Clinical Trial Result Information

Title of Study:
Randomized, Double-Blind, Double-Dummy, Parallel Groups, Multi-Center Study to Compare the Efficacy and Safety of Monthly Oral Administration of 100 mg and 150 mg Ibandronate with 2.5 mg Daily Oral Ibandronate in Post-Menopausal Osteoporosis; Year 2 Analysis

Fast Facts:

Protocol number:	BM16549
Sponsor:	F Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	Bonviva/Boniva
Generic name:	ibandronate
Phase of development:	III
Therapeutic area, approved indication:	Postmenopausal osteoporosis
Date of report:	9/29/2005

Clinical study summary:
This randomized double-blind, double-dummy, parallel-group, multi-center study was designed to compare the efficacy, safety and tolerability of monthly treatment with100mg and 150mg oral Bonviva (ibandronate) with daily treatment using 2.5mg oral Bonviva in patients with post-menopausal osteoporosis. All medications were taken for a total of 24 months.

Study center(s) :
This study was conducted in the United States, Canada, Italy, Denmark, the United Kingdom, Poland, South Africa, France, Brazil, Australia, Switzerland, Belgium, the Czech Republic, Hungary, Norway, and Romania

Objectives:
(1) To demonstrate non-inferiority of lumbar spine bone mineral density (BMD) changes of oral Bonviva 100 mg and 150 mg using monthly dosing regimens versus an active control, oral Bonviva 2.5 mg daily; and (2) To assess the overall tolerability and safety of the treatment regimens.

Methodology:
Patients were randomly allocated in a double-blind manner to 1 of 4 treatment groups (2.5 mg/day, 50/50 mg/month, 100 mg/month, 150 mg/month) and stratified to 1 of 3 strata (BMD T-score < –2.5 and ≥ –3.0, < –3.0 and ≥ –3.5, < –3.5 and ≥ –5.0). All patients received daily with calcium (500 mg) and vitamin D (400 IU) supplementation. Lumbar spine (L2-L4) and proximal femur BMD measured by dual-energy X-ray absorptiometry at baseline and after 1 and 2 treatments were read at a central reading center. Samples for serum c-telopeptide of a -chain of type I collagen (CTX) and bone-specific alkaline phosphatase (BSAP) were collected at baseline and at 3, 6, 12, and 24 months. Adverse events (AEs) were recorded continuously, and laboratory tests for safety were conducted at baseline and at Months 3, 6, 9, 12, 18, and 24.

Number of patients (planned/analyzed):
1609 randomized; 1602 received treatment:

Diagnosis and main criteria for inclusion:
Women 55–80 years of age with post-menopausal osteoporosis ≥5 years after menopause; measurable BMD of spine and hip; mean lumbar spine BMD (L2-L4) T-score < –2.5 and ≥ –5.0; ambulatory and not anticipated to become hospitalized, immobilized, or bedridden during the trial.

Test product, dose and mode of administration or test procedure:
Bonviva 50mg tablets: 100mg (50mg/day on 2 consecutive days/po/monthly and daily oral placebo; 100mg (2x50mg/day taken on single day/po/monthly and daily oral placebo; 150mg (3x50mg/day taken on single day/po/monthly and daily oral placebo.

Duration of treatment:
24 months.

Reference therapy, dose and mode of administration or reference procedure:
Bonviva 2.5mg tablets: 2.5mg/po/daily and monthly oral placebo

Criteria for evaluation (efficacy, safety):
Primary efficacy parameter: Relative change from baseline at 1 year in mean lumbar spine (L2-L4) BMD.

Secondary efficacy parameters: (1) Relative change from baseline at 2 years in mean lumbar spine (L2-L4) BMD (confirmatory analysis); (2) Absolute change from baseline at 1 and 2 years in mean lumbar spine (L2-L4) BMD; (3) Relative and absolute changes from baseline at 1 and 2 years in mean proximal femur BMD; (4) Percentage of BMD responders; and (5) Relative and absolute changes in serum CTX.

Safety: (1) AEs; and (2) Laboratory tests.

Statistical methods:
To determine non-inferiority, a 1-sided 97.5% confidence interval (CI) of the difference of the means between each of the 3 oral dose regimens and the active control, oral Bonviva 2.5 mg daily regimen, was constructed using an analysis of variance model. Monthly dosing regimens were considered as comparable (as judged by non-inferiority) to the 2.5-mg daily regimen if the lower bound of the 1-sided 97.5% CI was ≥ –1 percentage point at Year 1. The primary analysis was based on the per-protocol population after 1 year of treatment; however, all analyses were repeated for the intent-to-treat population to demonstrate the robustness of the results. A confirmatory analysis was performed on data after 2 years of treatment using the same analysis. The non-inferiority level was set at –1.3 percentage points.

