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| Joan Bathon, M.D. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
D2E7 (Adalimumab) Abstracts 467 Adalimumab (D2E7) Monotherapy in the Treatment of Patients with Severely Active Rheumatoid Arthritis (RA). This was a safety and efficacy study of adalimumab (D2E7), a fully human anti-TNF-a monoclonal antibody, as monotherapy in patients with long-standing, severely active RA who had failed prior DMARD therapy. Methods: The trial was a 26-week, double-blind, randomized, placebo-controlled trial of adalimumab in patients with active RA. DMARDs were washed out for 4 weeks. Patients were then randomized to 1 of 5 treatment groups: adalimumab 20 mg every other week (eow) or weekly, adalimumab 40 mg eow or weekly, or placebo. Results: 544 patients were enrolled (77% female, mean age 53 years). Baseline disease activity (RA duration 11 yrs, TJC 34, SJC 20, HAW 1.9, DAS 28 score 7, CRP 5.2 mg/dL) indicated severely active RA. All adalimumab regimens demonstrated superior efficacy compared to placebo (see below).
Injection site reactions occurred in 19.4% of the adalimumab treated patients compared to 7.3% of controls. Adverse event-related withdrawls occurred in 5.3% of adalimumab treated patients and 2.7% of placebo patients. Serious infections occurred in 11 of 434 adalimumab-treated patients. Conclusions: Monotherapy with adalimumab provided significant improvement in the signs and symptoms and disability associated with long-standing, severely active RA despite previous failures with multiple DMARDs. Editorial Comment: These results are consistent with the Phase II trial conducted in North America with adalimumab as monotherapy, although the ACR responses were somewhat more modest in the current study. This may be due to the fact that this European cohort of patients had more severe disease than the North American cohort, as evidenced by the high DAS scores and CRP levels. Abstracts 468 Adalimumab (D2E7), a Fully Human Anti-TNF-a Monoclonal Antibody, Inhibits the Progression of Structural Joint Damage in Patients with Active RA Despite Concomitant Methotrexate (MTX) Therapy. This study evaluated the safety, efficacy and radiological outcomes of adalimumab in patients with active RA who were incomplete responders to MTX therapy. Methods: This was a 52-week, double-blind, randomized, placebo-controlled trial in patients with active RA on stable doses of MTX. Patients were randomly assigned to 1 of 3 treatment groups: 1) placebo; 2) adalimumab 20 qwk; 3) 40 mg every other wk (eow). Radiographs were taken at baseline and 52 weeks, digitized, randomized for sequence and treatment, and blinded for scoring by 2 readers. Results: 619 patients were randomized. Mean baseline characteristics were: age 57 yrs, 75% female, disease duration 11 yrs, TJC 28, SJC 19, CRP 1.7 mg/dL, HAQ 1.5, and MTX dose 16.6 mg/wk. At week 52, in additional to significant better ACR responses compared to placebo, the adalimumab treatment groups exhibited a lower rate of radiographic progression (see table below).
Conclusions: Adalilmumab given sc weekly (20 mg) or eow (40 mg) with concomitant MTX significantly inhibited progression of joint damage as assessed radiographically. The 2 adalimumab doses were comparably effective and well tolerated. Editorial Comment: That adalimumab suppresses progression of structural joint damage was first suggested by an open label study in Europe in which xrays were examined retrospectively. The current study now confirms this desirable feature of adalimumab, at least when given in combination with MTX. The progression in the control MTX group is relatively low, presumably because MTX is providing some background efficacy in suppressing structural damage even though the patients continued to have clinically active disease. Abstracts 1537 Safety and Efficacy of Adalimumab (D2E7), a Fully Human Anti-TNF-a Monoclonal Antibody, Given in nCombination with Standard Antirheumatic Therapy: Safety Trial of Adalimumab in Rheumatoid Arthritis (STAR). This study was performed to evaluate the safesty and efficacy of the addition of adalimumab (D2E7) to standard of care with DMARDs, corticosteroids and/or NSAIDs. Methods: Patients were randomized to adalimumab 40 mg SQ every other week (n=318) or placebo (n=318) for 24 weeks. Patients continued to receive prestudy DMARDs at stable doses, corticosteroids and NSAIDs. Mean baseline characteristics were similar for the two groups. A total of 84% of patients were taking concomitant DMARDS (56% were taking 1 DMARD; 28% were taking 2 to 4 DMARDs). The most frequent concomitant DMARDs were MTX (59%), antimalarials (25%), leflunomide (14%), sulfasalazine (10%), and parenteral gold (6%). Results: Safety results were