Clinical Trial Result Information

Protocol number
ML18057

Title of Study
A prospective, open-label, multicenter study to evaluate the change in bone turnover markers after once monthly oral ibandronate therapy in treatment naïve postmenopausal osteoporosis patients.

Sponsor
Roche Laboratories Inc.

Company division
Pharmaceutical

Product name
Bonviva/Boniva

Generic name
ibandronate

Therapeutic area
Post-Menopausal Osteoporosis

Clinical study summary
This was an open-label, multicenter study in treatment-naïve postmenopausal women with newly diagnosed osteoporosis, evaluating the effect of monthly oral Boniva therapy on markers of bone turnover. The study was also designed to determine whether providing patients with bone turnover marker information increases their confidence in the effectiveness of Boniva.

Study center(s)
41 study centers in the United States.

Phase of development
IV

Objectives
Primary: To determine whether early response of bone turnover marker (BTM) C-terminal telopeptide of type 1 collagen (CTX) at one month is a significant predictor of once monthly oral Boniva efficacy as measured by BTM percent change at 6 months in treatment naïve postmenopausal osteoporosis patients.
Secondary: To quantify efficacy of once-a-month oral Boniva by monitoring the change in BTM as measured by urine N-terminal telopeptide of type 1 collagen (NTX), serum procollagen type 1 N-terminal propeptide (P1NP), serum osteocalcin, and serum bone-specific alkaline phosphatase (BSAP).
To determine whether sharing efficacy information with patients using BTM data affects patient confidence that Boniva therapy is effective.
To investigate the association between degree of change in BTM and confidence.

Methodology
Eligible patients took one Boniva 150mg tablet a month and a combination calcium + vitamin D supplement twice daily for 6 months. Patients were randomized to 1 of 2 groups at a 1:1 ratio:
Group 1: BTM results measured at baseline through Month 3 were discussed with the patient by the physician or study coordinator at Month 4 + 7 days.
Group 2: BTM results were not discussed with the patient at Month 4 + 7 days.

Bone turnover markers were measured at baseline, Day 7, Month 1, Month 2, Month 3, Month 4 + 7 days, and Month 6. At 6 months, patients completed a Boniva Confidence Scale (BCS) to measure the patient's confidence level that Boniva therapy is: (1) effectively treating osteoporosis and (2) reducing the risk of fracture. Comparison of scores between groups was performed at 6 months to evaluate the perception of effectiveness of Boniva therapy with and without a physician or study coordinator consultation. Adverse events were monitored continuously during the study. Safety laboratory tests were measured at the screening visit and the final visit.

Extended Treatment Period
Patients who wished to continue treatment after completing the initial 6-month treatment period were offered the option to participate in the extended treatment period. A symptom-directed assessment was to be performed if there were any adverse changes from baseline to the patient's state. Safety laboratory tests were performed at the end of each 6-month interval, as applicable.

Number of patients (planned/analyzed)
Planned: 265 patients. Enrolled: 308 patients.

Diagnosis and main criteria for inclusion
Treatment-naïve postmenopausal women with newly diagnosed osteoporosis.

Test product, dose and mode of administration or test procedure
Bonviva (ibandronate sodium) 150mg / oral / once-monthly / 6 months.

Duration of treatment
6 months

Reference therapy, dose and mode of administration or reference procedure
N/A

Criteria for evaluation (efficacy, safety)
Efficacy: Primary: Percent change from baseline at 6 months in serum CTX.
Secondary: Percent change from baseline at 6 months in urine NTX, serum P1NP, serum osteocalcin, serum BSAP.

Patient Confidence: Proportion of patients who were confident that Boniva is effective in treating osteoporosis at 6 months and reduces the risk of breaking a bone at 6 months.

Safety: Adverse events (including clinical vertebral and non-vertebral fractures) and safety laboratory tests.

Statistical methods
Sample Size: A sample size of 224 patients was adequate with 80% power to detect an R-squared of 0.03 or higher (correlation r>0.2) attributed to 1 predictor variable (BTM percent change at 1 month in the primary analysis) using an F-test with a significance level (alpha) of 0.05. This sample size could detect an effect size of about 0.2 assuming the standard deviation of Month 1 and Month 6 BTM percent change is 20% and 50%, respectively. Assuming 15% dropout in the study, approximately 265 patients were to be enrolled.

Primary Analysis: The primary endpoint was percent change from baseline at 6 months in serum CTX. The 95% confidence interval was constructed for the mean percent change from baseline serum CTX at Month 6.
Multiple regression models were applied to determine whether early BTM response at 1 week or 1 month was a significant predictor of monthly oral Boniva efficacy at 6 months, in the treatment of naïve postmenopausal osteoporosis patients. Covariates to be adjusted included age, race, previous history of osteoporotic fracture, time since menopause, concomitant medications, serum vitamin D, and baseline serum CTX.

Secondary Analyses: Similar analyses were conducted for other BTM measurements. These included: mean change from baseline at Month 6 in serum CTX, and mean change and mean percent change from baseline at 6 months in urine NTX, serum P1NP, serum osteocalcin, and serum BSAP.
A Chi-square test with continuity correction was applied to test the significance of consult/non-consult (Group 1/Group 2) difference in Boniva confidence endpoints.

