14 CLINICAL STUDIES

14.1 Rheumatoid Arthritis

The efficacy and safety of SIMPONI were evaluated in 3 multicenter, randomized, double-blind, controlled trials (Trials RA-1, RA-2, and RA-3) in 1542 patients ≥ 18 years of age with moderately to severely active RA, diagnosed according to the American College of Rheumatology (ACR) criteria, for at least 3 months prior to administration of trial agent. Patients were required to have at least 4 swollen and 4 tender joints. SIMPONI was administered subcutaneously at doses of 50 mg or 100 mg every 4 weeks. Double-blinded controlled efficacy data were collected and analyzed through Week 24. Patients were allowed to continue stable doses of concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs and patients may have received oral MTX during the trials.

Trial RA-1 evaluated 445 patients who were previously treated (at least 8 to 12 weeks prior to administration of trial agent) with one or more doses of a biologic TNF blocker without a serious adverse reaction. Patients may have discontinued the biologic TNF blocker for a variety of reasons. Patients were randomized to receive placebo (N=150), SIMPONI 50 mg (N=147), or SIMPONI 100 mg (N=148). Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), and/or hydroxychloroquine (HCQ) during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited.

Trial RA-2 evaluated 444 patients who had active RA despite a stable dose of at least 15 mg/week of MTX and who had not been previously treated with a biologic TNF blocker. Patients were randomized to receive background MTX (N=133), SIMPONI 50 mg + background MTX (N=89), SIMPONI 100 mg + background MTX (N=89), or SIMPONI 100 mg monotherapy (N=133). The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited.

Trial RA-3 evaluated 637 patients with active RA who were MTX naïve and had not previously been treated with a biologic TNF blocker. Patients were randomized to receive MTX (N=160), SIMPONI 50 mg + MTX (N=159), SIMPONI 100 mg + MTX (N=159), or SIMPONI 100 mg monotherapy (N=159). For patients receiving MTX, MTX was administered at a dose of 10 mg/week beginning at Week 0 and increased to 20 mg/week by Week 8. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited.

The primary endpoint in Trial RA-1 and Trial RA-2 was the percentage of patients achieving an ACR 20 response at Week 14 and the primary endpoint in Trial RA-3 was the percentage of patients achieving an ACR 50 response at Week 24.

In Trials RA-1, RA-2, and RA-3, the median duration of RA disease was 9.4, 5.7, and 1.2 years and 99%, 75%, and 54% of the patients used at least one DMARD in the past, respectively. Approximately 77% and 57% of patients received concomitant NSAIDs and low dose corticosteroids, respectively, in the 3 pooled RA trials.

Clinical Response

In the 3 RA trials, a greater percentage of patients treated with the combination of SIMPONI and MTX achieved ACR responses at Week 14 (Trials RA-1 and RA-2) and Week 24 (Studies RA-1, RA-2, and RA-3) versus patients treated with the MTX alone. There was no clear evidence of improved ACR response with the higher SIMPONI dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). In Trials RA-2 and RA-3, the SIMPONI monotherapy groups were not statistically different from the MTX monotherapy groups in ACR responses. Table 2 shows the proportion of patients with the ACR response for the SIMPONI 50-mg and control groups in Trials RA-1, RA-2, and RA-3. In the subset of patients who received SIMPONI in combination with MTX in Trial RA-1, the proportion of patients achieving ACR 20, 50 and 70 responses at Week 14 were 40%, 18%, and 12%, respectively, in the SIMPONI 50-mg + MTX group (N=101) compared with 17%, 6%, and 2%, respectively, in the placebo + MTX group (N=103). Table 3 shows the percent improvement in the components of the ACR response criteria for the SIMPONI 50-mg + MTX and MTX groups in Trial RA-2. The percentage of patients achieving ACR 20 responses by visit for Trial RA-2 is shown in Figure 1. ACR 20 responses were observed in 38% of patients in the SIMPONI 50-mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.

