Roche trials database

Protocol number:

BA20341

Title of Study:

A randomized, open label study evaluating the effect on renal function of intravenous Bonviva given by injection or infusion, compared with oral alendronate, in postmenopausal women with osteoporosis at high risk for renal disease.

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

Bonviva/Boniva

Generic name:

ibandronate [Bonviva/Boniva]

Therapeutic area:

• Post-Menopausal Osteoporosis

Clinical study summary:

This randomized study was designed to evaluate the effect on renal function of Bonviva/Boniva (ibandronate) administered as an injection compared to an intravenous infusion, and alendronate orally administered once weekly, in patients with post-menopausal osteoporosis at high risk for renal disease. Patients were randomized to one of following treatment arms; Group A: Bonviva/Boniva injection, Group B: Bonviva/Boniva infusion, Group C: alendronate.

Study center(s):

39 centers in Argentina, Brazil, Mexico, South Africa, Switzerland, U.S.A.

Phase of development:

IV

Objectives:

The primary objective was to assess the absolute change (mL/min) from baseline in the actual glomerular filtration rate (GFR), measured by the abbreviated Modification of Diet in Renal Disease (MDRD) formula, after 9 months or 40 weeks in this 1-year study.

The secondary objective were as follows: To assess absolute and relative changes at all time-points in actual GFR, measured by both the abbreviated MDRD and Cockcroft-Gault (CG) formulae, and the changes in urine albumin-to-creatinine ratios, and assess the overall safety of both Bonviva/Boniva regimens as compared to alendronate. An additional secondary endpoint was to characterize C_max of Bonviva/Boniva in a subset of patients.

Methodology:

No patients underwent screening procedures without having signed the subject informed consent. All patients received 12 months (or 52 weeks) of treatment and were followed for an additional period of 15 days after treatment completion. The protocol required the assessment of each patient’s renal function before each injection/infusion of Bonviva/Boniva (Groups A and B) and prior to dispensing a 3-month supply of alendronate (Group C). Before any dosing visit, patients were scheduled for a pre-dose visit for laboratory tests of serum and urine samples. Stopping rules applied to all patients with clinically significant increases in serum creatinine and/or increase in urine albumin and/or decrease in GFR. If the stopping criteria were met a second time during the study, the patient was to permanently discontinue the study. At screening and at visit 9, 25-OH-vitamin D, hemoglobin and HbA1C were measured in all patients. For all treatment groups, following blood and urine parameters were evaluated during the screening period and during the study: Blood - serum creatinine, albumin, blood urea nitrogen (BUN) and serum electrolytes (total calcium and phosphate). Urine - albumin-to-creatinine ratio (mg/g) (ACR), α1-microglobulin-to-creatinine ratio (mg/g), N-acetyl-β-D-glucosaminidase (U/g). All laboratory parameters were evaluated by a central laboratory.

Blood samples were collected in a subset of 60 patients (30 from treatment group A and 30 from treatment group B) to evaluate the maximum Bonviva/Boniva serum concentrations.

Adverse events and laboratory test parameters were assessed throughout the study.

Number of patients (planned/analyzed):

801 patients planned and enrolled

Diagnosis and main criteria for inclusion:

Adult, female patients >=60 years of age and over 5 years postmenopausal with confirmed osteoporosis and at increased risk for renal disease.

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

Group A: ibandronate 3 mg intravenous injection every 3 months

Group B: ibandronate 3 mg intravenous infusion every 3 months

Duration of treatment:

12 months

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

Group C: alendronate 70 mg orally once weekly

Criteria for evaluation (efficacy, safety):

Pharmacokinetics

C_max of Bonviva/Boniva in treatment groups A and B

Safety

Primary: Change (mL/min) from baseline in actual GFR (using the abbreviated MDRD formula) after 9 months (or 40 weeks) of treatment. The 9 months of treatment corresponds to the time period required to administer 4 injections or infusions of Bonviva/Boniva. The Bonviva/Boniva injection arm was compared to the Bonviva/Boniva infusion and to the 70 mg alendronate once-weekly arms.

