Clinical Trial Result Information

Protocol number
ML18058

Title of Study
PRIOR Study--And open label, multi-center study to determine level of adherence to monthly oral or every three month intravenous ibandronate treatment in postmenopausal women with osteoporosis or osteopenia, who are GI intolerant of daily and/or weekly alendronate or risedronate.

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 to determine the level of adherence to monthly oral or 3 monthly intravenous Boniva (ibandronate) treatment in post-menopausal women with osteoporosis or osteopenia who had suffered GI intolerance to treatment with alendronate or risedronate.

Study center(s)
58 centers in the United States.

Phase of development
IV

Objectives
Primary: To conclude that the adherence rate in the monthly oral (PO) Boniva group was not lower than the adherence rate in the quarterly intravenous (IV) Boniva group.
Secondary: To determine severity and frequency of gastrointestinal (GI) events at screening, month 1, month 4, month 7, and month 10 as per the GI Experience Survey; to determine the proportion of patients who experienced a change in severity or frequency of GI symptoms at month 1, month 4, month 7, or month 10 compared to screening.

Methodology
Patients who satisfied all entry criteria chose to enter 1 of the 2 treatment groups: Group 1 (monthly PO Boniva) or Group 2 (every 3 months IV Boniva). Patients in Group 1 received a 3-month supply of their oral monthly Boniva at baseline and each interim visit (months 3, 6, 9). Patients in Group 2 were administered their quarterly IV Boniva dose at baseline and at each interim visit. Patients in both groups were maintained on the chosen treatment for up to 12 months. Once during the study, patients could chose to switch treatment groups due to side effects (eg, GI side effects, injection site reaction, and influenza-like illness). At baseline, all patients received copies of the GI Experience Survey to be completed on their own at month 1, month 4, month 7 and month 10, based on their tolerance to the previous dose of Boniva. Safety laboratory tests and medication adherence checks were completed at intervals throughout the study, and monitoring of adverse events and concomitant medications occurred on a continuous basis.

Number of patients (planned/analyzed)
Planned: 517. Enrolled: 545.

Diagnosis and main criteria for inclusion
Postmenopausal women diagnosed with osteoporosis or osteopenia who had previously been treated with alendronate or risedronate and were unable to tolerate the GI side effects.

Test product, dose and mode of administration or test procedure
Boniva (ibandronate sodium): 150mg/PO/once monthly; 3mg/IV/q3months.

Duration of treatment
12 months

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

Criteria for evaluation (efficacy, safety)
Patient Outcomes: Primary: Proportion of patients who had an adherence ≥75% using only monthly PO Boniva or using only quarterly IV Boniva.
Secondary: Proportion of patients who had an adherence ≥75% using Boniva, including both switch and non-switch data; severity and frequency of GI events at screening, month 1, month 4, month 7 and month 10; proportion of patients who experienced a change in severity or frequency of GI events at month 1, month 4, month 7 and month 10 compared to that of screening.
Safety: Adverse events (AEs), including fracture-related AEs and acute phase reaction (APR) AEs; safety laboratory tests (blood).

Statistical methods
Sample Size: The planned sample size of 517 patients provided approximately 80% power to demonstrate that the adherence rate of the quarterly IV group was not 20% more than that of the monthly oral group. This calculation was based on a 1-tailed test of non-inferiority at the 5% significance level assuming that the quarterly IV group had an adherence rate of 75% and the monthly oral group had an adherence rate of 67%. This calculation also assumed that 23% of the enrolled patients would select monthly oral therapy.

Primary Analysis: For the primary analysis, a patient was considered adherent to the original therapy she selected at baseline if the patient had ≥75% adherence using either monthly PO Boniva or only quarterly IV Boniva. Discontinued patients were included in the adherence rate calculation.