Table 2: Trials RA-1, RA-2, and RA-3 Proportion of Patients with an ACR Response *
	Trial RA-1 Active RA previously treated with one or more doses of TNF blockers		Trial RA-2 Active RA, despite MTX		Trial RA-3 Active RA, MTX Naïve
	Placebo ± DMARDs †	SIMPONI 50 mg ± DMARDs †	Background MTX	SIMPONI 50 mg + Background MTX	MTX	SIMPONI 50 mg + MTX
* Approximately 78% and 58% of the patients received concomitant NSAIDs and low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day), respectively, during the 3 pooled RA trials. † DMARDs in Trial RA-1 included MTX, HCQ, and/or SSZ (about 68%, 8%, and 5% of patients received MTX, HCQ, and SSZ, respectively). ‡ N reflects randomized patients. § NA = Not applicable, as data was not collected at Week 14 in Trial RA-3. ¶ Not significantly different from MTX monotherapy.
N ‡	150	147	133	89	160	159
ACR 20
Week 14	18%	35%	33%	55%	NA §	NA §
Week 24	16%	31%	28%	60%	49%	62%
ACR 50
Week 14	7%	15%	10%	35%	NA §	NA §
Week 24	4%	16%	14%	37%	29%	40%
ACR 70
Week 14	2%	10%	4%	13%	NA §	NA §
Week 24	2%	9%	5%	20%	16%	24% ¶

Table 3: Trial RA-2 ─ Median Percent Improvement from Baseline in the Individual ACR Components at Week 14 *
	Background MTX	SIMPONI 50 mg + Background MTX
Note: Baseline values are medians.
* In Trial RA-2, about 70% and 85% of patients received concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs during the trials, respectively. † N reflects randomized patients; actual number of patients evaluable for each endpoint may vary.
N †	133	89
Number of swollen joints (0–66)
Baseline	12	13
Week 14	38%	62%
Number of tender joints (0–68)
Baseline	21	26
Week 14	30%	60%
Patient's assessment of pain (0–10)
Baseline	5.7	6.1
Week 14	18%	55%
Patient's global assessment of disease activity (0–10)
Baseline	5.3	6.0
Week 14	15%	45%
Physician's global assessment of disease activity (0–10)
Baseline	5.7	6.1
Week 14	35%	55%
HAQ score (0–3)
Baseline	1.25	1.38
Week 14	10%	29%
CRP (mg/dL)
Baseline	0.8	1.0
Week 14	2%	44%

*: The same patients may not have responded at each timepoint.

Figure 1: Trial RA-2 – Percentage of Patients Achieving ACR 20 Response by Visit: Randomized Patients *

Physical Function Response in Patients with RA

In Trials RA-1 and RA-2, the SIMPONI 50-mg groups demonstrated a greater improvement compared to the control groups in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24: 0.23 vs. 0.03 in RA-1, 0.47 vs. 0.13 in RA-2, respectively. Also in Trials RA-1 and RA-2, the SIMPONI 50-mg groups compared to the control groups had a greater proportion of HAQ responders (change from baseline > 0.22) at Week 24: 43% vs. 27%, 65% vs. 35%, respectively.

14.2 Psoriatic Arthritis

The safety and efficacy of SIMPONI were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial in 405 adult patients with moderately to severely active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite NSAID or DMARD therapy (Trial PsA). Patients in this trial had a diagnosis of PsA for at least 6 months with a qualifying psoriatic skin lesion of at least 2 cm in diameter. Previous treatment with a biologic TNF blocker was not allowed. Patients were randomly assigned to placebo (N=113), SIMPONI 50 mg (N=146), or SIMPONI 100 mg (N=146) given subcutaneously every 4 weeks. Patients were allowed to receive stable doses of concomitant MTX (≤ 25 mg/week), low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. The primary endpoint was the percentage of patients achieving ACR 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24.

Patients with each subtype of PsA were enrolled, including polyarticular arthritis with no rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal (DIP) joint arthritis (15%), spondylitis with peripheral arthritis (11%), and arthritis mutilans (1%). The median duration of PsA disease was 5.1 years, 78% of patients received at least one DMARD in the past, and approximately 48% of patients received MTX, and 16% received low dose oral steroids.

