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ABSTRACT: OBJECTIVE: There is a need for comparative studies to provide evidence-based treatment guidance for biologics in RA. This is the first head-to-head study in RA, which compared subcutaneous abatacept versus adalimumab both with background methotrexate (MTX). METHODS: Patients with active RA, naïve to biologic therapy, and an inadequate response to MTX were randomly assigned to 125 mg SC abatacept weekly or 40 mg SC adalimumab bi-weekly, both in combination with MTX in a 2 year study. The primary end point was non-inferiority by ACR 20 response at 1 year. RESULTS: Of the 646 patients that were randomized and treated; 86.2% and 82% patients completed 12 months (abatacept vs. adalimumab). At 1 year, 64.8% and 63.4% of patients demonstrated an ACR20 response; the estimated difference [95% CI] between groups was 1.8 [-5.6, 9.2]) demonstrating the non-inferiority of abatacept versus adalimumab. All efficacy measures showed similar results and kinetics of response. Rates of radiographic non-progression (mTSS≤SDC) were 84.8% and 88.6%; mean changes from baseline in mTSS of 0.58 and 0.38. Incidence of serious adverse events (SAEs) was 10.1% and 9.1%; serious infections 2.2% and 2.7%. Discontinuations due to adverse events were 3.1% versus 6.1%, due to SAEs were 1.3% versus 3%. Injection site reactions occurred in 3.8% versus 9.1% (p=0.006). CONCLUSIONS: SC abatacept demonstrated comparable efficacy versus adalimumab with similar kinetics of response and inhibition of radiographic progression at 1 year. The safety was generally similar other than significantly more local injection site reactions with adalimumab. © 2012 American College of Rheumatology.
Arthritis & Rheumatism 11/2012; · 7.87 Impact Factor
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ABSTRACT: To evaluate abatacept safety and efficacy over 5 years in patients with rheumatoid arthritis (RA) who had inadequate response to anti-tumor necrosis factor (TNF) therapy in the ATTAIN trial.
Patients completing the 6-month, double-blind (DB) placebo-controlled period were eligible to enter the longterm extension (LTE), where all patients received abatacept every 4 weeks (∼10 mg/kg, according to weight range). Safety, efficacy, physical function, and health-related quality of life were monitored throughout.
In total, 317 patients (218 DB abatacept, 99 DB placebo) entered the LTE; 150 (47.3%) completed it. Overall incidences of serious adverse events, infections, serious infections, malignant neoplasms, and autoimmune events did not increase during the LTE versus the DB period. American College of Rheumatology responses with abatacept at Month 6 were maintained over 5 years. At Year 5, among patients who received abatacept for 5 years and had available data, 38/103 (36.9%) achieved low disease activity as defined by the 28-joint Disease Activity Score (DAS28)/C-reactive protein (CRP); 23/103 (22.3%) achieved DAS28/CRP-defined remission. Health Assessment Questionnaire response was achieved by 62.5% of patients remaining on treatment at Year 5; mean improvements from baseline in physical component summary and mental component summary scores were 7.34 and 6.42, respectively. High proportions of patients maintained efficacy and physical function benefits or improved their disease state at each timepoint throughout the LTE, if remaining on abatacept treatment.
Safety remained consistent, and abatacept efficacy was maintained from 6 months to 5 years, demonstrating the benefits of switching to abatacept in this difficult-to-treat population of patients with RA previously failing anti-TNF therapy.
The Journal of Rheumatology 07/2012; 39(8):1546-54. · 3.69 Impact Factor
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Michael Schiff,
Mauro Keiserman,
Christine Codding,
Suthin Songcharoen,
Alberto Berman,
Sauithree Nayiager,
Cristina Saldate,
Richard Aranda,
Jean-Claude Becker,
Marleen Nys,
Manuela le Bars,
Diane Moniz Reed,
Coralie Poncet,
Maxime Dougados
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ABSTRACT: To assess the efficacy and safety of abatacept in biological-naive patients with rheumatoid arthritis and an inadequate response to methotrexate treated in the long-term extension (LTE) of the ATTEST trial.
Patients randomly assigned to abatacept, placebo or infliximab completing the 1-year double-blind period were eligible to receive abatacept ∼10 mg/kg in the open-label LTE. Efficacy to year 2 is presented for patients randomly assigned to abatacept or infliximab who switched to open-label abatacept. Safety data are presented for all patients entering LTE regardless of double-blind treatment.
