Roche trials database

Protocol number:

MA17904

Title of Study:

Open label, parallel group, multicenter study of two IV ibandronate dose regimens (2 mg every 2 months and 3 mg every 3 months) in women with postmenopausal osteoporosis who completed trial BM16550

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

ibandronate [Bonviva/Boniva]

Generic name:

ibandronate

Therapeutic area:

• Post-Menopausal Osteoporosis

Clinical study summary:

This open label, parallel group, multicenter study was designed to evaluate the long-term  efficacy and safety of  Bonviva/Boniva (ibandronate)  in women with post-menopausal osteoporosis. Patients received one of the following two regimens:

  2 mg Bonviva/Boniva IV every 2 months (2 mg IV q 2 mo)

  3 mg Bonviva/Boniva IV every 3 months (3 mg IV q 3 mo)

Patients were allocated to one of the two open label IV Bonviva/Boniva regimens based on the double-blind IV regimen received in study BM16550 as follows:

  Patients previously allocated in study BM16550 to the double-blind, 2-monthly IV regimen (2 mg Bonviva/Boniva) or placebo IV every 2 months) were allocated to open label IV Bonviva/Boniva 2 mg IV q 2 mo;

  Patients previously allocated in study BM16550 to the double-blind, 3-monthly IV regimen (3 mg Bonviva/Boniva or placebo IV every 3 months) were allocated to open label IV Bonviva/Boniva 3 mg IV q 3 mo.

  Patients previously treated with oral Bonviva/Boniva 2.5 mg daily were switched to IV Bonviva/Boniva based on the placebo regimen to which they were originally allocated.

All patients received calcium 500 mg/day (upper limit 1500 mg/day) and Vitamin D 400 IU/day (upper limit 400 IU/day 

Study center(s):

39 centers in Australia, Belgium, Czech Republic, Denmark, France, Germany, Hungary, Italy, Mexico, Norway, Poland, South Africa, Spain, United States and the United Kingdom

Phase of development:

IV

Objectives:

Efficacy objectives were to investigate lumbar spine and total hip BMD changes after long-term treatment (up to 5 years) with IV Bonviva/Boniva; and to investigate trough and peak serum CTX suppression at steady state

Safety objectives were to assess the long-term safety and tolerability of IV Bonviva/Boniva therapy

Methodology:

The total treatment duration of study MA17904 was 36 months (3 years) and the total treatment duration of the core study BM16550 and LTE study MA17904 combined was 60 months (5 years). BMD was measured by a single dual X-ray absorptiometry (DXA) scan of the lumbar spine (mean BMD of at least two vertebrae (L2 - L4) that were not fractured and not affected by an osteoarthritic process to such a degree that accurate measurement of BMD would be considered jeopardized by the central reading center) and of the hip (total hip, femoral neck, trochanter) at the time of enrollment and at months 12, 24, and 36. Samples for serum CTX were collected at baseline, 6, 12, 24, and 36 months in a subset of approximately 200 patients from selected centers (100 patients from each treatment group). Adverse events were recorded continuously, and laboratory tests for safety were conducted at baseline and at Months 12, 24, and 36

Number of patients (planned/analyzed):

781 patients enrolled and treated

Diagnosis and main criteria for inclusion:

Female patients with postmenopausal osteoporosis having completed study BM16550 and who had complied with the IV regimen during the second year of study BM16550 for 75% or more

Test product, dose and mode of administration or test procedure:

Ibandronate 2 mg/3 mL; 3 mg/3 mL

Ibandronate (Ro 200-5450) in glass vials for IV injection, containing either

 2 mg in 3 mL IV every 2 months

 3 mg in 3 mL IV every 3 months

Ibandronate was administered by IV injection over 15-30 seconds

Duration of treatment:

Up to 3 additional years following core study BM16550

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

N/A

Criteria for evaluation (efficacy, safety):

Efficacy:

Primary: Relative change (%) from MA17904 baseline at 36 months in mean lumbar spine (L2 - L4) BMD.

Secondary: Relative change (%) from MA17904 baseline in mean total hip BMD at 36 months; relative change (%) from MA17904 baseline of serum CTX at trough suppression at 36 months of treatment; relative change (%) from MA17904 baseline of serum CTX at peak suppression after having completed 6 months of IV ibandronate treatment.

