Comparison of the effects of once-monthly versus once-daily risedronate in postmenopausal osteoporosis: a phase II, 6-month, multicenter, randomized, double-blind, active-controlled, dose-ranging study.

BACKGROUND: Risedronate 5 mg/d is approved by the US Food and Drug Administration for the treatment and prevention of postmenopausal osteoporosis. Once-monthly dosing options might increase treatment compliance and persistence. OBJECTIVE: The aim of this study was to compare the tolerability and efficacy of 3 once-monthly risedronate dosing regimens with those of risedronate 5 mg/d. METHODS: This Phase II, 6-month, randomized, double-blind, active-controlled, dose-ranging study was conducted at 13 clinical research centers and hospitals in Croatia, Poland, Canada, and the United States between April 2004 and June 2005. Post-menopausal women aged 50 to 85 years with a lumbar spine T-score <-2.0 were randomly assigned to 1 of 4 treatment groups: risedronate 100, 150, or 200 mg/mo or 5 mg/d (active control), administered PO for 6 months. Evaluation of tolerability, the primary study objective, was based on adverse-event (AE) profiles and clinical laboratory values. Efficacy evaluation, a secondary objective, was a noninferiority comparison of the changes from baseline in bone mineral density (BMD) and bone turnover markers (BTMs). RESULTS: Of 370 patients randomized (91, 88, 88, and 103 patients in the risedronate 100-, 150-, and 200-mg/mo and 5-mg/d groups, respectively), 57% were > or =65 years of age and 99% were white; 316 patients (85.4%) completed the study. Completion rates were not significantly different across treatment groups, nor were reasons for discontinuation. Between-group differences in the incidences of treatment-emergent AEs, serious AEs, and upper gastrointestinal (GI) AEs were nonsignificant. Overall, 6 (7%), 14 (16%), 6 (7%), and 9 patients (9%) withdrew because of AEs in the 100-, 150-, and 200-mg/mo and 5 mg/d groups, respectively. GI disorders were the AEs that most frequently led to study withdrawal (5 [5.5%], 7 [8.0%], 4 [4.5%], and 6 [5.8%]). No trends were observed in the nature or frequency of other AEs causing withdrawal. All serious AEs were considered unrelated to treatment, with the exception of erosive esophagitis in 1 patient (1%) who received the 5-mg/d dose. Mean percentage increases in BMD were 2.10%, 2.99%, and 3.38% with risedronate 100, 150, and 200 mg/mo, respectively, versus 3.05% with 5 mg/d. At the 2 higher monthly doses, the changes from baseline in BMD were not significantly different from those in the 5-mg/d group. Mean BTM values were decreased significantly from baseline in all 4 treatment groups, and the changes from baseline at 6 months at the 2 higher monthly doses were not significantly different from those at 5 mg/d. CONCLUSIONS: Overall, in this study, the safety profiles of risedronate 100, 150, and 200 mg/mo were not different from that of risedronate 5 mg/d. Changes in efficacy measures in the monthly treatment groups were considered dose related and were not significantly different between the 5-mg/d group and the 150- and 200-mg/mo groups; similarity was greatest with 150 mg/mo.

Monthly dosing with risedronate 50 mg on three consecutive days a month compared with daily dosing with risedronate 5 mg: a 6-month pilot study.

OBJECTIVE: Risedronate 5 mg daily significantly reduces the incidence of vertebral and non-vertebral osteoporotic fractures in postmenopausal women. We compared the efficacy and tolerability of risedronate 50 mg administered on 3 consecutive days per month, with and without a loading dose, with those of risedronate 5 mg daily in a randomized, double-blind study. METHODS: Subjects were postmenopausal women 65-80 years old with low bone mineral density (BMD) (T-score < or = -2). Subjects received risedronate 5 mg daily for 6 months (n = 48), risedronate 150 mg (50-mg doses on 3 consecutive days) monthly for 6 months (n = 50), or a loading dose of risedronate 15 mg daily for 1 month followed by 150 mg (50-mg doses on 3 consecutive days) monthly for 5 months (n = 52). RESULTS: Within 1 week, statistically significant reductions in urine N-telopeptide, the primary efficacy measure, were observed in all three groups. After 6 months, the least squares (LS) mean differences (95% confidence intervals [CI]) from the change in the 5 mg daily group (-39.88) were -3.54% (-15.71; 8.64) for the 150 mg monthly and -2.02% (-14.13;10.10) for the loading dose + 150 mg monthly groups. Mean percent changes in serum alpha-C-telopeptide, bone-specific alkaline phosphatase, and BMD, secondary efficacy measures, after 6 months were also similar for the three groups. The LS mean differences (95% CI) from the mean percent change in BMD in the 5 mg daily group (3.22%) were 0.20 (-1.15; 1.55) for the 150 mg monthly and -0.58 (-1.93; 0.76) for the loading dose + 150 mg monthly groups. The safety profile of the monthly regimens was similar to that of the 5 mg daily regimen and consistent with product labeling. CONCLUSIONS: A monthly regimen of risedronate 50 mg on 3 consecutive days per month was similar to risedronate 5 mg daily with respect to its effect in suppressing bone turnover and increasing BMD and its safety profile in women with postmenopausal osteoporosis. This study was not powered to be a confirmatory trial for non-inferiority; therefore, additional study is needed.

The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial.

OBJECTIVE: To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease-modifying antirheumatic drugs (DMARDs), including biologic agents. METHODS: A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10-25 mg/week); no other DMARDs were permitted. RESULTS: Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (-1.79, -2.05, -0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo. CONCLUSION: Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.