Responders to open-label adalimumab then randomized to placebo-controlled trial
Patients (n = 133) who had at least American College of Rheumatology Pediatric 30% (ACR Pedi 30) responses during the open-label lead-in phase were then randomized to a double-blind phase and received adalimumab or placebo eow for up to 32 weeks. Dr. Lovell pointed out that although the trial initially used an individualized dosing scheme for adalimumab, based on body-surface area, the latter part of the extension phase used a fixed dose based on body weight (20 mg for patients weighing <30 kg and 40 mg for patients weighing ≥30 kg), which is the dosing FDA approved for adalimumab in JRA.
“This is the first study done with and without [MTX], which has been an extraordinarily safe drug. The FDA required the adalimumab monotherapy arm, mainly for completeness. Although the study was not powered to determine the efficacy of adalimumab with vs without MTX, it does provide some reassurance to clinicians that the way TNF-inhibitors are typically used in JRA—which is to add a TNF-inhibitor if MTX does not provide enough control—is both safe and effective,” Dr. Lovell told MSKreport.com.
In the open-label lead-in part of the study, there were ACR Pedi 30 responses at week 16 in 94% of patients who were also taking MTX, and in 74% of those taking adalimumab alone.
“Among patients not receiving [MTX], disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P = .03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P = .02),” the investigators wrote.
More responses at 48 weeks with adalimumab, and responses continued for 2 years
At 48 weeks during the double-blind study, significantly more patients treated with adalimumab plus MTX had ACR Pedi 30, 50, 70, or 90 responses compared with those receiving placebo plus MTX. “Response rates were sustained after 104 weeks of treatment,” Dr. Lovell reported.
There were possibly adalimumab-related serious adverse events in 14 patients, and 27 patients (16%) had at least one positive test for anti-adalimumab antibody. “Development of anti-adalimumab antibody did not lead to a greater rate of discontinuation of the study drug, nor did it increase the incidence of serious adverse events,” the authors wrote. However, this was a higher rate of anti-adalimumab response than the 5% reported in clinical trials of adult RA patients.
“The most important unanswered question about adalimumab in JRA pertains to long-term safety. We reported convincing safety data for up to 2 years of continuous use, but what about the young patient who might be taking this drug for 10 to 15 years? We don't have those data yet,” Dr. Lovell said.
Translating research into practice
The researchers point out that the open-label lead-in phase closely resembles what is actually done in clinical practice, where patients are given a new drug open-label for a period of time to determine whether it will work. “If a patient does not have a response to an active treatment after a period of time (16 weeks or so, as in the current trial), a physician will probably consider other treatment options. For patients who do have a response, treatment will be continued,” they write.
Dr. Lovell said in clinical practice, adalimumab should be tried for at least 12 to 16 weeks to determine a patient's responsiveness. He noted that responses in the study continued to appear even later than 12 weeks. “Trying adalimumab for less than 12 weeks is not sufficient and it risks missing some patients who would be helped by adding this drug to their regimen.”
Dr. Lovell also emphasized that this trial was in young patients with polyarticular JRA and should not be overly generalized to patients with other presentations.
Reference
1. Lovell DJ, Ruperto N, Goodman S, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359:810-820.
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