14 CLINICAL STUDIES

14.1 Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

The safety and effectiveness of RITUXAN in relapsed, refractory CD20+ NHL were demonstrated in 3 single-arm studies enrolling 296 patients.

NHL Study 1

A multicenter, open-label, single-arm study was conducted in 166 patients with relapsed or refractory, low-grade or follicular, B-cell NHL who received 375 mg/m2 of RITUXAN given as an intravenous infusion weekly for 4 doses. Patients with tumor masses > 10 cm or with > 5,000 lymphocytes/µL in the peripheral blood were excluded from the study.

Results are summarized in Table 11. The median time to onset of response was 50 days. Disease-related signs and symptoms (including B-symptoms) resolved in 64% (25/39) of those patients with such symptoms at study entry.

NHL Study 2

In a multicenter, single-arm study, 37 patients with relapsed or refractory, low-grade NHL received 375 mg/m2 of RITUXAN weekly for 8 doses. Results are summarized in Table 11.

NHL Study 3

In a multicenter, single-arm study, 60 patients received 375 mg/m2 of RITUXAN weekly for 4 doses. All patients had relapsed or refractory, low-grade or follicular, B-cell NHL and had achieved an objective clinical response to RITUXAN administered 3.8–35.6 months (median 14.5 months) prior to retreatment with RITUXAN. Of these 60 patients, 5 received more than one additional course of RITUXAN. Results are summarized in Table 11.

Bulky Disease

In pooled data from studies 1 and 3, 39 patients with bulky (single lesion > 10 cm in diameter) and relapsed or refractory, low-grade NHL received RITUXAN 375 mg/m2 weekly for 4 doses. Results are summarized in Table 11.

Table 11 Summary of RITUXAN Efficacy Data in NHL by Schedule and Clinical Setting
	Study 1 Weekly × 4 N=166	Study 2 Weekly × 8 N=37	Study 1 and Study 3 Bulky disease, Weekly × 4 N=39*	Study 3 Retreatment, Weekly × 4 N=60
* Six of these patients are included in the first column. Thus, data from 296 intent-to-treat patients are provided in this table. † Kaplan-Meier projected with observed range. ‡ "+" indicates an ongoing response. § Duration of response: interval from the onset of response to disease progression.
Overall Response Rate	48%	57%	36%	38%
Complete Response Rate	6%	14%	3%	10%
Median Duration of Response†, ‡, §	11.2	13.4	6.9	15.0
(Months) [Range]	[1.9 to 42.1+]	[2.5 to 36.5+]	[2.8 to 25.0+]	[3.0 to 25.1+]

14.2 Previously Untreated, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

The safety and effectiveness of RITUXAN in previously untreated, low-grade or follicular, CD20+ NHL were demonstrated in 3 randomized, controlled trials enrolling 1,662 patients.

NHL Study 4

A total of 322 patients with previously untreated follicular NHL were randomized (1:1) to receive up to eight 3-week cycles of CVP chemotherapy alone (CVP) or in combination with RITUXAN 375 mg/m2 on Day 1 of each cycle (R-CVP) in an open-label, multicenter study. The main outcome measure of the study was progression-free survival (PFS) defined as the time from randomization to the first of progression, relapse, or death.

Twenty-six percent of the study population was >60 years of age, 99% had Stage III or IV disease, and 50% had an International Prognostic Index (IPI) score greater than or equal to 2. The results for PFS as determined by a blinded, independent assessment of progression are presented in Table 12. The point estimates may be influenced by the presence of informative censoring. The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment.

Table 12 Efficacy Results in NHL Study 4
	Study Arm
	R-CVP N=162	CVP N=160
* p < 0.0001, two-sided stratified log-rank test. † Estimates of Cox regression stratified by center.
Median PFS (years)*	2.4	1.4
Hazard ratio (95% CI)†	0.44 (0.29, 0.65)

NHL Study 5

An open-label, multicenter, randomized (1:1) study was conducted in 1,018 patients with previously untreated follicular NHL who achieved a response (CR or PR) to RITUXAN in combination with chemotherapy. Patients were randomized to RITUXAN as single-agent maintenance therapy, 375 mg/m2 every 8 weeks for up to 12 doses or to observation. RITUXAN was initiated at 8 weeks following completion of chemotherapy. The main outcome measure of the study was progression-free survival (PFS), defined as the time from randomization in the maintenance/observation phase to progression, relapse, or death, as determined by independent review.

Of the randomized patients, 40% were greater than or equal to 60 years of age, 70% had Stage IV disease, 96% had ECOG performance status (PS) 0–1, and 42% had FLIPI scores of 3–5. Prior to randomization to maintenance therapy, patients had received R-CHOP (75%), R-CVP (22%), or R-FCM (3%); 71% had a complete or unconfirmed complete response and 28% had a partial response.

PFS was longer in patients randomized to RITUXAN as single agent maintenance therapy (HR: 0.54, 95% CI: 0.42, 0.70). The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment.

Figure 1
Kaplan-Meier Plot of IRC Assessed PFS in NHL Study 5

NHL Study 6

A total of 322 patients with previously untreated low-grade, B-cell NHL who did not progress after 6 or 8 cycles of CVP chemotherapy were enrolled in an open-label, multicenter, randomized trial. Patients were randomized (1:1) to receive RITUXAN, 375 mg/m2 intravenous infusion, once weekly for 4 doses every 6 months for up to 16 doses or no further therapeutic intervention. The main outcome measure of the study was progression-free survival defined as the time from randomization to progression, relapse, or death. Thirty-seven percent of the study population was greater than 60 years of age, 99% had Stage III or IV disease, and 63% had an IPI score greater than or equal to 2.

