L12 - Efficacy and Safety of Tocilizumab in Patients with Systemic Juvenile Idiopathic Arthritis: 2-Year Data From a Phase III Clinical Trial

Tuesday, November 8, 2011: 3:45 PM
W375c (McCormick Place West)
Fabrizio De Benedetti1, Hermine Brunner2, Nicolino Ruperto3, Andrew Kenwright4, Clare Devlin4, Inmaculada Calvo3, Ruben Cuttica3, Angelo Ravelli3, Rayfel Schneider2, Despina Eleftheriou3, Carine H. Wouters3, Ricardo Xavier3, Lawrence S. Zemel2, Eileen M. Baildam3, Ruben Burgos-Vargas2, Pavla Dolezalova3, Stella Maris Garay3, Rik Joos3, Alexei Grom2, Nico Wulffraat3, Zbigniew Zuber3, Francesco Zulian3, Alberto Martini3 and Daniel Lovell5, 1IRCCS Ospedale Pediatrico Bambino Gesł, Rome, Italy, 2Pediatric Rheumatology Collaborative Study Group, Cincinnati, OH, 3Paediatric Rheumatology International Trials Organization, Genoa, Italy, 4Roche, Welwyn Garden City, United Kingdom, 5Pediatric Rheumatology Collaborative Study Group (PRCSG)
Presentation Number: L12

Background/Purpose: Excessive interleukin-6 (IL-6) production has been implicated in the pathogenesis of systemic juvenile idiopathic arthritis (sJIA). The IL-6 receptor inhibitor tocilizumab (TCZ) was investigated for the treatment of patients (pts) with sJIA in the ongoing, global, 3-part, 5-y, phase III, multicenter TENDER study. Long-term efficacy and safety (up to 104 wk) of TCZ are presented.

Method: 112 pts aged 2-17 y with active, refractory sJIA (≥6 mo; inadequate response to previous nonsteroidal anti-inflammatory drugs [NSAIDs] and oral corticosteroids [oral CS]) were randomly assigned 2:1 to TCZ (8 mg/kg if body weight ≥30 kg; 12 mg/kg if <30 kg, n=75) or placebo (n=37) every 2 wk for 12 wk in part 1; all pts received open-label TCZ in part 2 (to 104 wk). Pts who escaped to open-label TCZ in part 1 also entered part 2. Stable doses of NSAIDs and methotrexate (MTX) were continued, with oral CS tapering permitted according to predefined criteria. The data were cut for each ongoing pt at the wk 104 infusion based on date of randomization, with baseline in the longer term extension considered the first dose of TCZ.  At the data cut (May 31, 2011), 61 pts had received at least 104 wk of TCZ treatment, 32 of the ongoing pts in the study had not yet reached 104 wk of TCZ treatment, and 20 withdrew, including 1 who withdrew at wk 104 (safety, 9; insufficient therapeutic response, 5; other nonsafety, 6).

Result: Main baseline characteristics included mean disease duration of 5.2 years, mean active joint count of 19.8, and presence of fever (temperature ≥37.5°C in the past 7 days) in 43% of pts. High proportions of pts treated with TCZ achieved JIA ACR70/90 responses and maintained these responses over time (Table 1A). Mean joint counts decreased over time; by wk 104, 55% of pts had 0 active joints and 31% had inactive disease status. In pts on oral CS at baseline, 60% were able to discontinue oral CS by wk 104 (Table 1A); mean oral CS dose decreased from 0.30 mg/kg/d at baseline to 0.04 mg/kg/d at wk 104. Forty-seven serious adverse events (SAEs) occurred in 35 pts (Table 1B); 15 SAEs were considered by the investigator to be related (remotely, possibly, or probably) to TCZ. Twenty-two serious infection AEs were reported in 20 pts; 8 were reported as related to TCZ (gastroenteritis, otitis media, pharyngotonsillitis, septic arthritis, streptococcal sepsis, tonsillitis, upper respiratory infection, varicella), and all but 1 resolved (pt death). At the data cut, 3 pts died (1, suspected tension pneumothorax; 1, road traffic accident [both reported as unrelated]; 1 suspected streptococcal sepsis [possibly treatment related]).

Conclusion: TENDER 2-y results demonstrated that long-term treatment with TCZ was highly effective and had a favorable risk-benefit ratio in pts with severe, refractory, persistent sJIA.