A pooled analysis of the subset of patients who received 2 mg IV q 2 mo or 3 mg IV q 3 mo Bonviva/Boniva during study BM16550 and continued on the same IV regimen in study MA17904 for a total duration of up to 5 years was performed. Endpoints evaluated were the relative (%) and absolute (g/cm2) change from BM16550 baseline of mean lumbar spine (L2 – L4), total hip, femoral neck, and trochanter BMD at 12, 24, 36, 48, and 60 months and the relative (%) and absolute (ng/mL) median change from BM16550 baseline of trough serum CTX at 2, 3, 4, 6, 12, 24, 30, 36, 48, and 60 months

Post Hoc: Procollagen 1 N-terminal propeptide (P1NP): a serum biomarker of bone formation. Samples obtained to determine serum CTX during the study were used to determine the levels of P1NP. Samples analyzed for P1NP included yearly assessments only for LTE patients that participated in the LTE Bone Turnover substudy and include their assessments during the core study BM16550. The same analyses specified for serum CTX were performed with P1NP

Safety: Safety parameters included clinical adverse events, serious adverse events (including deaths), premature withdrawals due to adverse events, and adverse events of special interest including vertebral and non-vertebral fractures, APRs, and clinical laboratory tests. Additional safety parameters: histomorphometry of transiliac bone biopsies for patients participating in the bone biopsy substudy (month 34 or month 35)

Statistical methods:

Descriptive summary statistics (mean, SD, median, range) for BMD endpoints; 95% CIs for mean relative changes presented using parametric methodology. For serum CTX and serum P1NP, 95% CIs for median relative changes presented by treatment group using non-parametric methodology

Summary (efficacy, safety, other results):

Efficacy:

The two treatment groups were well balanced with respect to demographic and baseline characteristics. Mean BMD T-scores at MA17904 baseline were similar in the two treatment groups lumbar spine (L2 - L4): -2.56 SD and -2.66 SD in the 2 mg IV q 2 mo group and 3 mg IV q 3 mo group, respectively; total hip: -1.45 SD and -1.44 SD, respectively). Median serum CTX at MA17904 baseline was 0.213 ng/mL in the 2 mg IV q 2 mo group and 0.223 ng/mL in the 3 mg IV q 3 mo group. Over the 3-year duration of study MA17904, a clinically meaningful increase in mean lumbar spine (L2 – L4) BMD was seen in both treatment groups relative to baseline. By 36 months, the mean increase in lumbar spine (L2 – L4) BMD was 1.98% (95% C to 2.53%) in the 3 mg IV q 3 mo group. In the 2 mg IV q 2 mo group, after 12 and 24 months, mean increases versus MA17904 baseline in total hip BMD of 0.45% and 0.05%, respectively, were seen while after 36 months, a mean change relative to MA17904 baseline of -0.15% occurred. Following 12 months of treatment, a small increase versus MA17904 baseline in total hip BMD of 0.13% was seen in the 3 mg IV q 3 mo group followed by mean changes in total hip BMD relative to MA17904 baseline at Months 24 and 36 of -0.05% and -0.26%, respectively. Based on the 95% CI for mean total hip, changes observed at Months 24 and 36 were not significant suggesting that BMD increases achieved after 24 months of IV Bonviva/Boniva treatment in the core study (BM16550) were maintained during the LTE study (MA17904). The femoral neck BMD increases achieved over the initial 2-year treatment period in the core study (BM16550) were generally maintained with increases relative to MA17904 baseline at all time points. Similarly, trochanter BMD showed a small increase relative to MA17904 baseline at all time points and in both treatment groups over the course of the study. When analyzed according to the actual treatment that was received during the BM16550 (core) vs MA17904 (LTE) studies (ie, IV treatment throughout the core and LTE studies and patients that switched from Bonviva/Boniva 2.5 mg oral daily in the core study to IV in MA17904), over the course of the study and at all time points, mean lumbar spine (L2 – L4) BMD increased relative to MA17904 baseline in each patient group and were consistently higher in the two groups of patients that switched from oral Bonviva/Boniva in study BM16550 to IV treatment in MA17904. Similar results were reported for mean total hip, femoral neck, and trochanter BMD increases relative to MA17904 baseline.

