Clinical Trial Result Information

Protocol number
MF 4433

Title of Study
A single-center, randomized, parallel and cross-over, placebo-controlled study of the efficacy and safety of daily and intermittent ibandronate administration in the treatment of postmenopausal osteoporosis.

Sponsor
Roche Global Development

Company division
Pharmaceutical

Product name
Bonviva/Boniva

Generic name
ibandronate

Therapeutic area
Postmenopausal Osteoporosis

Clinical study summary
This study was a 2-year, double-blind, randomized, parallel group, placebo-controlled study. Patients were randomized to receive one of the following 3 treatments:
1 2.5mg Bonviva po daily
2 20mg Bonviva po intermittent
3 Placebo po
Placebo patients were crossed over to active treatment after 1 year.

Study center(s)
1 center in Denmark.

Phase of development
II

Objectives
To investigate the efficacy and safety of intermittent oral and continuous oral administration of Bonviva in the long-term treatment of postmenopausal osteoporosis.

Methodology
BMD and laboratory efficacy and safety assessments were performed at least quarterly according to a predefined schedule and were performed using standard methodology. Adverse events were collected continuously throughout the trial.

Number of patients (planned/analyzed)
Planned: 240 patients. Randomized: 240 patients.

Diagnosis and main criteria for inclusion
Diagnosis: postmenopausal osteoporosis.
Inclusion criteria: Age ≥55 years; Time since menopause ≤5 years; BMD of either ≤-2.5 SD-T-score for the total of [L₂-L₄], or ≤-2.5 SD-T-score of the femoral neck; informed consent.

Test product, dose and mode of administration or test procedure
Bonviva (ibandronate) given for 2 years as 2.5 mg daily, or as 20 mg given every other day for 12 doses at the start of every 3 month cycle.

Duration of treatment
2 years.

Reference therapy, dose and mode of administration or reference procedure
Placebo given daily for 1 year followed by cross-over in the second year to active oral Bonviva treatment given as 2.5 mg daily or 20 mg given every other day for 12 doses at the start of every 3 month cycle.

Criteria for evaluation (efficacy, safety)
Efficacy: Primary: the relative change in bone mineral density (BMD) of the lumbar spine [L₂-L₄] compared to baseline.
Secondary: BMD of vertebrae L2, L3, and L4; BMD of distal forearm; BMD of proximal femur (total, neck, trochanter, intertrochanter, Ward's triangle); Urinary calcium excretion (creatinine corrected); Urinary CTX excretion (creatinine corrected); Urinary NTX excretion (creatinine corrected); Serum osteocalcin concentration; Serum total alkaline phosphatase concentration; Serum bone-specific alkaline phosphatase concentration; Serum parathyroid hormone concentration.
Safety: Adverse events (AE); laboratory parameter of renal function liver function, hematology, and serum electrolytes.

Statistical methods
Data were summarized using descriptive statistics.

Summary (efficacy, safety, other results)
Efficacy: Bonviva therapy was demonstrated to be superior to placebo in increasing lumbar spine BMD. Increases in lumbar spine [L₂-L₄] BMD were observed to be significantly greater at Year 1 in both the daily and intermittent treatment arms compared to placebo (p< 0.0001). Increases in lumbar spine BMD were already observed to be significant after 3 months in the Bonviva treatment groups and BMD continued to increase throughout the first year of treatment. Median lumbar spine BMD increased in the daily and intermittent Bonviva arms by 4.8% and 4.6% relative to baseline after 1 year compared to an increase of 1.2% in the placebo arm. Equivalency was also demonstrated at Year 2 for the two Bonviva regimens, with median lumbar spine BMD increasing by 5.2% and 6.4% relative to baseline in the daily and intermittent arms respectively. Bonviva therapy with either the daily or intermittent regimen increased BMD at the hip, trochanter and intertrochanter relative to placebo and maintained suppression of markers of bone resorption by >60% after two years of therapy.

Safety: The oral administration of Bonviva, either 2.5 mg daily or 20 mg intermittently, was well tolerated over the 2 year duration of the study and both active regimens resulted in similar safety profiles. During the first year, adverse events were most commonly reported in the digestive, respiratory or general body systems and upper respiratory infection was the most commonly reported AE in the placebo (28%) as well as the daily (21%) and intermittent (18%) Bonviva groups. The incidence of gastrointestinal AEs was very similar in the placebo (35%), daily (35%) and intermittent (30%) treatment groups with the exception of a higher incidence of diarrhea observed in the active treatment groups. Diarrhea was reported for substantially fewer placebo patients (1%) during the first year of the study compared to either the daily (11%) or intermittent (10%) Bonviva treatment groups. No cases of diarrhea were observed however in patients crossed-over from placebo treatment to Bonviva treatment in the second year.
Four AEs leading to death were reported during the trial and SAEs were reported for 33 patients. No deaths or SAEs were considered to be related to the study medication. Of the 44 patients withdrawing from treatment due to an AE, 20 withdrew due to AEs considered possibly or probably related to the study medication. The observed incidences of SAEs, treatment-related AEs and treatment-related AEs leading to withdrawal were similar in Year 1 for the placebo and active treatment arms.
Analysis of the laboratory safety data for renal function, hepatic function, electrolytic balance and hematology did not identify any trends raising clinical concern. Decreases in mean serum alkaline phosphatase concentrations were observed in all treatment groups but were not considered to be of clinical concern and were consistent with the expected effects of bisphosphonate and calcium therapy.

Conclusions
This study demonstrated that 2.5 mg daily Bonviva or 20 mg intermittent Bonviva significantly increased lumbar spine [L₂-L₄] BMD relative to placebo over 1 year and that these two regimens were equally efficacious in increasing lumbar spine [L₂-L₄] BMD over a period of 2 years. Additionally, it was demonstrated that Bonviva increased BMD in the total hip, trochanter and intertrochanter, suppressed bone turnover, and was well tolerated by patients being treated for post-menopausal osteoporosis over a period of 2 years.

Publications (references, if available)
B. J. Riis, J. Ise, T. von Stein, Y. Bagger, and C. Christiansen. Journal of Bone and Mineral Research 2001; 16:1871 – 1878.

Date of report
4/1/2002