Clinical Response in Patients with PsA

SIMPONI ± MTX, compared with placebo ± MTX, resulted in significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ACR 20 response at Week 14 in Trial PsA (see Table 4). There was no clear evidence of improved ACR response with the higher SIMPONI dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). ACR responses observed in the SIMPONI-treated groups were similar in patients receiving and not receiving concomitant MTX. Similar ACR 20 responses at Week 14 were observed in patients with different PsA subtypes. However, the number of patients with arthritis mutilans was too small to allow meaningful assessment. SIMPONI 50-mg treatment also resulted in significantly greater improvement compared with placebo for each ACR component in Trial PsA (Table 5). Treatment with SIMPONI resulted in improvement in enthesitis and skin manifestations in patients with PsA. However, the safety and efficacy of SIMPONI in the treatment of patients with plaque psoriasis has not been established.

The percentage of patients achieving ACR 20 responses by visit for Trial PsA is shown in Figure 2. ACR 20 responses were observed in 31% of patients in the SIMPONI 50-mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.

Table 4: Trial PsA - Proportion of Patients with ACR Responses
	Placebo ± MTX *	SIMPONI 50 mg ± MTX *
Bold text indicates primary endpoint.
* In Trial PsA, about 48%, 16%, and 72% of the patients received stable doses of MTX (≤ 25 mg/week), low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and NSAIDs, respectively. † N reflects randomized patients.
N †	113	146
ACR 20
Week 14	9%	51%
Week 24	12%	52%
ACR 50
Week 14	2%	30%
Week 24	4%	32%
ACR 70
Week 14	1%	12%
Week 24	1%	19%

Table 5: Trial PsA - Percent Improvement in ACR Components at Week 14
	Placebo ± MTX *	SIMPONI 50 mg ± MTX *
Note: Baseline are median values.
* In Trial PsA, about 48%, 16%, and 78% of the patients received stable doses of MTX (≤ 25 mg/week), low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and NSAIDs, respectively. † N reflects randomized patients; actual number of patients evaluable for each endpoint may vary by timepoint.
N †	113	146
Number of swollen joints (0–66)
Baseline	10.0	11.0
Week 14	8%	60%
Number of tender joints (0–68)
Baseline	18.0	19.0
Week 14	0%	54%
Patient's assessment of pain (0–10)
Baseline	5.4	5.8
Week 14	-1%	48%
Patient's global assessment of disease activity (0–10)
Baseline	5.2	5.2
Week 14	2%	49%
Physician's global assessment of disease activity (0–10)
Baseline	5.2	5.4
Week 14	7%	59%
HAQ score (0–10)
Baseline	1.0	1.0
Week 14	0%	28%
CRP (mg/dL) (0–10)
Baseline	0.6	0.6
Week 14	0%	40%

*: The same patients may not have responded at each timepoint.

Figure 2: Trial PsA – Percentage of ACR 20 PsA Responders by Visit: Randomized Patients *

Physical Function Response in Patients with PsA

In Trial PsA, SIMPONI 50 mg demonstrated a greater improvement compared to placebo in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24 (0.33 and -0.01, respectively). In addition, the SIMPONI 50-mg group compared to the placebo group had a greater proportion of HAQ responders (≥ 0.3 change from baseline) at Week 24: 43% vs. 22%, respectively.

14.3 Ankylosing Spondylitis

The safety and efficacy of SIMPONI were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial in 356 adult patients with active ankylosing spondylitis according to modified New York criteria for at least 3 months (Trial AS). Patients had symptoms of active disease [defined as a Bath AS Disease Activity Index (BASDAI) ≥ 4 and VAS for total back pain of ≥ 4, on scales of 0 to 10 cm] despite current or previous NSAID therapy. Patients were excluded if they were previously treated with a biologic TNF blocker or if they had complete ankylosis of the spine. Patients were randomly assigned to placebo (N=78), SIMPONI 50 mg (N=138), or SIMPONI 100 mg (N=140) administered subcutaneously every 4 weeks. Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), hydroxychloroquine (HCQ), low dose corticosteroids (equivalent to < 10 mg of prednisone a 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 14. Placebo-controlled efficacy data were collected and analyzed through Week 24.

In Trial AS, the median duration of AS disease was 5.6 years, median duration of inflammatory back pain was 12 years, 83% were HLA-B27 positive, 24% had prior joint surgery or procedure, and 55% received at least one DMARD in the past. During the trial, the use of concomitant DMARDs and/or NSAIDs was as follows: MTX (20%), SSZ (26%), HCQ (1%), low dose oral steroids (16%), and NSAIDs (90%).

