Clinical Trial Result Information
- Protocol number:
- Title of Study:
- Double-blind, partially randomized, parallel group, multicenter study to assess the efficacy and safety of 100 mg and 150 mg monthly oral ibandronate in women with postmenopausal osteoporosis having completed the phase III oral ibandronate trial BM16549
- Hoffmann-La Roche
- Company division:
- Product name:
- ibandronate [Bonviva/Boniva]
- Generic name:
- Therapeutic area:
- Post-Menopausal Osteoporosis
- Clinical study summary:
This double-blind, partially randomized, two-arm study was designed to evaluate 100 mg versus 150 mg oral ibandronate [Bonviva/Boniva] monthly in patients with post-menopausal osteoporosis. Patients were allocated treatment or partially randomized according to the treatment received in study BM16549:
- Patients previously treated with ibandronate 100 mg monthly continued on 100 mg monthly (Group A)
- Patients previously treated with ibandronate 150 mg monthly continued on 150 mg monthly (Group B)
- Patients previously treated with 2.5 mg daily or 100 mg monthly over 2 consecutive days (50/50 mg) were randomized to either Group A or Group B.
All patients received calcium 500 mg/day (upper limit 1500 mg), and vitamin D 400 IU/day (upper limit 400 IU/day).
- Study center(s):
31 centers in Belgium, Brazil, Czech Republic, Denmark, France, Germany, Hungary, Italy, Mexico, Norway, Poland, Spain, United Kingdom, United States
- Phase of development:
The efficacy objectives were to investigate lumbar spine and total hip bone mineral density (BMD) changes after long-term treatment (up to 5 years) with ibandronate PO 100 mg and 150 mg monthly and to investigate serum C-terminal peptide of type I collagen (CTX) changes at trough and at peak suppression (steady state).
The safety objectives were to assess the long-term tolerability and safety of oral monthly ibandronate therapy.
Eligible patients were either allocated or randomized into one of the two treatment groups (Group A or Group B), depending on their previous treatment in BM16549. Patients previously treated with ibandronate 100 mg continued on 100 mg monthly (Group A). Patients previously treated with ibandronate 150 mg monthly continued on 150 mg monthly (Group B). Patients previously treated with 2.5 mg daily or 100 mg monthly over 2 consecutive days (50/50 mg) were randomized to either group A or B. In order to ensure double-blind conditions for those patients re-randomized into the study, two differently sized tablets were used (i.e., a double-dummy technique). Once a month, the patient had to take two tablets at once, one containing the active drug and one containing placebo. All patients received daily supplementation with calcium (500 mg) and vitamin D (400 IU). BMD was measured by a single dual X-ray absorptiometry 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 month 12, 24 and 36. Samples for serum CTX were collected at baseline, and at 6, 12, 24 and 36 months in a subpopulation of 150 patients from selected centers (75 patients from each 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):
- 719 enrolled and treated
- Diagnosis and main criteria for inclusion:
Patients upon successful completion of Bonviva study BM16549, with at least 75% compliance; ambulatory.
- Test product, dose and mode of administration or test procedure:
Ibandronate 100 mg or 150 mg tablets administered orally once a month. Placebo 100 mg or 150 mg tablets administered orally once a month.
- Duration of treatment:
- 36 months
- Reference therapy, dose and mode of administration or reference procedure:
- Criteria for evaluation (efficacy, safety):
• Relative (%) and absolute g/cm2) change from baseline of MA17903 in mean lumbar spine (L2 – L4) BMD at 12, 24 and 36 months
• Relative (%) and absolute g/cm2) change from baseline of MA17903 in total hip BMD at 12, 24 and 36 months
• relative (%) and absolute (ng/mL) change from baseline of MA17903 of trough serum CTX at 12, 24 and 36 months
• relative (%) and absolute (ng/mL) change from baseline of MA17903 of post-dose suppression of serum CTX at 6 months of treatment.