Summary (efficacy, safety, other results)
The mean percent change from baseline in serum CTX in ITT patients (observed cases) was -55.26 (95% CI: -62.25, -48.27) at Month 6 or final visit (primary endpoint). Similar results were observed for other BTMs (secondary endpoints) (see table below).

Mean Values	Serum CTX	Urine NTX	Serum P1NP	Osteocalcin	Serum BSAP
% change from Baseline 95% CI	-55.26 (-62.25, -48.27)	-45.98 (-49.91, -42.06)	-58.14 (-61.40, -54.88)	-41.51 (-43.95, -39.08)	-35.24 (-37.50, -33.19)

BSAP = bone-specific alkaline phosphate; CI = confidence interval; NTX = N-terminal telopeptide of type 1 collagen; P1NP = procollagen type 1 N-terminal propetide.

 Multiple regression models were applied to determine if serum CTX response at 1 week or 1 month was a significant predictor of monthly oral Boniva efficacy at 6 months in treatment-naïve postmenopausal osteoporosis patients. Using these models, percent change in serum CTX at 1 week was found to be a significant predictor of percent change in serum CTX at Month 6 (P=0.0001) along with other covariates, and percent change in serum CTX at 1 month was found to be a significant predictor of percent change in serum CTX at Month 6 (P<0.0001) along with other covariates.
However, simple regression analyses of percent change in serum CTX from baseline at Month 6 and serum CTX at Week 1 or Month 1 were not statistically significant (P=0.127 and P=0.283, respectively), implying that serum CTX response at 1 week or 1 month may not be a significant predictor of monthly oral Boniva efficacy at 6 months in treatment-naïve postmenopausal osteoporosis patients.
Secondary endpoints for Boniva confidence included proportions of patients who were confident at Month 6 that Boniva: (1) was effective in treating osteoporosis, (2) reduced the risk of breaking a bone, and (3) was effective in treating osteoporosis or reduced the risk of breaking a bone. A Boniva confidence responder was defined as a patient who reported a response of ‘confident’ or ‘very confident’ on the 2 items (osteoporosis and fracture) in the Boniva Confidence Scale. For both items, the proportion of Boniva confidence responders at Month 6 was higher in the consult group compared with the non-consult group. Analysis of the difference between the 2 groups was statistically significant for all BCS endpoints, suggesting that sharing efficacy information with patients increases their confidence that Boniva therapy is effective.

Safety: Once-monthly Boniva 150mg was generally well tolerated in this study. The majority of patients (85.1%) received the planned regimen of 6 doses, indicating patients were highly compliant.
In total, 68.5% of patients experienced AEs during the treatment period. The system organ class categories with the highest frequency of AEs were musculoskeletal and connective tissue disorders (29.2% of patients), gastrointestinal disorders (24.4% of patients), and infections and infestations (23.4% of patients). The most common AEs were diarrhea (8.4%) and arthralgia (7.1%). A total of 2.3% patients had fracture-related AEs, and 12.4% patients had flu-like AEs.
Most adverse events were judged by the investigator to be mild or moderate in intensity. The most common severe AEs were back pain (1.6% patients) and diarrhea (1.6% patients). All other severe AEs occurred in ≤2 patients. A total of 1.9% patients had at least 1 severe drug-related (possible or probable) adverse event. The most common severe drug-related AE was diarrhea (1.6% patients).
Approximately 75% of adverse events were considered by the investigator to be unrelated or remotely related to study medication. The most common drug-related AEs were diarrhea (possible, 6.5%; probable 1.0%), dyspepsia (possible 1.9%; probable 1.3%), nausea (possible, 1.6%; probable 1.8%), and arthralgia (possible 1.9%).
There were no deaths during this study. There were 23 SAEs during treatment or within 15 days after discontinuing study medication, all of which were considered unrelated or remotely related to Boniva. The most common SAE was supraventricular tachycardia (2 patients). Of the 24 AEs resulting in withdrawal, 7 were judged by the investigator as unrelated or remotely related to Boniva; 17 were judged by the investigator as possibly or probably related to Boniva. The most common AEs leading to withdrawal were influenza-like illness (3 patients), diarrhea (2 patients) and bone pain (2 patients).
Mean and median changes from baseline in laboratory parameters were small (usually <5%). Similarly, the frequency of individual patient shifts from normal at baseline to outside the normal reference range (low or high) at end of treatment was small (<5% of patients). The most common marked laboratory abnormality was low calcium (3% patients). Three patients had elevated ALT reported as a marked laboratory abnormality.

Conclusions
Treatment with once-monthly Boniva 150mg for 6 months resulted in a significant reduction in bone turnover and resorption as assessed by bone turnover markers. Consulting with patients about their response to treatment significantly increased their confidence that Boniva therapy was effective. Evidence that serum CTX response at 1 week or 1 month is able to predict monthly oral Boniva efficacy at 6 months was conflicting. Once-monthly Boniva 150mg was generally well tolerated in this study.

Publications (references, if available)
Binkley N, Sebba A, Kohles J et al. Bone turnover marker changes in response to monthly ibandronate in women naive to bisphosphonates. 7th International Symposium on Osteoporosis. April 18th, 2007. Poster #43.

Date of report
9/1/2006

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