Clinical Trial Result Information

Protocol number
BM16550

Title of Study
DIVA study. Randomized, Double-Blind, Parallel Groups, Multicenter Study to Compare the Efficacy and Safety of 2 intravenous (iv) Ibandronate Dose Regimens (2 mg q 2 mo, 3 mg q 3 mo) With 2.5 mg Daily Oral Ibandronate in Postmenopausal Osteoporosis.

Sponsor
F Hoffman-La Roche Ltd

Company division
Pharmaceutical

Product name
Bonviva/Boniva

Generic name
ibandronate

Therapeutic area
Osteoporosis

Clinical study summary
This is a Phase III multicenter study to compare the efficacy, safety and tolerability of iv ibandronate (Bonviva) regimens of 2 mg every 2 months (2 mg q 2 mo) and 3 mg every 3 months (3 mg q 3 mo) with that of an approved oral Bonviva dose of 2.5 mg daily. Year 1 and Year 2 analyses are presented.

Study center(s)
58 centers in Austria, Belgium, Czech Republic, Denmark, France, Germany, Great Britain, Hungary, Italy, Norway, Spain, Poland, South Africa, Australia, Mexico, Canada, and the United States.

Phase of development
III

Objectives
Primary: To determine whether or not the Bonviva dose regimens of either 2 mg q 2 mo or 3 mg q 3 mo, administered as an iv injection over 15 to 30 seconds, are inferior to oral Bonviva 2.5 mg taken daily.

Secondary: To assess the overall tolerability and safety of Bonviva dose regimens of 2 mg q 2 mo and 3 mg q 3 mo.

Methodology
Patients were randomized to receive Bonviva either as a 2.5 mg oral tablet daily or as an iv injection of 2 mg q 2 mo or 3 mg q 3 mo, and stratified into 1 of 3 strata according to their baseline lumbar spine (L2–L4) BMD T-score (< –2.5 and ≥ –3.0, < –3.0 and ≥ –3.5, < –3.5 and ≥ –5.0). All patients received daily supplementation with calcium (500 mg) and vitamin D (400 IU). Lumbar spine (L2–L4) and proximal femur BMD, measured by dual-energy X-ray absorptiometry at baseline and after 1 year of treatment, was read by a central reading center. Samples for serum CTX (C-telopeptide of the α-chain of type I collagen) were collected at baseline and at Months 2, 4, 6, 12 and 24 for patients receiving iv Bonviva 2 mg q 2 mo and at baseline and at Months 3, 6, 12 and 24 for patients receiving iv Bonviva 3 mg q 3 mo and were measured by a central laboratory. Adverse events were recorded continuously, and laboratory tests for safety were conducted at baseline and at Months 4, 8, 12, 16, 20 and 24 months for patients receiving iv Bonviva 2 mg q 2 mo and at baseline and at Months 3, 6, 9, 12, 15, 18, 21 and 24 months for patients receiving iv Bonviva 3 mg q 3 mo.

Number of patients (planned/analyzed)
1395 randomized; 1358 intent-to-treat (ITT); 1104 per-protocol population; 1382 safety population.

Diagnosis and main criteria for inclusion
Post-menopausal osteoporosis; women ≥5 years after menopause; aged 55–80 years; measurable BMD of the spine and hip; mean lumbar spine BMD (L2–L4) T-score < –2.5 and ≥ –5.0; patients who were ambulatory at the beginning of the trial, and who were not anticipated to become hospitalized, immobilized, or bedridden during the course of the trial; written informed consent.

Test product, dose and mode of administration or test procedure
Bonviva 2 mg/iv/q 2 mo; Bonviva 3 mg/iv/q 3 mo.

Duration of treatment
24 months.

Reference therapy, dose and mode of administration or reference procedure
Bonviva: 2.5 mg/po/daily; placebo: iv/q 2 mo, iv/q 3 mo, po/daily.

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) Absolute change from baseline at 1 year in mean lumbar spine (L2–L4) BMD; (2) relative and absolute change from baseline at 1 year in total hip, trochanter, femoral neck BMD; (3) percentage of BMD responders; (4) relative and absolute change in serum CTX.

