For patients with early rheumatoid arthritis who achieved remission on full-dose etanercept plus methotrexate, continuing this combination treatment at a reduced dose controlled the disease better than did methotrexate alone or placebo in the randomized, controlled PRIZE trial.
The results of the PRIZE (Productivity and Remission in a Randomized Controlled Trial of Etanercept vs. Standard of Care in Early Rheumatoid Arthritis) trial, which was designed and funded by Pfizer, also showed that maintenance therapy with etanercept plus methotrexate increased the number of patients with sustained remission and extended the duration of remission after treatment was discontinued. However, it did not alter the radiographic progression of RA, said Dr. Paul Emery of the Leeds Institute of Rheumatic and Musculoskeletal Medicine at Leeds (England) University, and his associates.
Dr. Paul Emery
The trial, conducted at 57 medical centers in Europe and Asia during 2009-2012, included 193 patients who responded to the combination therapy during a 1-year, open-label phase (N. Engl. J. Med. 2014;371:1781-92).
This open-label phase consisted of subcutaneous injections of 50 mg etanercept plus oral methotrexate initiated at a dose of 10 mg/week and adjusted up to a maximum dose of 25 mg/week during the first 8 weeks. Patients who did not have low disease activity, defined as a 28-joint Disease Activity Score (DAS28) of 3.2 or less, at week 13 or 26 received glucocorticoids as rescue medication unless contraindicated or if they had unacceptable side effects.
The patients who met the criteria for response during the open-label phase by having a DAS28 of 3.2 or less at week 39 and a DAS28 of less than 2.6 at 1 year were randomly assigned in a double-blind fashion to 39 weeks of 25 mg etanercept plus methotrexate (63 participants), placebo injection plus methotrexate (65 participants), or a double placebo (65 participants). Afterward, the study treatments were withdrawn and 131 participants were followed to week 65.
The primary efficacy endpoint of the trial was the proportion of patients who had sustained remission at the end of the double-blind maintenance phase. With DAS28-defined remission, this percentage was significantly higher for patients who received etanercept plus methotrexate (79%) than for those who received methotrexate alone (54%) or placebo alone (38%). When remission was defined by the stricter American College of Rheumatology and European League Against Rheumatism (ACR-EULAR) criteria, the differences were still significant: 68%, 46%, and 23%, respectively.
At this time, 78% of patients who received combination therapy achieved a normal score on the Health Assessment Questionnaire-Disability Index (HAQ-DI), compared with 72% of those who received methotrexate alone and 45% of those who received placebo. The difference was statistically significant between the combination-therapy group and the placebo group, the investigators said.
At week 65, which was 26 weeks after all study treatments had been withdrawn, a significantly higher percentage of patients in the combination-therapy group than in the methotrexate group or the placebo group met both sets of remission criteria and still had a normal HAQ-DI score, although the percentages between the two active treatment groups were not significantly different when examining only those who met DAS28 remission criteria or those who had a normal HAQ-DI score.
But patients in the combination-therapy group remained in remission significantly longer than did those in the other study groups, and their mean DAS28 scores were significantly lower.
However, there were no differences among the three study groups in radiographic progression of RA measured at the hands, wrists, and feet at the end of the double-blind phase.
Rates of serious adverse events were 5% with combination therapy, 3% with methotrexate alone, and 3% with placebo during the maintenance phase of the trial and 0%, 0%, and 6%, respectively, during the treatment-withdrawal phase.
This study was limited in that it included only patients newly diagnosed as having RA who had not received any other treatments. Therefore the findings may not be generalizable to patients with RA of longer duration and those who have undergone other treatments, Dr. Emery and his associates said.
This study was funded by Pfizer, maker of etanercept (Enbrel); Pfizer also designed the study, collected and analyzed the data, and participated in writing the report. Dr. Emery reported ties to AbbVie, Bristol-Myers Squibb, Pfizer, UCB, Merck Sharpe & Dohme, Roche, and Takeda, and his associates reported ties to numerous industry sources.