Secondary: Change (mL/min) from baseline in mean GFR (using the CG formula); relative change (%) from baseline in mean actual GFR (using the abbreviated MDRD and the CG formulas); relative (%) and absolute (μmol/L) change from baseline in mean serum creatinine; number of patients with medically important serum creatinine changes; incidence of adverse events, laboratory test parameter abnormalities and vital signs abnormalities.

Statistical methods:

The 3 mg intravenous Bonviva/Boniva injection was compared to the other group by means of non-inferiority tests. The following null hypotheses were tested sequentially at the 2.5% (one-sided) significance level:

– H01: There is a difference of more than 3 mL/min in favor of the 3 mg Bonviva/Boniva infusion every 3 months group compared to the 3 mg Bonviva/Boniva injection every 3 months group.

– H02: There is a difference of more than 3 mL/min in favor of the 70 mg alendronate once-weekly group compared to the 3 mg Bonviva/Boniva injection every 3 months group.

The injection dosing regimen was to be considered as non-inferior to both the Bonviva/Boniva infusion and alendronate oral dosing regimens if the lower bound of the two-sided 95% confidence interval for the difference in change in GFR was greater than or equal to -3 mL/min for both comparisons. The two-sided 95% confidence interval of the mean of the difference between the 3 mg intravenous injection group and each of the 3 mg infusion group and the 70 mg alendronate once-weekly group was computed using an ANOVA model controlling for actual GFR (using the abbreviated MDRD formula) at baseline and an indicator for presence of the following risk factors associated with the deterioration of renal function: arterial hypertension and/or diabetes mellitus.

Secondary analyses of the primary variable were also performed including a non-parametric approach and sub-group analyses for medically reasonable classes found at baseline. Additionally, an analysis was performed for the primary variable controlling for whether patients were enrolled before or after the implementation of protocol version C.

For continuous variables, differences between treatment groups in mean changes from baseline were investigated using an ANOVA model controlling for GFR at baseline. Descriptive statistics were used to summarize C_max, incidence of adverse events, laboratory test parameter abnormalities and vital signs.

Summary (efficacy, safety, other results):

SAFETY

Primary Parameter

The primary parameter of the study was the change (mL/min) from baseline in mean actual GFR (abbreviated MDRD formula using the patients’ actual body surface area) after 9 months (or 40 weeks) of treatment. In all three treatment arms, 9 months of treatment with Bonviva/Boniva or alendronate had no clinically significant effect on the GFR and the mean absolute change in GFR (-0.5 mL/min to -1.6 mL/min) observed in the three treatment arms was in the range of the change in GFR which would be expected in this patient population. The 95% confidence interval for the difference in mean change in actual GFR between the 3 mg Bonviva/Boniva injection and 3 mg Bonviva/Boniva infusion arms was -1.980 mL/min to 0.504 mL/min. The 95% confidence interval for the difference in mean change in actual GFR between the 3 mg Bonviva/Boniva injection and 70 mg alendronate arms was -0.597 mL/min to 1.913 mL/min.

In both cases, the lower bound of the interval did not reach the pre-defined non-inferiority limit of -3 mL/min. Therefore, the null hypotheses of the statistical model were rejected and it was concluded that the Bonviva/Boniva 3 mg every 3 months injection treatment regimen was non-inferior to the Bonviva/Boniva 3 mg every 3 months infusion regimen and to the once weekly 70 mg alendronate regimen with respect to an effect on renal function in women with postmenopausal osteoporosis, including those at increased risk for renal disease.

The robustness of the non-inferiority results of the Bonviva/Boniva 3 mg every 3 months injection to the Bonviva/Boniva 3 mg every 3 months infusion and to weekly oral alendronate was further tested by additional analyses on the primary efficacy parameter. These included intent-to-treat analyses as well as an analysis based on the actual strata into which patients were enrolled, a secondary non-parametric analysis of the primary endpoint and an analysis controlling for patients enrolled under randomization strata prior to Protocol Version C. The results of all the above additional (sensitivity) analyses of the primary endpoints support the conclusion of the primary analysis.