Of 431 patients randomly assigned, 79.8% remained on abatacept at year 2. At years 1 and 2, 19.7% and 26.1% of abatacept and 13.3% and 28.6% of infliximab-to-abatacept patients achieved disease activity score 28-defined remission (<2.6). Safety with abatacept during the cumulative study period was consistent with the double-blind experience, with no increase in adverse event incidence following the switch to abatacept.
In methotrexate-inadequate responders, abatacept efficacy was maintained over 2 years. For infliximab-to-abatacept patients, efficacy improvements were seen in year 2 after patients switched to abatacept. Switching directly from infliximab to abatacept was well tolerated. These data demonstrate that abatacept provides sustained responses and consistent safety, suggesting that switching from infliximab to abatacept is a viable treatment option.
Annals of the rheumatic diseases 09/2011; 70(11):2003-7. · 8.11 Impact Factor
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ABSTRACT: To assess the impact of certolizumab pegol (CZP) on patient-reported outcomes (PROs) in rheumatoid arthritis (RA), and to interpret these results using number needed to treat (NNT), and associations between PRO responses and longer term outcomes.
A total of 619 patients with active RA were randomised to CZP 200 or 400 mg, or placebo plus methotrexate (MTX). PROs assessed included pain, patient's global assessment of disease activity (PtGA), physical function, fatigue and health-related quality of life. Treatment impact on PROs, NNT to achieve simultaneous improvements in multiple PROs and correlations between PROs were calculated. Times to onset of improvements greater than or equal to minimum clinically important differences (MCIDs) in pain as a determinant of clinical outcomes at week 24 were compared between week 6 and 12 responders, and in patients with improvements in pain ≥ MCID at week 12 (week 12 responders/non-responders).
CZP 200 and 400 mg plus MTX were associated with rapid, clinically meaningful improvements in all PROs. The NNT for subjects to report changes ≥MCID in up to five PROs was two to three, and five for all six PROs (pain, PtGA, physical function, fatigue and short-form 36-item Physical and Mental Component Summary Scores). More patients with improvements ≥MCID in pain at week 6 than those at week 12 had lower disease activity at week 24. Week 12 pain responders had better clinical outcomes at week 24 than non-responders.
The data demonstrate that CZP provides broad relief from the burden of RA. Trial registration number NCT00160602.
Annals of the rheumatic diseases 03/2011; 70(6):996-1002. · 8.11 Impact Factor
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Michael Schiff
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ABSTRACT: Significant advances in our understanding of RA and its management have been made in the past decade, resulting in earlier intervention with biologic DMARDs, particularly in patients with evidence of aggressive, erosive disease. Here, one such biologic therapy, the T-cell co-stimulation modulator abatacept, is discussed, exploring clinical evidence published to date on its use in patients with very early arthritis/early RA who are MTX naïve, and in patients with established RA and an inadequate response to MTX or TNF antagonists. Data from relevant clinical trials are overviewed, discussing the clinical efficacy of abatacept in early disease, the clinical outcomes over long-term treatment in different patient populations and the effects of abatacept on structural damage. Findings from integrated safety analyses of abatacept clinical trial data, representing 10,366 patient-years of exposure are described, and clinically important safety events, including serious infections, malignancies and autoimmune events, are highlighted. It is concluded that abatacept represents an effective treatment option with an established safety profile across different patient populations, including patients with both early and erosive RA and those with established disease. Furthermore, efficacy data from studies in patients with early disease suggest that the risk-benefit profile of abatacept may be more favourable when introduced earlier in the treatment paradigm.
Rheumatology (Oxford, England) 09/2010; 50(3):437-49. · 4.24 Impact Factor
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ABSTRACT: This study evaluated the platelet inhibitory effects of low-dose enteric-coated aspirin (EC-ASA) when used concomitantly with maximum over-the-counter (OTC) doses of naproxen sodium (NAPSO) or acetaminophen to determine whether NAPSO and acetaminophen interfere with the anti-platelet effect of aspirin.
Phase I, randomized, open-label, multi-dose, three-period, parallel group, pharmacodynamic trial conducted in healthy male and female volunteers (n = 47 randomized subjects and n = 37 evaluable subjects), mean age 40.2 years. All subjects received 5 days of EC-ASA 81 mg once daily followed by 5 days of EC-ASA 81 mg once daily alone or co-administered with either NAPSO 220 mg three times daily or acetaminophen 1 g four times daily. Primary outcome measure: Inhibition of serum thromboxane B(2) (TXB(2)), as a marker of platelet cyclooxygenase-1 (COX-1) inhibition, measured on Day 11.