Safety parameters: Adverse events, laboratory tests.

Statistical methods
A parametric analysis of relative change (%) from baseline at Month 12 of mean lumbar spine (L2–L4) BMD was conducted. Treatment effect was the difference in the mean values of the corresponding iv Bonviva regimen and the oral Bonviva regimen. Analysis of variance of the relative change from baseline was performed controlling for geographic location and baseline BMD. A confirmatory analysis was performed on the data after 2 years of treatment, using the same analysis.

The primary analysis was based on the per-protocol population; however, all analyses were repeated for the intent-to-treat population to demonstrate the robustness of the results.

Summary (efficacy, safety, other results)
Efficacy: The study met its primary objective to show non-inferiority of lumbar spine (L2 – L4) BMD changes after one year of treatment with both IV Bonviva regimens versus daily oral treatment with 2.5 mg Bonviva.
The mean percent increase in lumbar spine (L2-L4) BMD relative to baseline in both IV treatment groups at one year (5.1% in 2 mg q 2 mo and 4.8% in the 3 mg q 3 mo) and at two years (6.4% in 2 mg q 2 mo and 6.3% in 3 mg q 3 mo) were non-inferior to the 2.5 mg oral daily regimen (Year 1, 3.8%; Year 2, 4.8%). The increases in lumbar spine (L2-L4) BMD in both IV groups were shown to be superior to that seen in the 2.5 mg oral daily treatment group after one and two years of treatment (p<0.001 at Year 1 and Year 2).
In a responder analysis, after one and two years of treatment, significantly more patients treated with IV Bonviva q 2 mo or q 3 mo than with 2.5 mg oral daily Bonviva responded to treatment with an increase in BMD values ≥ baseline at the lumbar spine, femoral neck, total hip, and trochanter. The proportion of patients with 6% or higher increase from baseline in lumbar spine BMD was greater in both IV treatment groups after one and two years of treatment: Year 1: 2 mg q 2 mo (38.3%) and 3 mg q 3 mo (36.8%) compared to the 2.5 mg oral daily group (25.8%); Year 2: 2 mg q 2 mo (53.1%) and 3 mg q 3 mo (49.4%) compared to the 2.5 mg oral daily group (37.7%). For both the 2 mg q 2 mo IV and 3 mg q 3 mo IV treatment groups, the incidence of responders was significantly greater than in the 2.5 mg daily treatment group after one and two years of treatment (p = 0.002 to p<0.001). Thus, both IV treatment regimens resulted in greater increases in BMD, translated by higher responder rates than the approved daily oral regimen, with no clinical difference between the 2 mg q 2 mo IV and 3 mg q 3 mo IV treatment groups.
At the proximal femur, BMD increased at the total hip (1.8% to 2.5%), femoral neck (1.6% to 2.3%), and trochanter (3.0% to 4.0%) in all groups after one year of treatment with Bonviva. After two years of treatment, BMD had increased further in the total hip (2.2% to 3.4%), femoral neck (2.2% to 2.8%), and trochanter (3.5% to 5.0%) in all treatment groups. The mean increase from baseline in proximal femur BMD after one and two years of treatment was greater in both IV treatment groups for the total hip, femoral neck, and trochanter compared to the 2.5 mg daily oral treatment group.
For the total hip and trochanter, this increase in BMD in both IV treatment groups was shown to be superior to that in the 2.5 mg daily treatment group after one and two years of treatment. After one year of treatment, the increase in femoral neck BMD in the 3 mg q 3 mo IV group was shown to be superior to the 2.5 mg daily group.
In this study, serum samples for CTX were collected just prior to the patient receiving their IV dose of Bonviva. Thus, the values measured represent the trough or residual activity of the previous dose. Because of the treatment schedule, the groups are directly comparable only at months 6, 12, and 24. All dosing regimens of Bonviva significantly reduced bone resorption as assessed by serum CTX. Following oral daily 2 mg q 2 mo IV and 3 mg q 3 mo IV dosing with Bonviva, there was a rapid and pronounced decrease in median serum CTX seen during the first 6 months of treatment, and median values in all treatment groups had fallen by ≥ 50% from baseline. In all treatment groups, CTX values appeared to reach a nadir between 6 months and one year of treatment and the majority of patients had post-treatment CTX values normally seen in premenopausal women. In the responder analysis, more than 50% of patients in all treatment groups had a trough serum CTX decrease from baseline of ≥ 50%, representing the least significant change after one and two years of treatment, and 20% to 40% of patients had a trough serum CTX decrease from baseline of ≥ 70%.