There was a reduction in the risk of progression, relapse, or death (hazard ratio estimate in the range of 0.36 to 0.49) for patients randomized to RITUXAN as compared to those who received no additional treatment.

NHL Study 11

RITUXAN in combination with chemotherapy was evaluated in Inter-B-NHL Ritux 2010 (NCT01516580), a multicenter, open-label, randomized trial of patients with previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL aged 6 months and older. Advanced stage is defined as Stage III with elevated lactose dehydrogenase (LDH) level [LDH greater than twice the institutional upper limit of the adult normal values] or stage IV B-cell NHL or B-AL. LMB therapy was administered based on the clinical group classification of group B (stage III with high LDH and non-central nervous system (CNS) (Stage IV), group C1 (B-AL, CNS positive and cerebrospinal fluid (CSF) negative) and C3 (CSF positive).

Patients were randomized to Lymphome Malin B (LMB) chemotherapy (corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide and triple drug [methotrexate/cytarabine/ corticosteroid] intrathecal therapy) alone or in combination with RITUXAN or non-U.S. licensed rituximab, administered as six infusions of RITUXAN IV at a dose of 375 mg/m2 BSA (two doses during each of the two induction courses and one during each of the two consolidation courses) as per the LMB scheme [see Dosage and Administration (2.2)].

The trial was planned to enroll 600 patients with 1:1 randomization. The randomization was stopped early for efficacy after 362 patients had been enrolled (181 in each arm) according to the first planned interim analysis result. A total of 328 randomized patients, aged 6 months and older, were included in the efficacy analyses, of which one patient under 3 years of age received intravenous RITUXAN or non-U.S.-licensed rituximab in combination with LMB chemotherapy. Demographic and disease characteristics of the randomized trial population are displayed in Table 13:

Table 13: Demographics and Disease Characteristics of the Randomized Trial Population - ITT
	RITUXAN + LMB Chemotherapy N = 164	LMB Chemotherapy N = 164
BSA= Body Surface Area, B-AL=B-Cell Acute Leukemia, DLBCL= Diffuse Large B-cell Lymphoma, NHL= Non-Hodgkin's Lymphoma , CNS= Central Nervous System
Male	82%	84%
Female	18%	17%
Age (years)
Median (range)	8 (2, 17)	7 (1, 17)
Age group
6 months to less than 3 years	0.6%	4%
3 to less than 12 years	71%	71%
12 to less than 18 years	29%	25%
BSA (m2)
Median (range)	1.0 (0.6, 2.3)	0.97 (0.5, 2.7)
Therapeutic group
Group B high-risk	49%	51%
Group C1	40%	40%
Group C3	11%	10%
Disease Type
B-AL	37%	34%
Burkitt or Burkitt-like NHL	55%	56%
DLBCL	8%	8%
Bone marrow involvement	45%	45%
CNS involvement	27%	27%

Efficacy was established based on event-free survival (EFS), where an event was defined as occurrence of progressive disease, relapse, second malignancy, death from any cause, or non-response as evidenced by detection of viable cells in residue after the second CYVE course, whichever occurs first.

Efficacy analyses were performed in 328 randomized patients with a median follow-up of 3.1 years. The results are described in Table 14.

Table 14: Overview of Efficacy Results (ITT population)
Analysis	LMB (N = 164)	R-LMB (N=164)
CI = confidence interval; EFS = event-free survival; HR = hazard ratio; ITT = intent-to-treat
* Event-free survival rate was calculated based on 38 event. † two-sided unstratified log-rank test, testing null hypothesis of equality of event-free survivorship in randomization arms R-LMB and LMB against alternative hypothesis "event-free survivorship in group R-LMB is higher than in LMB." The analysis was based on 53% of information where the p-value boundary was 0.014. ‡ R-LMB Versus LMB
EFS*	28 events	10 events
	Two-sided unstratified log-rank test p-value 0.0012†
	Adjusted Cox HR‡ 0.32 (90% CI: 0.17, 0.58)

As of data cutoff date of 31 December 2017, there were 20 and 8 deaths reported in LMB arm and R-LMB arm, respectively, with an estimated overall survival (OS) HR of 0.36 (95% CI, 0.16 - 0.81). No formal statistical test was conducted for overall survival and therefore the OS result is considered descriptive.

14.3 Diffuse Large B-Cell NHL (DLBCL)

The safety and effectiveness of RITUXAN were evaluated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1854 patients. Patients with previously untreated diffuse large B-cell NHL received RITUXAN in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

NHL Study 7

A total of 632 patients age greater than or equal to 60 years with DLBCL (including primary mediastinal B-cell lymphoma) were randomized in a 1:1 ratio to treatment with CHOP or R-CHOP. Patients received 6 or 8 cycles of CHOP, each cycle lasting 21 days. All patients in the R-CHOP arm received 4 doses of RITUXAN 375 mg/m2 on Days –7 and –3 (prior to Cycle 1) and 48–72 hours prior to Cycles 3 and 5. Patients who received 8 cycles of CHOP also received RITUXAN prior to Cycle 7. The main outcome measure of the study was progression-free survival, defined as the time from randomization to the first of progression, relapse, or death. Responding patients underwent a second randomization to receive RITUXAN or no further therapy.