Table 1A. Efficacy Endpoints (ITT Population)

 

Wk 12a

Wk 52b

Wk 78b

Wk 104b

Placebo
(N=37)

TCZ
(N=75)

TCZ
(N=106)

TCZ
(N=101)

TCZ
(N=65)

JIA ACR70, n (%)

3 (8)e

53 (71)e

92 (87)g

88 (87)g

57 (88)g

JIA ACR90, n (%)

2 (5)e

28 (37)e

67 (63)g

72 (71)g

46 (71)g

Active joints, mean (SD)

9.5 (9.0)f

7.3 (11.9)f

2.8 (6.4)c

1.9 (4.1)c

1.9 (3.6)c

No active joints, n (%)

2 (5)

12 (16)

50 (47)g

53 (52)g

36 (55)g

Inactive disease, n (%)

NA

NA

28 (26)g

36 (36)g

20 (31)g

CHAQ-DI, mean (SD)

1.30 (0.98)f

0.94 (0.77)f

0.67 (0.75)c

0.63 (0.72)c

0.55 (0.71)c

Oral CS cessation, n (%)c,d

NA

NA

48 (52)

54 (61)

25 (60)

NA, not applicable; CHAQ-DI, Childhood Health Assessment Questionnaire–Disability Index.
aBaseline was date of randomization.
bBaseline was first dose of TCZ.
cPts who withdrew have been excluded at postwithdrawal visits.
dPercentage is based on only those pts who were on oral CS at baseline and reached a nominal visit day on which dose was calculated.
ePercentage is based on all pts; those who withdrew (for any reason) or escaped are assumed to have been nonresponders.
fPts who withdrew or escaped have been excluded.
gPercentage is based on number of pts who reached time point + pts who withdrew because of insufficient therapeutic response and are assumed to have been nonresponders.

Table 1B. Cumulative Safety (Safety Population, N=112)

 

Prior Safety Updatea

Wk 104b

Exposure to TCZ, y

157.46

202.03

Rate of SAEs/100 PY (n)

24.8 (39)

23.3 (47)

Rate of serious infection AEs/100 PY (n)

11.4 (18)

10.9 (22)

SAEs related (remotely, possibly, probably) to TCZ/100 PY (n)

8.3 (13)

7.4 (15)

Macrophage activation syndrome/100 PY (n)

1.9 (3)

1.5 (3)

AEs leading to withdrawal/100 PY (n)

3.8 (6)c

3.0 (6)c

Deaths/100 PY (n)

0.6 (1)

1.5 (3)

PY, pt years.
aIncludes all safety data in the database up to and including August 10, 2010.
bIncludes all safety data in the database up to the wk 104 infusion (based on date of randomization) for each pt. The last date for this was May 31, 2011.
cIncludes 2 withdrawals because of transaminase increases that were protocol mandated.


Keywords: juvenile idiopathic arthritis (JIA), pediatric rheumatology and tocilizumab

Disclosure: F. De Benedetti, Abbott Laboratories, Hoffmann-La Roche, Novartis, Novimmune, Pfizer, 2 ; H. Brunner, Physician leading the PRCSG Coordinating Center, Steering Committee Member , 9 ; N. Ruperto, Roche Pharmaceuticals, 8, Roche payment to the hospital where I worked, 5 ; A. Kenwright, Roche Products Ltd, 1, Roche Products Ltd, 3 ; C. Devlin, Roche Products Ltd, 1, Roche Products Ltd, 3 ; I. Calvo, None; R. Cuttica, None; A. Ravelli, None; R. Schneider, Roche Products Ltd, Hoffmann-La Roche Canada), Innomar Strategies, 5 ; D. Eleftheriou, None; C. H. Wouters, None; R. Xavier, Roche, Pfizer, Janssen, 5, Roche, Pfizer, Janssen, 8, Roche, Pfizer, 2 ; L. S. Zemel, None; E. M. Baildam, Roche Pharmaceuticals, 8 ; R. Burgos-Vargas, Abbott, BMS, Merck Sharp Dohme, Pfizer, Roche , 1, Abbott, BMS, Merck Sharp Dohme, Pfizer, Roche, 1, Abbott, BMS, Merck Sharp Dohme, Pfizer, Roche, 9, Abbott Immunology Pharmaceuticals, 2 ; P. Dolezalova, None; S. M. Garay, None; R. Joos, None; A. Grom, Novartis Pharmaceuticals, 5 ; N. Wulffraat, None; Z. Zuber, None; F. Zulian, None; A. Martini, Roche Pharmaceuticals, 5 ; D. Lovell, Hoffmann-La Roche, Inc., 5 .