Clinical Trial Result Information

Protocol number
MF 4380

Title of Study
Efficacy and safety of long-term, intermittent iv ibandronate treatment in women with postmenopausal osteoporosis.

Sponsor
Roche Global Development

Company division
Pharmaceutical

Product name
Bonviva/Boniva

Generic name
ibandronate

Therapeutic area
Post-Menopausal Osteoporosis

Clinical study summary
This was a 3-year, multicenter, double-blind, randomized, placebo-controlled study. Patients were randomized to one of the following treatment groups:

1. 0.5mg Bonviva iv once every 3 months
2. 1.0mg Bonviva iv once every 3 months
3. Placebo iv once every 3 months

Patients received the study medication as an iv bolus injection once every 3 months for 3 years

Study center(s)
68 centers in Belgium, Canada, Czech Republic, Denmark, France, Germany, Netherlands, Norway, Poland, UK, United States

Phase of development
III

Objectives
To investigate the long-term efficacy and safety of Bonviva administered iv once every 3 months to postmenopausal osteoporotic women.

Methodology
Clinical assessments were performed at baseline and at regularly scheduled intervals for the safety and efficacy parameters. Patients were scheduled for study visits every 3 months up to month 36. Lateral radiographs of the thoraco-lumbar spine were performed at the screening visit to determine the presence of prevalent fractures. Thereafter, radiographs were performed annually for the assessment of incident fractures. Bone mineral density was measured using Dual Energy X-ray Absorptiometry (DEXA). Measurements were made of the lumbar spine (L₁-L₄), the proximal femur, and the non-dominant distal forearm.

Number of patients (planned/analyzed)
A total of 2860 patients were enrolled.

Diagnosis and main criteria for inclusion
Women aged ≥55 years and ≥5 years since menopause with postmenopausal osteoporosis: bone mineral density in ≥1 vertebra of the lumbar spine (L₁-L₄) between -2.0 and -5.0 standard deviations (SD) T-score, and with 1-4 prevalent vertebral fractures.

Test product, dose and mode of administration or test procedure
Bonviva (ibandronate) iv 0.5 mg. or 1.0 mg once every 3 months. All patients received oral doses of calcium (500 mg/day) and vitamin D (400 IU/day) as dietary supplements.

Duration of treatment
3 years.

Reference therapy, dose and mode of administration or reference procedure
Placebo iv.

Criteria for evaluation (efficacy, safety)
The primary efficacy variable was the rate of patients with new incident vertebral fractures at 3 years of treatment with the study medication. Secondary variables included: number of new vertebral fractures per patient; clinical vertebral fractures; other clinical fractures; BMD; urinary calcium; CTX and NTX excretion; osteocalcin, bone-specific isotype of alkaline phosphatase and PTH concentration; height; pain; and disability.

Statistical methods
Analysis of the primary efficacy variable was performed using the life-table survival method. Analyses of time-to-event for clinical vertebral fractures and for effect of treatment on osteoporotic non-vertebral fractures used Kaplan Meier survival analysis and log-rank tests to evaluate pairwise differences between treatment groups. Unpaired t-tests were used for the comparison of treatment groups, based primarily on the 3-year visit, for absolute and relative change in BMD. Confidence intervals for the pair-wise comparisons were used to assess differences between all groups. An ANOVA was used to investigate the treatment effect on the relative and absolute 3-year BMD changes, adjusting for baseline BMD as a covariate.

Summary (efficacy, safety, other results)
Efficacy: This study failed to achieve a statistically and medically significant reduction in the primary endpoint of new morphometric vertebral fracture reduction over 3 years. The cumulative incidence of new vertebral fractures at 3 years in the ITT and PP populations was numerically lower for both Bonviva groups relative to placebo. After 3 years of treatment, the incidence of new vertebral fractures was 10.7%, 8.7%, and 9.2% for the placebo, 0.5 mg and 1.0 mg groups respectively, for the ITT population, and this difference did not reach statistical significance. The risk of having multiple vertebral fractures was statistically and medically significantly reduced in both Bonviva groups compared with placebo, however the number of patients who experienced multiple fractures was small. Clinical osteoporotic fractures (all clinical fractures including vertebral, but excluding those of skull, face, hands, and feet) were numerically lower in patients treated with Bonviva, but did not differ significantly from placebo. Significant, dose-dependent increases of BMD in the lumbar spine and hip, and in two regions of the forearm were observed in both Bonviva-treated groups when compared to placebo. Urinary NTX and CTX, serum BSAP and osteocalcin (biochemical markers of bone turnover) were significantly reduced in a dose-dependent pattern by Bonviva treatment.

Safety: No safety concerns were identified and Bonviva treatment was well tolerated. The most frequently reported adverse events were upper respiratory infection, accidental injury, back pain, arthralgia, and osteoporotic fracture, and these events were reported in a similar proportion of patients in each group. Adverse events reported with a ≥1% higher incidence in both active treatment groups compared with the placebo group included myalgia, sinusitis, headache, joint disorder, asthenia, and injection site reactions. A somewhat higher proportion of patients in the 1.0 mg Bonviva group withdrew from treatment due to adverse events compared with the other groups: 8%, 9%, and 12%, in the placebo, 0.5 mg, and 1.0 mg groups, respectively. The most common adverse events leading to withdrawal from treatment were osteoporotic fractures and myalgia. Serious adverse events were reported by a similar proportion of patients in all treatment groups. A total of 38 patients died during the study; 29 of these patients died while on treatment: 11, 7, and 11 patients in the placebo, 0.5 mg and 1.0 mg groups, respectively. There were no clinically significant changes from baseline in any laboratory variable for each of the 3 treatment groups.

Conclusions
The results indicate that 1.0 mg Bonviva administered intravenously every 3 months was suboptimal for the treatment of postmenopausal osteoporosis. No safety concerns were identified and the treatment was well tolerated.

Date of report
5/1/2002