Clinical Trial Result Information

Protocol number
ML18160

Title of Study
Randomised, open-label, multi-centre, study designed to reflect routine clinical care in order to assess persistence on treatment in women with post-menopausal osteoporosis receiving once-monthly ibandronate with a patient support programme versus once-weekly alendronate.

Sponsor
Roche Products Ltd

Company division
Pharmaceutical

Product name
Bonviva/Boniva

Generic name
ibandronate

Therapeutic area
Post-Menopausal Osteoporosis

Clinical study summary
This was a randomized, open-label study comparing the level of persistence on treatment in women with postmenopausal osteoporosis taking monthly Bonviva (with a patient support program), and those taking weekly alendronate. Bonviva was administered at a monthly oral dose of 150mg, and alendronate at a weekly oral dose of 70mg, for a duration of 6 months.

Study center(s)
103 centers in the UK.

Phase of development
IV

Objectives
Primary objective: To assess persistence on treatment (time on therapy) of the once monthly dosing regimen of Bonviva with a patient support programme versus once weekly dosing of alendronate in a routine clinical setting.
Secondary objective: To ascertain the reasons for discontinuation from treatment. To ascertain the sensitivity of the measure of persistence.

Methodology
Following a screening period of up to 30 days, eligible patients were randomized into either Group A (i.e., oral Bonviva 150 mg once-monthly plus a patient support programme*) or Group B (i.e., oral alendronate 70 mg once-weekly) in a 1:1 ratio. The randomization was stratified according to age (below 70 years and 70 years and above). The planned duration of treatment was six months in total.*
The Patient Support Programme (PSP) consisted of a monthly phone call to the patient to deal with any queries the patient may have had and refer appropriately. This program is currently available to UK patients. It also included a welcome pack after the initial phone call and a newsletter three months after enrolment into the study.

Number of patients (planned/analyzed)
1000 patients planned, 1103 patients enrolled (561 Bonviva, 542 alendronate).

Diagnosis and main criteria for inclusion
Post-menopausal women with osteoporosis diagnosed according to the clinical judgment of the treating physician. Informed written consent had to be given by the patient.

Test product, dose and mode of administration or test procedure
Bonviva (ibandronate) 150 mg, administered orally once monthly.

Duration of treatment
Six months.

Reference therapy, dose and mode of administration or reference procedure
Alendronate 70mg, administered orally once weekly.

Criteria for evaluation (efficacy, safety)
Primary Endpoint: The primary endpoint of the study was the persistence rate at six months and time to failure to persist.
Secondary Endpoints: The secondary endpoints were the number of patients who discontinued from treatment and their reason for discontinuation, the number of patients who were on medication at the end of the trial (had prescription 6 filled), and the number of patients who had at least 5 out of the 6 prescriptions filled.
Secondary Safety Endpoints: The secondary safety endpoints were the incidence of adverse events at six months.

Statistical methods
Time to failure data were analyzed using survival analysis techniques: both the Kaplan-Meier method and a Cox’s proportional hazards model were used. The statistical significance of the difference between the Kaplan-Meier curves of the two treatment groups has been tested using the log-rank and Wilcoxon Gehan tests. The Cox’s proportional hazards model included the stratification variable as a covariate. Frequency distributions were presented for each secondary parameter.
Primary and secondary analyses were performed on the ITT (Intent to Treat) and PP (per Protocol) populations.

Summary (efficacy, safety, other results)
Efficacy: Primary endpoint: A statistically significant difference was found between the two treatment groups for the primary endpoint of time to failure to persist during the six months (p-value<0.0001, log-rank test and Wilcoxon Gehan tests) in favor of the Bonviva group. The estimated proportion of patients persisting with treatment at month six was 56.56% in the Bonviva treatment group compared to 38.60% in the alendronate group, giving a 47% improvement in proportion persisting. After an initially poorer persistence for Bonviva users, the trend was reversed and Bonviva users who continued after 30 days had a reduced risk of discontinuation. The statistically significant difference persisted after adjusting for age group (HR=0.538; 95% CI= [0.44:0.66]). Similar results to the ITT population were observed in the PP population.
Secondary endpoints: A significantly higher proportion of patients redeemed their last prescription in the Bonviva group compared to the alendronate group (405 [74.9%] vs 349 [68.0%]; chi square test p-value=0.014). Similarly, a significantly higher proportion of patients filled at least 5 out of 6 prescriptions in the Bonviva group compared to the alendronate group (434 [80.2%] vs. 376 [73.3%]; chi square test p-value=0.008).
A significantly higher proportion of patients discontinued the study in the alendronate group as compared to the Bonviva group (134 [25.3%] vs. 107 [19.6%]; chi square test p-value=0.023). The main reason for study discontinuation was “adverse events” (127 patients in total), with similar proportions of patients in the two treatment (65 [11.9%] patients in the Bonviva group and 62 [11.7%] patients in the alendronate group; chi square test p-value=0.934). Gastrointestinal disorders were the most common reason for withdrawal.
In patients aged below 70 years, similar results to the whole cohort were observed. In the stratum of patients aged 70 years and above, a higher proportion of patients discontinued the study due to an adverse event in the alendronate group compared to the Bonviva group (61 [26.5%] vs 44 [18.5%]; chi square test p-value=0.037).
Similar results to the ITT population were observed for the PP population.

Safety: The overall incidence of AEs was 68.5% in the Bonviva group and 74.3% in the alendronate group. The incidence of Serious Adverse Events (SAEs) was comparable between the two treatment groups.
The most commonly reported Treatment Emergent Adverse Events were gastrointestinal disorders and musculoskeletal and connective tissue disorders. Higher incidences of gastrointestinal disorders were reported in the stratum aged below 70 years (in total 140 [22.9%] patients) than in the stratum aged 70 years and above (in total 91 [19.4%] patients) in both treatment arms.

Conclusions
Persistence on treatment was significantly increased for women who received monthly Bonviva (with a patient support programme) over weekly treatment with alendronate.
Both drugs were found to be well tolerated.

Publications (references, if available)
Cooper A et al. International Journal of Clinical Practice (2006); 60(8):896-905

Date of report
5/1/2006

Click here for the protocol registry listing of this trial.