Among all enrolled patients, 62% had centrally confirmed DLBCL histology, 73% had Stage III–IV disease, 56% had IPI scores greater than or equal to 2, 86% had ECOG performance status of < 2, 57% had elevated LDH levels, and 30% had two or more extranodal disease sites involved. Efficacy results are presented in Table 15. These results reflect a statistical approach which allows for an evaluation of RITUXAN administered in the induction setting that excludes any potential impact of RITUXAN given after the second randomization.

Analysis of results after the second randomization in NHL Study 7 demonstrates that for patients randomized to R-CHOP, additional RITUXAN exposure beyond induction was not associated with further improvements in progression-free survival or overall survival.

NHL Study 8

A total of 399 patients with DLBCL, age greater than or equal to 60 years, were randomized in a 1:1 ratio to receive CHOP or R-CHOP. All patients received up to eight 3-week cycles of CHOP induction; patients in the R-CHOP arm received RITUXAN 375 mg/m2 on Day 1 of each cycle. The main outcome measure of the study was event-free survival, defined as the time from randomization to relapse, progression, change in therapy, or death from any cause. Among all enrolled patients, 80% had Stage III or IV disease, 60% of patients had an age-adjusted IPI greater than or equal to 2, 80% had ECOG performance status scores less than 2, 66% had elevated LDH levels, and 52% had extranodal involvement in at least two sites. Efficacy results are presented in Table 15.

NHL Study 9

A total of 823 patients with DLBCL, aged 18–60 years, were randomized in a 1:1 ratio to receive an anthracycline-containing chemotherapy regimen alone or in combination with RITUXAN. The main outcome measure of the study was time to treatment failure, defined as time from randomization to the earliest of progressive disease, failure to achieve a complete response, relapse, or death. Among all enrolled patients, 28% had Stage III–IV disease, 100% had IPI scores of less than or equal to 1, 99% had ECOG performance status of < 2, 29% had elevated LDH levels, 49% had bulky disease, and 34% had extranodal involvement. Efficacy results are presented in Table 15.

Table 15 Efficacy Results in NHL Studies 7, 8, and 9
	Study 7 (n = 632)		Study 8 (n = 399)		Study 9 (n = 823)
	R-CHOP	CHOP	R-CHOP	CHOP	R-Chemo	Chemo
Main outcome	Progression-free survival (years)		Event-free survival (years)		Time to treatment failure (years)
* NE = Not reliably estimable. † R-CHOP vs. CHOP. ‡ Significant at p < 0.05, 2-sided. § Kaplan-Meier estimates.
Median of main outcome measure	3.1	1.6	2.9	1.1	NE*	NE*
Hazard ratio†	0.69‡		0.60‡		0.45‡
Overall survival at 2 years§	74%	63%	69%	58%	95%	86%
Hazard ratio†	0.72‡		0.68‡		0.40‡

In NHL Study 8, overall survival estimates at 5 years were 58% vs. 46% for R-CHOP and CHOP, respectively.

14.4 Ninety-Minute Infusions in Previously Untreated Follicular NHL and DLBCL

In NHL Study 10, a total of 363 patients with previously untreated follicular NHL (n=113) or DLBCL (n=250) were evaluated in a prospective, open-label, multi-center, single-arm trial for the safety of 90-minute rituximab infusions. Patients with follicular NHL received rituximab 375 mg/m2 plus CVP chemotherapy. Patients with DLBCL received rituximab 375 mg/m2 plus CHOP chemotherapy. Patients with clinically significant cardiovascular disease were excluded from the study. Patients were eligible for a 90-minute infusion at Cycle 2 if they did not experience a Grade 3-4 infusion-related adverse event with Cycle 1 and had a circulating lymphocyte count less than or equal to 5,000/mm3 before Cycle 2. All patients were pre-medicated with acetaminophen and an antihistamine and received the glucocorticoid component of their chemotherapy prior to RITUXAN infusion. The main outcome measure was the development of Grade 3-4 infusion-related reactions on the day of, or day after, the 90-minute infusion at Cycle 2 [see Adverse Reactions (6.1)].

Eligible patients received their Cycle 2 rituximab infusion over 90 minutes as follows: 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes [see Dosage and Administration (2.1)]. Patients who tolerated the 90-minute rituximab infusion at Cycle 2 continued to receive subsequent rituximab infusions at the 90-minute infusion rate for the remainder of the treatment regimen (through Cycle 6 or Cycle 8).

The incidence of Grade 3-4 infusion-related reactions at Cycle 2 was 1.1% (95% CI [0.3%, 2.8%]) among all patients, 3.5% (95% CI [1.0%, 8.8%]) for those patients treated with R-CVP, and 0.0% (95% CI [0.0%, 1.5%]) for those patients treated with R-CHOP. For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions was 2.8% (95% CI [1.3%, 5.0%]). No acute fatal infusion-related reactions were observed.

14.5 Chronic Lymphocytic Leukemia (CLL)

The safety and effectiveness of RITUXAN were evaluated in two randomized (1:1) multicenter open-label studies comparing FC alone or in combination with RITUXAN for up to 6 cycles in patients with previously untreated CLL [CLL Study 1 (n=817)] or previously treated CLL [CLL Study 2 (n=552)]. Patients received fludarabine 25 mg/m2/day and cyclophosphamide 250 mg/m2/day on days 1, 2 and 3 of each cycle, with or without RITUXAN. In both studies, seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of RITUXAN-based therapy.

