Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
The MIRAI study evaluated a sequential exposure to 2 defined biologics under rigorous study conditions within a homogeneous population of biological naïve patients (pts) with moderate/severe active RA who inadequately responded to traditional DMARDs. This study investigated the early response to the IL-6 inhibitor tocilizumab (TCZ); non-responders to TCZ subsequently received 1 cycle of rituximab (RTX; anti-CD20 therapy).
Methods:
We report the results of the final analysis (first-pat-in: MAR-2011; last-pat-out: FEB-2014) of MIRAI (NCT01332994), a German, multicenter, two-arm, open-label, phase-III-study. All pts received 4 TCZ infusions (8 mg/kg, q4w; 1st treatment period) until week 16. Partial responders (ΔDAS28>1.2 or DAS28≥2.6 and ≤3.2) received further 4 TCZ infusions (8 mg/kg, q4w); non-responders (ΔDAS28≤1.2 and DAS28>3.2) received subsequent RTX treatment (1g each at weeks 16 and 18). All pts with a 2nd treatment period (TCZ or RTX) completed study at week 32. Primary endpoint: pts in remission (DAS28 <2.6) at week 16 (expected 45%). Secondary endpoints: DAS28/ACR response at week 32, patient-reported outcomes, B-cells, adverse events (AE).
Results:
519 pts (ITT-Main/Safety; mean age: 56 years, females 67.8%) received TCZ in the 1st treatment period. 504 pts received concomitant DMARDs (mostly MTX, 365 pts). At week 8, a clinically relevant DAS28 reduction (>1.2) from baseline was seen in 81.5% of pts. At week 16, 222 pts (42.8%) were in remission and completed study, 213 pts received a 2nd TCZ period (ITT-TCZ2), only 27 non-responder initiated subsequent RTX (ITT-RTX). At week 32, 117 of 213 pts achieved remission under continued TCZ therapy, and 10 of 27 pts showed a clinically relevant DAS28 reduction from week 16 after 1 cycle RTX.
Total incidence of drug related AEs/SAEs: 38.3%/4.4%. Drug-related serious infections occurred in 10 pts (1.9%). One death possibly related to TCZ was reported (fall plus craniocerebral injury). No RTX related SAEs were reported.
Conclusion:
Early response to TCZ was demonstrated by a rapid improvement of RA symptoms until week 16. Initially partial responders to TCZ benefited from a continued TCZ therapy. Notably, the proportion of TCZ non-responders was low (27 of 519 pts); about 1/3 of these pts clearly benefited from subsequent RTX therapy with lasting effects until week 66.
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All patients (ITT-main/Safety), 1st treatment period TCZ: results from baseline to week 16
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Parameter
|
Baseline
|
Week 8
|
Week 16
|
|
DAS28, mean ± SD (n) |
5.7 ± 1.0 (516) |
3.0 ±1.4 (491) |
2.6 ± 1.3 (485) |
|
DAS28 <2.6, n (%) |
0 (0.0) |
208 (40.1) |
222 (42.8) |
|
DAS28 ≤3.2, n (%) |
1 (0.2) |
295 (56.8) |
357 (68.8) |
|
ΔDAS28 >1.2, n (%)* |
– |
423 (81.5) |
447 (86.1) |
|
EULAR-Response good, n/N (%)* |
– |
291 (56.1) |
354 (68.2) |
|
EULAR-Response moderate, n (%)* |
– |
159 (30.6) |
105 (20.2) |
|
SDAI, mean ± SD (n) |
32.6 ± 11.6 (512) |
14.6 ±10.7 (492) |
11.7 ± 10.1 (475) |
|
SDAI ≤3.3, n (%) |
0 (0.0) |
59 (11.4) |
89 (17.1) |
|
CDAI, mean ± SD (n) |
30.9 ± 11.2 (519) |
14.3 ±10.6 (497) |
11.4 ± 9.9 (485) |
|
CDAI ≤2.8, n (%) |
0 (0.0) |
56 (10.8) |
86 (16.6) |
|
ACR20, n (%)* |
– |
317 (61.1) |
348 (67.1) |
|
ACR50, n (%)* |
– |
174 (33.5) |
237 (45.7) |
|
ACR70, n (%)* |
– |
79 (15.2) |
127 (24.5) |
|
HAQ-DI, mean ± SD (n) |
1.24 ± 0.67 (513) |
0.85 ± 0.66 (490) |
0.75 ± 0.67 (472) |
|
ΔHAQ-DI >0.22, n (%)* |
– |
299 (57.6) |
317 (61.1) |
|
