Roche trials database

Protocol number:

BA18492

Title of Study:

Double-blind, placebo-controlled, randomized, multicenter study to assess the efficacy and safety of oral ibandronate once monthly in postmenopausal women with osteopenia.

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

ibandronate [Bonviva/Boniva]

Generic name:

ibandronate

Therapeutic area:

• Post-Menopausal Osteopenia

Clinical study summary:

This was a double-blind, randomized, placebo-controlled, multicenter study investigating the efficacy and safety of 1 year of treatment with 150 mg once monthly oral Boniva (ibandronate) in the prevention of bone loss in postmenopausal osteopenic women. After a screening period of up to 2 months, eligible subjects were randomized into one of two treatment groups and received active study medication or corresponding placebo, respectively. Patients randomized to Group A received 150 mg Boniva orally once monthly. Patients randomized to Group B received a matching placebo tablet orally once monthly. Subjects received 12 months of treatment and were followed for an additional period of 15 days.

Study center(s):

10 centers in United States

Phase of development:

IV

Objectives:

The objectives were to investigate the efficacy and safety of 1 year of treatment with 150 mg once monthly oral Boniva in the prevention of bone loss in postmenopausal osteopenic women using the relative change from baseline in mean lumbar-spine bone mineral density (BMD) as the primary endpoint.

Methodology:

Randomized subjects were treated with monthly oral Bonviva for 12 months and followed for an additional 15 days. Efficacy was evaluated by BMD measurements at the lumbar spine and proximal femur at screening and at month 12. BMD assessments were carried out by a central laboratory. Blood samples for the biochemical marker of bone turnover, sCTX, were collected in the morning while subjects were in a fasting state. Serum CTX was analyzed centrally at baseline and months 3, 6, and 12. Safety information was collected throughout the treatment phase and during the 15-day post-treatment follow-up period. Clinical vertebral and non-vertebral fractures that occurred during the study were reported as adverse events and assessed as part of safety information (and not as efficacy information). All fractures were confirmed by a radiograph and documented with a radiologist's report. Safety laboratory tests were done at screening and at months 3, 6, and 12.

Number of patients (planned/analyzed):

160 enrolled and treated

Diagnosis and main criteria for inclusion:

Postmenopausal women ambulatory at the beginning of the trial, between the ages of 45 and 60 years old, with baseline mean lumbar spine BMD T-score <-1.0 and >-2.5 (L2-L4) and, baseline proximal femur (total hip, trochanter, femoral neck) BMD T-score >-2.5.

Test product, dose and mode of administration or test procedure:

Once-monthly, single tablet of Boniva (ibandronate) 150 mg administered orally.

Duration of treatment:

12 months

Reference therapy, dose and mode of administration or reference procedure:

Placebo, single tablet administered orally.

Criteria for evaluation (efficacy, safety):

Primary: Relative change (%) from baseline in mean lumbar spine (L2-L4) BMD at 12 months of treatment.
Secondary: Absolute change (g/cm²) from baseline in mean lumbar spine (L2-L4) BMD at month 12; relative (%) and absolute (g/cm²) change in mean BMD from baseline in proximal femur (total hip, trochanter, femoral neck) at month 12; percent responders defined as: subjects with mean lumbar spine BMD above or equal to baseline at month 12, subjects with proximal femur BMD above or equal to baseline at month 12, subjects with both lumbar spine and proximal femur BMD above or equal to baseline at month 12; and relative (%) and absolute (ng/mL) change from baseline sCTX at months 3, 6, and 12.
Safety: Adverse events and laboratory test parameter abnormalities

Statistical methods:

The statistical null hypothesis tested after 12 months of treatment was:
H⁰ (null hypothesis): There was no statistically significant difference between monthly treatment with 150 mg oral Boniva and monthly treatment with placebo in relative change from baseline of mean lumbar spine (L2-L4 BMD).
H¹ (alternative hypothesis): There was a statistically significant difference between monthly treatment with 150 mg oral Boniva and monthly treatment with placebo in relative change from baseline of mean lumbar spine (L2-L4 BMD).
Treatment groups were compared by means of an ANOVA model including independent factors for treatment group and time since menopause (defined as a binary variable; 0.5 to 3.0 years and >3.0 years) and the individual baseline L2-L4 BMD T-Score.