• Relative (%) and absolute g/cm2) change from baseline of MA17903 in femoral neck BMD at 12, 24 and 36 months
• Relative (%) and absolute g/cm2) change from baseline of MA17903 in trochanter BMD at 12, 24 and 36 months
A pooled analysis of the subset of patients who received 100 mg or 150 mg monthly ibandronate during study BM16549 and continued this regimen in study MA17903 for a total duration of up to 5 years was performed. Endpoints evaluated were:
• Relative (%) and absolute g/cm2) change from baseline of BM16549 in mean lumbar spine (L2 – L4), total hip, femoral neck and trochanter BMD at 12, 24, 36, 48 and 60 months
• Relative (%) and absolute (ng/mL) change from baseline of BM16549 of trough serum CTX at 3, 6, 12, 24, 36, 48 and 60 months.
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.
For serum P1NP, the analysis of the 3-year long-term extension data in study MA17903 included baseline (Month-24 visit of study BM16549), 12 24 and 36 months. For the 5-year pooled data, the analysis included baseline (Visit 1 (pre-treatment) in study BM16549), 12, 24, 36, 48 and 60 months.
Adverse Events (including clinical vertebral and non-vertebral fractures)
Clinical laboratory tests (blood: hemoglobin, albumin, creatinine, blood urea nitrogen, total calcium, phosphate, magnesium, ALT [SGPT])
Renal safety – change from baseline of MA17903 and BM16549 in calculated creatinine clearance (Cockcroft-Gault method) and serum creatinine.
- 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 P1NP, 95% CIs for median relative changes presented by treatment group using non-parametric methodology.
- Summary (efficacy, safety, other results):
The two treatment groups were well balanced with respect to demographic and baseline characteristics. Mean BMD T scores at MA17903 baseline were similar in the two treatment groups (lumbar spine [L2—L4]: -2.61 and -2.56 in the 100 mg and 150 mg monthly group, respectively; total hip: -1.43 and 1.28, respectively). Median serum CTX at MA17903 baseline was 0.208 ng/mL in the 100 mg monthly group and 0.190 ng/mL in the 150 mg monthly group.
Over the three year duration of study MA17903 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 2.18% (95% CI: 1.63% to 2.73%) in the 100 mg monthly group and 2.43% (95% CI: 1.90% to 2.96%) in the 150 mg monthly group. The proximal femur BMD increases achieved over the initial 2 year treatment period in the core study BM16549 were generally maintained with a slight non-significant decrease over the 3 year treatment period in extension study MA17903. Total hip BMD showed small non-significant decreases from baseline at all timepoints to month 36 in the 100 mg monthly group. In the 150 mg monthly group increases relative to baseline were seen after 12 and 24 months with a small non-significant decrease relative to baseline at month 36. Trochanter BMD measurements showed a small increase relative to MA17903 baseline at all timepoints and in both treatment groups over the course of the study. A similar response was seen in the 150 mg monthly group with respect to femoral neck BMD measurements with mean increases from MA17903 baseline being seen at all timepoints. In the 100 mg monthly group, small mean increases in femoral neck BMD were seen relative to MA17903 baseline after 12 months and 24 months with a small non-significant decrease being seen after 36 months of treatment.
A pooled analysis of efficacy data excluding those patients who had been re-randomized to monthly ibandronate treatment from daily or 50/50 mg monthly ibandronate at MA17903 baseline was performed in order to further characterize the long-term efficacy in patients who had received monthly ibandronate treatment (100 mg or 150 mg) in study BM16549 and continued on the same dose regimen in study MA17903 (i.e., received up to a total of 5 years monthly treatment with either 100 mg or 150 mg ibandronate). In this analysis, 100 mg or 150 mg monthly ibandronate treatment resulted in year on year increases in mean lumbar spine (L2—L4) BMD relative to BM16549 baseline with no evidence of a diminution in efficacy even after 5 years of treatment; mean relative change from baseline was 8.17% in the 100 mg monthly group and 8.43% in the 150 mg monthly group. For the proximal femur, mean total hip and mean femoral neck BMD measurements both showed clinically relevant increases relative to BM16549 baseline after 1 and 2 years of ibandronate treatment. However, after year 2 an apparent plateau was reached with no further increases in BMD in either the 100 mg monthly or 150 mg monthly groups. With respect to trochanter BMD measurements, mean increases relative to BM16549 baseline were seen in both treatment groups after 1, 2 and 3 years of treatment after which an apparent plateau was reached for the 100 mg monthly group. A further small increase in BMD measurements was seen after 48 months in the 150 mg monthly group relative to baseline, however, the subsequent timepoint (month 60) showed a lesser increase.