Mean inhibition of TXB(2) on Day 11 was >99% for subjects taking EC-ASA alone as well as for those who received EC-ASA co-administered with NAPSO or acetaminophen. For subjects taking EC-ASA monotherapy, mean serum TXB(2) inhibition was 99.7% (range 99.0-100%), for those taking EC-ASA with acetaminophen it was 99.6% (range 98.3-99.9%), and for those taking EC-ASA with NAPSO, mean serum TXB(2) inhibition was 99.7% (range 99.2-100%). STUDY LIMITATION: Small sample size and open-label trial design.
The anti-platelet effect of EC-ASA 81 mg once daily was maintained following its co-administration with maximum OTC doses of NAPSO or acetaminophen.
Current Medical Research and Opinion 06/2010; 26(6):1497-504. · 2.38 Impact Factor
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ABSTRACT: Prescription dose naproxen has been reported to have an antiplatelet effect similar to low-dose aspirin (ASA). This study evaluated the platelet inhibitory effects of over-the-counter (OTC) doses of naproxen sodium (NAPSO) compared to that of a prescription dose of NAPSO and to low-dose enteric-coated aspirin (EC-ASA).
This was a phase I, open-label, randomized, placebo-controlled, two-way crossover, multi-dose, pharmacodynamic trial conducted in healthy male and female volunteers (n = 48, mean age = 41.7 years). All subjects received 7 days of either prescription dose NAPSO (550 mg twice daily), OTC doses of NAPSO (220 mg two or three times daily), or placebo twice daily (period 1). After a minimum 6-day washout period, all subjects then received 7 days of EC-ASA 81 mg once daily (period 2). All study medications were taken by mouth.
Inhibition of serum thromboxane B(2) (TXB(2)), as a marker of platelet cyclooxygenase-1 (COX-1) inhibition, measured 24 h after the day 7 morning dose. This was measured after both period 1 and period 2.
After 7 days of treatment in period 1, mean inhibition of TXB(2) was 47% for placebo and > or =98% for all doses of NAPSO. After 7 days of EC-ASA 81 mg, mean inhibition of TXB(2) was > or = 97% (period 2).
Out-patient study setting.
These data suggest that OTC doses of NAPSO (220 mg two or three times daily) have an antiplatelet effect similar to EC-ASA 81 mg and to prescription dose NAPSO (550 mg twice daily).
Current Medical Research and Opinion 09/2009; 25(10):2471-7. · 2.38 Impact Factor
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ABSTRACT: This analysis examined clinical and radiographic responses to methotrexate (MTX), etanercept (ETN), and combination ETN and MTX in patients with moderate versus severe rheumatoid arthritis (RA) in both early and late disease.
Data from the Trial of Etanercept and Methotrexate With Radiographic Patient Outcomes (TEMPO) and the Early Rheumatoid Arthritis trials were used. Patients were classified with moderate or severe RA based on Disease Activity Score including 28-joint count (DAS28). Outcomes included DAS28 remission, DAS28 low disease activity, Health Assessment Questionnaire (HAQ), American College of Rheumatology (ACR) scores, Total Sharp Score (TSS) progression, no radiographic progression (annualized change in TSS > or = 0), change from baseline in TSS, and the change in TSS for patients who had radiographic progression (TSS > 0).
Patients with moderate disease generally achieved better clinical outcomes than patients with severe disease, including significant differences in DAS28 remission, low disease activity, and HAQ < or =0.5 at Month 12. Patients with baseline severe disease had higher ACR and DAS responses than patients with moderate disease.
Patients with severe RA disease activity achieved substantial clinical improvement with high-dose MTX and/or ETN treatment, but patients with moderate disease were more likely to reach a lower disease activity state. These findings were independent of disease duration. The results support the opportunity for excellent clinical outcomes, particularly with combination therapy, in patients with moderate RA.
The Journal of Rheumatology 03/2009; 36(3):522-31. · 3.69 Impact Factor
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ABSTRACT: To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year, randomised, placebo-controlled, double-blind phase, followed by an open-label, long-term extension (LTE).
