Clinical Trial Result Information

Title of Study:
Double-blind, placebo-controlled, randomized, multicenter study of the efficacy and safety of ibandronate (BM 21.0955) during an extended two year partial crossover study of patients enrolled in MF 4380 (3-year post-menopausal osteoporosis treatment study) using an intermittent i.v. injection regimen of 0.5 mg and 1 mg every 3 months.

Fast Facts:

Protocol number:	MF 4492
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:	5/1/2002

Clinical study summary:
Study MF 4492 was a randomized, placebo-controlled, double-blind, partial crossover study in patients suffering from post-menopausal osteoporosis who had completed MF 4380. Patients were to receive intermittent (every 3 months) iv injections of placebo, 0.5 mg or 1.0 mg Bonviva for 2 years. In addition to study medication, all patients were to receive supplemental doses of calcium (500 mg/day) and vitamin D (400 IU/day). The study was discontinued prematurely by the Sponsor following the outcome of the Phase 3 fracture trial, MF 4380, in women with postmenopausal osteoporosis. In that study, the magnitude of fracture reduction with doses of 0.5 mg and 1.0 mg administered every 3-months was suboptimal and thus the primary endpoint of the study was not met.

MF 4380 treatment group	MF 4492 treatment group
Bonviva I.V., 0.5 mg	Bonviva I.V., 0.5 mg (50%) or Placebo (50%)
Bonviva I.V., 1.0 mg	Bonviva I.V., 1.0 mg (50%) or Placebo (50%)
Placebo I.V.	Bonviva I.V., 1.0 mg

Study center(s) :
15 centers in North America.

Objectives:
MF 4492 was designed to investigate the resolution of the effect of iv Bonviva treatment (i.e. to investigate how the cessation of bisphosphonate treatment may influence safety, bone mineral density and biochemical markers of bone turnover). However, because of the premature termination of the study, the study objective could not be met.

Methodology:
All safety data for study MF 4492 were collected through to the final assessment for all patients who received at least one dose of study medication. Measurements for the primary efficacy endpoint [bone mineral density (BMD) of lumbar spine] were performed at the patient’s final visit. All other efficacy assessments were discontinued without a formal assessment.

Number of patients (planned/analyzed):
A total of 194 patients were randomized into the trial.

Diagnosis and main criteria for inclusion:
Postmenopausal females, having completed MF 4380 according to the protocol.

Test product, dose and mode of administration or test procedure:
Bonviva (ibandronate); intravenous bolus injection of 0.5 mg or 1.0 mg every 3 months

Duration of treatment:
2 years planned

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

Criteria for evaluation (efficacy, safety):
Efficacy: Primary: The relative change in bone mineral density (BMD) of the lumbar spine (L1-L4) at study end compared to baseline.
The secondary variables assessed for efficacy were the change in BMD at the proximal femur and distal forearm, height, pain and disability, pharmacoeconomics, and change in biochemical markers of bone turnover.
Safety: Adverse events (AE); laboratory parameters of renal function, hepatic function, hematology and electrolytes.

Statistical methods:
Only a very abbreviated analysis of the efficacy data was performed.

Summary (efficacy, safety, other results):
Efficacy: Lumbar spine BMD increased in patients re-randomized from placebo to 1.0 mg and continued to increase in patients not having changed treatment group between MF 4380 and MF 4492, whereas BMD decreased when Bonviva treatment was stopped in patients re-randomized from 1.0 mg or 0.5 mg to placebo.

Safety: The intravenous administration of Bonviva was well tolerated. The most commonly reported AEs were upper respiratory infection, arthralgia, back pain, osteoporosis fracture, accidental injury and sinusitis.
A total of 4 patients withdrew prematurely from the study due to adverse events, one patient in the 0.5 mg group (death, not related to treatment) and 3 patients in the 1.0 mg group (all 3 withdrawals due to drug-related AEs). A total of 19 patients (9.8%) experienced a serious adverse event during the study. None of these was considered to be related to the study drug.
Analysis of the laboratory safety data for both hematology and blood biochemistry did not identify any trends raising clinical concern.

Conclusions:
Results from this study showed that patients receiving intermittent iv injections of Bonviva every 3 months had a safety profile similar to those on placebo. No safety concerns were identified in the Bonviva treated groups, and treatment was well tolerated.