Clinical Trial Result Information

Protocol number
ML18056

Title of Study
A prospective, open-label, multi-center, two-part study to investigate patient satisfaction with monthly dosed ibandronate therapy in women with postmenopausal osteoporosis or osteopenia transitioned from once-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 a prospective, open-label, multicenter, 2-part, 6-month study to assess patient satisfaction with, and preference for, monthly Boniva treatment in postmenopausal women who had previously been treated with weekly alendronate or risedronate.

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

Phase of development
IV

Objectives
Primary: Part A: To determine the percentage of current weekly bisphosphonate users for whom monthly Boniva represents a potentially more satisfactory therapeutic option using a Candidate Identification Questionnaire (CIQ).
Part B: To assess the utility of the CIQ administered in Part A in identifying patients who were most likely to express improvement in satisfaction with transition to monthly Boniva therapy.
Secondary: Part A: None
Part B: To assess the compliance with 6 doses of monthly Boniva treatment; to assess preference for either monthly Boniva or weekly alendronate or risedronate; to follow patients currently experiencing frequent gastrointestinal (GI) symptoms on a weekly therapy, for improvement with a monthly regimen.

Methodology
In Part A, eligible patients completed the 3 items in the CIQ. Any patient who completed the questionnaire was offered the option to participate in Part B and begin study drug if she met the inclusion and exclusion criteria. Patients who entered Part B of the study discontinued their current weekly bisphosphonate and began a monthly regimen of Boniva. Patients were to take one Boniva 150 mg oral tablet a month for 6 months. The medication was to be taken in the morning, after an overnight fast, in an upright position, with a full glass of plain water. Patients were to stay upright and remain fasting for at least 60 minutes after drug intake. Patients were given an option to receive a monthly reminder to take their medication. Patients enrolled in Part B completed the OPSAT-Q at the baseline and final visits to assess their satisfaction with Boniva therapy. A Preference Questionnaire (Pref-Q) was administered at the final visit. Adverse events were monitored continuously during the study. Safety laboratory tests were measured at the screening visit and final visit for patients who enrolled in Part B. A follow-up evaluation 15 days after the completion of treatment was performed by telephone. 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 performed at 3 month intervals 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)
Enrolled: Part A - 2212; Part B - 1813.

Diagnosis and main criteria for inclusion
Part A: Ambulatory women who had been receiving once-weekly alendronate or risedronate for the treatment or prevention of postmenopausal osteoporosis for a minimum of 3 months. Part B: Women who completed Part A of the study and met the inclusion and exclusion criteria required to enter Part B.

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

Duration of treatment
6 months

Criteria for evaluation (efficacy, safety)
Primary: Part A: Number and proportion of current weekly bisphosponate users in Part A who responded ‘yes’ to any of the items in the CIQ.
Part B: Number and proportion of patients who demonstrated improvement from their baseline satisfaction score after 6 months of Boniva.
Secondary: Part A: None.
Part B: No. and % of eligible weekly bisphosphonate users at screening who elected to enter Part B; no. and % of patients who reported an improved satisfaction score after 6 months of monthly Boniva therapy as compared to weekly alendronate or risedronate at baseline; no. and % of patients who reported preference for either monthly Boniva or weekly alendronate or risedronate; no. and % of patients who had ≥80% compliance with 6 monthly doses of Boniva; no. and % of patients who chose a monthly reminder to take Boniva; no. and % of patients who reported an improvement in the frequency of GI symptoms per month; no. and % of patients by age and activity level reporting high satisfaction according to the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q); individual domain scores from the OPSAT-Q at baseline and month 6.
Safety: Adverse events; safety laboratory tests.

Statistical methods
Patients in Part A of the study completed the 3 items in the Candidate Identification Questionnaire (CIQ) (YES or NO response, relating to preference for monthly dosing, stomach upsets after osteoporosis medication, and compliance with dosing schedule). Patients enrolled in Part B of the study completed the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q) at baseline and month 6. The satisfaction scores obtained from the 4 domains of the OPSAT-Q were used to derive a Composite Satisfaction Score (CSS) scaled from 0 to 100. Patients with a positive change from their baseline CSS at month 6 were considered satisfied with once-monthly dosing of Boniva (satisfaction responders).

Primary Hypothesis: H_o: The satisfaction responder rates are the same between the YES and the NO group.
H_a: The satisfaction responder rate of the YES group is higher than that of the NO group.
The Cochran-Mantel-Haenszel test stratified by history of osteoporotic fracture was used to test the primary hypothesis (satisfaction responder rates between CIQ YES and CIQ NO groups at month 6).

Sample Size: A sample size of 1776 patients enrolled in Part B provided approximately 90% power to demonstrate that the satisfaction rate was higher in the YES group than in the NO group at a significance level of 0.05. This calculation was based on the assumption that 75% of patients would be in the YES group, the satisfaction rate of the YES group was 65% and that of the NO group was 55%.
The sample size was adjusted for a 25% drop out rate. Therefore, no more than 1332 patients in YES group were to be enrolled in Part B of the study to ensure adequate power to perform the primary analysis.