Patients continued etanercept (25 mg twice weekly) and were randomised to receive abatacept 2 mg/kg (n = 85) or placebo (n = 36). As the effective dose of abatacept was established as 10 mg/kg in a separate trial, all patients received abatacept 10 mg/kg and etanercept during the LTE.
A total of 121 patients were randomised; 80 completed double-blind treatment and entered the LTE. During double-blind treatment, the difference in the percentage of patients achieving the primary end point (modified American College of Rheumatology (ACR) 20 response at 6 months) was not significant between groups (48.2% v 30.6%; p = 0.072). At 1 year, no notable changes in modified ACR responses were observed. Subsequent to the dosing change, similar modified ACR responses were seen during the LTE. Significant improvements in quality of life were observed with abatacept and etanercept versus placebo and etanercept in five of the eight short-form 36 subscales at 1 year. More abatacept and etanercept-treated patients experienced serious adverse events (SAEs) at 1 year than patients receiving placebo and etanercept (16.5% v 2.8%), with 3.5% v 0% experiencing serious infections.
The combination of abatacept (at a dose of 2 mg/kg during the double-blind phase and 10 mg/kg during the LTE) and etanercept was associated with an increase in SAEs, including serious infections, with limited clinical effect. On the basis of the limited efficacy findings and safety concerns, abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment.
Annals of the Rheumatic Diseases 03/2007; 66(2):228-34. · 8.73 Impact Factor
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Josef S Smolen,
Chenglong Han,
Désirée van der Heijde,
Paul Emery,
Joan M Bathon,
Edward Keystone,
Joachim R Kalden, Michael Schiff,
Mohan Bala,
Daniel Baker,
John Han,
Ravinder N Maini,
E William St Clair
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ABSTRACT: To evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis (RA).
Methotrexate (MTX)-naive patients with active early RA were randomly allocated to receive MTX plus placebo or MTX plus infliximab (3 mg/kg or 6 mg/kg) at weeks 0, 2, and 6 and then every 8 weeks through week 46. Data for patients younger than age 65 years were included in the analyses. A patient was categorized as employable if he or she was employed or felt well enough to work if a job were available.
The change in actual employment was not significantly different between patients receiving MTX plus infliximab and those receiving MTX plus placebo (0.5% versus 1.3%; P > 0.5). However, the proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the group receiving MTX plus infliximab compared with that in the group receiving MTX alone (8% versus 14%; P = 0.05). Patients who were treated with infliximab plus MTX had a significantly greater likelihood of improvement rather than deterioration in employability (odds ratio 2.4; P < 0.001); this likelihood was not significantly greater in patients receiving MTX alone. The proportion of employed patients who lost workdays during the trial was smaller in the MTX plus infliximab group than in the MTX-alone group (P = 0.010).
The actual employment rates among patients in the 2 treatment groups were not different. However, patients with early RA who were treated with MTX plus infliximab had a higher probability of maintaining their employability compared with those who were treated with MTX alone.
Arthritis & Rheumatism 04/2006; 54(3):716-22. · 7.87 Impact Factor
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Josef S Smolen,
Désirée M F M Van Der Heijde,
E William St Clair,
Paul Emery,
Joan M Bathon,
Edward Keystone,
Ravinder N Maini,
Joachim R Kalden, Michael Schiff,
Daniel Baker,
Chenglong Han,
John Han,
Mohan Bala
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ABSTRACT: To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX.
Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54.
C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX-only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (> or = 3 mg/dl) and ESR (> or = 52 mm/hour) tertiles in the MTX-only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS > or = 10.5) showed less progression with infliximab plus MTX compared with MTX alone (-0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab.
High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.
Arthritis & Rheumatism 04/2006; 54(3):702-10. · 7.87 Impact Factor
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ABSTRACT: In a phase 2 study, to assess the efficacy and safety of pegsunercept, a soluble tumor necrosis factor receptor type I, for the treatment of rheumatoid arthritis (RA).
Patients were randomized to receive weekly subcutaneous injections of placebo (n = 61) or active drug [400 microg/kg (n = 67) or 800 microg/kg (n = 66)] for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. Secondary efficacy measures included ACR50 and ACR70 responses, and changes in individual ACR components at Week 12. Safety assessments included summaries of adverse events including infectious episodes.
Treatment with pegsunercept resulted in a significantly higher ACR20 response at Week 12 in the 800 microg/kg group (45%) compared with the placebo group (26%; p = 0.020). The treatment effect of pegsunercept (both doses) over the study period showed statistically significant improvement for most ACR components and health related quality of life, with the 800 microg/kg group showing greater clinical improvements in efficacy measures. The overall incidence of adverse events and infectious episodes was similar among the treatment and placebo groups.