Secondary endpoint analyses provided results which were consistent with the analyses of the primary parameter after 9 months treatment, 12 months treatment and all other time-points for all parameters. These secondary endpoint analyses included changes from baseline in mean actual GFR using the abbreviated MDRD and Cockcroft Gault formulae, changes from baseline in serum creatinine, and changes in serum albumin to creatinine ratio.

Subgroup analyses were performed for medically reasonable classes found at baseline, including age, baseline GFR (≥ 35 - <60 vs. ≥ 60 mL/min), baseline GFR (≥ 35 - <47.5 vs. ≥ 47.5 - <60 vs. ≥ 60 mL/min), presence of diabetes, presence of hypertension, presence of diabetes and hypertension. Results in subgroups with a reasonable number of patients were consistent with the overall analyses. However, in those limited by a small sample size, no conclusions could be drawn.

Exploratory analyses evaluated potential differences with respect to the effects of study treatment on renal function using the surrogate markers of proximal tubular damage, α1-microglobulin and N-acetyl-β-D-glucosaminidase.

There were no statistically significant or clinically relevant differences between the treatment regimens with respect to mean change from baseline in either marker of renal function.

PHARMACOKINETIC RESULTS

The C_max observed after 5 minutes after injection was approximately 50% higher compared to the Cmax obtained after infusion. After 4 administrations, the geometric mean C_max values were 422 μg/L and 281 μg/L after injection and infusion, respectively. Within the same treatment group (injection, infusion), a slight increase in C_max was observed after multiple doses (4 administrations every 3 months) compared to one single dose.

GENERAL SAFETY RESULTS

Following 12 months of study treatment, the proportion of patients reporting at least one adverse event was comparable between the three treatment arms (83-85%). The overall adverse event profile was similar between the two Bonviva/Boniva treatment arms, and any differences between the Bonviva/Boniva and alendronate treatment arms were most likely a result of the different modes of drug administration. The body systems most affected for the Bonviva/Boniva treatment arms were the same for the three treatment groups, namely, musculoskeletal and connective tissue disorders, infections and infestations, gastrointestinal disorders and nervous system disorders.

Among the most frequently reported adverse events, some, such as influenza, hypertension, myalgia, musculoskeletal pain, dizziness, headache, influenza-like illness, depression, fall, anemia, constipation and vomiting had a slightly higher incidence in the Bonviva/Boniva treatment arms compared with the alendronate treatment arms. On the other hand, the incidence of some adverse events associated with the gastrointestinal system, including diarrhea, dyspepsia, and upper abdominal pain showed a higher incidence in the alendronate treatment arm than in either Bonviva/Boniva treatment arm.

Overall, treatment-related adverse events were slightly higher in the Bonviva/Boniva 3 mg injection and 3 mg infusion arms (30.8% and 27.8%, respectively) than in the 70 mg oral alendronate arm (19.9%). The difference was mainly due to most frequently reported treatment-related adverse events, such as myalgia, arthralgia, influenza-like illness, back pain, musculoskeletal pain, dizziness and headache. The incidence of clinical fractures during the trial was generally well balanced between the three treatment arms (Bonviva/Boniva injection 4.2%, Bonviva/Boniva infusion 3.0%, alendronate 3.7%) as was the incidence of clinical osteoporotic fractures (4.2% in the Bonviva/Boniva injection arm, 2.7% in the Bonviva/Boniva infusion arm and 3.0% in the weekly alendronate arm.

There were 5 deaths reported during the trial (1 in the Bonviva/Boniva injection arm, 2 in the Bonviva/Boniva infusion arm and 1 in the alendronate arm). The causes of the deaths included autoimmune thrombocytopenia, cardiac arrest, pulmonary embolism, and respiratory failure. In addition, one further patient in the alendronate arm died after completing the full course of study treatment (date of death unknown). This patient died as a result of a ruptured cerebral aneurysm. All deaths were considered unrelated to study treatment by the investigator.