Safety: After one and two years of treatment, Bonviva was well tolerated in this study whether given as an oral daily tablet or as an intermittent IV injection. The proportion of patients reporting adverse events was comparable in all groups and there was no clinically relevant difference among the treatment groups in terms of the nature and frequency of adverse events reported, other than the incidence of acute phase reactions/influenza like illness, which, as expected, occurred more frequently in the IV treatment groups. The incidence of adverse events leading to premature withdrawal from trial treatment over the two years of the study was similar across all treatment groups, and in all treatment groups the majority of these premature withdrawals occurred within the first 3 to 6 months after starting treatment.
The serious adverse event profile in terms of body systems and the type of serious adverse events seen in all treatment groups after two years of treatment was similar to that seen at one year. The overall incidence of serious adverse events after two years of treatment was slightly higher in the 2 mg q 2 mo IV group (16.3%) compared to the 2.5 mg oral daily and 3 mg q 3 mo IV groups (14.4% and 13.2%, respectively).
Eight patients died in the two years of follow up with the distribution of fatal events being similar in each treatment group. All deaths were assessed by the investigators as unrelated to treatment, and predisposing conditions or confounding factors were present in all patients.
The ECG substudy conducted during the first year of the study suggests there is no effect of ibandronate on heart rate, AV conduction (as measured by the PR interval duration), cardiac depolarization (as measured by the QRS duration), or cardiac repolarization (as defined by QTcF analyses). No marked morphological changes were observed.
Over the two years of the study, 85 of 1382 patients (6.2%) experienced a clinical fracture. After one and two years of treatment the incidence of clinical fractures was slightly lower in both of the IV Bonviva treatment groups (Year 1, 2.8% to 2.9%; Year 2, 5.8% in both IV groups) compared to the 2.5 mg oral daily group (Year 1, 3.7%; Year 2, 6.9%). Importantly, there was no evidence that intermittent IV dosing resulted in a greater risk of fractures than the daily oral administration.
The incidence of renal events reported over the two year study was low, and the proportion of patients with renal adverse events was similar in all three treatment groups (18 patients [3.9%] in the 2.5 mg daily oral dose, 20 patients [4.5%] in the 2 mg q 2 mo IV group, and 15 patients [3.2%] in the 3 mg q 3 mo IV group).
There were no clinically relevant changes seen in the laboratory safety parameters in any of the treatment groups.

Conclusions
The results of this study demonstrated that both the 2 mg q 2 mo and the 3 mg q 3 mo IV Bonviva dose regimens were non-inferior and increased BMD significantly relative to the approved oral daily dose regimen. Differences between the two IV regimens in BMD change were marginal and not clinically relevant. In both Year 1 and Year 2 of this study, serum CTX levels observed post treatment were well within the premenopausal range in the vast majority of patients in all three treatment groups. The two IV treatment regimens were well tolerated with no evidence of significantly decreased tolerability and safety at the higher 3 mg q 3 mo IV Bonviva dosing regimen. It is concluded that both IV Bonviva regimens have a positive risk/benefit profile, and are clinically equivalent in terms of efficacy and safety.

Publications (references, if available)
Eisman J. et al. Intermittent intravenous ibandronate injections are an effective treatment option in postmenopausal osteoporosis: 2 year results from DIVA. Osteoporos Int 2006; 17 (Suppl.2): S212 (Abstract P316SA)
Zaidi M.et al. Safety and tolerability profile of intravenous ibandronate injection is similar to daily oral dosing: DIVA 2 year analysis. Osteoporos Int 2006; 17 (Suppl. 2): S219-200 (Abstract P337SA)

Date of report
9/1/2005

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