14 CLINICAL STUDIES

14.1 Clinical Studies in RA

The safety and efficacy of KINERET have been evaluated in three randomized, double-blind, placebo-controlled trials of 1790 patients ≥ 18 years of age with active rheumatoid arthritis (RA). An additional fourth study was conducted to assess safety. In the efficacy trials, KINERET was studied in combination with other disease-modifying antirheumatic drugs (DMARDs) other than Tumor Necrosis Factor (TNF) blocking agents (Studies 1 and 2) or as a monotherapy (Study 3).

Study 1 involved 899 patients with active RA who had been on a stable dose of methotrexate (MTX) (10 to 25 mg/week) for at least 8 weeks. All patients had at least 6 swollen/painful and 9 tender joints and either a C-reactive protein (CRP) of ≥ 1.5 mg/dL or an erythrocyte sedimentation rate (ESR) of ≥ 28 mm/hr. Patients were randomized to KINERET or placebo in addition to their stable doses of MTX. The first 501 patients were evaluated for signs and symptoms of active RA. The total 899 patients were evaluated for progression of structural damage.

Study 2 evaluated 419 patients with active RA who had received MTX for at least 6 months including a stable dose (15 to 25 mg/week) for at least 3 consecutive months prior to enrollment. Patients were randomized to receive placebo or one of five doses of KINERET subcutaneous daily for 12 to 24 weeks in addition to their stable doses of MTX.

Study 3 evaluated 472 patients with active RA and had similar inclusion criteria to Study 1 except that these patients had received no DMARD for the previous 6 weeks or during the study. Patients were randomized to receive either KINERET or placebo. Patients were DMARD-naïve or had failed no more than 3 DMARDs.

Study 4 was a placebo-controlled, randomized trial designed to assess the safety of KINERET in 1414 patients receiving a variety of concurrent medications for their RA including some DMARD therapies, as well as patients who were DMARD-free. The TNF blocking agents etanercept and infliximab were specifically excluded. Concurrent DMARDs included MTX, sulfasalazine, hydroxychloroquine, gold, penicillamine, leflunomide, and azathioprine. Unlike Studies 1, 2 and 3, patients predisposed to infection due to a history of underlying disease such as pneumonia, asthma, controlled diabetes, and chronic obstructive pulmonary disease (COPD) were also enrolled [see Adverse Reactions ( 6)] .

In Studies 1, 2 and 3, the improvement in signs and symptoms of RA was assessed using the American College of Rheumatology (ACR) response criteria (ACR 20, ACR 50, ACR 70). In these studies, patients treated with KINERET were more likely to achieve an ACR 20or higher magnitude of response (ACR 50and ACR 70) than patients treated with placebo ( Table 3). The treatment response rates did not differ based on gender or ethnic group. The results of the ACR component scores in Study 1 are shown in Table 4.

Most clinical responses, both in patients receiving placebo and patients receiving KINERET, occurred within 12 weeks of enrollment.

Table 3: Percent of Patients with ACR Responses in Studies 1 and 3
ap < 0.05, KINERET versus placebo
bp < 0.01, KINERET versus placebo
cp < 0.001, KINERET versus placebo
	Study 1 (Patients on MTX)		Study 3 (No DMARDs)
				KINERET
Response	Placebo (n = 251)	KINERET 100 mg/day (n = 250)	Placebo (n = 119)	75 mg/day (n = 115)	150 mg/day (n = 115)
ACR 20 Month 3 Month 6	24% 22%	34% a 38% c	23% 27%	33% 34%	33% 43% a
ACR 50 Month 3 Month 6	6% 8%	13% b 17% b	5% 8%	10% 11%	8% 19% a
ACR 70 Month 3 Month 6	0% 2%	3% a 6% a	0% 1%	0% 1%	0% 1%

Table 4: Median ACR Component Scores in Study 1
aHealth Assessment Questionnaire; 0 = best, 3 = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
bVisual analog scale; 0 = best, 100 = worst
cScale 0 to 68
dScale 0 to 66
		Placebo/MTX		KINERET/MTX 100 mg/day
		(n = 251)		(n = 250)
Parameter (median)		Baseline	Month 6	Baseline	Month 6

Patient Reported Outcomes
	Disability index a	1.38	1.13	1.38	1.00
	Patient global assessment b	51.0	41.0	51.0	29.0
	Pain b	56.0	44.0	63.0	34.0
Objective Measures
	ESR (mm/hr)	35.0	32.0	36.0	19.0
	CRP (mg/dL)	2.2	1.6	2.2	0.5
Physician's Assessments
	Tender/painful joints c	20.0	11.0	23.0	9.0
	Physician global assessment b	59.0	31.0	59.0	26.0
	Swollen joints d	18.0	10.5	17.0	9.0

A 24-week study was conducted in 242 patients with active RA on background methotrexate who were randomized to receive either etanercept alone or the combination of KINERET and etanercept. The ACR 50response rate was 31% for patients treated with the combination of KINERET and etanercept and 41% for patients treated with etanercept alone, indicating no added clinical benefit of the combination over etanercept alone. Serious infections were increased with the combination compared to etanercept alone [see Warnings and Precautions ( 5.1)] .

In Study 1, the effect of KINERET on the progression of structural damage was assessed by measuring the change from baseline at month 12 in the Total Modified Sharp Score (TSS) and its subcomponents, erosion score, and joint space narrowing (JSN) score. 2Radiographs of hands/wrists and forefeet were obtained at baseline, 6 months and 12 months and scored by readers who were unaware of treatment group. A difference between placebo and KINERET for change in TSS, erosion score (ES) and JSN score was observed at 12 months ( Table 5).