comparable between patients treated with adalimumab plus standard of care versus those receiving placebo plus standard of care. No significant differences in adverse events, serious adverse events, infections and serious infections were observed between the two groups, except for injection site reactions which were more common in the adalimumab group than the placebo group (19.5% vs 11.6%). The adalimumab group had superior ACR responses compared to the placebo group. Conclusions: The addition of adalimumab 40 mg SQ every other week to standard of care was well tolerated and did not result in increased incidence in the rates of adverse events or infections. Editorial Comment: These data are encouraging since combination therapy is an increasingly popular trend in the treatment of RA patients. The important question that remains unanswered and that was not addressed in this study is the relative safety of combining anti-TNF and anti-IL-1 agents for the treatment of RA. Please see Abstract 464 below. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Abstract 1541 Safety of Anakinra (Interleukin-1 Receptor Antagonist) in Patients Receiving Standard Treatments for Rheumatoid Arthritis: A Large Phase III Study Please see EULAR 2002 Highlights. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Abstract 463 A Phase 2B Multi-Center, Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Efficacy of Two Different Doses of CTLA4Ig Administered Intravenously to Subjects with Active Rheumatoid Arthritis (RA) While Receiving Methotrexate CTLA4IG binds to CD-80 and -86 receptors on antigen presenting cells, preventing their interaction with the CD-28 receptor on T cells, thus causing inhibition of T cell proliferation and cytokine release. This was a 12 month study to assess the safety and efficacy of CTLA4Ig in subjects with active RA despite MTX. Methods: 339 patients with active RA despite MTX were randomized to 1 or 3 treatment arms: 1) MTX + placebo; 2) MTX + CTLA4Ig 2 mg/kg; and 3) MTX + CTLA4Ig 10 mg/kg. Analysis was by intention-to-treat. Primary endpoint was ACR20 response. Results: Demographic features and disease activity were similar in all 3 treatment groups. Average disease duration was 10 years; mean age was 54 years; 80% of patients were women; mean swollen joint and tender joint counts were 21 and 29, respectively; and, mean CRP was 3.0 mg/dL. ACR responses at 6 months are shown below (similar responses were observed at 12 months but are not shown here):
*P < 0.05 compared to placebo/MTX controls. Type and frequency of adverse events were similar in the three treatment groups. In general, the drug was well tolerated. Conclusions: CTLA4Ig is the first therapy directed at inhibition of T cell proliferation/function to show efficacy in RA. The observed efficacy was dose dependent, and the adverse event profile was acceptable (at least in this short-term study). Editorial Comment: This study builds on prior studies with CTLA4Ig demonstrating efficacy against placebo. The current data are encouraging and exciting because this therapy offers a unique approach to treatment of RA as the first successful anti-T cell therapy to date. It should be noted that the ACR responses are more modest than those observed with the anti-TNF agents, etanercept, infliximab and D2E7. Abstract 464 A Pilot, Multi-Center, Randomized, Double-Blind, Placebo Controlled Study of CTLA4Ig (2 mg/kg) given monthly in combination with Etanercept in Active Rheumatoid Arthritis (RA). See rational for CTLA4Ig in abstract 463 above. This study was a 6-month, double-blind, placebo-controlled study to assess the safety and efficacy of CTLA4Ig in patients with active RA despite background etanercept. Methods: 121 patients with active RA (> 10 tender and > 8 swollen joints) despite background etanercept (25 mg s.c. 2/wk) were enrolled in the study. Subjects were randomized to receive either placebo (n=36) or CTLA4Ig 2 mg/kg (n=85). The primary outcome was ACR20 response. However, because of the low CRP levels in patients on etanercept, the ACR20 response rate was modified to require 2 of 4 (rather than 3 of 5) parameters other than swollen/tender joints. Results: Mean age was 50 yrs; mean disease duration was 14 yrs; mean disease activity was 29 tender, and 20 swollen, joints. The modified ACR 20 response rates were as follows:
*p < 0.05 compared to placebo Type and frequency of serious and non-serious adverse events was similar in the two groups. Conclusions: A modest ACR20 response, compared to placebo, was observed in the CTLA4Ig group. Editorial Comment: Combining an anti-T cell therapy with an anti-TNF therapy makes a lot of sense and has the potential for synergistic efficacy. Although the ACR responses seen in this study were modest, only the low dose of CTLA4Ig was examined because of safety concerns. It will be interesting to see in upcoming Phase III studies whether the 10 mg/kg dose of CTLA4Ig will exhibit more impressive efficacy in combination with etanercept, and particularly whether this combination will be superior to CTLA4Ig + MTX (see abstract 463 above). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Abstract 1499 A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial of Humanized Anti-interleukin-6 (IL-6) Receptor Monoclonal Antibody (MRA) in Rheumatoid Arthritis (RA) This study was performed to evaluate the safety and efficacy of an anti-IL-6 monoclonal antibody (MRA) for the treatment of active RA patients who had failed DMARDs and to find the optimal dose. Methods: 164 patients with active RA were randomized to 4 or 8 mg/kg MRA or placebo (n=54, 55 and 53, respectively), given intravenously every month for 3 months. DMARDs were washed out but low dose prednisone and NSAIDs could be continued. The primary endpoint was ACR20 response at 12 weeks. Results: Baseline characteristics were similar in the 3 groups with mean ESR of 65 mm/hr, CRP of 5.0 mg/dL. ACR-20, -50, and 70 responses at 12 weeks were significantly higher in the MRA groups compared to placebo.
Biochemical markers of bone formation (serum osteocalcin and P1CP) significantly increased in the 8 mg/kg group. The overall incidences of adverse events, serious events, and infections were similar in the three groups. One patient treated with MRA experienced reactivation of chronic EV virus and died. Conclusion: Treatment with MRA was effective and appeared to be well tolerated. Editorial Comment: IL-6 plays a major role in the systemic features and in B cell maturation/activation in RA. This study strongly supports the efficacy of this treatment in relieving the signs and symptoms of RA. It will be interesting in future studies to determine whether radiographic progression can be slowed/halted by anti-IL6 therapy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Abstract 446 Efficacy and Safety of Rituximab, a B-Cell Targeted Chimeric Monoclonal Antibody: A Randomized, Placebo-Controlled Trial in Patients with Rheumatoid Arthritis. Rituximab is an anti-CD20 monoclonal antibody that depletes B cells. In a previous open label study in a small number of patients, rituximab given in combination with cyclophosphamide (CTX) and steroids had some efficacy. The current study is a randomized, double-blind, placebo controlled trial in RA. Methods: 161 RA patients were enrolled who were: 1) RF positive; 2) receiving MTX > 10 mg/wk; 3) had active disease (> 8 swollen and tender joints; elevated ESR/CRP). Forty patients each were randomized to 1 of 4 treatment groups: 1) MTX only; 2) Rituximab alone (2 x 1g iv); 3) Rituximab (2 x 1g i.v.) plus CTX (2 x 750 mg i.v.); and 4) Rituximab (2 x 1g i.v.) and continued MTX. All groups also received a 17 day course of steroids (100 mg Solumedrol i.v. X 4, then tapering; 910 mg total). Results: The primary outcome was ACR50 response at 60 months. An interim analysis of the first 120 patients is shown below:
*p < 0.05 (Fisher's exact T test comparing MTX with each rituximab group. All 3 rituximab treatment arms were well tolerated with similar levels and types of adverse events compared to MTX alone. The titer of RF decreased in all Rituximab groups (and transiently in the placebo group), but anti-pneumococcal antibodies and levels of total immunoglobulins did not decrease. Conclusions: Rituximab in combination with CTX or MTX conferred additional benefit above MTX alone. B cell depletion was well tolerated. Editorial Comments: This study extends the prior study by including controls with Rituximab alone and MTX alone. Although the ACR responses in the Rituximab combination groups look encouraging, the comparison to MTX alone is flawed by setting the allowable MTX dose at a 10 mg/wk minimum. [In most clinical trials now, patients must have failed 15 mg or higher per week.] In the final data, it will be important to know what the mean MTX dose was before getting too excited about the comparison data. Also, it is not clear how much of the improvement in the control groups (MTX alone and Rituximab alone) is due to steroid dosing. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Abstract 465 Dose Escalation of Intramuscular (im) Methotrexate (MTX) for Patients with Active Rheumatoid Arthritis (RA) Does Not Improve Disease Control - a Randomised Placebo Controlled Trial. A dose response relationship for oral MTX (up to 22 mg/week) in patients with active RA has previously been shown (J Rheum 1989;16:313). The safety and efficacy of higher doses of MTX are unknown. This study was performed to examine whether dose escalation of i.m. MTX from 15 mg to 45 mg/wk improves disease control in RA. Methods: Enrollees were patients with active RA (disease activity score-28 [DAS 28] > 3.20 despite MTX 15-20 mg/wk for 8 weeks followed by MTX 15 mg/wk i.m. for 6 wks prior to randomization. After enrollment patients received monthly dose escalation of MTX by 10 mg/wk up to 45 mg/wk i.m. if the DAS 28 remained > 2.5 units. The control group received stable dose MTX of 15 mg i.m. with placebo escalation. All assessments were double blind. All patients received 5 mg folic acid/wk. Primary outcome was DAS < 3.2 units. Secondary outcome was improvement in DAS 28 of > 1.2 units, ACR 20/50/70 response, and others. Results: 27 patients were randomized to each of the two treatment groups. There was no significant difference in demographic characteristics between control and active treatment groups for age, gender, disease duration (mean 9.5 yrs), number of previous DMARDs(median 2), % RF positive, % with erosions, number receiving oral steroids or baseline disease activity. Mean and median doses of MTX achieved in the active treatment group were 40 and 45 mg/wk, respectively. There were no significant differences in the primary or secondary outcomes between the groups: 3.7% in each group achieved a DAS 28 < 3.2 units, and 18.5% in each group improved in DAS 28 by > 1.2 units. Conclusions: Increasing the dose of i.m. MTX from 15 mg/wk to 45 mg/wk in RA patients with active disease did not result in improved disease control. Editorial Comment: This is a very provocative study with results that would not have been predicted by most RA investigators. Only 1 patient in each group achieved a DAS 28 score < 3.2; thus, not even a placebo response was observed. It will be very important to see if these results are reproduced in another controlled study. One of the flaws of the current study was that the clinical evaluations that preceded the double blind component of the study were performed off-site, presumably by personnel different from those in the randomized phase of the trial. This could introduce a large margin of error. A very useful piece of information gleaned from this study, however, was the high tolerance of RA patients for quite high doses of MTX. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Abstract 440 A Randomized Trial of Methotrexate (MTX) in Medium Versus Higher Doses in Children with Juvenile Idiopathic Arthritis (JIA) Who Failed on Standard Dose MTX in low dose has proven efficacy compared to placebo in juvenile idiopathic arthritis (JIA). However, the efficacy and safety of higher dose MTX is unproven in JIA. These investigators compared, in a multinational (20 countries) randomized trial, the safety and efficacy of MTX in medium (15 mg/m2/week, maximum dose 20 mg/week) versus high dose (30 mg/m2/week, maximum dose 40 mg/week) in children with polyarticular JIA who failed to improve significantly on standard dose MTX (8-12.5 mg/m2/week). Methods: 633 patients with polyarticular JIA were started on MTX in standard dose (8-12.5 mg/m2/week), administered orally (os), subcutaneously (sc) or intramuscularly (im) in an open-label fashion for 6 months. At the end of the 6 months, those who did not meet criteria for ACR30 response criteria (for JIA/JRA) and who were eligible for enrollment were randomzied to medium or high dose MTX. The intention-to-treat analysis was applied for data analysis. Results: At the end of the 6-month open label period, 455 (72%) of the 633 patients had improved with standard dose MTX. Out of the 145 non-responders, 80 were eligible and agreed to be enrolled into the double-blind, randomized phase. 40 patients received high dose and 40 received low dose MTX. ACR30 responses were as follows:
Both doses were tolerated well and there was no difference in frequency of adverse events between the two dosage groups. Conclusion: For patients who do not respond to standard dose MTX, increasing the dose to the intermediate range can provide additional improvement/efficacy without incurring significant toxicity. An increase to the high dose range did not appear to convey an advantage over the medium dose. Editorial Comment: These are encouraging results. Despite the popular use of MTX to treat pediatric and adult RA for nearly two decades, we know little about the most effective dose. This is an attempt to fill that knowledge gap and the results are encouraging for those reluctant to increase MTX doses in children. The failure to control MTX dose and to have standardized assessments in the screening, open-label phase is a potential flaw in this study; nonetheless, the randomized phase was well designed and appeared to have strict entry criteria. (top of section)
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