The primary null hypothesis and alternative hypotheses were as follows:
H₀:P_IV – P_O ≥20%
H_A:P_IV – P_O <20%
where P_IV and P_O are the adherence rates for quarterly IV Boniva and monthly PO Boniva, respectively.
A 2-sided 90% confidence interval for P_IV-P_O was constructed. If the upper limit of this confidence interval was less than 20%, then non-inferiority of the adherence rate of PO group compared to the adherence rate of IV group could be concluded. The per-protocol analysis population was specified as the primary population for analysis of adherence to original therapy.
Secondary Analyses: Adherence to Boniva overall: A patient was considered adherent to Boniva therapy overall if she had ≥75% adherence using either monthly PO Boniva or quarterly IV Boniva (included both switch and non-switch data). Adherence to Boniva therapy overall was analyzed in the same manner as adherence to original therapy.

Gastrointestinal (GI) Tolerance: The severity and frequency of GI symptoms were assessed by the GI Experience Survey completed by patients at screening (baseline) and months 1, 4, 7, and 10.

Summary (efficacy, safety, other results)
Patient Outcome: Of the 545 patients enrolled in the study, 149 (27.3%) chose the monthly PO Boniva regimen (PO group) and 396 (72.7%) chose the quarterly IV Boniva regimen (IV group) at the baseline visit.
Adherence rates to original therapy in the per-protocol population for the PO and IV groups were 69.7% and 82.9%, respectively. The between-group difference in adherence rates with 2-sided 90% CI was 12.4% (5.1, 19.7). Since the upper limit of the 2-sided 90% CI was within the pre-specified non-inferiority limit of 20%, it could be concluded that the adherence rate to original therapy in the monthly PO Boniva group was not inferior to that in the quarterly IV Boniva group. In the ITT population, the between-group difference in adherence rate with 2-sided 90% CI was 12.7% (5.4, 20.0). The results of the analysis of adherence rates to original therapy in the ITT population did not meet the criterion of non-inferiority, although the upper limit of the 2-sided 90% CI fell on the pre-specified non-inferiority limit of 20%.
Adherence rates to Boniva therapy overall (switch and non-switch data) in the per-protocol population for the PO and IV groups were 76.6% and 84.9%, respectively. The between-group difference in adherence rates with 2-sided 90% CI was 7.6% (0.9, 14.3). The results of the analysis of adherence to Boniva therapy using the ITT population were similar to those using the per-protocol population.
For all patients (non-switch and switch), the mean baseline GI tolerance score was similar in the PO and IV treatment groups (54.1 and 51.0, respectively). At month 1, the mean score improved substantially to 79.3 (PO group) and 84.4 (IV group). After month 1, the GI intolerance score continued to increase slightly but consistently at months 4, 7, and 10, reaching 85.2 in the PO group and 87.9 in the IV at month 10. The mean score of the IV group was slightly but consistently higher than that of the PO group at all post-baseline assessments. The change from baseline in GI tolerance score was statistically significant at all post-baseline assessments in both treatment groups. The GI tolerance scores for patients who remained on their original therapy (non-switch) were similar to the scores for all patients. For patients who switched treatment, improvement in GI tolerance score was greater in the patients in the IV group both before and after treatment switch, as compared with the PO group.
For patients with GI symptoms present at baseline, the majority reported improved symptom severity and frequency scores from baseline at all post-baseline assessments. The majority of patients improved at month 1 (>70% and >65% for severity and frequency, respectively), and the proportion of patients with improvement increased to ≥90% and >85% respectively at month 10. The proportion of patients reporting improvement on severity and frequency was consistently higher in the IV group at month 1, but was comparable between the 2 treatment groups by month 7. The proportion of patients worsening was generally small (<10%) and comparable between the 2 treatment groups.

