Background/Purpose: Certolizumab pegol (CZP), an inhibitor of TNF-alpha, has demonstrated rapid and sustained efficacy in RA patients.  Switching from one anti-TNF therapy to another has been investigated in many open-label (OL) uncontrolled studies, but in few controlled trials.  This 24-week study (12 weeks double-blind (DB) CZP or placebo followed by 12 weeks OL CZP) examined the effect of treatment with CZP or placebo on measures of disease activity in patients with active RA on stable concomitant DMARD therapy who had discontinued a TNF-alpha inhibitor other than CZP due to a secondary loss of efficacy.

Methods: The initial 12-week phase randomized 37 subjects (2:1 ratio) who were secondary non-responders (primary non-responders were excluded) or intolerant of TNF-alpha inhibitors to either CZP (27 subjects) or placebo (10 subjects) in addition to background MTX or other DMARDs.  CZP was administered subcutaneously in approved doses.  The pre-specified primary endpoint was the ACR 20 response at Week 12. After the Week 12 visit, all subjects could continue (blinded to initial treatment) with OL CZP for an additional 12 weeks. (NCT01147341).

Results: 37 subjects were randomized; 35 (26 on CZP and 9 on placebo) completing at least 4 weeks of dosing were analyzed for efficacy. Demographic/baseline characteristics (mean) of the 2 treatment groups were similar: age 56 vs 59 years, disease duration 12 vs 14 years, MTX dose 16.4 vs 16.1 mg/week, and DAS-CRP 5.48 vs 5.44 (placebo vs active).  Efficacy results (initial 12 weeks) are as follows:

* two-sided p-value from Fisher’s exact test

24-Week Data: 8 of the 9 subjects randomized to placebo (all non-responders) continued into OL; 5/8 (67%) attained ACR 20, 7/8 (87.5%) of these had CDAI improvement ≥13.9 after the switch to CZP.  Five of the CZP-treated subjects who were initially ACR 20, but not ACR 50, responders improved to ACR 50 or 70 responses with OL treatment.

In the initial 12 weeks, adverse events occurred in 16/27 (59.3%) CZP subjects and 4/10 (40%) placebo subjects. One serious adverse event of G-I bleeding (considered unrelated to CZP) occurred in the open-label phase. There were no other serious adverse events, deaths, neoplasms, opportunistic or serious infections.

Conclusion: In this controlled study of secondary non-responders to TNF inhibitors, the primary efficacy endpoint (ACR 20) and most secondary endpoints showed significant improvement with CZP compared to placebo.  The ACR 20 response rate observed with CZP (>60%) is higher than that reported in most previous studies of incomplete TNF responders. With OL CZP dosing for the final 12 weeks, improved efficacy was seen in most subjects who had previously received placebo.  In addition, CZP demonstrated good safety and tolerability.  This study supports the use of CZP in RA patients who are secondary non-responders to anti-TNF therapies or intolerant to them.