Clinical Trial Result Information

Title of Study:
A randomized, two arm, placebo controlled study to compare the efficacy of intravenous loading doses followed by maintenance treatment with oral ibandronic acid versus zoledronic acid in patients with skeletal metastases experiencing moderate to severe pain.

Fast Facts:

Protocol number:	BO18039
Sponsor:	Hoffmann-La Roche
Company division:	Pharmaceutical
Product name:	Bondronat
Generic name:	ibandronate
Phase of development:	III
Therapeutic area, approved indication:	Pain, Bone Neoplasms, Neoplasm Metastasis
Date of report:	10/1/2007

Clinical study summary:
This was a multicenter, randomized, active-controlled, double-blind, parallel group trial to compare the efficacy and safety of Bondronat (ibandronic acid) and zoledronic acid in patients with metastatic bone disease. Recruitment was prematurely terminated, due to slow accrual of patients.

Study center(s) :
34 centers in Argentina, Australia, Canada, Chile, Greece, Guatemala, Hungary, Italy, Mexico, Panama, Poland, Russian Federation, UK and USA.

Objectives:
Primary: To compare the difference in pain responses between treatment with Bondronat vs. zoledronic acid in patients with malignancy and painful metastatic bone disease.
Secondary: Time to and duration of pain response based on the WORST PAIN and AVERAGE PAIN scales of the BPI; analgesic consumption; opioid side-effects; WHO Performance Score; quality of life measured by the EORTC QLQ-C30 scale and FACT-BP scale; patient global assessment.

Methodology:
Bondronat was administered as a loading dose of 6mg intravenously daily for 3 days, followed by treatment with 50mg orally every day starting at day 22. Zoledronic acid was administered in a dose of 4mg intravenously every 3-4 weeks, depending on the underlying chemotherapy regimens patients were receiving. Patients received intravenous zoledronic acid placebo on Days 2 and 3 of the first zoledronic acid treatment only. Patients randomized to oral Bondronat received i.v. placebo infusions every 3-4 weeks. Patients randomized to zoledronic acid received placebo tablets starting at day 22. Treatment was continued for 24 weeks. Patients recorded their pain on the WORST PAIN and the AVERAGE PAIN scales of BPI, as well as daily analgesic use, on a nightly basis, and recorded the degree to which their pain interfered with normal functioning and any opiod side-effects weekly. WHO Performance Status, patient quality of life based on the EORTC QLQ-C30 instrument and quality of life based on the FACT-BP, were recorded. Patients had skeletal surveys performed at baseline and at Weeks 12 and 24 as part of the monitoring of SREs. Adverse events and laboratory safety parameters were assessed throughout.

Number of patients (planned/analyzed):
Planned: 450. Enrolled: 99.

Diagnosis and main criteria for inclusion:
Patients with malignancies, documented bone metastases and bone pain secondary to bone metastatic disease with a mean pain score of ≥5 over a 7-day Baseline period on the WORST PAIN scale of the BPI.

Test product, dose and mode of administration or test procedure:
Bondronat (ibandronic acid) 6mg i.v. infusion Days 1, 2, and 3 followed by maintenance with 50mg orally every day starting on Day 22.

Duration of treatment:
24 weeks

Reference therapy, dose and mode of administration or reference procedure:
Zoledronic acid 4mg i.v. infusion Day 1, followed by maintenance with 4mg i.v. every 3-4 weeks.

Criteria for evaluation (efficacy, safety):
Efficacy: Starting on Day 1 of the trials patients recorded their 'WORST PAIN' of the BPI, and their 'AVERAGE PAIN' of the BPI on an electronic diary nightly, and their analgesic consumption on a paper diary nightly.
Additional  assessments included: opioid side-effects; the EORTC QLQ-C30 Quality of Life instrument and FACT-BP Questionnaire; WHO PS; patients global assessment.

Safety: Adverse events, safety laboratory measurements including serum creatinine and urinalysis, skeletal surveys and recording of skeletal related events (SREs).

Statistical methods:
For the primary variable, Fisher's exact tests were to be performed. Frequency rates and exact 95%-confidence intervals were to be estimated for each treatment group. The difference in the frequency rates between the treatment groups was to be estimated together with 97.5%-confidence intervals according to the Anderson-Hauck approach.
For secondary variables time to event methods (Kaplan-Meier and Cox regression) were to be applied and comparisons made with Mantel-Haenszel Chi-square tests.

Summary (efficacy, safety, other results):
Efficacy: Due to the early discontinuation of recruitment the sample size was significantly lower than planned, and the protocol-defined efficacy analysis was not sufficiently powered to demonstrate a statistically or clinically meaningful difference between treatments.

Safety: Overall, 71% of patients in the Bondronat treatment group and 82% of patients in the zoledronic acid treatment group reported at least one adverse event during the trial. Gastrointestinal disorders were the most frequently reported adverse events, the most common being nausea which was reported by 22% of patients in the Bondronat group and 8% of patients in the zoledronic acid treatment group. In general, the types of adverse event reported during the trial were similar in the two treatment groups. Anemia (4 Bondronat patients, 3 zoledronic acid patients) was the most frequently reported grade III event in either treatment group.
A total of 11 patients (22%) in the Bondronat group and 9 patients (18%) in the zoledronic acid group died. The most common reason for death was disease progression of the underlying cancer. None of the deaths was considered related to trial treatment.
Serious adverse events were reported by 39% (19/49) of patients in the Bondronat group and 32% (16/50) of patients in the zoledronic acid group. The most common individual SAE was anemia reported in 1 Bondronat patient and 3 zoledronic acid patients. During the study, 16% of patients in the Bondronat group and 12% of patients in the zoledronic acid treatment group discontinued treatment because of one or more adverse events.
Adverse events of special interest in this patient population receiving bisphosphonate therapy were skeletal related events and renal events. There were no differences between the treatment groups with respect to the frequency of skeletal related adverse events, and the time to first skeletal related event was similar between the two groups. The incidence of renal events in both groups was low and no marked deterioration in renal function was seen in either treatment group during the treatment period. Among the small percentage of patients for whom a deterioration in renal function was observed, a slight difference between the treatment groups, in favour of the Bondronat treatment group, was seen with respect to the time to renal deterioration, but this difference was not considered to be of clinical relevance.
The mean changes from baseline in hematology, blood chemistry and urinalysis parameters were similar in the two treatment groups and there were no clinically relevant differences between the treatment groups with respect to grade 3 or grade 4 laboratory test parameter values reported during the study. Changes from baseline values in vital signs parameters were also comparable in the Bondronat and zoledronic acid treatment groups.

Conclusions:
The results of this prematurely terminated study demonstrate that a regimen of 3 consecutive i.v. doses of Bondronat over 3 days followed by maintenance therapy with oral Bondronat 50mg daily had a comparable safety profile to that of zoledronic acid 4mg every 3-4 weeks in patients with bone pain due to metastatic bone disease. No new or unexpected safety findings were identified which would alter the known safety profile of Bondronat in cancer patients with bone metastases.

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