As was demonstrated in study BM16549, bone resorption (as measured by serum CTX) was suppressed after three months of treatment, reaching a nadir at six months, and remained suppressed at a similar level throughout the two years of the trial. The baseline assessment of study MA17903 corresponded to the Month 24 visit of study BM16549, 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 BM16549 (MA17903 baseline) would not be expected. Over the course of the long-term extension study MA17903 and at all time points, median trough serum CTX concentrations tended to increase slightly over time relative to MA17903 baseline in both treatment groups but still remained within the premenopausal range over the 3-year treatment period.
The analysis of 5-year pooled serum CTX data represents results for patients who had started treatment with ibandronate 100 mg p.o. monthly or 150 mg p.o. monthly in study BM16549 and continued on the same dose of oral ibandronate in study MA17903 (excluding patients treated with 50/50 mg monthly and 2.5 mg ibandronate oral daily in study BM16549). This analysis confirmed a rapid and pronounced decrease in median serum CTX values during the first 3 months of ibandronate treatment (-50.0% and -68.1% in the 100 mg p.o. monthly and 150 mg p.o. monthly groups, respectively) that was maintained at ≥ 50% below baseline BM16549 values in both oral treatment groups for the remainder of the study. At all time points, the decrease in serum CTX in the 150 mg p.o. monthly group was greater than in the 100 mg p.o. monthly group. After 5 years of ibandronate treatment, suppression of bone resorption was still substantial in the 100 mg p.o. monthly and 150 mg p.o. monthly groups with median decreases in serum CTX relative to BM16549 baseline of -52.3%, and -56.2%, respectively, with absolute values that remained within the premenopausal range.
A post-hoc analysis of serum P1NP was performed on the data from the serum samples collected for the analysis of serum CTX. Serum P1NP, a bone formation marker, was analyzed in order to provide more scientific evidence to evaluate bone turnover in patients receiving long-term monthly oral ibandronate for the treatment of post menopausal osteoporosis. The decision to perform a post-hoc analysis of serum P1NP levels, in addition to serum CTX, was also based on the fact that serum P1NP is a highly sensitive, stable and specific marker of bone formation. As with serum CTX, over the course of the 3-year MA17903 long-term extension study, median trough serum P1NP concentrations slightly increased over time relative to MA17903 baseline. However, in the pooled analyses, and as with serum CTX, in those patients who received five continuous years of treatment with 100 mg or 150 mg monthly oral ibandronate, median serum P1NP values decreased relative to BM16549 baseline. A rapid and pronounced decrease from baseline in median serum P1NP values was seen during the first 12 months of ibandronate treatment (-68.9% and -74.5% in the 100 mg p.o monthly and 150 mg p.o. monthly groups, respectively). At all time points, the decrease in P1NP in the 150 mg p.o. monthly group was greater than in the 100 mg p.o. monthly group. Over the remaining 4 years of the study, serum P1NP values consistently remained significantly below BM16549 baseline values further supporting the continuity of suppression of bone turnover. After 5 years of ibandronate treatment, suppression of bone turnover was still apparent in the 100 mg p.o monthly and 150 mg p.o. monthly groups, with a median decrease in serum P1NP relative to BM16549 baseline of -54.8% and -61.0%, respectively. It is important to note that median absolute values of serum P1NP achieved after two years of treatment in study BM16549 were within the premenopausal range as defined by Synarc and were maintained within this range for up to 5 years of the treatment with oral ibandronate.
