Background/Purpose: In the US, the recommended starting dose of Tocilizumab (TCZ) is 4 mg/kg (q4w) with an increase to 8 mg/kg (q4w) based on clinical response. However, analyses of responses experienced by patients increasing TCZ dose from 4 mg/kg to 8 mg/kg have been limited by a uniform escape escalation criterion used across phase III trials: patients randomized to 4 mg/kg who did not experience a 20% improvement in TJC and SJC at Week 16 increased the dose to 8 mg/kg. This sub-analysis of the ACTSTAR study evaluated the response of patients following an increase in TCZ dose after or at Week 8 based on joint counts or investigator discretion, respectively. Safety and efficacy outcomes of the full study were reported previously. 

Methods: ACT-STAR was a phase 3b, 24-wk, open-label, multicenter US study that evaluated adults with active RA who had an inadequate clinical response or safety/tolerability issues with prior DMARD therapy. This sub-analysis examined patients initiating TCZ 4 mg/kg who continued their current synthetic DMARD. Per study protocol, patients who did not achieve ≥20% improvement in TJC and SJC at Week 8 were to increase TCZ dose to 8 mg/kg. After Week 8, the protocol allowed TCZ dose escalation to 8 mg/kg per physician discretion. Study visits occurred at BL and 4 weeks after each infusion.

Results: Of the 363 patients randomized to receive TCZ 4 mg/kg, 68 increased to 8 mg/kg after Week 8, 142 patients increased to 8 mg/kg at Week 8 and 152 patients received only 4 mg/kg (1 patient was not dosed).  Among patients who increased dose afterWeek 8, ACR20 response at Week 24 was achieved by 58.8% of patients, ACR50 by 36.8% of patients and ACR70 11.8% of patients. Mean DAS28 decreased from 5.76 at BL to 4.45, 4.20 and 3.77 at Weeks 8, 16 and 24, respectively. ACR core components improved initially and continued to improve following dose escalation (Table). Of these patients who escalated at Week 8, which was enriched for non-responders due to study design, ACR20, 50 and 70 responses were achieved in 30.3%, 12.0% and 3.5% of patients at Week 24. Mean DAS28 decreased from 5.69 at BL to 5.39 at Week 8 (prior to protocol defined dose escalation) and to 4.32 and 4.17 at Weeks 16 and 24 (after dose escalation), respectively. Similar improvements across ACR core components were observed (Table). The most common serious adverse events pre- and post-dose increase were serious infections (SI); 1/142 (0.7%) patient experienced SI prior to dose increase, 0 patients who escalated after Week 8 experienced SIs and 3/142 (2.1%) patients experienced SI post Week 8 dose increase. Eight patients withdrew from the study due to adverse events; 2 patients who escalated after Week 8 and 6 patients who increased at Week 8. 

Conclusion: Patients who escalated TCZ dose from 4 mg/kg to 8 mg/kg after or at Week 8 based on joint counts or investigator discretion were observed to have improvements in DAS28 and ACR core components following dose escalation.

Table:

		Change from baseline
	Baseline	Week 8	Week 16	Week 24
Patients who increased dose from 4 mg/kg to 8 mg/kg after Week 8 (n = 68)
DAS28, mean (SD) [n]	5.76 (0.97) [68]	-1.29 (1.1) [66]	-1.59 (1.3) [66]	-1.95 (1.4) [61]
CRP, mg/dL (SD) [n]	1.08 (1.3) [68]	-0.19 (1.3) [66]	-0.36 (1.5) [67]	-0.62 (2.8) [62]
TJC, mean (SD) [n]	29.57 (13.5) [68]	-12.73 (10.0) [67]	-13.12 (14.3) [67]	-15.33 (14.3) [67]
SJC, mean (SD) [n]	19.32 (11.6) [68]	-9.07 (8.1) [67]	-8.72 (13.2) [67]	-10.34 (12.4) [67]
Patient Global VAS (SD) [n]	63.91 (20.7) [68]	-19.37 (22.8) [67]	-20.10 (26.3) [67]	-25.00 (25.3) [67]
Physician Global VAS (SD) [n]	64.93 (18.2) [68]	-24.12 (22.3) [67]	-22.36 (24.3) [66]	-29.82 (23.8) [67]
Patients who increased dose from 4 mg/kg to 8 mg/kg at Week 8 (n = 142)
DAS28, mean (SD) [n]	5.69 (1.03) [142]	-0.31 (0.9) [139]	-1.38 (1.1) [134]	-1.47 (1.2) [120]
CRP, mg/dL (SD) [n]	1.64 (2.5) [142]	-0.15 (2.0) [139]	-1.19 (2.6) [134]	-1.02 (2.7) [120]
TJC, mean (SD) [n]	28.73 (14.6) [142]	0.27 (10.5) [142]	-8.33(13.4) [138]	-9.37(13.5) [127]
SJC, mean (SD) [n]	18.06 (11.0) [142]	0.56 (8.2) [142]	-5.10 (8.1) [138]	-5.96 (9.2) [127]
Patient Global VAS (SD) [n]	65.17 (19.4) [142]	-5.32 (20.4) [142]	-14.60 (23.4) [138]	-16.63 (23.5) [127]
Physician Global VAS (SD) [n]	63.91 (17.9) [142]	-8.45 (22.2) [142]	-23.02 (26.1) [133]	-25.92 (25.5) [127]

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