Clinical Trial Result Information
Title of Study:
Prospective, multicenter study to evaluate the renal safety of 6 mg ibandronic acid infusions over 15 min or 60 min in patients with metastatic bone disease due to breast cancer
Fast Facts:
| Protocol number: | ML17632 |
| Sponsor: | Roche Pharma (Switzerland) AG |
| Company division: | Pharmaceutical |
| Product name: | Bondronat |
| Generic name: | ibandronate |
| Phase of development: | II |
| Therapeutic area, approved indication: | Pain; Bone Neoplasms; Neoplasm Metastasis |
| Date of report: | 10/2/2006 |
Clinical study summary:
This was a prospective, parallel-group, open-label, randomized, multidose multicenter trial to evaluate the renal safety of Bondronat, administered over 2 different infusion times, in patients with metastatic bone disease.
Study center(s) :
A total of 18 centers in Austria, Germany and Switzerland.
Objectives:
Primary: To evaluate the renal safety of 6mg i.v. infusions of Bondronat over 15 min by estimating the percentage of patients with an increase in serum creatinine of ≥44.2μmol/L (=0.5 mg/dL) from baseline.
Secondary: 1) To evaluate the absolute and relative percentage change in serum creatinine from baseline to last available assessment. 2) To evaluate the absolute and relative percentage change in calculated and measured creatinine clearance from baseline to last available assessment. 3) To assess the absolute differences from baseline of tubular and glomerular markers: N-acetyl-β-glucosaminidase, α1-microglobulin and microalbuminuria. 4) To evaluate the effect on reduction of bone pain, analgesic requirement and WHO performance status. 5) To assess the safety and tolerability profile of Bondronat.
Methodology:
Patients satisfying the entry criteria for the study were randomized to receive 6mg Bondronat by either a 15 min or 60 min constant-rate i.v. infusion. Patients were then treated with the same regimen every 3 or 4 weeks (depending on their chemotherapy cycle schedule) for 6 months. Serum creatinine was assessed and reviewed before each infusion. Routine laboratory tests, vital signs, a physical examination, WHO performance status assessment as well as bone pain and analgesic assessments were performed at each visit. Adverse events were monitored continuously throughout the study.
Number of patients (planned/analyzed):
130 Randomized; 127 evaluated for efficacy and safety (101 in 15 min infusion arm, and 26 in 60 min infusion arm).
Diagnosis and main criteria for inclusion:
Female patients ≥18 years of age with histologically or cytologically confirmed breast cancer, at least one osteolytic, mixed or blastic bone metastasis confirmed by X-ray, CT or MRI scan, a life expectancy >6 months and WHO performance status 0-2 at screening.
Test product, dose and mode of administration or test procedure:
Bondronat 6mg i.v. infusion administered over 15 min or 60 min every 3-4 weeks.
Duration of treatment:
6 months
Criteria for evaluation (efficacy, safety):
Efficacy: The main parameters of efficacy were the assessment of bone pain, performed using a visual analogue scale (VAS), analgesic use, and WHO performance status.
Safety: The primary safety parameter was the percentage of patients with a serum creatinine increase of ≥44.2 µmol/L (=0.5 mg/dL) from baseline. Renal safety was also assessed by the measurement of creatinine clearance (CLcr) and markers of tubular and glomerular damage: microalbumin, α1-microglobulin, N-acetyl-β-D-glucosaminidase (NAG).
Adverse events, laboratory safety parameters and vital signs were also assessed and a physical examination performed.
Statistical methods:
For the primary parameter the percentage of patients with a serum creatinine increase of ≥44.2 µmol/L (=0.5 mg/dL) from baseline with a 95% confidence interval was calculated. Descriptive statistics were used to analyze the secondary parameters.
Summary (efficacy, safety, other results):
Efficacy: Mean bone pain scores and mean analgesic scores were virtually unchanged over the course of the study and a slight increase in WHO performance status scores was seen. There were no differences between the treatment arms with respect to the change from baseline in any of these efficacy parameters.
Safety: The primary study variable assessing the renal safety of the 15 minute infusion of Bondronat was the percentage of patients with an increase in serum creatinine of ≥44.2 µmol/L (=0.5 mg/dL) from baseline. Two patients in the 15 minute infusion arm of the study and 0 patients in the 60 minute infusion arm met the criteria for the primary study variable; however, the previous medical history or concurrent disease status of both patients were the most likely underlying reasons for the observed elevations in serum creatinine.
No clinically relevant changes from baseline were seen in either treatment arm for any of the secondary renal safety parameters. Furthermore, urinary markers of renal tubular function and the marker of glomerular permeability exhibited no clinically relevant changes over time in either treatment arm.
The most frequently reported adverse event on both treatment arms was nausea which was recorded by 27% of patients in the 60 minute infusion arm compared with 14% of patients in the 15 minute infusion arm. Futhermore, leukopenia (12% vs. 4%), lymphadenopathy (8% vs. 1%), disease progression (12% vs. 3%), alopecia (12% vs. 3%) and Palmar-Plantar erythrodysaesthesia syndrome (12% vs. 2%) were all reported at a higher incidence in the 60 min infusion arm compared with the 15 minute infusion arm. Gastrointestinal disorders such as vomiting (12% vs 4%) and diarrhea (10% vs 0%) were reported at a notably higher incidence in the 15 minute infusion arm, as were nasopharyngitis (11% vs 4%), urinary tract infection (10% vs 4%) and cough (10% vs 0%). A total of 3 patients in the 15 minute infusion arm and 3 patients in the 60 minute infusion arm experienced an adverse event leading to death during the study or within 28 days of the last dose of study treatment. None of the deaths was considered related to trial treatment.
A total of 25% of patients receiving the 15 minute infusion and 31% receiving the 60 minute infusion recorded at least one serious adverse event during the study. In general, there were no marked differences between the treatment groups in either the frequency or type of serious adverse events recorded. One patient experienced a serious adverse event (osteonecrosis of the jaw) considered related to trial treatment. This SAE resolved with sequalae following treatment.
Seven patients, 5 in the 15 minute infusion arm and 2 in the 60 minute infusion arm, were withdrawn as a result of an adverse event. Four of these AEs, all of which occurred in the 15 minute infusion arm, were considered at least possibly related to trial treatment.
No clinically relevant changes in any of the laboratory parameters or vital signs data were seen.
Conclusions:
Bondronat administered as a 6 mg iv infusion over 15 minutes every 3 or 4 weeks was well tolerated with a safety profile consistent with that of the 60 minute infusion. No evidence for any treatment-related deterioration in renal function was seen, as assessed by the change from baseline in serum creatinine, calculated creatinine clearance or in the urinary excretion of markers of glomerular and tubular function. There were no new or unexpected adverse events compared to those already known for Bondronat and no clinically relevant changes in laboratory parameters or vital signs data were seen.
Click here for the protocol registry listing of this trial.