In CLL Study 1, 30% of patients were 65 years or older, 31% were Binet stage C, 45% had B symptoms, more than 99% had ECOG performance status (PS) 0–1, 74% were male, and 100% were White. In CLL Study 2, 44% of patients were 65 years or older, 28% had B symptoms, 82% received a prior alkylating drug, 18% received prior fludarabine, 100% had ECOG PS 0–1, 67% were male and 98% were White.

The main outcome measure in both studies was progression-free survival (PFS), defined as the time from randomization to progression, relapse, or death, as determined by investigators (CLL Study 1) or an independent review committee (CLL Study 2). The investigator assessed results in CLL Study 2 were supportive of those obtained by the independent review committee. Efficacy results are presented in Table 16.

Table 16 Efficacy Results in CLL Studies 1 and 2
	Study 1* (Previously untreated)		Study 2* (Previously treated)
	R-FC N = 408	FC N = 409	R-FC N = 276	FC N = 276
* As defined in 1996 National Cancer Institute Working Group guidelines.
Median PFS (months)	39.8	31.5	26.7	21.7
Hazard ratio (95% CI)	0.56 (0.43, 0.71)		0.76 (0.6, 0.96)
P value (Log-Rank test)	< 0.01		0.02
Response rate (95% CI)	86% (82, 89)	73% (68, 77)	54% (48, 60)	45% (37, 51)

Across both studies, 243 of 676 RITUXAN-treated patients (36%) were 65 years of age or older and 100 RITUXAN-treated patients (15%) were 70 years of age or older. The results of exploratory subset analyses in elderly patients are presented in Table 17.

Table 17 Efficacy Results in CLL Studies 1 and 2 in Subgroups Defined by Age*
	Study 1		Study 2
Age subgroup	Number of Patients	Hazard Ratio for PFS (95% CI)	Number of Patients	Hazard Ratio for PFS (95% CI)
* From exploratory analyses.
Age less than 65 yrs	572	0.52 (0.39, 0.70)	313	0.61 (0.45, 0.84)
Age greater than or equal to 65 yrs	245	0.62 (0.39, 0.99)	233	0.99 (0.70, 1.40)
Age less than 70 yrs	736	0.51 (0.39, 0.67)	438	0.67 (0.51, 0.87)
Age greater than or equal to 70 yrs	81	1.17 (0.51, 2.66)	108	1.22 (0.73, 2.04)

14.6 Rheumatoid Arthritis (RA)

Reducing the Signs and Symptoms: Initial and Re-Treatment Courses

The efficacy and safety of RITUXAN were evaluated in two randomized, double-blind, placebo-controlled studies of adult patients with moderately to severely active RA who had a prior inadequate response to at least one TNF inhibitor. Patients were 18 years of age or older, diagnosed with active RA according to American College of Rheumatology (ACR) criteria, and had at least 8 swollen and 8 tender joints.

In RA Study 1 (NCT00468546), patients were randomized to receive either RITUXAN 2 × 1,000 mg + MTX or placebo + MTX for 24 weeks. Further courses of RITUXAN 2 × 1,000 mg + MTX were administered in an open label extension study at a frequency determined by clinical evaluation, but no sooner than 16 weeks after the preceding course of RITUXAN. In addition to the intravenous premedication, glucocorticoids were administered orally on a tapering schedule from baseline through Day 14. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24 of the placebo-controlled period are shown in Table 18.

In RA Study 2 (NCT00266227), all patients received the first course of RITUXAN 2 × 1,000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either RITUXAN 2 × 1,000 mg + MTX or placebo + MTX, the majority between Weeks 24–28. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24, before the re-treatment course, and at Week 48, after retreatment, are shown in Table 18.

Table 18 ACR Responses in RA Study 1 and RA Study 2 (Percent of Patients) (Modified Intent-to-Treat Population)
Inadequate Response to TNF Antagonists
Study 1 24 Week Placebo-Controlled (Week 24)				Study 2 Placebo-Controlled Retreatment (Week 24 and Week 48)
Response	Placebo + MTX n = 201	RITUXAN + MTX n = 298	Treatment Difference (RITUXAN – Placebo)* (95% CI)	Response	Placebo + MTX Retreatment n = 157	RITUXAN + MTX Retreatment n = 318	Treatment Difference (RITUXAN – Placebo)†,‡,* (95% CI)
* For RA Study 1, weighted difference stratified by region (US, rest of the world) and Rheumatoid Factor (RF) status (positive greater than 20 IU/mL, negative < 20 IU/mL) at baseline; For RA Study 2, weighted difference stratified by RF status at baseline and greater than or equal to 20% improvement from baseline in both SJC and TJC at Week 24 (Yes/No). † In RA Study 2, all patients received a first course of RITUXAN 2 × 1,000 mg. Patients who experienced ongoing disease activity were randomized to receive a second course of either RITUXAN 2 × 1,000 mg + MTX or placebo + MTX at or after Week 24. ‡ Since all patients received a first course of RITUXAN, no comparison between Placebo + MTX and RITUXAN + MTX is made at Week 24.
ACR20				ACR20
Week 24	18%	51%	33% (26%, 41%)	Week 24	48%	45%	NA
				Week 48	45%	54%	11% (2%, 20%)
ACR50				ACR50
Week 24	5%	27%	21% (15%, 27%)	Week 24	27%	21%	NA
				Week 48	26%	29%	4% (-4%, 13%)
ACR70				ACR70
Week 24	1%	12%	11% (7%, 15%)	Week 24	11%	8%	NA
				Week 48	13%	14%	1% (-5%, 8%)

Improvement was also noted for all components of ACR response following treatment with RITUXAN, as shown in Table 19.

