Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P. Infliximab (chimeric anti-tumour necrosis factor monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate. ATTRACT Study Group.
Overall Study Question
The ATTRACT study was designed to test whether the addition of infliximab (a chimeric human-mouse anti-TNF monoclonal antibody) would provide clinical benefit to patients who had active rheumatoid arthritis despite methotrexate treatment. Patients were included in the study if they had active rheumatoid arthritis despite treatment with oral or parenteral methotrexate at a stable dose of at least 12.5 mg/week, and stable doses of corticosteroids (10 mg/kg or less of prednisone) and NSAIDs. The primary outcome was a 20% improvement (according to American College of Rheumatology [ACR] criteria) at the 30 week visit without requiring a surgical joint procedure.
Are the Results of the Study Valid?
Was assignment of patients randomized?
Yes. Yes. Eligible patients diagnosed with rheumatoid arthritis with evidence of active disease despite treatment with methotrexate were randomized (in a double-blind fashion) to receive placebo or one of four treatment regimens of infliximab at either 3 mg/kg or 10 mg/kg given every 4 weeks or every 8 weeks and placebo infusions on interim 4 week visits to maintain blinding. All infusions were given over 2 hours.
Were all patients who entered the trial properly accounted for and attributed at its conclusion?
Yes. 428 patients were enrolled and randomized as follows: 88 to placebo (35 discontinued [d/c’d] prematurely), 86 to 3 mg/kg every 8 weeks (16 d/c’d), 86 to 3mg/kg every 4 weeks (11 d/c’d) , 87 to 10mg/kg every 8 weeks (8 d/c’d) and 81 to 10 mg/kg every 4 weeks. The most common reason for premature discontinuation was inefficacy.
The primary outcome (the ACR defined 20% improvement) was analyzed as intention-to-treat whereas safety was assessed by an on treatment analysis.
Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Yes. The study was blinded to both the investigators and the patients. The pharmacist at each site held the unblinding code. An evaluator, who had no prior knowledge of other clinical indices and was not involved in the clinical care of the study patient, assessed the joint scores.
Were the groups similar at the start of the trial?
Yes. The baseline characteristics of the five treatment groups were well matched in terms of both disease activity (functional class, rheumatoid factor, and duration of disease) and prior to treatment history (previous joint surgery, DMARD exposure and methotrexate dose and duration). Patients in all arms had recalcitrant rheumatoid arthritis of comparable severity.
Aside from the experimental intervention, were the groups treated equally?
Yes. All patient groups were reported to have been treated equally. The doses of methotrexate and corticosteroids at baseline were allowed to continue throughout the trial in all arms.
Overall, are the results of the study valid?
What were the Results?
How large was the treatment effect?
All groups treated with infliximab had a significantly higher proportion reaching the 20% improvement as specified by the ACR (primary outcome) compared to placebo at 30 months (all p<0.001). The odds ratios (95% CI) were 3.9 (2.0-7.6), 3.9(2.0-7.6), 4.0 (2.1-8.1), and 5.4(2.7-10.6) for the 3 mg/kg every 8 weeks, 3 mg/kg every 4 weeks, 10 mg/kg every 8 weeks, and 10 mg/kg every 4 weeks, respectively. The NNT (and corresponding 95% CI) to generate one additional patient with 20% improvement was 4 (3-8), 4 (3-8), 4(3-7), 3(2-5) for each of the infliximab groups, respectively.
Adverse events between the infliximab arms and the placebo arm were similar. However, the frequency of any infection was significantly higher in those receiving 10 mg/kg every four weeks (73%) vs. placebo (40%). This finding was not significant for the other infliximab regimens and there were no differences between treatment arms for serious (life-threatening or requiring hospitalization) infections. Infusion related reactions occurred in 16-20% of infliximab recipients (depending on treatment arm) compared to 10% of placebo recipients (p=0.477). No delayed hypersensitivity reactions were reported in the trial.
How precise was the estimate of the treatment effect?
The 95% CI and corresponding NNT at 30 months are as stated above. It can be seen that none of the CI include zero and thus are statistically significant. In addition, the range of odds ratios represented in the CI are clinically significant.
Will the Results Help Me in Caring for My Patients?
Can the results be applied to my patient care?
Yes. The results of this trial can be applied to patients with moderate to severe rheumatoid arthritis who are not currently controlled on methotrexate despite receiving adequate doses. It would appear that anti-tumour necrosis factor agents are an efficacious addition at much lower toxicity than other currently available disease-modifying agents.
Were all clinically important outcomes considered?
Yes. The American College of Rheumatology 20% improvement criteria are comprehensive (20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acute-phase reactant) measures of disease activity. However, it may have been useful in the trial to have included resource utilization measurements and a generic and disease-specific quality of life measure.
Are the likely treatment benefits worth the potential harms and costs?
Yes. Although the numbers needed to treat in this analysis are relatively small compared to other adopted interventions, the cost of this therapy is very high. However, the economic burden associated with severe rheumatoid arthritis is also high thus creating the question “Are the costs of infliximab offset by the downstream avoided costs of rheumatoid arthritis care avoided?” Therefore, a formal economic evaluation should be completed which addresses this question in terms of the benefits and costs in patients treated with infliximab + methotrexate compared to methotrexate alone.
Prior to the availability of the results of recent trials of infliximab, methotrexate has been the gold-standard DMARD for use in rheumatoid arthritis. Methotrexate has been traditionally prescribed alone or in combination with other disease modifying drugs. Unfortunately, many patients do not respond or tolerate these agents and thus discontinuation and relapse are common. This trial confirms the added benefit of infliximab in rheumatoid arthritis when added to methotrexate. In addition, it appeared that this agent was well tolerated (although it may cause a dose-related increased risk of infection). Of note, not all patients treated with infliximab + methotrexate responded (proportion of patients reaching the 20% ACR improvement ranged between 50 and 60%). Thus, further research is required into why some patients do not respond to this treatment and further modalities for this group need to be developed.