Farhad Sedarati

Once-monthly oral ibandronate compared with weekly oral alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study

ABSTRACT Objective: Oral ibandronate 150 mg is the first bisphosphonate approved for once-monthly treatment of postmenopausal osteoporosis. To investigate whether once-monthly ibandronate 150 mg increases lumbar spine and total hip bone mineral density (BMD) to the same degree as weekly alendronate 70 mg. Research design and methods: This was a 12-month, randomised, multinational, multicentre, double-blind, double-dummy, parallel-group, non-inferiority trial, conducted in 65 centres in North America, Latin America, Europe and South Africa. The study included postmenopausal women, mean lumbar spine (L2–L4) BMD T-score < −2.5 and ≥−5.0. Patients received either ibandronate 150 mg once monthly or alendronate 70 mg once weekly. Main outcome measures: Co-primary efficacy endpoints were 12-month change (%) from baseline in mean lumbar spine and total hip BMD. Changes (%) from baseline in trochanter and femoral neck BMD were also evaluated. Adverse events were monitored throughout. Once-monthly ibandronate was considered non-inferior to weekly alendronate if the lower boundary of the one-sided 97.5% confidence interval (CI) (or two-sided 95% CI) was ≥ −1.41% for lumbar spine and ≥−0.87% for total hip. Results: Mean relative 12-month changes were 5.1% and 5.8% (95% CI for difference, −1.13, −0.23) in lumbar spine and 2.9% and 3.0% (95% CI for difference, −0.38, 0.18) in total hip BMD with once-monthly ibandronate and weekly alendronate, respectively; meeting the non-inferiority criteria at both sites. Gains in trochanter and femoral neck BMD were similar with both treatments. Both regimens were well tolerated. Trial registration: The MOTION study is registered with the International Federation of Pharmaceutical Manufacturers and Associations trial portal, under the ID number MM17385. Conclusions: Once-monthly ibandronate was shown to be clinically comparable to weekly alendronate at increasing BMD after 12 months in both the lumbar spine and total hip.

Twelve weeks of follow-up is sufficient for the determination of sustained virologic response in patients treated with interferon α for chronic hepatitis C

BACKGROUND/AIMS The current standard for the determination of sustained virologic response in patients treated for hepatitis C is undetectable hepatitis C virus (HCV) RNA 24 weeks following the completion of therapy. Sensitive molecular tests may permit earlier determination of sustained virologic response following the completion of therapy in end-of-treatment responders. METHODS We examined this possibility in 1441 patients, who received 48 weeks of treatment with either standard or pegylated interferon alpha-2a. HCV RNA was determined by polymerase chain reaction assay (Amplicor HCV Monitor vs. 2.0) at baseline and monitored at 4-week intervals throughout the treatment and 24-week post-treatment follow-up periods. RESULTS End-of-treatment and sustained response were achieved in 624 and 342 patients, respectively. For all treatments, relapse was most frequent at weeks 52 and 56 and became rare following week 60. Only six patients out of 348 patients (2%) became HCV RNA positive between weeks 60 and 72. Analysis of baseline characteristics failed to identify a specific set of parameters associated with early relapse. CONCLUSIONS This finding suggests that determination of HCV RNA levels at 12 weeks of follow-up may be sufficient for making decisions related to the management of most patients treated with standard or pegylated interferon alpha.

Assessment, by Transcription-Mediated Amplification, of Virologic Response in Patients with Chronic Hepatitis C Virus Treated with Peginterferon α-2a

ABSTRACT Transcription-mediated amplification (TMA) is an isothermal, autocatalytic target amplification method which has the potential to detect less than 50 hepatitis C virus (HCV) RNA copies/ml (10 IU/ml). The TMA assay was used to assess the presence of residual HCV RNA in plasma from patients treated with polyethylene glycol-modified interferon α-2a (peginterferon α-2a) who showed a virologic relapse after the end of therapy. Stored end-of-treatment and end-of-follow-up plasma samples from 177 of 267 patients treated with peginterferon α-2a (S. Zeuzem et al., N. Engl. J. Med. 343:1666–1672, 2000) were available for retesting by TMA. Plasma samples from patients in the same study who exhibited virologic relapse after treatment with standard interferon α-2a served as controls. Virologic response during the trial was defined as HCV RNA that was undetectable using a PCR-based test system with a sensitivity of 50 IU/mL (Cobas Amplicor HCV version 2.0) and was compared with TMA-based retesting results (VERSANT HCV RNA Qualitative Assay). Residual HCV RNA was detected in 4 of 60 cases (7%) by the TMA technology in end-of-treatment plasma samples from patients who relapsed after receiving peginterferon α-2a and in 6 of 18 patients (33%) following therapy with standard interferon α-2a. For peginterferon α-2a-treated patients with sustained virologic response, HCV RNA was detectable by TMA in end-of-treatment samples in 3 of 78 cases but in none of the end-of-follow-up samples. For all end-of-treatment and end-of-follow-up plasma samples of virologic nonresponders, a complete concordance between the PCR-based assay and TMA was observed. In conclusion, in patients with virologic relapse after the end of therapy, according to PCR, who were treated with peginterferon α-2a or standard interferon α-2a, residual HCV RNA was detectable in end-of-treatment samples by the TMA-based assay in 7 or 33% of cases, respectively. The lower rate of residual HCV RNA detection by TMA for patients treated with peginterferon α-2a than that for patients treated with standard interferon α-2a may be due to the maintained antiviral pressure of the long-acting peginterferon α-2a at the end-of-treatment visit.

