Clinical Trial Result Information
Protocol number
MM17385
Title of Study
A randomized, double-blind, double-dummy, parallel-group, multicenter study to compare the efficacy and safety of once monthly oral administration of 150mg ibandronate with once weekly oral administration of 70mg alendronate in postmenopausal osteoporosis - a non-inferiority tral.
Sponsor
Hoffmann-La Roche Ltd
Company division
Pharmaceutical
Product name
Bonviva/Boniva
Generic name
ibandronate
Therapeutic area
Post-Menopausal Osteoporosis
Clinical study summary
This was a randomized, double-blind, double-dummy, parallel-group trial. Eligible patients with postmenopausal osteoporosis were randomly assigned to one of two treatment groups to receive monthly Bonviva (ibandronate) or weekly alendronate.
Study center(s)
84 centers in Argentina, Belgium, Brazil, Denmark, France, Germany, Hungary, Norway, Poland, Russia, South Africa, Spain, United Kingdom and United States.
Phase of development
III
Objectives
Primary: To investigate if a monthly dose of 150mg Bonviva was able to increase bone mineral density (BMD) at the lumbar spine and at the total hip to the same degree as a weekly dose of 70mg alendronate after 12 months of treatment.
Secondary: To compare the increase of BMD at the trochanter after treatment with a monthly dose of 150mg Bonviva and a weekly dose of 70mg alendronate after 12 months of treatment, and to assess the overall tolerability and safety of both regimens.
Methodology
Randomized patients were to be treated for 12 months. Efficacy was evaluated by taking BMD scan images at 12 months, which were assessed by the central reading center and compared with the respective baseline values. Blood samples for biochemical markers of bone turnover, serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) concentrations, were taken at baseline, and at intervals up to at least 3 weeks after month 12 dosing. Safety information was collected throughout the treatment phase and also during the 15-day post-treatment follow-up period.
Number of patients (planned/analyzed)
1760 randomized, 1733 treated.
Diagnosis and main criteria for inclusion
Ambulatory women of 55 to 84 years of age and at least 5 years after menopause with postmenopausal osteoporosis and a mean lumbar spine BMD (L2 to L4) T-score of <-2.5 and ≥-5.0 at screening.
Test product, dose and mode of administration or test procedure
150mg Bonviva (ibandronate) administered orally once monthly and alendronate placebo administered orally once weekly.
Duration of treatment
12 months
Reference therapy, dose and mode of administration or reference procedure
70mg alendronate administered orally once weekly and Bonviva placebo administered orally once monthly.
Criteria for evaluation (efficacy, safety)
Efficacy: Primary: Relative changes (%) from baseline in mean lumbar (L2 to L4) BMD and total hip BMD at 12 months.
Secondary: Absolute changes (g/cm2) from baseline in mean lumbar spine (L2 to L4) BMD and total hip BMD at 12 months; relative (%) and absolute changes (g/cm2) in trochanter BMD at 12 months from the baseline value; relative and absolute changes from baseline in serum CTX and P1NP in a subset (30%) of the total population at baseline, 3 months, 6 months and 12 months.
Safety: Adverse events and laboratory abnormalities.
Statistical methods
This was a non-inferiority trial. To determine whether the Bonviva monthly treatment regimen was non-inferior to the alendronate weekly treatment regimen, a one-sided 97.5% confidence interval of the mean difference of the relative change in lumber spine (L2 to L4) BMD and total hip BMD at 12 months from baseline between the monthly Bonviva dose regimen and the weekly alendronate regimen was constructed. The monthly Bonviva dosing regimen was to be considered non-inferior to the weekly alendronate regimen if the lower bound of the one-sided 97.5% confidence interval was greater than or equal to -1.41 percentage point for the lumbar spine BMD and -0.87 percentage point for the total hip BMD. Analyses of two-sided 95% confidence intervals were presented for the clinical study report. These provide a lower bound equal to that of a one-sided 97.5% confidence interval.
Summary (efficacy, safety, other results)
Efficacy: The primary efficacy parameters, namely the relative changes in mean lumbar spine (L2 to L4) BMD and total hip BMD at 12 months from baseline, were both improved. The two-sided 95% confidence interval of the difference in mean lumbar spine BMD changes at 12 months from baseline between Bonviva and alendronate was ( -1.13%,-0.23%) in the per-protocol population and (-1.12%,-0.27%) in the intent to treat population, for which the lower bounds were greater than the non-inferiority level of -1.41%. The two-sided 95% confidence interval of the difference in the total hip BMD changes at 12 months from baseline between Bonviva and alendronate was (-0.38%, 0.18%) in the per-protocol population and (-0.43%, 0.10%) in the intent-to-treat population, for which the lower bounds were greater than the non-inferiority level of -0.87%. Therefore, the null hypothesis of the statistical model was rejected and it was concluded that the monthly 150mg Bonviva treatment regimen was non inferior to the weekly 70mg alendronate treatment regimen in the patient population evaluated.