A pooled analysis of efficacy data in a subset of patients that received Bonviva/Boniva 2 mg IV q 2 mo or 3 mg IV q 3 mo for the 5-year core and LTE study periods was performed to further characterize the long-term efficacy of Bonviva/Boniva. In this analysis, Bonviva/Boniva 2 mg IV q 2 mo or 3 mg IV q 3 mo treatment resulted in consistent year on year increases in mean lumbar spine (L2 - L4) BMD relative to BM16550 baseline with mean relative changes from baseline of 8.38% and 8.05% in the 2 mg IV q 2 mo group and 3 mg IV q 3 mo group, respectively. The BMD changes at total hip, femoral neck, and trochanter BMD observed during the continuous long-term 5-year treatment period with IV Bonviva/Boniva from the extension study as well as from pooled analyses provide evidence of the sustained efficacy of IV Bonviva/Boniva treatment. In the pooled responder analysis, following 60 months of IV Bonviva/Boniva treatment, the proportion of patients in both treatment groups that were classified as responders for the lumbar spine (L2 – L4) and total hip BMD were 89.0% to 93.0% and 78.3% to 77.8%, respectively.

In this LTE study, initial serum CTX data that were analyzed by year (for interim analyses) using the ELISA method were inconsistent with other efficacy parameters (ie, BMD, P1NP) as well as Bone Biopsy Substudy histomorphometry data. Synarc Laboratory subsequently identified an explanation for this inconsistency and recommended that the data be reanalyzed batched by patient (as opposed to by year) using the Elecsys method that was used in the core study BM16550. As a result, LTE serum CTX data were reanalyzed using the Elecsys method so that results could then be comparable with data from the initial 2- year core study BM16550. The baseline assessment of study MA17904 corresponded to the 24-month visit of study BM16550, therefore it would be expected that the maximal inhibition of serum CTX would already have occurred between 6 and 12 months in this study and further decreases from the values recorded at the 24-month time point in study BM16550 (MA17904 baseline) would not be expected. OverI: 1.46% to 2.50%) in the 2 mg IV q 2 mo group and 2.06% (95% CI: 1.58% the course of the extension MA17904 study and at all time points, median trough serum CTX concentrations tended to increase over time relative to MA17904 baseline in both treatment groups but still remained within the premenopausal ranges over the 3-year treatment. In addition, serum CTX changes seen in the 2 mg IV q 2 mo and 3 mg IV q 3 mo treatment groups in the extension study cannot be directly viewed as a continuing effect of the same doses in the core study as both treatment groups in the extension study also included patients who were previously receiving daily oral  dosing. A pooled analysis was therefore performed to avoid this confounding factor. The analysis of 5-year pooled serum CTX data represents results for treatment in patients who had started treatment with Bonviva/Boniva 2 mg IV q 2 mo or 3 mg IV q 3 mo in study BM16550 and continued on IV Bonviva/Boniva in study MA17904. This analysis confirmed a rapid and pronounced decrease in median serum CTX values during the first 6 months (as early as after the first injection) of Bonviva/Boniva treatment (≥50% from baseline in both treatment groups) that was maintained in both IV treatment groups up to year 2 (24 months). For the remaining three years of the study, median serum CTX values remained approximately 40% below BM16550 baseline values. After 5 years of Bonviva/Boniva treatment, suppression of bone resorption was still substantial in the 2 mg IV q 2 mo and 3 mg IV q 3 mo groups with median decreases in serum CTX relative to BM16550 baseline of -47.2%, and -36.0%, respectively, and absolute values remaining within premenopausal range.

Of note, in a post hoc analysis, a serum biochemical marker of bone formation, amino-terminal propeptide of type I procollagen or serum P1NP, was analyzed. Serum P1NP is a marker for osteoblast activity and was analyzed in order to provide more scientific evidence to evaluate bone turnover in patients receiving long-term, intermittent IV Bonviva/Boniva for the treatment of PMO. The decision to perform a post hoc analysis of serum P1NP levels in addition to serum CTX was also based also on the fact that serum P1NP is a highly sensitive and specific marker reflecting bone turnover via osteoblast activity. As with serum CTX, over the course of the 3-year MA17904 extension study, median trough serum P1NP concentrations increased over time relative to MA17904 baseline. However, in the pooled analyses and as with serum CTX, in those patients who received five continuous years of treatment with IV Bonviva/Boniva, median serum P1NP values continuously decreased relative to BM16550 baseline in both IV treatment groups. A rapid and pronounced decrease from baseline in median serum P1NP values was seen during the first 12 months of Bonviva/Boniva treatment (-74.0% and -62.5% in the 2 mg IV q 2 mo and 3 mg IV q 3 mo, respectively). Serum P1NP values declined more slowly thereafter but consistently remained significantly below BM16550 baseline values further supporting the continuity of suppression of bone turnover. After 5 years of Bonviva/Boniva treatment, suppression of bone turnover was still apparent in the 2 mg IV q 2 mo and 3 mg IV q 3 mo groups with a median decrease in serum P1NP relative to BM16550 baseline of -57.5% and -45.0%, respectively. It is important to note that median absolute values of serum P1NP achieved after the first year of treatment in study BM16550 were within premenopausal range as defined by Synarc Laboratory and were maintained within this range during the course of the treatment with IV Bonviva/Boniva.