Table 19 Components of ACR Response at Week 24 in RA Study 1 (Modified Intent-to-Treat Population)
Inadequate Response to TNF Antagonists
Parameter (median)	Placebo + MTX (n = 201)		RITUXAN + MTX (n = 298)
Parameter (median)	Baseline	Wk 24	Baseline	Wk 24
* Visual Analogue Scale: 0 = best, 100 = worst. † Disability Index of the Health Assessment Questionnaire: 0 = best, 3 = worst.
Tender Joint Count	31.0	27.0	33.0	13.0
Swollen Joint Count	20.0	19.0	21.0	9.5
Physician Global Assessment*	71.0	69.0	71.0	36.0
Patient Global Assessment*	73.0	68.0	71.0	41.0
Pain*	68.0	68.0	67.0	38.5
Disability Index (HAQ)†	2.0	1.9	1.9	1.5
CRP (mg/dL)	2.4	2.5	2.6	0.9

The time course of ACR 20 response for RA Study 1 is shown in Figure 2. Although both treatment groups received a brief course of intravenous and oral glucocorticoids, resulting in similar benefits at Week 4, higher ACR 20 responses were observed for the RITUXAN group by Week 8. A similar proportion of patients achieved these responses through Week 24 after a single course of treatment (2 infusions) with RITUXAN. Similar patterns were demonstrated for ACR 50 and 70 responses.

Figure 2
* The same patients may not have responded at each time point.
Percent of Patients Achieving ACR 20 Response by Visit* RA Study 1 (Inadequate Response to TNF Antagonists)

Radiographic Response

In RA Study 1, structural joint damage was assessed radiographically and expressed as changes in Genant-modified Total Sharp Score (TSS) and its components, the erosion score (ES) and the joint space narrowing (JSN) score. RITUXAN + MTX slowed the progression of structural damage compared to placebo + MTX after 1 year as shown in Table 20.

Table 20 Mean Radiographic Change From Baseline to 104 Weeks in RA Study 1
Inadequate Response to TNF Antagonists
Parameter	RITUXAN 2 × 1,000 mg + MTX*	Placebo + MTX†	Treatment Difference (Placebo – RITUXAN)	95% CI
* Patients received up to 2 years of treatment with RITUXAN + MTX. † Patients receiving Placebo + MTX. Patients receiving Placebo + MTX could have received retreatment with RITUXAN + MTX from Week 16 onward. ‡ Based on radiographic scoring following 104 weeks of observation.
Change during First Year
TSS	0.66	1.77	1.11	(0.47, 1.75)
ES	0.44	1.19	0.75	(0.32, 1.19)
JSN Score	0.22	0.58	0.36	(0.10, 0.62)
Change during Second Year‡
TSS	0.48	1.04	—	—
ES	0.28	0.62	—	—
JSN Score	0.20	0.42	—	—

In RA Study 1 and its open-label extension, 70% of patients initially randomized to RITUXAN + MTX and 72% of patients initially randomized to placebo + MTX were evaluated radiographically at Year 2. As shown in Table 20, progression of structural damage in RITUXAN + MTX patients was further reduced in the second year of treatment.

Following 2 years of treatment with RITUXAN + MTX, 57% of patients had no progression of structural damage. During the first year, 60% of RITUXAN + MTX treated patients had no progression, defined as a change in TSS of zero or less compared to baseline, compared to 46% of placebo + MTX treated patients. In their second year of treatment with RITUXAN + MTX, more patients had no progression than in the first year (68% vs. 60%), and 87% of the RITUXAN + MTX treated patients who had no progression in the first year also had no progression in the second year.

Lesser Efficacy of 500 Vs. 1,000 mg Treatment Courses for Radiographic Outcomes

RA Study 3 (NCT00299104) is a randomized, double-blind, placebo-controlled study which evaluated the effect of placebo + MTX compared to RITUXAN 2 × 500 mg + MTX and RITUXAN 2 × 1,000 mg + MTX treatment courses in MTX-naïve RA patients with moderately to severely active disease. Patients received a first course of two infusions of rituximab or placebo on Days 1 and 15. MTX was initiated at 7.5 mg/week and escalated up to 20 mg/week by Week 8 in all three treatment arms. After a minimum of 24 weeks, patients with ongoing disease activity were eligible to receive re-treatment with additional courses of their assigned treatment. After one year of treatment, the proportion of patients achieving ACR 20/50/70 responses were similar in both RITUXAN dose groups and were higher than in the placebo group. However, with respect to radiographic scores, only the RITUXAN 1,000 mg treatment group demonstrated a statistically significant reduction in TSS: a change of 0.36 units compared to 1.08 units for the placebo group, a 67% reduction.

Physical Function Response

RA Study 4 (NCT00299130) is a randomized, double-blind, placebo-controlled study in adult RA patients with moderately to severely active disease with inadequate response to MTX. Patients were randomized to receive an initial course of RITUXAN 500 mg, RITUXAN 1,000 mg, or placebo in addition to background MTX.