Efficacy and tolerability of once-monthly oral ibandronate (150 mg) and once-weekly oral alendronate (70 mg): additional results from the Monthly Oral Therapy With Ibandronate For Osteoporosis Intervention (MOTION) study.

BACKGROUND The MOTION (Monthly Oral Therapy with Ibandronate for Osteoporosis Intervention) study reported that once-monthly ibandronate was noninferior to once-weekly alendronate in terms of increasing bone mineral density (BMD) at the lumbar spine and total hip over 12 months. On analysis of secondary and exploratory end points in MOTION, which included trochanter and femoral neck BMD, monthly ibandronate was found to be noninferior to weekly alendronate. The coprimary, secondary, and exploratory BMD end points from MOTION have been previously reported. OBJECTIVE This report presents additional results from the MOTION study, including response rates in terms of lumbar spine and total hip BMD gains above baseline; findings from a comparison of serum concentrations of bone turnover markers; and tolerability analysis, including adverse events that led to withdrawal and gastrointestinal (GI) adverse events. METHODS MOTION was a 12-month (with 15-day follow-up), randomized, multinational, multicenter, double-blind, double-dummy, parallel-group, noninferiority study in postmenopausal women aged 55 to <85 years with osteoporosis. Patients were randomly assigned to receive 150-mg-monthly oral ibandronate and weekly alendronate-matched placebo, or 70-mg-weekly oral alendronate and monthly ibandronate-matched placebo, for 12 months. At baseline, day 7 of treatment, 3 and 6 months, 6 months + 7 days, and 12 months, serum concentrations of markers of bone resorption (C-telopeptide of the a chain of type 1 collagen [sCTX]) and bone formation (serum N-terminal propeptides of type 1 collagen) were measured in a subset of the total trial population. At baseline and month 12, BMD was measured using dual-energy x-ray absorptiometry. Exploratory analyses of patients whose spine, total hip, and trochanter BMD at 12 months were above baseline (responders) were also performed. RESULTS A total of 1760 women were enrolled (ibandronate, 887 patients; alendronate, 873). The median changes in the trough concentrations of sCTX were -75.5% with monthly ibandronate and -81.2% with weekly alendronate. The percentage of patients with mean lumbar spine and total hip BMD gains above baseline (responders) were 90% and 87%, respectively, for ibandronate and 92% and 90%, respectively, for alendronate. GI adverse events were reported in <or=30% of patients per group during this 1-year study. CONCLUSION The data from these postmenopausal women with osteoporosis suggest that once-monthly 150-mg ibandronate therapy provided clinically comparable efficacy in terms of BMD response, reductions in bone turnover, and GI tolerability similar to that of weekly 70-mg alendronate.

Efficacy and safety of monthly oral ibandronate in the prevention of postmenopausal bone loss.

INTRODUCTION Monthly oral ibandronate has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with osteoporosis, but its efficacy has not been investigated in women with low bone mass. The objective of this study was to examine the efficacy and safety of monthly oral ibandronate (150 mg) treatment in postmenopausal women with low bone mass. METHODS This 1-year, double-blind, placebo-controlled, randomized study enrolled ambulatory postmenopausal women aged 45-60 years with baseline lumbar spine (LS) BMD T-score<-1.0 and >-2.5 and baseline T-score>-2.5 at the total hip, trochanter, and femoral neck (collectively defined as the proximal femur) and no prior vertebral or low-trauma osteoporotic fractures at baseline. Subjects received either 150 mg monthly oral ibandronate or placebo. All subjects received calcium and vitamin D supplements. The primary endpoint was the relative change from baseline (%) in mean LS BMD at 1 year (intent-to-treat population). Treatment groups were compared by means of a two-way ANOVA model which adjusted for independent factors including treatment group, baseline LS BMD T-score, and time since menopause. Responder analyses examined the percentage of participants with changes from baseline in LS BMD and proximal femur BMD>or=0%. Adverse events and safety laboratory parameters were monitored continuously. RESULTS A total of 77 women received monthly ibandronate and 83 women received placebo. Subjects treated with ibandronate achieved larger increases in LS BMD after 1 year compared with subjects receiving placebo (3.7% vs -0.4% [difference of 4.1%, p<0.0001]). After 3 months, median serum C-terminal telopeptide of type I collagen levels were reduced by >55% in the ibandronate group compared with approximately 4% in the placebo group. At 1 year, 88.2% of the participants treated with ibandronate achieved increases in LS BMD>or=0% compared with 38.6% of subjects receiving placebo. Treatment regimens were well tolerated in both the ibandronate-treated and placebo groups. CONCLUSION Monthly ibandronate therapy prevents bone loss in postmenopausal women with low bone mass.