Summary (efficacy, safety, other results)
Efficacy: In the ITT population, 70.4% of all patients were categorized as satisfaction responders (ie. had a positive change from baseline in their CSS after 6 months of once-monthly Boniva 150 mg therapy). The proportion of satisfaction responders in the CIQ YES and NO groups was 71.1% and 67.7%, respectively. The estimated odds ratio of the response rates in the YES group relative to the NO group was 1.18 (95% CI: 0.90, 1.54), indicating that patients in the CIQ YES group were 1.18 times more likely to be a satisfaction responder than patients in the CIQ NO group (p=0.2429). Similar analyses were performed using other definitions for a satisfaction responder; for all responder definitions, the estimated odds ratio of the response rate in the YES group relative to the NO group was greater than 1, but the difference between CIQ groups was not statistically significant. Based on these analyses, it was concluded that response in the CIQ was not able to reliably predict patient satisfaction with once-monthly Boniva treatment as assessed by the OPSAT-Q using criteria specified in the protocol. At month 6, 73.6% of ITT patients preferred the monthly dosing schedule and 8.1% preferred the weekly dosing schedule. Among patients who preferred monthly dosing, the most common reasons were that it was easier to follow for a long period of time (73.5%) and it fitted better into their lifestyle (69.8%). The preference rate for the monthly regimen at month 6 was 85.9% in the CIQ YES group and 79.2% in the CIQ NO group. The estimated odds ratio (95% CI) of the response rates in the YES group relative to the NO group was 1.60 (1.15, 2.23), (P=0.0048), suggesting that the CIQ might be useful for predicting patients’ preference for a monthly dosing regimen.
In total, 94.0% patients were compliant with monthly Boniva dosing. Overall, 44.8% of patients requested a monthly reminder to take their study medication and 55.2% of patients opted not to receive a monthly reminder.
The proportion of patients who reported an improvement in GI symptoms following treatment with once-monthly Boniva 150 mg was evaluated using the subset of patients who reported GI disturbance at baseline. For all patients, >60% reported an improvement in heartburn or acid reflux and >70% reported an improvement in stomach upset other than heartburn or acid reflux. Analysis of the OPSAT-Q responses by age showed that satisfaction responder rates were higher in the <65 year age group (76.5%) relative to the ≥65 year age group (65.2%). With regard to activity level, satisfaction responder rates were higher in the group that was not working (73.9%) relative to the group that was working (68.2%). The distribution of responses was generally similar in the CIQ YES and NO groups.

Safety: The body system categories most commonly affected with AEs were infections and infestations (13.5% of patients), gastrointestinal disorders (12.5% of patients), and musculoskeletal and connective tissue disorders (12.2% of patients). The most common AE was dyspepsia (2.5% of patients). A total of 2.4% of patients had 43 fracture-related AEs.
Most adverse events were judged by the investigator to be mild or moderate in intensity. Life-threatening AEs (all reported as SAEs) included pulmonary embolism (2 patients), accident (1 patient, unrelated death), pulmonary mass (1 patient), atrial fibrillation (1 patient), acute myocardial infarction (1 patient, unrelated death), large-cell carcinoma of the respiratory tract (1 patient), and pancreatic cancer (1 patient). All life-threatening AEs were judged by the investigator to be unrelated to study medication. Twenty-four (1.4%) patients had at least 1 drug-related (possible or probable) severe adverse event.
Most adverse events were considered by the investigator to be unrelated or remotely related to the study medication. The most common drug-related AEs were dyspepsia (possible 20 patients; probable 12), gastroesophageal reflux disease (possible 19; probable 6), nausea (possible 18; probable 3), arthralgia (possible 16; probable 1) and diarrhea (possible 10; probable 3).
There were 2 unrelated deaths during the study or within 15 days of discontinuing study medication, one due to an ATV accident and one due to a myocardial infarction.
Fifty-four (3.2%) patients experienced a total of 72 treatment-emergent SAEs. The most common SAEs were chest pain (4 patients) and atrial fibrillation (3 patients), breast cancer (3 patients) and syncope (3 patients). All 72 SAEs were judged by the investigator as unrelated or remotely related to study drug.
Sixty-nine (4.1%) patients experienced a total of 86 treatment-emergent AEs that resulted in discontinuation of study treatment. The most common individual AEs leading to withdrawal were dyspepsia (7 patients) and gastroesophageal reflux disease (6 patients). Of the 86 AEs resulting in withdrawal, 32 were judged by the investigator as unrelated or remotely related to Boniva; 54 were judged by the investigator as possibly or probably related to Boniva.
The most common marked laboratory abnormalities were decreased hemoglobin, hematocrit and WBCs; decreased electrolytes (chloride, phosphate and sodium); elevated phosphate; and elevated ALT. Increased ALT was reported as an AE for 2 patients, and increased blood calcium was reported as an AE for 3 patients.

Conclusions
Among ITT patients taking once-monthly Boniva 150 mg for 6 months, 70.4% reported an improvement in their level of satisfaction with osteoporosis/osteopenia medication based on the OPSAT-Q. The Candidate Identification Questionnaire (CIQ) with items related to previous experience with once weekly bisphosphonate therapy was not able to reliably predict patient satisfaction with once-monthly Boniva treatment as assessed by the OPSAT-Q using criteria specified in the protocol. Once monthly Boniva 150 mg was generally well tolerated in this study.

Publications (references, if available)
Bonnick SL, Tanner SB, Martens M et al. Improved patient satisfaction with once-monthly ibandronate in women previously receiving once-weekly alendronate or risedronate for postmenopausal osteoporosis or osteopenia. JBMR. 2006; 21(Suppl 1):S285.

Date of report
9/1/2006

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