Physical function was assessed at Weeks 24 and 48 using the Health Assessment Questionnaire Disability Index (HAQ-DI). From baseline to Week 24, a greater proportion of RITUXAN-treated patients had an improvement in HAQ-DI of at least 0.22 (a minimal clinically important difference) and a greater mean HAQ-DI improvement compared to placebo, as shown in Table 21. HAQ-DI results for the RITUXAN 500 mg treatment group were similar to the RITUXAN 1,000 mg treatment group; however radiographic responses were not assessed (see Dosing Precaution in the Radiographic Responses section above). These improvements were maintained at 48 weeks.

Table 21 Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 in RA Study 4
	Placebo + MTX n = 172	RITUXAN 2 × 1,000 mg + MTX n = 170	Treatment Difference (RITUXAN – Placebo)* (95% CI)
* Adjusted difference stratified by region (US, rest of the world) and rheumatoid factor (RF) status (positive greater than or equal to 20 IU/mL, negative less than 20 IU/mL) at baseline. † Minimal Clinically Important Difference: MCID for HAQ = 0.22.
Mean Improvement from Baseline	0.19	0.42	0.23 (0.11, 0.34)
Percent of patients with "Improved" score (Change from Baseline greater than or equal to MCID)†	48%	58%	11% (0%, 21%)

14.7 Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

Induction Treatment of Adult Patients with Active Disease (GPA/MPA Study 1)

A total of 197 patients with active, severe GPA and MPA (two forms of ANCA Associated Vasculitides) were treated in a randomized, double-blind, active-controlled, multicenter, non-inferiority study, conducted in two phases – a 6 month remission induction phase and a 12 month remission maintenance phase. Patients were 15 years of age or older, diagnosed with GPA (75% of patients) or MPA (24% of patients) according to the Chapel Hill Consensus conference criteria (1% of the patients had unknown vasculitis type). All patients had active disease, with a Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA) greater than or equal to 3, and their disease was severe, with at least one major item on the BVAS/GPA. Ninety-six (49%) of patients had new disease and 101 (51%) of patients had relapsing disease.

Patients in both arms received 1,000 mg of pulse intravenous methylprednisolone per day for 1 to 3 days within 14 days prior to initial infusion. Patients were randomized in a 1:1 ratio to receive either RITUXAN 375 mg/m2 once weekly for 4 weeks or oral cyclophosphamide 2 mg/kg daily for 3 to 6 months in the remission induction phase. Patients were pre-medicated with antihistamine and acetaminophen prior to RITUXAN infusion. Following intravenous corticosteroid administration, all patients received oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The RITUXAN group did not receive additional therapy to maintain remission. The main outcome measure for both GPA and MPA patients was achievement of complete remission at 6 months defined as a BVAS/GPA of 0, and off glucocorticoid therapy. The pre-specified non-inferiority margin was a treatment difference of 20%. As shown in Table 22, the study demonstrated non-inferiority of RITUXAN to cyclophosphamide for complete remission at 6 months.

Table 22 Percentage of Patients with GPA/MPA Who Achieved Complete Remission at 6 Months (Intent-to-Treat Population)
	RITUXAN (n = 99)	Cyclophosphamide (n = 98)	Treatment Difference (RITUXAN – Cyclophosphamide)
* The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis. † Non-inferiority was demonstrated because the lower bound was higher than the prespecified non-inferiority margin (-3% greater than -20%).
Rate	64%	53%	11%
95.1%* CI	(54%, 73%)	(43%, 63%)	(-3%, 24%) †

Complete Remission (CR) at 12 and 18 months

In the RITUXAN group, 44% of patients achieved CR at 6 and 12 months, and 38% of patients achieved CR at 6, 12, and 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of CR), 38% of patients achieved CR at 6 and 12 months, and 31% of patients achieved CR at 6, 12, and 18 months.

Retreatment of Flares with RITUXAN

Based upon investigator judgment, 15 patients received a second course of RITUXAN therapy for treatment of relapse of disease activity which occurred between 8 and 17 months after the induction treatment course of RITUXAN.

Follow up Treatment of Adult Patients with GPA/MPA who have achieved disease control with other Immunosuppressant (GPA/MPA Study 2)

A total of 115 patients (86 with GPA, 24 with MPA, and 5 with renal-limited ANCA-associated vasculitis) in disease remission were randomized to receive azathioprine (58 patients) or non-U.S.-licensed rituximab (57 patients) in this open-label, prospective, multi-center, randomized, active-controlled study. Eligible patients were 21 years and older and had either newly diagnosed (80%) or relapsing disease (20%). A majority of the patients were ANCA-positive. Remission of active disease was achieved using a combination of glucocorticoids and cyclophosphamide. Within a maximum of 1 month after the last cyclophosphamide dose, eligible patients (based on BVAS of 0), were randomized in a 1:1 ratio to receive either non-U.S.-licensed rituximab or azathioprine.

The non-U.S.-licensed rituximab was administered as two 500 mg intravenous infusions separated by two weeks (on Day 1 and Day 15) followed by a 500 mg intravenous infusion every 6 months for 18 months. Azathioprine was administered orally at a dose of 2 mg/kg/day for 12 months, then 1.5 mg/kg/day for 6 months, and finally 1 mg/kg/day for 4 months; treatment was discontinued after 22 months. Prednisone treatment was tapered and then kept at a low dose (approximately 5 mg per day) for at least 18 months after randomization. Prednisone dose tapering and the decision to stop prednisone treatment after month 18 were left at the investigator's discretion.