Table 5: Mean Radiographic Changes Over 12 Months in Study 1
* Differences and 95% confidence intervals for the differences in change scores between Placebo/MTX and KINERET/MTX
** Based on Wilcoxon rank-sum test
	Placebo/MTX (N = 450)		KINERET 100 mg/day /MTX (N = 449)		Placebo/MTX vs. KINERET/MTX
	Baseline	Change at Month 12	Baseline	Change at Month 12	95% Confidence Interval*	p-value**
TSS	52	2.6	50	1.7	0.9 [0.3, 1.6]	< 0.001
Erosion	28	1.6	25	1.1	0.5 [0.1, 1.0]	0.024
JSN	24	1.1	25	0.7	0.4 [0.1, 0.7]	< 0.001

The disability index of the Health Assessment Questionnaire (HAQ) was administered monthly for the first six months and quarterly thereafter during Study 1. Health outcomes were assessed by the Short Form-36 (SF-36) questionnaire. The 1-year data on HAQ in Study 1 showed more improvement with KINERET than placebo. The physical component summary (PCS) score of the SF-36 also showed more improvement with KINERET than placebo but not the mental component summary (MCS).

14.2 Clinical Studies in NOMID

The efficacy of KINERET was evaluated in a prospective, long-term, open-label and uncontrolled study which incorporated a withdrawal period in a subset of 11 patients. This study included 43 NOMID patients 0.7 to 46 years of age treated for up to 60 months. Patients were given an initial KINERET dose of 1–2.4 mg/kg body weight. During the study, the dose was adjusted by 0.5 to 1 mg/kg increments to a protocol-specified maximum of 10 mg/kg daily, titrated to control signs and symptoms of disease. The maximum dose actually studied was 7.6 mg/kg/day. The average maintenance dose was 3 to 4 mg/kg daily. In general, the dose was given once daily, but for some patients, the dose was split into twice daily administrations for better control of disease activity.

NOMID symptoms were assessed with a disease-specific Diary Symptom Sum Score (DSSS), which included the prominent disease symptoms fever, rash, joint pain, vomiting, and headache. In addition, serum amyloid A (SAA), hsCRP, and ESR levels were monitored. Changes in clinical and laboratory parameters from baseline to Months 3 to 6 and from Month 3 (before withdrawal) to the end of the withdrawal period were assessed in the subset of patients who underwent withdrawal. The estimated changes from baseline in DSSS are summarized through Month 60 in Table 6. Results were consistent across all subgroups, including age, gender, presence of CIAS1 mutation, and disease phenotype. Improvements occurred in all individual disease symptoms comprising the DSSS ( Table 7), as well as in the serum markers of inflammation. For the 11 patients who went through a withdrawal phase, disease symptoms and serum markers of inflammation worsened after withdrawal and promptly responded to reinstitution of KINERET therapy. Upon withdrawal of treatment, the median time until disease flare criteria were met was 5 days.

Table 6. Estimated change from baseline in DSSS in NOMID patients (N=29)
*Mean (SD) baseline value was 4.5 (3.2)
Time point	Estimated mean change from baseline in DSSS*	95% confidence interval
Month 3-6	-3.5	-3.7 to -3.3
Month 12	-3.6	-3.9 to -3.3
Month 36	-3.5	-3.8 to -3.2
Month 60	-3.5	-3.8 to -3.1

Table 7. Individual diary key symptom scores by visit (ITT diary population)
*mean (SD)
Visit (month)	Number of patients	Fever score*	Rash score*	Joint pain score*	Vomiting score*	Headache score*
Baseline	29	0.5 (0.8)	1.9 (1.1)	1.2 (1.1)	0.1 (0.2)	0.9 (1.0)
1	28	0.1 (0.1)	0.3 (0.5)	0.2 (0.3)	0.0 (0.0)	0.2 (0.3)
3	26	0.1 (0.2)	0.1 (0.2)	0.2 (0.4)	0.0 (0.1)	0.1 (0.2)
6	25	0.0 (0.1)	0.1 (0.1)	0.2 (0.4)	0.0 (0.1)	0.2 (0.3)
12	24	0.1 (0.1)	0.1 (0.2)	0.1 (0.2)	0.0 (0.1)	0.1 (0.2)
36	19	0.0 (0.2)	0.0 (0.2)	0.1 (0.3)	0.0 (0.0)	0.2 (0.6)
60	15	0.0 (0.0)	0.1 (0.3)	0.3 (0.7)	0.0 (0.0)	0.1 (0.3)

KINERET treatment also appeared to be associated with improvement of, or stability in, assessments of other NOMID disease manifestations, such as CNS, audiogram, and visual acuity data, up to Month 60.

14.3 Clinical Studies in DIRA

The safety and efficacy of KINERET were evaluated in a long-term natural history study including 9 DIRA patients (ages 1 month to 9 years at the start of KINERET treatment) treated with KINERET for up to 10 years. All patients had genetically confirmed DIRA. The starting dose of KINERET was 1 to 2 mg/kg/day in the 6 patients for which the dose was reported. The dose was then individually adjusted to reach a stable efficacious dose to control active inflammation. The highest KINERET dose studied was 7.5 mg/kg/day. At the last visit during the first KINERET treatment period, the dose ranged between 2.2 and 6.1 mg/kg/day. Inflammatory remission was defined as achievement of all of the following criteria: CRP ≤ 5 mg/L, no pustulosis, no inflammatory bone disease, and no concomitant glucocorticosteroid use. All 9 patients achieved inflammatory remission while on KINERET treatment.