Clinical Trial Result Information

Title of Study:
Multicenter, double-blind, placebo-controlled, randomized, dose-finding study on the efficacy and safety of ibandronate (BM 21.0955) during 2 years’ treatment in patients with postmenopausal osteoporosis using an intermittent (every 3 months) iv injection of 1 mg or 2 mg.

Fast Facts:

Protocol number:	MF 4470
Sponsor:	Roche Global Development
Company division:	Pharmaceutical
Product name:	Bonviva/Boniva
Generic name:	ibandronate
Phase of development:	II
Therapeutic area, approved indication:	Postmenopausal Osteoporosis
Date of report:	3/1/2002

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

1. 1 mg Bonviva .iv, once every 3 months
2. 2 mg Bonviva iv, once every 3 months
3. Placebo i., once every 3 months.

Patients received the study medication as an iv bolus injection once every 3 months for at least 1 year but for no more than 2 years (2 years initially planned for all patients).

This study was terminated prematurely by the sponsor following the outcome of another study, MF 4380, in women with postmenopausal osteoporosis. In that study, fracture reduction with quarterly doses of 0.5 and 1 mg ibandronate was suboptimal and the primary endpoint was not met. The sponsor decided, therefore, to terminate study MF 4470 in anticipation of a suboptimal result similar to that found in study MF 4380.

Study center(s) :
A total of 15 sites in Belgium, Denmark, France, Germany, Italy, Poland, Russia, UK

Objectives:
To investigate the efficacy, dose-response relationship and safety of two Bonviva doses given as intermittent intravenous (iv) administration in the long-term treatment of postmenopausal osteoporosis by using the relative change in lumbar spine BMD as the primary endpoint.

Methodology:
At the baseline visit (visit 1) patient received the first injection of Bonviva. Subsequent injections were administered at quarterly visits until the study was terminated. Efficacy and safety measures were taken according to the schedule of assessments. AEs were monitored continuously throughout the study.

Number of patients (planned/analyzed):
A total of 520 patients were randomized into the trial

Diagnosis and main criteria for inclusion:
Women aged 55-75 years, postmenopausal osteoporosis, time since last natural menstruation ≥5 years, mean lumbar spine BMD (L₁-L₄) < 2.5 T-score.

Test product, dose and mode of administration or test procedure:
1 or 2 mg Bonviva (ibandronate)/ iv bolus / quarterly

Duration of treatment:
12 months.

Reference therapy, dose and mode of administration or reference procedure:
Placebo / iv bolus / quarterly

Criteria for evaluation (efficacy, safety):
Efficacy: The primary efficacy variable was the relative change from baseline in BMD of lumbar spine (L₁-L₄) after 1 year of treatment.
Secondary efficacy parameters: BMD of proximal femur (total and subregions); relative change (from baseline and placebo) of BMD of proximal femur; total body bone mass and BMD of distal forearm; relative change (from baseline and placebo) in total body bone mass and BMD of distal forearm; height; change from baseline and placebo in rate of bone turnover; serum C-telopeptide (CTX) concentration; urinary CTX excretion; serum osteocalcin concentration.
Safety: The safety parameters monitored in this study were: AEs; renal and liver function; serum electrolyte concentrations; complete blood count (leukocytes and differential cell count); urinalysis.

Statistical methods:
The primary criterion for the evaluation of relative change in BMD was BMD of non-fractured vertebrae of the lumbar spine (L₁–L₄), defined as the sum of bone mass divided by the sum of area of all nonfractured vertebrae of the lumbar spine. The primary analysis of the change in lumbar spine BMD was performed on an ITT basis using the LVCF method for the 1-year treatment period. The pairwise comparisons of treatment effects were performed by the Wilcoxon rank sum test on a nominal level of α = 5%. In the analyses of the secondary efficacy variables, the BMD of all other sites was investigated as described for the primary variable. For biochemical markers of bone turnover, the same procedure was used. In the Bonviva groups, only measurements taken 2 - 4 months after an injection were included in the statistical evaluations.

Summary (efficacy, safety, other results):
Efficacy: The original primary efficacy variable in the protocol was relative change from baseline in BMD of lumbar spine (L₁-L₄) after 2 years of treatment. The study was terminated after all patients completed 1 year, therefore the analyses reported here include data gathered during the first year of the study. Despite the early termination, the 12-month data showed significant increases in BMD of lumbar spine (L₁-L₄), proximal femur and total body with Bonviva 1 mg and 2 mg compared to baseline. Bonviva 1 mg was less effective than 2 mg, but the increments observed were significant compared with placebo (i.e., lumbar spine BMD increased 5.0% in the 2-mg group, 2.8% in the 1-mg group with no change in the placebo group). Changes in BMD were associated with a significant reduction in both bone resorption and bone formation markers. After 12 months, there was a 62.5% reduction in the concentration of serum CTX, a 61.0% reduction in urinary CTX, and a 53.7% reduction in osteocalcin in the 2-mg group. The observed effects were more pronounced in the 2-mg group than in the 1-mg group.

Safety: The intravenous administration of Bonviva was well tolerated. Overall, the AE profile was similar in all three treatment groups. Upper respiratory infection, back pain, arthralgia, bronchitis, flu-syndrome, and headache were the most frequently reported AEs.
Acute phase reaction events were more frequent in the active treatment groups (23% in each active treatment group) than in the placebo group (14%). Flu syndrome and arthralgia were the most frequent APR events. Most patients experienced only a single event of this type; the number of patients experiencing multiple APR events was slightly higher in the 2.0 mg ibandronate group than in the other treatment groups.
A slightly higher percentage of patients in the 2.0 mg Bonviva (6%) withdrew from treatment than in the 1.0 mg Bonviva (3%) group and the placebo group (2%). A total of 44 patients (8%) experienced an SAE, with 9% in each Bonviva group and 6% in the placebo group reporting SAEs. Two patients (one in the placebo group and one in the 2.0 mg Bonviva group) died during the course of this study due to adverse events, which were not considered related to treatment.

Conclusions:
Bonviva given intermittently as an iv bolus injection was effective in increasing spine BMD as well as in reducing biochemical markers of bone turnover. Quarterly dosing for 1 year with 2 mg Bonviva resulted in an increase in spine BMD greater than that observed with 1 mg Bonviva: 5% vs. 3%, respectively. Quarterly dosing with 2 mg Bonviva resulted in a greater reduction in bone markers than with 1 mg. Intermittent treatment with Bonviva as an iv bolus injection was well accepted and no toxicity was observed. Quarterly dosing with 2 mg Bonviva was well tolerated, with a similar rate of APR events in both active treatment groups.