* Compared to baseline. CDAI = Clinical disease activity index; SD = Standard deviation; SDAI = Simplified disease activity index. |
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Partial TCZ responder (ITT-TCZ2), 2nd treatment period TCZ: results from week 16 to week 32
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|
Parameter
|
Week 16
|
Week 24
|
Week 32 (EOS)
|
|
DAS28, mean ± SD (n) |
3.3 ± 0.6 (213) |
2.6 ±1.1 (197) |
2.5 ± 1.2 (193) |
|
DAS28 <2.6, n (%) |
3 (1.4)** |
109 (51.2) |
117 (54.9) |
|
DAS28 ≤3.2, n (%) |
133 (62.4) |
145 (68.1) |
142 (66.7) |
|
ΔDAS28 >1.2, n (%)* |
208 (97.7) |
195 (91.5) |
181 (85.0) |
|
EULAR-Response good, n/N (%)* |
130 (61.0) |
145 (68.1) |
142 (66.7) |
|
EULAR-Response moderate, n (%)* |
80 (37.6) |
51 (23.9) |
44 (20.7) |
|
SDAI, mean ± SD (n) |
15.3 ± 7.6 (207) |
11.1 ±8.8 (190) |
10.0 ± 9.9 (189) |
|
SDAI ≤3.3, n (%) |
0 (0.0) |
23 (10.8) |
47 (22.1) |
|
CDAI, mean ± SD (n) |
15.0 ± 7.5 (213) |
10.9 ±8.6 (199) |
9.7 ± 9.8 (194) |
|
CDAI ≤2.8, n (%) |
0 (0.0) |
21 (9.9) |
41 (19.2) |
|
ACR20, n (%)* |
145 (68.1) |
155 (72.8) |
161 (75.6) |
|
ACR50, n (%)* |
69 (32.4) |
106 (49.8) |
117 (54.9) |
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ACR70, n (%)* |
18 (8.5) |
46 (21.6) |
73 (34.3) |
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HAQ-DI, mean ± SD (n) |
0.86 ± 0.67 (209) |
0.84 ± 0.66 (190) |
0.82 ± 0.68 (191) |
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ΔHAQ-DI >0.22, n (%)* |
130 (61.0) |
113 (53.1) |
122 (57.3) |
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* Compared to baseline. |
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TCZ non-responder (ITT-RTX), 2nd treatment period subsequent RTX: results from week 16 to week 32 incl. SFU at week 66
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Parameter
|
Week 16
|
Week 32 (EOS)
|
Week 66 (SFU)
|
|
DAS28, mean ± SD (n) |
5.1 ± 1.2 (27) |
4.0 ±1.5 (26) |
3.9 ± 1.5 (25) |
|
DAS28 <2.6, n (%) |
0 (0.0) |
4 (14.8) |
6 (22.2) |
|
DAS28 ≤3.2, n (%) |
0 (0.0) |
9 (33.3) |
8 (29.6) |
|
ΔDAS28 >1.2, n (%)* |
– |
10 (37.0) |
10 (37.0) |
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EULAR-Response good, n/N (%)* |
– |
7 (25.9) |
8 (29.6) |
|
EULAR-Response moderate, n (%)* |
– |
8 (29.6) |
3 (11.1) |
|
SDAI, mean ± SD (n) |
32.2 ± 14.9 (27) |
16.5 ±15.8 (24) |
16.6 ± 13.8 (25) |
|
SDAI ≤3.3, n (%) |
0 (0.0) |
5 (18.5) |
5 (18.5) |
|
CDAI, mean ± SD (n) |
31.4 ± 14.4 (27) |
16.6 ±16.5 (25) |
15.5 ± 13.7 (26) |
|
CDAI ≤2.8, n (%) |
0 (0.0) |
4 (14.8) |
5 (18.5) |
|
ACR20, n (%)* |
– |
11 (40.7) |
12 (44.4) |
|
ACR50, n (%)* |
– |
9 (33.3) |
7 (25.9) |
|
ACR70, n (%)* |
– |
6 (22.2) |
4 (14.8) |
|
HAQ-DI, mean ± SD (n) |
1.26 ± 0.74 (27) |
1.09 ± 0.68 (26) |
n.a. |
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ΔHAQ-DI >0.22, n (%)* |
– |
9 (33.3) |
n.a. |
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* Compared to week 16. |
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Disclosure:
T. Dörner,
Roche Pharmaceuticals, Chugai,
5,
Roche Pharmaceuticals, Chugai,
9;
H. P. Tony,
Roche Pharmaceuticals,
5;
G. Burmester,
Roche Pharmaceuticals, Abbott, Pfizer, UCB, Merck Sharp and Dohme, Bristol-Myers Squibb,
2,
Roche Pharmaceuticals, Chugai, Pfizer, UCB, Bristol-Myers Squibb,
5,
Roche Pharmaceuticals, Pfizer, Merck Sharp and Dohme, Abbott, Bristol-Myers Squibb,
8;
H. Schulze-Koops,
Roche Pharmaceuticals,
5,
Roche Pharmaceuticals,
8;
J. Kaufmann,
None;
P. Kästner,
None;
H. Kellner,
None;
R. Kurthen,
None;
S. Wagner,
None;
M. A. Peters,
Roche Pharmaceuticals,
3;
C. Iking-Konert,
Roche Pharmaceuticals, Chugai Pharma,
5.
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