In this 12 week dose-finding study of 194 patients, weekly subcutaneous dosing with pegsunercept showed beneficial effects in improving the signs and symptoms of RA. It appeared to be safe and well tolerated in this small number of patients. Significant clinical improvements were seen in patients in the 800 microg/kg group; however, this dose may be suboptimal, and further evaluation of this product with higher doses or a more frequent dosing regimen is warranted.
The Journal of Rheumatology 01/2006; 32(12):2303-10. · 3.69 Impact Factor
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Mark C Genovese,
Jean-Claude Becker, Michael Schiff,
Michael Luggen,
Yvonne Sherrer,
Joel Kremer,
Charles Birbara,
Jane Box,
Kannan Natarajan,
Isaac Nuamah,
Tracy Li,
Richard Aranda,
David T Hagerty,
Maxime Dougados
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ABSTRACT: A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy.
Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed.
After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group.
Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.
New England Journal of Medicine 10/2005; 353(11):1114-23. · 53.30 Impact Factor
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Désirée van der Heijde,
Herbert S B Baraf,
Cesar Ramos-Remus,
Andrei Calin,
Arthur L Weaver, Michael Schiff,
Margaret James,
Jan E Markind,
Alise S Reicin,
Agustin Melian,
Maxime Dougados
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ABSTRACT: To assess the efficacy, safety, and tolerability of etoricoxib, a cyclooxygenase 2 (COX-2) selective inhibitor, administered continuously over 52 weeks for the treatment of ankylosing spondylitis (AS).
This 2-part, multicenter, double-blind, parallel-group, 52-week study evaluated 2 doses of etoricoxib (90 and 120 mg) compared with naproxen at 1,000 mg. A 6-week, active-comparator- and placebo-controlled period (part I) was followed by a 46-week active-comparator-controlled period (part II). The primary outcome measures (on 100-mm visual analog scales) were patient's assessment of spine pain, patient's global assessment of disease activity, and the Bath Ankylosing Spondylitis Functional Index.
Of the 387 patients randomized to receive treatment, 301 (77.8%) completed part I and 284 (75.9%) completed part II. Compared with placebo over 6 weeks, those receiving 90 mg etoricoxib, 120 mg etoricoxib, and naproxen demonstrated significantly (P < 0.001) greater improvement in all primary end points; treatment effects (expressed as the difference in least squares mean change versus placebo) were 21-29 mm for spine pain, 18-25 mm for disease activity, and 11-15 mm for function. Compared with patients receiving naproxen, significantly greater improvement in all primary end points was demonstrated in the combined group receiving either 90 mg etoricoxib or 120 mg etoricoxib over 6 weeks, in each individual etoricoxib treatment group over 6 weeks, and in the combined etoricoxib group over 1 year (all P < 0.05); results for secondary and exploratory end points were generally consistent with those from the primary analysis. Among all groups, there were no significant differences in the incidence of overall clinical, drug-related, or serious adverse experiences (AEs) and discontinuations due to AEs. Safety observations during part II were generally consistent with those in part I.
Etoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy compared with placebo over 6 weeks, and compared with naproxen over 1 year. These study results demonstrate that etoricoxib is generally safe, well-tolerated, and efficacious for the treatment of AS.
Arthritis & Rheumatism 04/2005; 52(4):1205-15. · 7.87 Impact Factor
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ABSTRACT: To assess the effects of treatment with prasterone (dehydroepiandrosterone) on bone mineral density (BMD) in female patients with mild to moderate systemic lupus erythematosus (SLE) receiving chronic treatment with glucocorticoids.
Fifty-five female patients with SLE who had received prednisone (or glucocorticoid equivalent) </= 10 mg/day for >/= 6 months were treated for 1 year with either prasterone 200 mg/day (n = 24) or placebo (n = 31) in this randomized, double blind trial. Prasterone or placebo was added to each patient's one or more concomitant standard SLE medications, including glucocorticoids, nonsteroidal antiinflammatory drugs, antimalarials, methotrexate, azathioprine, and other immunosuppressives, which were to be maintained at fixed doses for the duration of the study.