After three years of treatment in study MA17903, a similar overall incidence of adverse events was reported in the 100 mg and 150 mg monthly treatment groups. The reporting frequency of gastrointestinal disorders was higher in the 150 mg monthly group compared with the 100 mg monthly group with the events dyspepsia, diarrhea, upper abdominal pain and nausea being the most commonly reported gastrointestinal events. The incidence of treatment related gastrointestinal adverse events was similar between groups.
There were, however, no differences of note between the 100 mg and the 150 mg monthly groups with regard to deaths, serious or severe/life-threatening adverse events, or premature withdrawals for adverse events. In addition, there were no clinically relevant changes from baseline in mean laboratory test values in either treatment group. The incidence of patients whose renal function decreased from a category of mild to moderate renal failure [CLcr 30—60 mL/min] to severe renal failure [CLcr < 30 mL/min] was low in both treatment groups (1.1% in the 100 mg monthly group; 0.3% in the 150 mg monthly group) and the overall change in renal function was as would be expected in an elderly population of osteoporotic women. Over the 3 years of the study, 10.3% (37/358) of patients in the 100 mg monthly group and 9.1% (33/361) of patients in the 150 mg monthly group experienced a clinical fracture. The incidence of clinical osteoporotic fractures (9.5% and 8.9% in the 100 mg and 150 mg monthly groups, respectively) and clinical non-osteoporotic fractures (1.4% and 0.3%, respectively) was similar in the two treatment groups, although a consistently numerically lower incidence of all types of fractures was seen in the 150 mg treatment group compared with the 100 mg monthly group.
Overview of Safety in Study MA17903
Ibandronate 100 mg monthly
Ibandronate 150 mg monthly
Patients with at least one…
N = 358
N = 176
N = 361
N = 176
adverse event considered at least remotely related to study treatment
severe adverse event
life-threatening adverse event
serious adverse event
AE leading to discontinuation of study drug
n/a: not assessed
In the pooled analysis of safety in patients who received treatment with 100 mg or 150 mg monthly ibandronate in study BM16549 and continued on the same dose regimen in study MA17903, no new safety signals were identified and the safety profile was comparable with that identified after two years of ibandronate treatment in study BM16549. As was shown in study BM16549, the most common AEs in the pooled analysis over 5 years were infections and infestations, AEs of the musculoskeletal system, gastrointestinal disorders and vascular disorders. There were no notable increases after a further 3 years of monthly treatment compared to after two years in study BM16549 in the incidence of AEs considered related to trial treatment, serious adverse events or in the development of clinical laboratory test abnormalities. There was no evidence for a detrimental effect of monthly ibandronate treatment on renal function based either on serum creatinine measurements or on calculated creatinine clearance.
The robust and substantial increases in lumbar spine (L2—L4) BMD in the 100 mg and 150 mg once‑monthly treatment groups which were shown over 2 years of ibandronate treatment in study BM16549, continued during the 3 years of monthly ibandronate treatment in study MA17903. The clinically relevant BMD increases for the proximal femur (total hip, femoral neck and trochanter) which were seen after 2 years treatment in BM16549 were maintained through five years of monthly ibandronate treatment.
The results showed that a rapid decrease in the levels of both markers of bone turnover (CTX and P1NP) achieved with oral monthly ibandronate treatment was maintained for up to 5 years with values within the normal premenopausal range.
No new or unexpected safety signals were identified over an additional three years of ibandronate treatment in study MA17903, the safety profile of patients receiving 100 mg monthly or 150 mg monthly ibandronate being similar to that seen after two years of ibandronate treatment in study BM16549.
Overall, the results of study MA17903 support the findings of study BM16549. The 150 mg monthly ibandronate dose remains the optimal dose for the treatment of women with postmenopausal osteoporosis demonstrating a consistent effect on BMD and bone turnover and a safety profile which is unchanged with long-term treatment.
- Date of report:
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This database is populated with information on the results of Roche-sponsored clinical trials.