Summary (efficacy, safety, other results):

Efficacy: Both the primary and secondary efficacy endpoints of the study were met. The study demonstrated that treatment with oral Boniva at a dose of 150 mg per month for 12 months increased mean BMD at the lumbar spine (L2-L4) and all three proximal femur sites. In addition, reductions in bone turnover, a valuable predictor of fracture risk, were observed with this 12-month Boniva dosing regimen.
The primary efficacy parameter, the relative (%) change from baseline at 12 months in mean BMD of the lumbar spine (L2-L4), was met. In the intent-to-treat population, at 12 months of treatment there was a statistically significant treatment effect (4.12%, p<0.0001) in favor of Boniva compared with placebo. Relative change from baseline at 12 months in mean BMD of the lumbar spine (L2-L4) was an increase of 3.73% for subjects treated with Boniva and was a decrease of -0.39% for subjects treated with placebo.
The robustness of the study results was further tested by sensitivity checks and additional analyses on the primary efficacy parameter. These included the evaluation of the results in the per protocol population and the effect of eliminating the adjustment for time since menopause as a stratification factor. The results from these additional analyses supported the conclusion of the primary efficacy analysis that the monthly 150-mg Bonviva treatment regimen prevented bone loss in postmenopausal osteopenic women.
Results for all secondary efficacy endpoints also favored treatment with Boniva over treatment with placebo, thus, lending further support to the results of the primary efficacy analysis. These secondary efficacy endpoints included absolute (g/cm²) change from baseline at 12 months in mean BMD of the lumbar spine (L2-L4), relative (%) change from baseline at 12 months in mean BMD of the proximal femur (total hip, trochanter, femoral neck), and relative (%) change from baseline at months 3, 6, and 12 in median sCTX.

Safety: A relatively healthy subject population was enrolled in this study. Adverse events were similar in the placebo and Boniva arms with respect to overall incidence (77% and 78%, respectively) and intensity (most events were mild to moderate in both arms, severe adverse events were experienced by 5% of subjects in the placebo group and 6% in the Boniva group).
The incidence of flu-like symptoms, eg, influenza-like illness, myalgia, arthralgia or nausea, typical for nitrogen containing bisphosphonates, were slightly higher in the Boniva treatment group, however, these events were generally mild to moderate in intensity, of short duration, and most were tolerated without requiring symptomatic interventions, dose modification or treatment withdrawal.
A higher percentage of treatment-related adverse events was observed in the Boniva arm (29%) than in the placebo arm (14%), this difference was mainly driven by influenza like illness and other adverse events attributable to the category “flu-like symptoms,” in Boniva treated subjects.
The incidence of treatment withdrawal for adverse events was slightly higher in Boniva subjects (7 patients, 9.1%) compared with placebo subjects (3 patients, 3.6%), mainly due to adverse events in the category of flu-like symptoms.
The incidence of clinical fractures was very low, with only 2 subjects in each group experiencing fractures. All fractures reported were associated with traumatic events.
There were no deaths during the study. None of the four serious adverse events (one in a placebo-treated subject and one in each of three Boniva-treated subjects) were considered by an investigator to be related to treatment.
There were no clinically relevant changes in mean hematology or clinical chemistry values. The majority of subjects in both treatment groups had values for all laboratory parameters at screening and during treatment that were within the respective reference ranges. No clinically relevant shift from baseline in laboratory test results were observed during the study. There was no evidence to suggest that monthly Boniva treatment led to clinically significant changes in renal or hepatic functions or serum electrolyte concentrations.

Conclusions:

Prevention of bone loss was demonstrated in postmenopausal osteopenic women who received an oral dose of 150 mg of Boniva once monthly for 12 months as assessed by the relative changes in mean BMD at the lumbar spine and proximal femur. There was a robust and statistically significant (p<0.0001) increase in BMD at the lumbar spine among subjects who received Boniva compared with those who received placebo. At 12 months of treatment, Boniva also significantly improved BMD of the proximal femur compared with baseline at all sites measured (total hip, trochanter, and femoral neck). These increases in BMD were accompanied by a sustained reduction in bone resorption marker sCTX in the Boniva-treated group but not in the placebo-treated group. As judged by comparison of subjects with increases in BMD at the lumbar spine and proximal femur (all sites combined and each site separately), the odds ratio for a response to treatment at month 12 favored Boniva-treated subjects over placebo-treated subjects.
The monthly doses of Boniva were well tolerated. With the expected exception of a greater incidence of flu-like symptoms among subjects treated with Boniva, the safety profile over time in this relatively healthy population was unchanged and similar in both treatment and placebo groups. No new safety-related issues were identified.

Publications (references, if available):

None

Date of report:

01.01.2008

Click here for the protocol registry listing of this trial.