BMD was significantly improved in patients who received prasterone compared to placebo. At the lumbar spine, there was a mean (SEM) gain in BMD of 1.7 +/- 0.8% in the prasterone group compared to a mean loss in BMD of -1.1 +/- 0.5% in the placebo group (p = 0.003 between groups). For the total hip, mean gain was 2.0 +/- 0.9% in the prasterone group vs a mean loss of -0.3 +/- 0.4% in the placebo group (p = 0.013 between groups). In the prasterone treatment group, the mean gains from baseline at both lumbar spine and hip were statistically significant.
Prasterone treatment prevented BMD loss and significantly increased BMD at both the lumbar spine and total hip in female patients with SLE receiving exogenous glucocorticoids.
The Journal of Rheumatology 04/2005; 32(4):616-21. · 3.69 Impact Factor
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E William St Clair,
Désirée M F M van der Heijde,
Josef S Smolen,
Ravinder N Maini,
Joan M Bathon,
Paul Emery,
Edward Keystone, Michael Schiff,
Joachim R Kalden,
Ben Wang,
Kimberly Dewoody,
Roberta Weiss,
Daniel Baker
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ABSTRACT: To compare the benefits of initiating treatment with methotrexate (MTX) and infliximab (anti-tumor necrosis factor alpha [anti-TNFalpha] monoclonal antibody) with those of MTX treatment alone in patients with rheumatoid arthritis (RA) of < or =3 years' duration.
RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor. One thousand forty-nine patients were randomly assigned in a 4:5:5 ratio to 3 treatment groups: MTX-placebo, MTX-3 mg/kg infliximab, and MTX-6 mg/kg infliximab. MTX dosages were rapidly escalated to 20 mg/week, and infliximab or placebo infusions were given at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46.
At week 54, the median percentage of American College of Rheumatology improvement (ACR-N) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group (38.9% and 46.7% versus 26.4%, respectively; P < 0.001 for both comparisons). Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone (mean +/- SD changes in van der Heijde modification of the total Sharp score at week 54: 0.4 +/- 5.8 and 0.5 +/- 5.6 versus 3.7 +/- 9.6, respectively; P < 0.001 for each comparison). In addition, physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group. Infliximab therapy was associated with a significantly higher incidence of serious infections, especially pneumonia.
For patients with active RA in its early stages, combination therapy with MTX and infliximab provides greater clinical, radiographic, and functional benefits than treatment with MTX alone.
Arthritis & Rheumatism 11/2004; 50(11):3432-43. · 7.87 Impact Factor
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ABSTRACT: To compare the analgesic efficacy and safety of nonprescription doses of naproxen sodium, ibuprofen, and placebo in patients with osteoarthritis (OA) of the knee.
In 2 identical multicenter, randomized, double-blind, placebo-controlled, multidose, parallel-design studies, patients aged > or = 25 years with OA were randomized to daily doses of naproxen sodium 660 mg, naproxen sodium 440 mg (patients > or = 65 years), ibuprofen 1200 mg, or placebo, for 7 days.
For investigator and patient assessment of knee joint pain, naproxen sodium (440/660 mg) and ibuprofen were clinically effective at relieving pain compared with placebo (n = 444); both treatments reduced the mean symptom score by 30-45%, compared with a 20-25% reduction with placebo. Naproxen sodium (440/660 mg) significantly improved all 7 symptoms from baseline compared with placebo, while ibuprofen significantly improved 5 of the symptoms. For the subgroup of patients aged > or = 65 years (n = 183), naproxen sodium 440 mg was significantly superior to placebo in all symptoms except pain on weight-bearing; ibuprofen only significantly reduced day pain. For daily diary evaluations, naproxen sodium and ibuprofen were effective in reducing all 6 symptoms; there was a trend toward higher efficacy for night-time pain with naproxen sodium 440/660 mg compared with ibuprofen. There were no significant differences in adverse event reporting between groups.
Over-the-counter doses of naproxen sodium (440/660 mg) and ibuprofen (1200 mg) effectively relieve pain in patients with mild to moderate OA of the knee. Naproxen sodium provided more effective pain relief for most variables compared with placebo, and for night pain compared with ibuprofen. Efficacy was combined with good safety and tolerability.