Safety:

After 3 years of treatment in study MA17904, the overall incidence of patients with adverse events was similar in the 2 mg IV q 2 mo and 3 mg IV q 3 mo treatment groups and the majority of adverse events in both treatment groups were mild or moderate in intensity. Infections and infestations were the most commonly affected SOC and they occurred in similar proportions of patients in the 2 mg IV q 2 mo and 3 mg IV q 3 mo groups. Other commonly affected SOCs, which also occurred in similar proportions of patients in both treatment groups, were musculoskeletal and connective tissue disorders, gastrointestinal disorders, vascular disorders, nervous system disorders, and injury, poisoning and procedural complications. Cardiac disorders were not reported frequently and were typical for a postmenopausal population. They were, however, reported more frequently in the 2 mg IV q 2 mo group compared to the 3 mg IV q 3 mo group and were primarily due to events suggestive of coronary heart disorders including angina pectoris, myocardial infarction, myocardial ischemia, coronary artery disease, and coronary artery arteriosclerosis. During the 3 years of trial treatment, a total of 24 patients experienced at least one of these events (21 patients in the 2 mg q 2 mo IV group and three patients in the 3 mg q 3 mo IV group). Five of 21 patients that received 2 mg IV q 2 mo reported more than one event (2 events each). In 4 patients (2 with angina pectoris, 1 with coronary artery arteriosclerosis, and 1 with myocardial ischemia), diagnostic procedures were performed but no treatment was initiated. The majority of events did not lead to discontinuation of study medication and occurred in patients that had either predisposing risk factors or a past medical history of cardiovascular disorders. None of the events were assessed by the investigator as related to study medication.

Deaths were not reported frequently but were slightly higher in the 2 mg IV q 2 mo group (2.1%, [8 patients]) compared to the 3 mg IV q 3 mo group (0.8%, [3 patients]). All deaths were assessed by the investigators as unrelated to treatment, and predisposing conditions or confounding factors were present in all patients. There were no differences of note between the 2 mg IV q 2 mo group and the 3 mg IV q 3 mo group with regard to serious or severe/life-threatening adverse events. In addition, there were no clinically relevant changes from baseline in mean or median laboratory test values in either treatment group.

A total of 11.0% of patients in the 2 mg IV q 2 mo group and 8.5% of patients in the 3 mg IV q 3 mo group experienced a clinical fracture during study MA17904, and the number of fractures was consistently numerically lower in the 3 mg IV q 3 mo group when compared to the 2 mg IV q 2 mo group. The incidence of clinical osteoporotic fractures (9.7% and 8.5% in the 2 mg IV q 2 mo and 3 mg IV q 3 mo groups, respectively) and clinical non-osteoporotic fractures (1.3% and 0.5%, respectively) was similar in the two treatment groups.

With the exception of one serious adverse event reported in a patient that received Bonviva/Boniva 2 mg IV q 2 mo (ulcerative colitis), all serious events reported during the 3-year MA17904 study were considered by the investigator to be unrelated to trial treatment.

Over the 3 years of the study, there was a total of 4 patients who were reported to have either chronic renal failure (2 patients in the 2 mg IV q 2 mo group) or renal failure (1 patient each in the 2 mg IV q 2 mo and the 3 mg IV q 3 mo groups). The majority of these events of chronic renal failure, renal failure, or renal impairment were based on a single elevated serum creatinine value as assessed by the local laboratory, occurred in patients who had higher serum creatinine levels present at baseline (ie, close to the upper limit of normal), or represented transient increases above the reference range in serum creatinine.

With the exception of one patient in the 2 mg IV q 2 mo group who experienced an increase in serum creatinine from 97 μmol/L and 83 μmol/L (at core study BM16550 and MA17904 baselines, respectively) to 142 μmol/L (on study day 786) (standard reference range: 0 - 133 μmol/L), all changes in serum creatinine remained within the standard reference range. All reported events of chronic renal failure and renal failure were reported as unrelated to the study medication. Seven events (in 7 patients) of renal impairment were considered by the investigator to be related to trial treatment: 3 patients in the 2 mg IV q 2 mo group and 4 patients in the 3 mg IV q 3 mo group.