Additional analyses for the primary efficacy endpoint (relative change in lumbar spine and total hip BMD at 12 months from baseline) were performed as confirmatory tests in order to assess the robustness of the primary analysis. The results of all the additional analyses of the primary efficacy endpoints support the conclusion of the primary efficacy analysis, ie, the monthly 150mg Bonviva treatment regimen is statistically comparable (non-inferior) to the weekly 70mg alendronate treatment regimen in patients with postmenopausal osteoporosis.
As a secondary efficacy parameter, the relative change (%) in trochanter BMD at month 12 from baseline was also consistent with the primary efficacy endpoints, with an increase of 4.2% in both treatment arms, suggesting a similar clinical effect of Bonviva and alendronate at the proximal hip.
The serum CTX and P1NP were sampled at multiple time points. In both treatment arms and at almost all sampling time points, the concentrations of serum CTX and P1NP decreased (the relative changes from baseline were negative), suggesting inhibition of bone turnover.
The pre-dose (residual) levels of sCTX and P1NP assessed immediately before dosing at months 3, 6, and 12 were substantially lower at month 3 compared with baseline and this reduction was sustained over the period of 12 months with both treatments. The median reduction from baseline to different pre-dose time points in serum CTX was 68% to75% in patients treated with Bonviva, compared with 82% to 83% in patients treated with alendronate. Median relative pre-dose reduction in P1NP concentration was also very similar between treatment arms at all times points; 58% to 68% in the Bonviva arm and 59% to 67% in the alendronate arm.
The post-dose levels of both sCTX and P1NP were assessed 7 days after the first dosing and 7 days after the month 6 monthly dosing. Rapid and more pronounced reduction in the resorption marker sCTX was observed after the first dose with Bonviva compared with alendronate (by 85% and 48%, respectively), while post-dose reductions at month 6 were very similar for Bonviva (88%) and alendronate (85%). There were almost no effects seen on P1NP with either treatment 7 days after the first dose, while similar post-dose reductions in P1NP were seen with Bonviva (67%) and alendronate (68%) 7 days after month 6.
Safety: Following 12 months of study treatment, the overall incidence of adverse events was comparable between the Bonviva- and alendronate-treated patients (75.4% vs. 73.6%). The body systems most affected were the same for the two groups, namely, gastrointestinal disorders, musculoskeletal and connective tissue disorders, infections, and nervous system disorders. The incidence of some frequent adverse events associated with gastrointestinal symptoms, including upper abdominal pain, nausea, gastritis, and abdominal pain, showed a lower incidence in the Bonviva arm than in the alendronate arm.
The incidence of “acute phase reaction-like symptoms” was higher in the monthly Bonviva treatment regimen (6.8%) than in the weekly alendronate treatment regimen (3.0%). The most common events were influenza-like illness (2.4%) and myalgia (1.6%) in the Bonviva arm compared with 0.5% and 0.7% reported respectively in the alendronate arm. These ‘acute phase reaction-like symptoms’ were usually reported during the first 2 months of treatment and infrequently reported during months 3 to 12, the vast majority were mild or moderate in severity, most were considered related to the study drug and all resolved without sequalae.
Fewer patients experienced serious adverse events in the Bonviva arm (4.5%) than in the alendronate arm (6.4%). Specifically, the incidence of serious gastrointestinal disorders, serious nervous system disorders and serious hepatobiliary disorders was lower in the Bonviva-treated patients.
The incidence of clinical fractures during the trial was balanced in the two groups (Bonviva 3.1% vs. alendronate 2.7%) as was the incidence of clinical osteoporotic fractures (2.1% in the Bonviva group vs. 2.0% in the alendronate group), clinical osteoporotic vertebral fractures (0.6% in each arm) and non-vertebral fractures (1.6% with Bonviva and 1.4% with alendronate), suggesting that both treatments could have similar clinical efficacy for clinical osteoporotic fractures.
There were 6 deaths reported during the trial (4 in the alendronate arm and 2 in the Bonviva arm), which were mainly caused by cardiovascular disorders, common in the population studied.
No clinically relevant laboratory test value abnormalities were seen. There was no evidence suggesting that the monthly Bonviva treatment regimen led to clinically significant changes in renal or hepatic functions or serum electrolyte concentrations as compared with the weekly alendronate treatment regimen.
Conclusions
The monthly 150mg Bonviva treatment regimen was non-inferior to the weekly 70mg alendronate treatment regimen in improving the lumbar spine and total hip BMD following 12 months of therapy in women with post-menopausal osteoporosis. Trochanter hip BMD increases as well as reductions in bone turnover markers were similar with both treatments.
The safety profile including incidence of clinical fractures was comparable between monthly 150mg Bonviva and weekly 70mg alendronate treatment regimens. No new safety signals of clinical significance were identified.
Date of report
5/1/2007
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