Clinical Trial Result Information

Title of Study:
A multicenter, open label, randomized study on the efficacy and safety of oral ibandronate (BM 21.0955) 2.5 mg taken either 30 or 60 minutes before breakfast during 12 months treatment in patients with postmenopausal osteoporosis.

Fast Facts:

Protocol number:	MF 4491
Sponsor:	Roche Global Development
Company division:	Pharmaceutical
Product name:	Bonviva/Boniva
Generic name:	ibandronate
Phase of development:	III
Therapeutic area, approved indication:	Postmenopausal Osteoporosis
Date of report:	10/1/2001

Clinical study summary:
This was a 48-week, multicenter, open-label, randomized study in two parallel groups. All patients were treated with 2.5 mg of oral Bonviva (ibandronate) daily, supplemented with 500 mg of calcium and 400 IU of vitamin D. Patients were randomly assigned to either a 30 or 60-minute post-dose fasting group.

Study center(s) :
6 centers in Denmark and the US.

Objectives:
The objective of the study was to demonstrate comparable efficacy of oral Bonviva 2.5 mg daily to increase bone mass when the period of post-dose fasting is reduced from 60 to 30 minutes.

Methodology:
Following the baseline assessments (visit 2), patients returned to the clinic at months 6 (visit 3) and 12 (visit 4). At visits 2-4, patients were assessed for adverse events and concomitant medications. At visits 1, 2 and 4, patients were assessed for BMD and laboratory values.

Number of patients (planned/analyzed):
A total of 213 patients were enrolled.

Diagnosis and main criteria for inclusion:
Women, at least 5 years since menopause, age 55-80 at time of randomization, with postmenopausal osteoporosis spine BMD T-score ≤ -2.5.

Test product, dose and mode of administration or test procedure:
Bonviva (ibandronate) 2.5 mg/oral/daily

Duration of treatment:
48 weeks

Reference therapy, dose and mode of administration or reference procedure:
None

Criteria for evaluation (efficacy, safety):
Efficacy: Primary efficacy parameter: relative change in BMD of the lumbar spine at L₁ – L₄ from baseline to the last available value (within 48-weeks of treatment). Secondary efficacy parameters: relative change from baseline to the end of treatment in BMD of proximal femur (total hip, trochanter, and femoral neck); change from baseline to the end of treatment in rate of bone turnover [urinary CTx excretion (ratio of CTx/creatinine), serum osteocalcin concentration].
Safety: The safety parameters assessed in the study included clinical laboratory assessments (hematology and blood chemistry), incidence of clinical adverse events, concomitant medications, and laboratory abnormalities.

Statistical methods:
Relative change from baseline in BMD of the lumbar spine (L₁-L₄). Change from baseline in BMD, absolute and relative, was described by parameters of location and dispersion for each treatment group. Change between baseline and the 48-week measurement was analyzed, as well as the difference between baseline and the last value observed. The last value under treatment replaced the missing value if the reason for drop-out was given as a decrease in BMD.

Summary (efficacy, safety, other results):
Efficacy: Baseline assessments of efficacy parameters were similar across the treatment groups for each study population (ITT and PP). Based on diary information, both treatment groups closely adhered to the dosing regimen, with a tighter distribution for the 30-minute fasting group compared to the 60-minute group. For the relative change in lumbar spine (L₁–L₄) BMD from baseline to the end of study (48 weeks), non-inferiority of the 30-minute group compared to the 60-minute group was not shown for the ITT and PP analyses. Similar results were found for the relative change in BMD for the trochanter, femoral neck, and total hip.
Decreased suppression of the bone turnover rate, assessed by the change from baseline in urinary CTx relative to creatinine ( 48.49% vs. –61.75%), and serum osteocalcin concentration ( 34.77% vs. –43.78%), was observed in the 30-minute group compared with the 60-minute group, (respectively).

Safety: Overall, the number of patients who experienced an AE in the 30-minute group was greater than in the 60 minute group. The most frequently reported AEs overall were respiratory tract infection, headache and dyspepsia. Incidence of AEs was similar for both treatments except for the ‘body as a whole’ system, where the 30-minute group experienced a greater incidence of AEs (22.4%) than the 60-minute group (12.3%). The most commonly reported events in the body system ‘body as a whole’ were back pain (5.6% vs. 2.8%), accidental injury (5.6% vs. 1.9%), and pain in extremities (4.7% vs. 2.8%).
No SAE was considered to be drug-related, and no deaths were reported during the study. The AEs most frequently leading to withdrawal were gastrointestinal pain, depression, dyspepsia and gastritis.
Eleven patients experienced marked laboratory abnormalities; five in the 30-minute group and six in the 60-minute group. High or low serum phosphate was observed in four patients, low lymphocytes in three patients, high GGT in three patients, and low platelets, low neutrophils, and high serum potassium were each observed in single patients.

Conclusions:
The key conclusions from this study in osteoporotic postmenopausal women treated for 48 weeks with oral Bonviva, 2.5 mg/day, were:
A 30-minute fasting interval following study drug intake resulted in a smaller increase in BMD of the lumbar spine than a 60-minute fasting interval. Similar results were found for the relative changes in BMD for the total hip, trochanter, and femoral neck. Bonviva was well tolerated by both treatment groups.