Planned follow-up was until month 28 (10 or 6 months, respectively, after the last non-U.S.-licensed rituximab infusion or azathioprine dose). The primary endpoint was the occurrence of major relapse (defined by the reappearance of clinical and/or laboratory signs of vasculitis activity that could lead to organ failure or damage, or could be life threatening) through month 28.

By month 28, major relapse occurred in 3 patients (5%) in the non-U.S.-licensed rituximab group and 17 patients (29%) in the azathioprine group.

The observed cumulative incidence rate of first major relapse during the 28 months was lower in patients on non-U.S.-licensed rituximab relative to azathioprine (Figure 3).

Figure 3 Cumulative Incidence Over Time of First Major Relapse in Patients with GPA/MPA
Patients were censored at the last follow-up dates if they had no event

Treatment of Pediatric Patients (GPA/MPA Study 4)

The study design consisted of an initial 6-month remission induction phase, and a minimum 12-month follow-up phase up to a maximum of 54 months (4.5 years) in pediatric patients 2 years to 17 years of age with GPA and MPA. Patients were to receive a minimum of 3 doses of intravenous methylprednisolone (30 mg/kg/day, not exceeding 1g/day) prior to the first RITUXAN or non-U.S.-licensed rituximab intravenous infusion. If clinically indicated, additional daily doses (up to three), of intravenous methylprednisolone could be given. The remission induction regimen consisted of four once weekly intravenous infusions of RITUXAN or non-U.S.-licensed rituximab at a dose of 375 mg/m2 BSA, on study days 1, 8, 15 and 22 in combination with oral prednisolone or prednisone at 1 mg/kg/day (max 60 mg/day) tapered to 0.2 mg/kg/day minimum (max 10 mg/day) by Month 6. After the remission induction phase, patients could receive subsequent RITUXAN or non-U.S.-licensed rituximab intravenous infusions on or after Month 6 to maintain remission and control disease activity.

The primary objectives of this study were to evaluate safety and PK parameters in pediatric GPA and MPA patients (2 years to 17 years of age). The efficacy objectives of the study were exploratory and principally assessed using the Pediatric Vasculitis Activity Score (PVAS).

A total of 25 pediatric patients 6 years to 17 years of age with active GPA and MPA were treated with RITUXAN or non-U.S.-licensed rituximab in a multicenter, open-label, single-arm, uncontrolled study (NCT01750697). The median age of patients in the study was 14 years and the majority of patients (20/25 [80%]) were female. A total of 19 patients (76%) had GPA and 6 patients (24%) had MPA at baseline. Eighteen patients (72%) had newly diagnosed disease upon study entry (13 patients with GPA and 5 patients with MPA) and 7 patients had relapsing disease (6 patients with GPA and 1 patient with MPA).

All 25 patients completed all four once weekly intravenous infusions for the 6-month remission induction phase. A total of 24 out of 25 patients completed at least 18 months from Day 1 (baseline).

The exploratory efficacy using the PVAS is described in Table 23.

Table 23 Percentage of Patients Who Achieved PVAS Remission by Month 6, 12 and 18 (GPA/MPA Study 4)
	Time to Follow Up Since Day 1
	Month 6 n=25	Month 12 n = 25	Month 18 n = 25
*PVAS remission is defined by a PVAS of 0 and achieved glucocorticoid taper to 0.2 mg/kg/day (or 10 mg/day, whichever is lower), or a PVAS of 0 on two consecutive readings greater than or equal to 4 weeks apart irrespective of glucocorticoid dose
* The efficacy results are exploratory and no formal statistical testing was performed for these endpoints
Response rate	56%	92%	100%
95% CI*	(34.9%, 75.6%)	(74.0%, 99.0%)	(86.3%, 100.0%)

Follow-Up Treatment

After the 6-month remission induction phase, patients who had not achieved remission or who had progressive disease or flare that could not be controlled by glucocorticoids alone received additional treatment for GPA and MPA, that could include RITUXAN or non-U.S.-licensed rituximab and/or other therapies, at the discretion of the investigator. Planned follow-up was until Month 18 (from Day 1).

Fourteen out of 25 patients (56%) received additional RITUXAN or non-U.S.-licensed rituximab treatment at or post Month 6, up to Month 18. Five of these patients received four once weekly doses (375 mg/m2) of intravenous RITUXAN or non-U.S.-licensed rituximab approximately every 6 months; 5 of these patients received a single dose (375 mg/m2) of RITUXAN or non-U.S.-licensed rituximab every 6 months, and 4 of these patients received various other RITUXAN or non-U.S.-licensed rituximab doses/regimens according to investigator. Of the 14 patients who received follow-up treatment between Month 6 and Month 18, 4 patients first achieved remission between Months 6 and 12 and 1 patient first achieved remission between Months 12 and 18. Nine of these 14 patients achieved PVAS remission by Month 6 but required additional follow-up treatment after Month 6.

14.8 Pemphigus Vulgaris (PV)

PV Study 1 (NCT00784589)

Non-U.S.-licensed rituximab in combination with short-term prednisone was compared to prednisone monotherapy as first-line treatment in 90 newly diagnosed adult patients with moderate to severe pemphigus (74 Pemphigus Vulgaris [PV] and 16 Pemphigus Foliaceus [PF]) in this randomized, open-label, controlled, multicenter study (PV Study 1). Patients were between 19 and 79 years of age and had not received prior therapies for pemphigus. In the PV population, 5 (13%) patients in the group treated with non-U.S.-licensed rituximab and 3 (8%) patients in the prednisone group had moderate disease and 33 (87%) patients in the group treated with non-U.S.-licensed rituximab and 33 (92%) patients in the prednisone group had severe disease according to disease severity defined by Harman's criteria.