Summary (efficacy, safety, other results):
Efficacy – This study met its primary objective, to show non-inferiority of lumbar spine (L2-L4) BMD changes after 1 year of treatment with oral Bonviva at monthly doses of 100 mg and 150 mg vs daily treatment with 2.5 mg Bonviva. For the lumbar spine, the mean increase in BMD relative to baseline in all monthly treatment groups (4.0%–4.8%) at 1 year was shown to be non-inferior to the 2.5-mg daily regimen (3.7%).

Relative Change (%) in Lumbar Spine (L2-L4) BMD (Per-Protocol Population: Year 1 and Year 2 Analysis)

During Year 2 of the study, mean lumbar spine BMD increased further in the monthly (5.3%–6.6%) and daily (5.0%) treatment groups, and the increase in the monthly treatment groups was shown to be non-inferior to that in the daily treatment group. The greatest increase in lumbar spine BMD after 1 and 2 years of treatment was seen in the 150-mg monthly Bonviva group.

For the 150-mg monthly treatment group only, this increase was shown to be superior to that seen in the 2.5-mg daily treatment group after 1 and 2 years of treatment. Furthermore, in a post hoc analysis, the mean increase in lumbar spine BMD after 1 and 2 years of treatment with 150-mg monthly Bonviva was superior to that seen with 100-mg monthly doses of Bonviva.

At the proximal femur, clinically meaningful increases from baseline in total hip (2.0%–3.0%), femoral neck (1.7%–2.2%), and trochanter (3.2%–4.6%) BMD after 1 year of treatment with Bonviva were seen with both the daily and monthly treatment regimens. After 2 years of treatment, BMD in the total hip (2.5%–4.2%), femoral neck (1.9%–3.1%), and trochanter (4.0%–6.2%) had increased further in all treatment groups. Increases in BMD at all hip sites in all monthly treatment groups after 1 and 2 years of treatment were greater than the increase in the daily treatment group, with the 150-mg monthly treatment group showing the greatest increase at all 3 sites. For the total hip and trochanter, this increase in BMD in the 100-mg and 150-mg monthly treatment groups was shown to be superior to that in the 2.5-mg daily treatment group after 1 and 2 years of treatment and was also superior for the increase in femoral neck BMD after 2 years of treatment.

The robust and substantial increase in lumbar spine and proximal femur BMD in the 150-mg monthly treatment group was confirmed during Year 2, when compared with the 100-mg monthly and 2.5-mg daily treatment groups.

After 1 and 2 years of treatment, significantly more patients treated with monthly doses of 150 mg than with daily doses of 2.5 mg Bonviva responded to treatment with an increase in BMD values ³ baseline at the lumbar spine. After 2 years of treatment, significantly more patients treated with monthly doses of 100 mg and 150 mg Bonviva than with daily doses of 2.5 mg Bonviva responded to treatment with an increase in BMD values ³ baseline at the femoral neck. After 1 and 2 years of treatment, significantly more patients treated with monthly doses of 100 mg or 150 mg Bonviva than with daily doses of 2.5 mg Bonviva responded to treatment with an increase in BMD values ³baseline at the total hip and trochanter. Irrespective of the definition, consistently more patients in the 150-mg monthly treatment group than in the other treatment groups responded to treatment at all BMD measurement sites. Similarly, for both the 100-mg and 150-mg monthly treatment groups, significantly more patients responded to treatment with an increase in lumbar spine BMD of ³6% or an increase in total hip BMD of ³3% after both 1 and 2 years of treatment than in the 2.5-mg daily treatment group.

Bone resorption was suppressed after 3 months of treatment with all dosing regimens, as assessed by serum CTX. Values appeared to reach a nadir at 6 months and remained suppressed throughout the 2 years of the trial. At all times points, the decrease in serum CTX was greater in the 150-mg monthly treatment group compared with the other groups. Significantly more patients in the 150-mg monthly group responded to treatment after 1 and 2 years with a decrease in serum CTX from baseline of ?50% or ?70% than in the daily treatment group.

 Time Course of Relative Change (%) in Serum CTX (Per-Protocol Population)

As observed for serum CTX, all dosing regimens of Bonviva decreased serum BSAP as a consequence of the coupling phenomenon observed with bone turnover. As expected for a marker of bone formation, the nadir of effect was observed from 6 months of treatment onward. Consistent with that seen for serum CTX, the greatest decrease in BSAP was observed in the 150-mg monthly Bonviva treatment group at all time points, and values reached a plateau of approximately 35%–40% (median decrease), indicating that the normal physiologic balance of resorption and formation is preserved.

Time Course of Relative Change (%) in Serum BSAP (Per-Protocol Population)

21600,21600">Safety – After both 1 and 2 years of treatment, the nature and frequency of AEs were similar in all 4 treatment groups and there were no differences of note with regard to deaths, serious or severe/life-threatening AEs, premature withdrawals for AEs, or laboratory test values. In particular, there were no differences among treatment groups in terms of upper gastrointestinal AEs. Thus, the AE profile seen after 2 years of treatment with daily or monthly Bonviva confirms the findings reported after 1 year of treatment.