The incidence of serious adverse events was similar in the Bonviva/Boniva injection arm (7.2%), Bonviva/Boniva infusion arm (5.7%) and oral alendronate arm (4.9%). The occurrence of serious adverse events was spread over many body systems and the body system with the most frequent serious adverse events being injury, poisoning and procedural complications. The only serious adverse event reported in more than one patient in any treatment arm was femur fracture experienced by 3 patients (1.1%) in the Bonviva/Boniva injection arm, 1 patient in the Bonviva/Boniva infusion arm and 1 patient in the 70 mg alendronate arm.

There were no differences with regards to renal safety parameters between the Bonviva/Boniva 3 mg every 3 months injection and Bonviva/Boniva 3 mg every 3 months infusion arms. The number of patients meeting 1 or 2 renal stopping rules was lower in the Bonviva/Boniva treatment arms than in the alendronate treatment arm (7 patients [2.7%] in the Bonviva/Boniva injection arm, 5 patients [1.9%] in the Bonviva/Boniva infusion arm and 11 patients [4.1%] in the alendronate arm met one stopping rule during the study, while 2 patients [0.8%] in each of the Bonviva/Boniva injection and Bonviva/Boniva infusion arms and 7 patients [2.6%] in the alendronate treatment arm met two stopping criteria during the study. Importantly, there was no difference between the treatment arms with respect to the percentage of patients who experienced a medically important change (increase) in serum creatinine during the study. Three patients in the Bonviva/Boniva injection arm, 4 patients in the Bonviva/Boniva infusion arm and 4 patients in the alendronate treatment arm experienced a medically important serum creatinine change during the study.

The percentage of patients with a shift from baseline to a worse renal function category during the trial was comparable in the Bonviva/Boniva injection, Bonviva/Boniva infusion and alendronate treatment arms. Furthermore the incidence of marked serum creatinine abnormalities was very low (0 patients in either Bonviva/Boniva treatment arm and 1 patient in the alendronate treatment arm).

With regards to other laboratory test parameters, no clinically relevant laboratory test value abnormalities were seen and marked laboratory test value abnormalities were rare. In particular, there was no evidence to suggest that the Bonviva/Boniva 3 mg every 3 months injection, Bonviva/Boniva 3 mg every 3 months infusion regimen or weekly oral alendronate regimen led to clinically significant changes in hepatic function or serum electrolyte concentrations.

Conclusions:

This study demonstrated that changes from baseline in renal function were comparable (non-inferior) at month 9 and month 12 in women with postmenopausal osteoporosis and who are at increased risk for renal disease receiving either Bonviva/Boniva intravenous quarterly injection, infusion or weekly oral alendronate 70 mg.

Despite the higher C_max achieved after injection, a comparable effect on renal function was observed in patients treated every 3 months with 3 mg Bonviva/Boniva injected intravenously or 3 mg Bonviva/Boniva infused intravenously.

There was no change in renal function in any treatment group over and above that which would be expected in this population of women with postmenopausal osteoporosis including those at higher risk of renal diseases.

The three treatment regimens were generally comparable with regards to the overall safety profile with any differences between the Bonviva/Boniva and alendronate treatment arms most likely being a result of the different modes of administration. There were no new or unexpected safety findings for the Bonviva/Boniva 3 mg every 3 months injection regimen.

The approved dosing regimen of Bonviva/Boniva 3 mg every 3 months intravenous injections is well tolerated in women with postmenopausal osteoporosis at increased risk for renal disease.

Publications (references, if available):

Miller P, Ragi E, Mautalen C et al. Effects of intravenous ibandronate injection on renal function in postmenopausal women with osteoporosis at high risk for renal disease compared with ibandronate infusion or oral alendronate-the DIVINE study; ASBMR Meeting, Oct 15-19, 2010.

Date of report:

01.12.2010

Click here for the protocol registry listing of this trial.