Description of infliximab studies

Four RCTs with infliximab encompassing at total of 2,992 patients were included in this review. The following published papers reported originally these RCTs: Maini 1999 ATTRACT study⁶⁸, Clair 2004 ASPIRE study¹¹⁰, Westhovens 2006 START study¹²⁵ and Schiff 2008 ATTEST study⁹⁶. A list of these trials, including comparators, endpoints and baseline patient characteristics are shown in Table 1. Detailed description of infliximab studies are presented in Appendix 8.5. In this section, we will give a short description about study characteristics.

5.3.2.1 Maini 1999 – ATTRACT study

ATTRACT trial⁶⁸ was a 30-week, double-blind, multicentre, placebo-controlled RCT that evaluated the effects of infliximab in patients with persistent, active RA despite MTX. Four hundred twenty-eight patients were randomized to receive 3 mg/kg/every 4 weeks or 3 mg/kg/every 8 weeks or 10 mg/kg/every 4 weeks or 10 mg/kg/every 8 weeks infliximab or placebo. All patients received their baseline dose of MTX. Prior to enrolment, patients were required to have ≥ 6 swollen and tender joints, and CRP ≥ 2 mg/dL. Patients were required to have been treated for MTX for at least 3 months with a stable dose of 12.5 mg/week or more, for at least four weeks before screening. The primary endpoint was ACR20 at 30 weeks.

5.3.2.2 Claire 2004 – ASPIRE study

ASPIRE trial¹¹⁰ was a 54 week randomized, placebo controlled study. The analysis compared the benefits of treatment with MTX and infliximab or treatment with methotrexate alone in patients with rheumatoid arthritis. One thousand forty-nine patients were randomized to receive MTX–placebo or MTX–3 mg/kg infliximab or MTX–6 mg/kg infliximab. Patients were excluded if they had any prior treatment with MTX or other DMARDs within 4 weeks of entry or had been treated with infliximab, etanercept, adalimumab or other anti-TNF agentⁱ. Prior to enrolment, patients were required to have 10 swollen and 12 tender joints and CRP

i In this report the following terminology are used interchangeably as synonyms: anti-TNFalpha therapy; anti-TNF agent, TNF-blockers; TNF-α blockers

2.0 mg/dL. The primary endpoint was the percentage of ACR improvement (ACR-N) from baseline to week 54.

5.3.2.3 Westhovens 2006 – START study

START study¹²⁵ was a 22 week randomized, placebo-controlled trial thatassessed the risk of serious infections of infliximab therapy. One thousand eighty-four patients were randomly assigned to receive placebo or 3mg/kg infliximab or 10mg/kg infliximab at weeks 0, 2, 6, 14.

All patients had to be received MTX for at least 3 months prior to randomization and had to have active disease in spite of receiving it. The MTX dose must have been stable for at least 4 weeks prior to randomization. Prior to enrolment patients had to have 6 swollen and 6 tender joints. The primary endpoint was the occurrence of serious infections through week 22.

5.3.2.4 Schiff 2008 – ATTEST study

ATTEST trial⁹⁶ was a 52 week phase III, randomised, double-blind, double-dummy, placebo- and active (infliximab) controlled multi-centre study that evaluated the efficacy and safety of abatacept or infliximab vs. placebo. Four hundred thirty-one patients were randomised to abatacept 10 mg/kg every 4 weeks or infliximab 3 mg/kg every 8 weeks or placebo every 4 weeks and background MTX. Patients were required to have ≥ 10 swollen and ≥ 12 tender joints and CRP ≥ 1 mg/dL. Patients had to have RA for at least 1 year and had to have an inadequate response to MTX. The primary endpoint was to evaluate a reduction in disease activity, measured by Disease Activity Score 28 with abatacept vs. placebo at 6 months.

Table 1 Characteristics of infliximab RCTs

INF 3 mg/kg/every 8 weeks+MTX INF 3 mg/kg/every 4 weeks+MTX INF10mg/kg/every 8 weeks+MTX weeks thereafter through week 46

INF 6mg/kg + MTX 0, 2, and 6, and every 8 weeks thereafter through week 46

placebo + MTX 0, 2, and 6, and every 8 weeks thereafter through week 46

373

ACR-N, change in total Sharp score, HAQ

occurrence of serious infections, ACR20, ACR50, ACR70, DAS28 with abatacept vs. inf.; EULAR; 6 low disease activity score, HAQ-DI;

response rates and mean changes in the physical and mental component summary scores; and eight subscales of the SF-36

DMARD IR: inadequate response to DMARD; MTX=methotrexate

5.3.2.5 Results from infliximab studies

5.3.2.5.1 Efficacy

There was a significant difference at 24 weeks in favour of the infliximab group compared to the placebo group with respect to the ACR20, ACR50 and ACR70 response (See Figure 2, Figure 3 and Figure 4). The NNTs were 5 (3-10), 5 (4-7) and 10 (8-14) treated patients to achieve one ACR20, ACR50 and ACR70 response, respectively.

Figure 2 Efficacy of infliximab 3 mg/kg on ACR20 response at six month

Figure 3 Efficacy of infliximab 3 mg/kg on ACR50 response at six month

Figure 4 Efficacy of infliximab 3 mg/kg on ACR70 response at six month

5.3.2.5.2 Tolerability and safety of infliximab treatment

There were no significant differences between infliximab and placebo groups with respect to withdrawals due to any reason (Figure 5). There was a significant difference between the two groups with respect to withdrawal due to any adverse events (RR 2.16, 95% CI: 1.18-3.95) in favour of placebo treated patients (Figure 6). There were no significant differences between infliximab and placebo treatment with respect to any AE, serious AE and serious infections (See Figure 7, Figure 8 and Figure 9).

The NNH (number needed to harm) was 25 (17-50) treated patients to cause one withdrawal due to adverse events. Similarly, NNHs were 50 (17-∞), 100 (33--∞) and 100 (33--∞) patients to cause one AE, serious AE and serious infection, respectively. There were no significant differences for safety endpoint of NNH between infliximab and placebo groups.

Figure 5 Tolerability of infliximab 3 mg/kg, withdrawal due to any reason at six month

Figure 6 Tolerability of infliximab 3 mg/kg, withdrawal due to adverse events at six month

Figure 7 Safety of infliximab 3 mg/kg, any adverse events at six month

Figure 8 Safety of infliximab 3 mg/kg, serious adverse events at six month

Figure 9 Safety of infliximab 3 mg/kg, serious infections at six month