An exploratory analysis investigated a cluster of various symptoms of =7 days’ duration that occurred within 3 days of monthly dosing (“acute-phase reaction-like symptoms”). Symptoms were reported in all 4 treatment groups, primarily after the first dose, and were typically of short duration and of mild to moderate intensity. The incidence of these events was higher in the monthly treatment groups and most frequent in the 150-mg monthly treatment group (9.1% compared with 7.1%, 7.6%, and 3.0% in the 50/50 mg monthly, 100-mg monthly, and 2.5-mg daily groups, respectively). This difference was mainly attributable to the higher rate of “acute-phase reaction” and “influenza-like illness” in the 150-mg monthly treatment group. As expected, very few new cases with acute-phase reactant–like symptoms were reported across all treatment groups during Year 2 of the study. Of note is that only 1 additional patient in each monthly treatment group reported an “influenza-like illness” during the course of Year 2.

Over the 2 years of the study, 112 of 1593 patients (7.0%) experienced a clinical fracture defined as a symptomatic radiologically confirmed fracture, including all vertebral and non-vertebral fractures. This incidence is similar to that reported with alendronate 70 mg once-weekly (7.3%) in a comparable population of patients.

Although data after 1 year of treatment showed a numerical imbalance in the number of clinical fractures reported as AEs between the daily treatment group (2.5%) and the monthly treatment groups (3.3%–4.8%), this was no longer the case after 2 years of treatment (2.5 mg daily, 6.6%; 50/50 mg monthly, 8.1%; 100 mg monthly, 6.3%; 150 mg monthly, 7.3%). These results support the concept that the imbalance seen after 1 year of treatment was due to a lower than expected rate of osteoporotic non-vertebral fractures in the daily treatment group. Indeed, after 2 years of treatment, rates for non-vertebral osteoporotic fractures were no higher in the monthly treatment groups (2.8%–4.5%) than in the daily treatment group (4.1%). The overall incidence of all non-vertebral fractures was no higher in the monthly treatment groups (5.1%–6.6%) than in the daily treatment group (5.1%), and slightly lower than that reported with risedronate 35 mg once weekly (8.5%) in a comparable population of patients.

No clinically relevant changes were seen in the laboratory safety parameters. In particular, there was no indication that treatment with monthly doses of 50/50 mg, 100 mg, or 150 mg Bonviva or daily dosing with 2.5 mg Bonviva led to clinically significant decreases in renal or hepatic function, or to decreases in serum calcium or magnesium.

Conclusions:
The increase in lumbar spine BMD in women with post-menopausal osteoporosis receiving monthly doses of 100 mg and 150 mg Bonviva for 1 and 2 years was shown to be non-inferior to that seen with daily doses of 2.5 mg Bonviva. After 1 and 2 years of treatment, there was a robust and substantial increase in BMD at the lumbar spine, total hip, trochanter, and femoral neck with all monthly doses, which was consistently greater than that seen with the daily regimen, and consistently greatest in the 150-mg monthly treatment group. The increase in lumbar spine BMD in the 150-mg monthly treatment group was superior to that in the 2.5-mg daily treatment group and 100-mg monthly treatment group after 1 and 2 years of treatment.

Significantly more patients responded to treatment in terms of BMD increases and a reduction in bone resorption in the 100-mg and 150-mg monthly treatment groups than in the 2.5-mg daily treatment group after 1 and 2 years of treatment, with patients in the 150-mg monthly treatment group consistently showing the greatest and most consistent response. Taking into consideration that BMD, bone turnover, and responder rates were consistently higher with the monthly dose of 150 mg compared with 100 mg, the 150-mg Bonviva dose appears to provide more patients with an optimal BMD level, which has been shown to further decrease the risk of vertebral fractures.

Over the duration of the study, all monthly doses of Bonviva were well tolerated and the safety profile was similar to that seen in the daily treatment arm. In particular, monthly dosing did not appear to be associated with an increase in upper gastrointestinal AEs or with a deterioration of renal function. Although the incidence of either “acute phase reaction” or “influenza-like illness” was slightly higher in the 150-mg monthly treatment group, each was easily manageable, related to the first dose, decreased with repeated dosing, and rarely led to discontinuation of trial treatment. Thus, no safety-related factors were identified that would mitigate against any of the 3 monthly regimens studied, and particularly against the 150-mg monthly Bonviva dose.

On balance, the monthly dose of 150-mg Bonviva is the most beneficial of the doses tested. This dose offers a more consistent and clinically meaningful benefit to women with post-menopausal osteoporosis, while the risk appears to be no greater than that seen with the other monthly doses or with daily dosing.

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