The Journal of Rheumatology 07/2004; 31(7):1373-83. · 3.69 Impact Factor
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Michael Schiff
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic disease with diverse and fluctuating manifestations. Because no single variable fully captures disease activity or severity, clinical trials of antirheumatic drugs typically employ composite indices, such as the American College of Rheumatology (ACR) core criteria, to assess disease status. Drug effects (as demonstrated with these indices) are usually assessed at discrete time points, which may obscure information about the time of onset or duration of improvements. An alternative methodology is the use of summary measurements based on area under the curve (AUC) analyses of disease activity. For these analyses, response is plotted over time, and the area under the response curve is calculated. Because disease variables are quantified over time, AUC measures summarize the therapeutic effects during the entire course of the trial or treatment course. Trials of RA agents have used AUC-based calculations in data analyses.
We examined the use of summary AUC measurements for the assessment of the effects of antirheumatic therapies.
Results provided by summary measurements from studies identified by a MEDLINE search (years, 1990-2002; search terms, rheumatoid arthritis, clinical trial, American College of Rheumatology, disease activity, and radiographic progression) were evaluated to assess the relevance of AUC analyses in the determination of disease activity.
Results from these trials suggest that summary AUC measurements produce more precise treatment-effect estimates and are more sensitive than end-of-study data to differences between slower and more rapidly acting agents. Some research suggests that AUC analyses may be more stable and more sensitive to interpatient differences than other measures. AUC measures based on numeric ACR scores have been used successfully to determine treatment effects over time.
Summary measurements are more sensitive to treatment differences than single-time-point assessments and should be considered for use in future RA clinical trials.
Clinical Therapeutics 04/2003; 25(3):993-1001. · 2.32 Impact Factor
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Daniel E Furst,
Kenneth Saag,
M Roy Fleischmann,
Yvonne Sherrer,
Joel A Block,
Thomas Schnitzer,
Joel Rutstein,
Andrew Baldassare,
Jeffrey Kaine,
Leonard Calabrese, [......], Michael Schiff,
C Michael Stein,
Yoichi Satoi,
Alan Matsumoto,
Jacques Caldwell,
Robert E Harris,
Larry W Moreland,
Eric Hurd,
David Yocum,
David A Stamler
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ABSTRACT: To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA).
This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes.
ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1-23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3-39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7-46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8-62.3%) (P < or = 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation > or =40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41-59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose tacrolimus groups (31-33%). Discontinuation for creatinine elevation occurred in the 3 mg (3.1%) and 5 mg (10.9%) tacrolimus groups.
Tacrolimus improved disease activity in methotrexate-resistant or -intolerant patients with RA. A dose response was observed when efficacy and toxicity were assessed at different doses. The optimal dose of tacrolimus appears to be >1 mg but < or=3 mg daily.
Arthritis & Rheumatism 09/2002; 46(8):2020-8. · 7.87 Impact Factor
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ABSTRACT: To evaluate whether treatment with prasterone (dehydroepiandrosterone [DHEA]) would allow the dosage of prednisone (or an equivalent corticosteroid) to be reduced to < or = 7.5 mg/day for 2 months or longer while maintaining stable or reduced disease activity in steroid-dependent women with systemic lupus erythematosus (SLE).
In a double-blind, randomized trial, 191 female SLE patients receiving prednisone (10-30 mg/day) were treated daily with either placebo, 100 mg of oral prasterone (an adrenal androgen), or 200 mg of oral prasterone for 7-9-months. At monthly intervals, corticosteroid dosages were reduced by algorithm in patients whose SLE Disease Activity Index (SLEDAI) score was stable or improved. Patients for whom a sustained reduction in the dosage of prednisone (< or = 7.5 mg/day) was achieved for at least the last 2 months of the 7-9-month treatment period were classified as responders.
Response rates were 41% in the placebo group, 44% in the 100-mg prasterone group, and 55% in the 200-mg group (P = 0.110, 200 mg versus placebo). Among the 137 subjects (45 in the placebo group, 47 in the 100-mg group, and 45 in the 200-mg group) who had active disease at baseline (defined as SLEDAI score >2), 29%, 38%, and 51%, respectively, were responders (P = 0.031 for 200 mg prasterone versus placebo). Acne was the most common adverse event but was generally mild. Clinical and laboratory changes primarily reflected androgenic effects of prasterone.
Among women with lupus disease activity, reducing the dosage of prednisone to < or = 7.5 mg/day for a sustained period of time while maintaining stabilization or a reduction of disease activity was possible in a significantly greater proportion of patients treated with oral prasterone, 200 mg once daily, compared with patients treated with placebo.
Arthritis & Rheumatism 08/2002; 46(7):1820-9. · 7.87 Impact Factor
