endpoints through Week 52. The efficacy was generally consistent with responses in patients with RA.