Safety: Before switching treatments, 82% of patients in each group reported at least one AE. The most common AE classes were gastrointestinal disorders (PO group 51%; IV group 38%), musculoskeletal and connective tissue disorders (PO group 34%; IV group 36%), infections and infestations (PO group 25%; IV group 29%), and general disorders and administration site conditions (PO group 13%; IV group 22%). Eight (5%) patients in the PO group and 21 (5%) patients in the IV group had fracture-related AEs, while 19 (13%) patients in the PO group and 68 (17%) patients in the IV group experienced acute phase reaction AEs. The most common AEs (expressed as patient incidence) before treatment switch were dyspepsia (PO group 16%; IV group 13%), nausea (PO group 14%; IV group 10%), and arthralgia (PO group 11%; IV group 9%). After treatment switch, the percentage of patients reporting AEs was comparable between the 2 treatment groups (PO group, 55% of patients; IV, 50% of patients).
The distribution of AEs by intensity was similar in the 2 treatment groups. Most AEs were judged by the investigator to be mild or moderate in intensity. The most common severe AEs were arthralgia (PO group <1%; IV group 2%), back pain (PO group <1%; IV group 2%), and dyspepsia (PO group 2%; IV group <1%). There were 2 life-threatening AEs (urinary tract infection and pericardial effusion) in the PO group, and 6 (gastrointestinal ischemia, pneumonia, cerebrovascular accident, pneumothorax, arteriosclerosis and colon cancer) in the IV group.
Before treatment switch, about half of the patients in both treatment groups reported AEs judged by the investigator to be related to trial medication: 53% patients in the PO group and 48% patients in the IV group. The most common treatment- related AEs were dyspepsia (PO group 15%; IV group 9%), nausea (PO group 12%; IV group 9%) and arthralgia (PO group 6%; IV group 6%). The most common severe treatment-related AE was arthralgia (PO group 0%; IV group 2%). There were no life-threatening treatment-related AEs.
There was 1 unrelated death due to pneumonia in a patient receiving IV Boniva. A total of 7% of patients in the PO group and 8% in the IV group reported SAEs. No SAEs occurred after patients switched treatment. The most common SAEs were infections and infestations (PO group <1%; IV group 3%) and SAEs associated with cardiac disorders (PO group 3%; IV group 2%). Only 2 patients (both in the PO group) had SAEs that were judged by the investigator to be related to trial medication (chest pain, shortness of breath, hypertension, exacerbation of congestive heart failure, exacerbation of COPD and constipation in one patient, and black stools in a second).
Before treatment switch, 17% of patients in the PO group and 10% in the IV group experienced 1 or more AEs that resulted in withdrawal from the study. The most common AEs leading to withdrawal were nausea (5 patients), gastroesophageal reflux disease (4 patients), dyspepsia (3 patients), and arthralgia (3 patients).
The most common marked laboratory abnormality was high phosphate (PO group, 8% patients; IV group, 3% patients). Overall, there were no clinically significant changes in vital signs or clinical laboratory parameters.

Conclusions
The majority (72.7%) of enrolled patients chose once-quarterly IV Boniva as initial therapy. During the study, a small proportion of patients switched treatment groups (4.0% in IV group and 7.4% in PO group). Adherence to originally chosen monthly PO Boniva therapy was non-inferior to adherence to originally chosen quarterly IV Boniva therapy based on the primary per-protocol analysis. The ITT analysis provided supportive results even though the results of the analysis fell exactly on the non-inferiority limit and thus did not meet the criterion. Adherence to overall Boniva therapy for patients who originally chose monthly PO therapy was non-inferior to that for those originally chose quarterly IV therapy. The majority of patients experienced an improvement in the severity and frequency of GI symptoms following Boniva therapy. Oral Boniva 150 mg once monthly and IV Boniva 3 mg once quarterly were generally well tolerated.

Publications (references, if available)
Laster A, Bone H, Kornowski A et al. Interim analysis of PRIOR study of ibandronate in patients intolerant of alendronate or risedronate: intravenous dosing is preferred. Journal of Bone and Mineral Research 2006; 21 (Suppl 1):s288 (Abstract).
Bonnick SL, Friend KE, Lewiecki EM et al. Ibandronate for patients intolerant of alendronate or risedronate: intravenous dosing is the preferred option. Journal of Clinical Densitometry 2006; 9(2):247 (Abstract).

Date of report
1/5/2007

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