Clinical Response in Patients with AS

In Trial AS, SIMPONI ± DMARDs treatment, compared with placebo ± DMARDs, resulted in a significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ASAS 20 response at Week 14 (see Table 6). There was no clear evidence of improved ASAS response with the higher SIMPONI dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). Table 7 shows the percent improvement in the components of the ASAS response criteria for the SIMPONI 50 mg ± DMARDs and placebo ± DMARDs groups in Trial AS.

The percentage of patients achieving ASAS 20 responses by visit for Trial AS is shown in Figure 3. ASAS 20 responses were observed in 48% of patients in the SIMPONI 50-mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.

Table 6: Trial AS – Proportion of ASAS Responders at Weeks 14 and 24
	Placebo ± DMARDs *	SIMPONI 50 mg ± DMARDs *
Bold text indicates primary endpoint.
* During the trial, the concomitant use of stable doses of DMARDS was as follows: MTX (21%), SSZ (25%), and HCQ (1%). About 16% and 89% of patients received stable doses of low dose oral steroids and NSAIDs during the trial, respectively. † N reflects randomized patients.
N †	78	138
Responders, % of patients
ASAS 20
Week 14	22%	59%
Week 24	23%	56%
ASAS 40
Week 14	15%	45%
Week 24	15%	44%

Table 7: Trial AS ─ Median Percent Improvement in ASAS Components at Week 14
	Placebo ± DMARDs *	SIMPONI 50 mg ± DMARDs *
* During the trial, the concomitant use of stable doses of DMARDS was as follows: MTX (21%), SSZ (25%), and HCQ (1%). About 16% and 89% of patients received stable doses of low dose oral steroids and NSAIDs during the trial, respectively. † N reflects randomized patients. ‡ BASFI is Bath Ankylosing Spondylitis Functional Index. § Inflammation is the mean of 2 patient-reported stiffness self-assessments in the Bath AS Disease Activity Index (BASDAI).
N †	78	138
ASAS components
Patient global assessment (0–10)
Baseline	7.2	7.0
Week 14	13%	47%
Total back pain (0–10)
Baseline	7.6	7.5
Week 14	9%	50%
BASFI (0–10) ‡
Baseline	4.9	5.0
Week 14	-3%	37%
Inflammation (0–10) §
Baseline	7.1	7.1
Week 14	6%	59%

*: The same patients may not have responded at each timepoint.

Figure 3:Trial AS – Percentage of AS Patients Achieving ASAS 20 Response by Visit: Randomized Patients *

14.4 Ulcerative Colitis

The safety and efficacy of SIMPONI were evaluated in 2 multicenter, randomized, double-blind, placebo-controlled clinical trials in patients ≥ 18 years of age (Trials UC-1 and UC-2).

Trial UC-1 was an induction trial conducted in patients with moderately to severely active ulcerative colitis (UC), defined as a Mayo score of 6 to 12 [the Mayo score ranges from 0 to 12 and has 4 subscales that are each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment]. At baseline, subjects also had an endoscopy subscore of 2 or 3 on a 3-point scale (an endoscopy score of 2 is defined by marked erythema, absent vascular pattern, friability, erosions; and a score of 3 is defined by spontaneous bleeding, ulceration). Patients were corticosteroid dependent (i.e., an inability to successfully taper corticosteroids without a return of the symptoms of UC) or had an inadequate response to or had failed to tolerate at least one of the following therapies: oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine.

Trial UC-1 was divided into 2 parts. In Part 1 (dose finding), patients were randomized to one of 4 treatment groups: 400 mg SIMPONI administered subcutaneously (SC) at Week 0 and 200 mg at Week 2 (400/200 mg), 200-mg SIMPONI SC at Week 0 and 100 mg at Week 2 (200/100 mg), 100-mg SIMPONI SC at Week 0 and 50 mg at Week 2 (100/50 mg), or placebo SC at Weeks 0 and 2. In Part 2 (dose confirming), efficacy was evaluated in 761 patients who were randomized to receive either 400 mg SIMPONI SC at Week 0 and 200 mg at Week 2, 200-mg SIMPONI SC at Week 0 and 100 mg at Week 2, or placebo SC at Weeks 0 and 2. SIMPONI 100/50-mg SC was not evaluated in Part 2; its safety and effectiveness has not been established in UC. Concomitant stable doses of oral aminosalicylates (5-ASA), oral corticosteroids (less than 40 mg/day), azathioprine (AZA), 6-mercaptopurine (6-MP), and/or methotrexate (MTX) were permitted. Patients who received previous TNF inhibitors were excluded. The primary endpoint was the percent of patients in clinical response at Week 6, defined as a decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, accompanied by a decrease in the rectal bleeding subscore of ≥ 1 or a rectal bleeding subscore of 0 (no blood seen) or 1 (streaks of blood with stool less than half the time).

