Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Tocilizumab (TCZ) Plus Methotrexate (MTX) in Rheumatoid Arthritis (RA) Patients (pts) Who Increased TCZ Dose from 4 mg/kg to 8 mg/kg: LITHE Radiographic and Safety Data.

Fleischmann4,  Roy M., Blanco2,  Ricardo, Castelar-Pinheiro3,  Geraldo, Vernon5,  Emma, Mela5,  Christopher, Kremer1,  Joel M.

Albany Medical College, Albany, NY
Hospital Marqués de Valdecilla Cantabria
Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil
Metroplex Clinical Research Center, Dallas, TX
Roche, Welwyn, United Kingdom

Purpose:

Results of the TCZ clinical development program have shown that for most endpoints, the 8 mg/kg dose is more effective than the 4 mg/kg dose. In the US, TCZ 4 mg/kg has been approved as the starting dose with a subsequent escalation to 8 mg/kg based on clinical response. This analysis evaluated the effect of increasing the TCZ dose from 4 to 8 mg/kg on inhibition of radiographic progression and safety in the LITHE study.

Methods:

RA pts with inadequate responses to MTX were randomly assigned to TCZ 4 or 8 mg/kg (TCZ4 or TCZ8) or placebo Q4W + MTX. From wk 16, blinded first-step rescue was allowed if pts had <20% improvement in SJC and TJC (eg, pts on placebo went to TCZ4, pts on TCZ4 or TCZ8 went to TCZ8). If <20% improvement persisted after 3 doses of blinded first-step rescue, pts received second-step rescue with TCZ8. At wk 52, pts were treated with open-label (OL) TCZ8 except those with >=70% improvement in SJC and TJC, who could continue blinded therapy to wk 104. X-rays were performed at baseline and wks 24, 52, 80, and 104. Data were analyzed in pts whose dose increased from TCZ4 to TCZ8. Data from this TCZ dose-escalation analysis must be interpreted with caution because 78 pts who withdrew (44 for safety, 8 for insufficient response, 26 for other reasons) from the study before dose escalation are not included. In addition, criteria for dose escalation and/or dose continuation were based on efficacy results that were predetermined per study protocol. Safety data are provided for all randomly assigned pts who received >=1 TCZ dose and who had at least 1 post-randomization safety assessment.

Results:

Of 1190 pts (393, 399, and 398 randomly assigned to placebo, TCZ4, and TCZ8, plus MTX, respectively), 451 pts increased their dose from TCZ4 to TCZ8. In these 451 pts, annualized rate of progression of Genant-modified Total Sharp Score, erosion, and joint space narrowing slowed after the dose increased from TCZ4 to TCZ8 (Table A). Rates/100 patient-years (PY) of serious adverse events (AEs) and serious infections were lower than previously reported (Kremer et al, EULAR 2010) before dose escalation but increased to rates comparable to those of the TCZ pooled groups (TCZ4, n =597, includes pts who received TCZ4 as initial or rescue therapy; TCZ8, n=983 pts, includes those who received TCZ8 as initial and/or rescue and/or OL therapy) after dose escalation (Table B). The low predose escalation event rates for the TCZ4 group are influenced by a selection bias—ie, pts who withdrew while on TCZ4 do not contribute safety data to the analysis of the switching group but continue to contribute to the rates in the TCZ4 pooled analysis.

Conclusions:

For this analysis of pts who increased dose, the annualized rate of progression was reduced after pts increased their TCZ dose from 4 to 8 mg/kg; safety in these pts after dose escalation was comparable to that in the TCZ pooled groups.

Table A. Mean (SD) Annualized Rate of Radiographic Progression by Treatment Increase up to Week 104 (n = 451)

 Predose increase (TCZ4) n = 451Postdose increase (TCZ8) n = 451
n336346
Genant-modified Total Sharp Score0.31 (1.07)0.10 (0.52)
Erosion0.20 (0.83)0.04 (0.36)
Joint space narrowing0.11 (0.53)0.06 (0.36)
Data collected after study withdrawal are excluded

Table B. Safety up to Week 104 Before and After TCZ Dose Increase and by Pooled Treatment Groups

 Dose escalation group n = 451aPooled treatment groupb
 Predose increase (TCZ4)Postdose increase (TCZ8)TCZ4 n = 597cTCZ8 n = 983d
Exposure, PY338.6475.9521.91320.4
Serious AEs/100 PY5.911.312.111.4
Serious infections/100 PY0.92.73.13.2
a 78 patients who received TCZ4 and withdrew (44 for safety, 8 for insufficient response, 26 for other reasons) from the study before dose escalation are not included.
b Patients in pooled treatment groups could be in both pooled groups and also in the dose-escalation group.
c All patients who received >=1 TCZ4 dose, including those initially assigned to placebo who received rescue with TCZ4 and those initially assigned to TCZ4, and whose only TCZ dose was 4 mg/kg; data are up to study withdrawal, when dose increased to TCZ8, or wk 104.
e All patients who received >=1 TCZ8, including patients initially assigned to placebo who received second-step rescue with TCZ8, patients initially assigned to TCZ4 who received rescue with TCZ8, patients initially assigned to TCZ8, patients whose only TCZ dose was 8 mg/kg, and patients on OL TCZ8; data are up to study withdrawal or wk 104.

To cite this abstract, please use the following information:
Fleischmann, Roy M., Blanco, Ricardo, Castelar-Pinheiro, Geraldo, Vernon, Emma, Mela, Christopher, Kremer, Joel M.; Tocilizumab (TCZ) Plus Methotrexate (MTX) in Rheumatoid Arthritis (RA) Patients (pts) Who Increased TCZ Dose from 4 mg/kg to 8 mg/kg: LITHE Radiographic and Safety Data. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2262
DOI: 10.1002/art.30025

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