There was no evidence of a detrimental effect of IV Bonviva/Boniva treatment on renal function based either on serum creatinine measurements or on calculated CrCl. Over the 3 years of study MA17904, the incidence of patients with a change in category from mild impairment (CrCl 60 - <90 mL/min) to moderate impairment (CrCl 30 - <60 mL/min) at any time during the study was 46/344 (13.4%) in the 2 mg IV q 2 mo group and 63/364 (17.3%) in the 3 mg IV q 3 mo group. The incidence of patients with a decrease in CrCl from moderate to severe (<30 mL/min) was low: 7/344 (2.0%) in the 2 mg IV q 2 mo group and no patients in the 3 mg IV q 3 mo group.

The pooled analysis of safety in patients who received treatment with Bonviva/Boniva 2 mg IV q 2 mo or 3 mg IV q 3 mo in study BM16550 for 2 years and continued on the same dose regimen in study MA17904 for an additional 3 years revealed no new safety signals compared with those already identified after 2 years of Bonviva/Boniva treatment in study BM16550. As seen in study BM16550, the most common adverse events in the pooled analysis over 5 years were infections and infestations, adverse events of the musculoskeletal system, and gastrointestinal disorders. There were no notable increases after 2 years of treatment in study BM16550 in the incidence of adverse events considered related to trial treatment, serious adverse events, or in the development of clinical laboratory test abnormalities.

The objective of the bone biopsy substudy was to evaluate the effect of the two IV Bonviva/Boniva regimens on the quality and mineralization of newly formed bone and on the bone remodeling process. The histomorphometric analysis of transiliac bone biopsies demonstrated a normal quality of newly formed bone and absence of defects in mineralization and continued reduction in bone remodeling within premenopausal rates after ~5 years of treatment with IV Bonviva/Boniva. These effects were similar with both IV regimens of Bonviva/Boniva treatment. Also, there was no evidence of a significant further change (reduction) in remodeling rates at 34 and 35 months compared to the rates at 22 and 23 months.

Conclusions:

The robust and substantial increases in lumbar spine (L2 – L4) BMD in the Bonviva/Boniva 2 mg IV q 2 mo and 3 mg IV q 3 mo treatment groups which were shown over two years of treatment in study BM16550 continued during the three years of IV Bonviva/Boniva treatment in study MA17904. Similarly, the clinically relevant BMD increases for the proximal femur (total hip, femoral neck, and trochanter) which were seen after two years treatment in BM16550 were maintained thereafter with intermittent IV Bonviva/Boniva treatment.

The marked and rapid suppression of serum CTX observed following administration of the first Bonviva/Boniva IV injection was retained in patients that received intermittent IV Bonviva/Boniva throughout the 5-year treatment period (core study BM16550 and LTE study MA17904). Suppression of serum P1NP values achieved after initial Bonviva/Boniva IV injections in the core study BM16550 were also maintained in patients that received intermittent Bonviva/Boniva throughout the 5-year treatment period further demonstrating the ability of either Bonviva/Boniva IV regimen to suppress postmenopausal bone resorption over time. Both serum CTX and P1NP baseline values were suppressed to and maintained within premenopausal levels throughout the 5-year course of treatment. In addition and consistent with BMD and bone turnover marker data, bone histomorphometry results demonstrated sustained long-term efficacy as well as safety of IV Bonviva/Boniva at the bone tissue level, thus providing more supporting evidence regarding long-term treatment with IV ibandronate in women with PMO.

No new or unexpected safety signals were identified over an additional three years of ibandronate treatment in study MA17904, and the safety profile of patients receiving 2 mg IV q 2 mo and 3 mg IV q 3 mo ibandronate was similar to that seen after two years of ibandronate treatment in study BM16550.

Overall, the results of study MA17904 support the efficacy and safety findings of study BM16550. The approved and marketed 3 mg IV q 3 mo ibandronate dose remains the preferred dose with a convenient dosing interval/frequency of administration for the treatment of women with PMO and demonstrates a consistent and sustained effect on BMD and bone turnover and a safety profile that remained unchanged during the additional 3 years of treatment (total of 5 years of long-term treatment data) 

Date of report:

01.01.2010

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