Patients were stratified by baseline disease severity (moderate or severe) and randomized 1:1 to receive either the non-U.S.-licensed rituximab and short-term prednisone or long-term prednisone monotherapy. Patients were pre-medicated with antihistamine, acetaminophen and methylprednisolone prior to infusion of the non-U.S.-licensed rituximab. Patients randomized to the group treated with non-U.S.-licensed rituximab received an initial intravenous infusion of 1,000 mg non-U.S.-licensed rituximab on Study Day 1 in combination with a short-term regimen of 0.5 mg/kg/day oral prednisone tapered off over 3 months if they had moderate disease or 1 mg/kg/day oral prednisone tapered off over 6 months if they had severe disease. All patients received a second intravenous infusion of 1,000 mg non-U.S.-licensed rituximab on Study Day 15. Maintenance infusions of 500 mg non-U.S.-licensed rituximab were administered at Months 12 and 18. Patients randomized to the prednisone monotherapy group received an initial 1 mg/kg/day oral prednisone tapered off over 12 months if they had moderate disease or 1.5 mg/kg/day oral prednisone tapered off over 18 months if they had severe disease. Patients in the group treated with non-U.S.-licensed rituximab who relapsed could receive an additional infusion of 1,000 mg non-U.S.-licensed rituximab in combination with reintroduced or escalated prednisone dose. Maintenance and relapse infusions were administered no sooner than 16 weeks following the previous infusion.

The primary endpoint for the study was complete remission (complete epithelialization and absence of new and/or established lesions) at Month 24 without the use of prednisone therapy for 2 months or more (CRoff for greater than or equal to 2 months).

The results of the trial are presented in Table 24.

Table 24 Percentage of Pemphigus Patients in Complete Remission Off Corticosteroid Therapy for Two Months or More (CRoff greater than or equal to 2 months) at Month 24, PV Study 1 (Intent-to-Treat Population)
	Non-U.S.-licensed rituximab + short-term prednisone N=46	Prednisone N=44
Number of responders (response rate [%])	41 (89%)	15 (34%)
PV patients	34/38 (90%)	10/36 (28%)
PF patients	7/8 (88%)	5/8 (63%)

PV Study 2 (NCT02383589)

In a randomized, double-blind, double-dummy, active-comparator, multicenter study, the efficacy and safety of RITUXAN compared to mycophenolate mofetil (MMF) were evaluated in patients with moderate-to-severe PV receiving 60-120 mg/day oral prednisone or equivalent (1.0-1.5 mg/kg/day) at study entry and tapered to reach a dose of 60 or 80 mg/day by Day 1. Patients had a confirmed diagnosis of PV within the previous 24 months and evidence of moderate-to-severe disease defined as a total Pemphigus Disease Area Index (PDAI) activity score of greater than or equal to 15. The study consisted of a screening period of up to 28 days, a 52-week double-blind treatment period, and a 48-week safety follow up period.

One hundred and thirty-five patients were randomized to treatment with RITUXAN 1,000 mg administered on Day 1, Day 15, Week 24 and Week 26 or oral MMF 2 g/day (starting at 1 g/day on Day 1 and titrated to achieve a goal of 2 g/day by Week 2) for 52 weeks in combination with an initial dose of 60 or 80 mg oral prednisone with the aim of tapering to 0 mg/day by Week 24. Randomization was stratified by duration of PV (within the 1 year prior to screening or greater than 1 year) and geographical region. A dual-assessor approach was used during the study for efficacy and safety evaluations to prevent potential unblinding.

One hundred and twenty-five patients (excluding exploratory data from ten telemedicine patients) were analyzed for efficacy (Modified Intent-to-Treat Population). The primary efficacy endpoint for this study was the proportion of subjects achieving sustained complete remission defined as achieving healing of lesions with no new active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone or equivalent, and maintaining this response for at least 16 consecutive weeks, during the 52-week treatment period.

Secondary endpoints included cumulative oral corticosteroid dose and the total number of disease flares.

The results of the trial are presented in Table 25.

Table 25 Percentage of PV Patients Who Achieved Sustained Complete Remission Off Corticosteroid Therapy for 16 Weeks or More at Week 52 (Modified Intent-to-Treat Population)
	RITUXAN (N=62)	MMF (N=63)	Difference (95% CI)
MMF = Mycophenolate mofetil. CI = Confidence Interval.
Number of responders (response rate [%])	25 (40.3%)	6 (9.5%)	30.80% (14.70%, 45.15%)

Glucocorticoid exposure

The median (min, max) cumulative oral prednisone dose at Week 52 was 2775 mg (450, 22180) in the RITUXAN group compared to 4005 mg (900, 19920) in the MMF group. Topical corticosteroid use and pre-infusion IV methylprednisolone were not included in this analysis. Prior to each infusion, the RITUXAN group received IV methylprednisolone 100 mg and the MMF group received IV saline solution.

Disease flare

Disease flare was defined as an appearance of 3 or more new lesions a month that do not heal spontaneously within 1 week or by the extension of established lesions in a patient who has achieved disease control. The total number of disease flares was lower in patients treated with RITUXAN compared to MMF (6 vs. 44).