Trial UC-2 was a randomized-withdrawal maintenance trial that evaluated 456 patients who achieved clinical response with SIMPONI induction and tolerated SIMPONI treatment. Patients were randomized to receive SIMPONI 50 mg, SIMPONI 100 mg or placebo administered subcutaneously every 4 weeks. Concomitant stable doses of oral aminosalicylates, azathioprine, 6-mercaptopurine, and/or methotrexate were permitted. Corticosteroids were to be tapered at the start of the maintenance trial. The primary endpoint was the percent of patients maintaining clinical response through Week 54.

Clinical Response, Clinical Remission and Improvement of Endoscopic Appearance of the Mucosa

In Trial UC-1, a greater proportion of patients achieved clinical response, clinical remission and had improvement of endoscopic appearance of the mucosa at Week 6 in the SIMPONI 200/100-mg group compared with the placebo group. The SIMPONI 400/200-mg group did not demonstrate additional clinical benefit over the SIMPONI 200/100-mg group. Clinical response was defined as a decrease from baseline in the Mayo score of ≥ 30% and ≥ 3 points, accompanied by a decrease in the rectal bleeding subscore of ≥ 1 or a rectal bleeding subscore of 0 or 1. Clinical remission was defined as a Mayo score ≤ 2 points, with no individual subscore > 1. Improvement of endoscopic appearance of the mucosa was defined as a Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability).

In Trial UC-2, a greater proportion of patients maintained clinical response through Week 54 in the SIMPONI 100-mg group compared with the placebo group. In Trial UC-2, SIMPONI-treated patients in clinical response (which included the subset of patients in clinical remission) in Trial UC-1, were again assessed for clinical remission at Week 30 and Week 54. A greater proportion of patients had clinical remission at both Weeks 30 and 54 without demonstrating a loss of response at any time point through Week 54 in the SIMPONI 100-mg group compared with the placebo group.

These results are shown in Table 8 below.

Table 8: The Proportion of Patients with UC in Clinical Response, Clinical Remission and with Improvement of Endoscopic Appearance of the Mucosa in Trials UC-1 and UC-2
* Patients who had a prohibited change in concomitant UC medication, an ostomy or colectomy, discontinued trial agent due to lack of therapeutic effect, or a dose adjustment in Trial UC-2 were considered not to be in clinical response, clinical remission or have an improvement in endoscopic appearance of the mucosa from the time of the event onward. † p<0.0001; ‡ p=0.0014; § Results in Trial UC-2 are based on patients who were in clinical response to SIMPONI at trial entry. ¶ Patients were assessed for UC disease activity by partial Mayo score every 4 weeks (loss of response was confirmed by endoscopy). Therefore, a patient who maintained clinical response was in response at each evaluation through Week 54. # p<0.001; Þ A patient had to be in remission at both Weeks 30 and 54 (without demonstrating a loss of response at any time point through Week 54) to achieve sustained remission. ß p=0.004
Trial UC-1 (6-Week Induction Trial)
	Placebo N=251	SIMPONI 200/100 mg N=253	Treatment difference (95% C.I.)
Clinical response *at Week 6	30%	51%	21% (12%, 29%) †
Clinical remission *at Week 6	6%	18%	11% (6%, 17%) †
Improvement of endoscopic appearance of the mucosa at Week 6 *	29%	42%	14% (5%, 22%) ‡
Trial UC-2 (54-Week Maintenance Trial) §
	Placebo N=154	SIMPONI 100 mg N=151	Treatment difference (95% C.I.)
Clinical response *through Week 54 ¶	31%	50%	19% (8%, 29%) #
Clinical remission *at both Week 30 and Week 54 Þ	16%	28%	12% (3%, 21%) ß