Subcutaneous Tocilizmab vs Placebo in Rheumatoid Arthritis

SUPPLEMENTAL DATA

Supplemental Tables

Table S1. ACR response rates for patients after receiving escape therapya

TCZ-SC
162 mg q2w / PBO-SC q2w
N, week 8 / 69 / 87
N, week 12 / 67 / 79
ACR20 response rates, no. (%)
8 Weeks after escape / 37 (53.6) / 54 (62.1)
12 Weeks after escape / 39 (58.2) / 57 (72.2)
ACR50 response rates, no. (%)
8 Weeks after escape / 10 (14.5) / 27 (31.0)
12 Weeks after escape / 12 (17.9) / 30 (38.0)
ACR70 response rates, no. (%)
8 Weeks after escape / 4 (5.8) / 12 (13.8)
12 Weeks after escape / 4 (6.0) / 12 (15.2)

Abbreviations: ACR20, ACR50, ACR 70 = 20%, 50%, and 70% improvements per American College of Rheumatology criteria; PBO-SC = subcutaneous placebo; q2w = every other week; TCZ-SC = subcutaneous tocilizumab.

a Patients were re-baselined at the time of escape therapy.

Table S2. Proportion of patients in different CDAI disease activity categories at Week 24a (ITT population)

TCZ-SC
162 mg q2w
(N = 437) / PBO-SC q2w
(N = 219)
No. of patients / 367 / 133
Remission, no. (%) / 42 (11.4) / 4 (3.0)
Low disease activity, no. (%) / 125 (34.1) / 30 (22.6)
Medium disease activity, no. (%) / 119 (32.4) / 55 (41.4)
High disease activity, no. (%) / 81 (22.1) / 44 (33.1)
Missing, no.b / 70 / 86

Abbreviations: CDAI = clinical disease activity index; PBO-SC = subcutaneous placebo; q2w = every other week; TCZ-SC = subcutaneous tocilizumab.

a CDAI categories: remission (CDAI ≤2.8); low disease activity (2.8<CDAI≤10); medium disease activity (10<CDAI≤22); high disease activity (CDAI>22).

b Missing values include withdrawals and escape patients.

Table S3. Laboratory results (safety population)

Variable / TCZ-SC
162 mg q2w
(N = 437) / PBO-SC q2w
(N = 218)
Change in ALT from normal at baseline to worst value
No.
≤ ULN, no. (%)
> ULN to 3 ´ ULN, no. (%)
> 3 ULN ´ to 5 ´ ULN, no. (%)
> 5 ´ ULN, no. (%) / 404
253 (57.9)
143 (32.7)
7 (1.6)
1 (0.2) / 203
171 (78.4)
28 (12.8)
4 (1.8)
0
Change in AST from normal at baseline to worst value
No.
≤ ULN, no. (%)
> ULN to 3 ´ ULN, no. (%)
> 3 ULN ´ to 5 ´ ULN, no. (%)
> 5 ´ ULN, no. (%) / 414
309 (70.7)
103 (23.6)
2 (0.5)
0 / 207
180 (82.6)
25 (11.5)
2 (0.9)
0
CTCAE grade for neutrophil levels, ANC/mm3
No.
Normal (≥ LLN), no. (%)
Grade 1 (1500 to < LLN), no. (%)
Grade 2 (1000 to < 1500), no. (%)
Grade 3 (500 to < 1000), no. (%)
Grade 4 (< 500), no. (%) / 430
342 (79.5)
50 (11.6)
22 (5.1)
15 (3.5)
1 (0.2) / 218
210 (96.3)
8 (3.7)
0
0
0
CTCAE grade for platelet levels, platelets/mm3
No.
Normal (≥ LLN), no. (%)
Grade 1 (75,000 to < LLN), no. (%)
Grade 2 (50,000 to < 75,000), no. (%)
Grade 3 (25,000 to < 50,000), no. (%)
Grade 4 (< 25,000), no. (%) / 430
399 (92.8)
29 (6.7)
2 (0.5)
0
0 / 218
218 (100)
0
0
0
0
Shift in cholesterol from baseline < 200 mg/dL to last value
No.
< 200 mg/dL (ie, no change), no. (%)
200 to < 240 mg/dL, no. (%)
≥ 240 mg/dL, no. (%) / 235
130 (29.7)
79 (18.1)
26 (5.9) / 130
112 (51.4)
15 (6.9)
3 (1.4)
Shift in HDL cholesterol from baseline < 40 mg/dL to last value
No.
< 40 mg/dL (ie, no change), no. (%)
40-60 mg/dL, no. (%)
≥ 60 mg/dL, no. (%) / 41
18 (4.1)
22 (5.0)
1 (0.2) / 29
15 (6.9)
13 (6.0)
1 (0.5)
Shift in LDL cholesterol from baseline < 100 mg/dL to last value
No.
< 100 mg/dL (ie, no change), no. (%)
100 to < 130 mg/dL, no. (%)
130 to < 160 mg/dL, no. (%)
≥ 160 mg/dL, no. (%) / 169
90 (20.6)
58 (13.3)
17 (3.9)
4 (0.9) / 92
74 (33.9)
18 (8.3)
0
0
Shift in triglycerides from baseline < 150 mg/dL to last value
No.
< 150 mg/dL (ie, no change), no. (%)
150-500 mg/dL, no. (%)
≥ 500 mg/dL, no. (%) / 301
232 (53.1)
69 (15.8)
0 / 157
142 (65.1)
15 (6.9)
0

Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; HDL = high-density lipoprotein; LDL = low-density lipoprotein; LLL = lower limit of normal; PBO-SC = subcutaneous placebo; q2w = every other week; TCZ-SC = subcutaneous tocilizumab; ULN = upper limit of normal.

Table S4. Adverse events stratified by weight

TCZ-SC
162 mg q2w
(N = 437) / PBO-SC q2w
(N = 218)
Adverse events, no. (%)
< 60 kg / 74 (62.2)
[n = 119] / 36 (62.1)
[n = 58]
60 to < 100 kg / 179 (61.3)
[n = 292] / 84 (56.4)
[n = 149]
≥ 100 kg / 21 (80.8)
[n = 26] / 6 (54.5)
[n = 11]
Serious adverse events, no. (%)
< 60 kg / 8 (6.7)
[n = 119] / 1 (1.7)
[n = 58]
60 to < 100 kg / 9 (3.1)
[n = 292] / 5 (3.4)
[n = 149]
≥ 100 kg / 3 (11.5)
[n = 26] / 2 (18.2)
[n = 11]

Abbreviations: PBO-SC = subcutaneous placebo; q2w = every other week; TCZ-SC = subcutaneous tocilizumab.


Supplemental Figures

Figure S1. The proportion of patients treated with either subcutaneous tocilizumab (TCZ-SC) or placebo (PBO-SC) every other week (q2w) who achieved 20%, 50% , and 70% improvements per American College of Rheumatology criteria (ACR20, ACR50, and ACR70) at week 24, by patients (A) receiving concomitant MTX or (B) other DMARDs at baseline and by (C) DMARD-IR patients and (D) TNF-IR patients.

Figure S2. Radiographic outcomes over 24 weeks for patients in the ITT population. The mean changes from baseline in the erosion score (A) and joint space narrowing score (B) are shown. PBO-SC = subcutaneous placebo; q2w = every other week; TCZ-SC = subcutaneous tocilizumab.

Figure S3. Mean (± standard error of the mean) C-reactive protein (CRP) levels (A) and erythrocyte sedimentation rates (ESRs) (B) over time in patients treated with either subcutaneous tocilizumab (TCZ-SC) or placebo (PBO-SC) in the safety population. The predefined CRP upper limit of normal (ULN) for this study was 0.99 mg/dL.

Brief narratives of patient deaths in BREVACTA

Patients A: A 56-year-old woman from the US died on day27 from hemophilus influenza sepsis, 9 days after the last dose of TCZ-SC.

Patient B: A 56-year-old woman from the Philippines died on day 16 from sepsis (likely of gastrointestinal cause), 15 days after the last dose of TCZ-SC. This patient had pancytopenia on hospital admission with local laboratory results of: white blood cell count 1.0´109 (normal range: 5-10´109), differential neutrophils 1% (normal range: 55-65%; not shown in the laboratory abnormality summaries as only the differential, and not the absolute neutrophil count, was provided), hemoglobin 11.4 g/dL (normal range: 13.5-18.0 g/dL), and platelet count 14´103/L (normal range: 150-400´103/L); she died on the same day.

Patient C: A 50-year-old woman from Brazil died on day133 from a lower respiratory tract infection and subsequent complications, including septic shock and pleural effusion, 102days after the last dose of TCZ-SC.