Clinical Trial Result Information

Title of Study:
Open-label, multicenter study to assess the persistance on treatment in women with postmenopausal osteoporosis receiving once-monthly ibandronic acid with either a patient support programme (PSP) or bone turnover marker monitoring (BM).

Fast Facts:

Protocol number:	ML18373
Sponsor:	Roche Products Ltd
Company division:	Pharmaceutical
Product name:	Bonviva/Boniva
Generic name:	ibandronate
Phase of development:	III
Therapeutic area, approved indication:	Post-Menopausal Osteoporosis
Date of report:	6/1/2007

Clinical study summary:
This was an open-label study in women with post-menopausal osteoporosis receiving once-monthly Bonviva (ibandronic acid), comparing persistence on therapy in patients enrolled in a patient support program (PSP), and patients provided with feedback on their bone turnover marker data (BM).

Study center(s) :
62 centers in the UK.

Objectives:
Primary: To assess persistence in treatment (time on therapy) of once monthly Bonviva when patients were randomized to either once-monthly Bonviva with a patient support programme (PSP) or once-monthly Bonviva with bone turnover marker monitoring (BM).
Secondary: To ascertain the reasons for discontinuation from treatment; to ascertain the sensitivity of the measure of persistence.

Methodology:
Patients were randomized in a 1:1 ratio (Group A: Group B). Patients in Group A received oral Bonviva with the PSP and patients in Group B received oral Bonviva with BM. The patients in Group A received written information about the PSP and subsequent contact was made only by telephone, by healthcare professionals (nurses). During each phone call made one to three days prior to monthly dosing the patients received information about osteoporosis and why it is important to take Bonviva on a regular basis in order to achieve the desired benefits.
Dosing instructions that needed to be followed were also emphasised.
Patients randomized to Group B provided urine samples at baseline, three weeks after the second dose, and three weeks after the fourth dose of Bonviva. Urinary N-telopeptide cross-links of collagen (uNTX), a biochemical marker of bone resorption, was analyzed and the results of these tests were fed back to the patient.
For both Group A and Group B, study medication was dispensed for one month's duration. Persistence on therapy was measured by counting the number of months of study therapy dispensed to the patient by the pharmacy (i.e. prescription refills). A patient was classified as failing to persist with treatment if they withdrew from the trial or if they missed one prescription cycle (one month), allowing a leeway of two weeks for patients to collect their prescriptions.
Any adverse events (AEs) occurring during the study were reported by the patient to the investigator, who detailed these on the patient's CRF.

Number of patients (planned/analyzed):
Planned: 600. 685 patients were recruited of whom 675 had their first prescription dispensed and included in analysis.

Diagnosis and main criteria for inclusion:
Women with postmenopausal osteoporosis diagnosed according to the clinical judgement of the treating physician.

Test product, dose and mode of administration or test procedure:
Bonviva (ibandronic acid) 150mg once-monthly; oral.

Duration of treatment:
6 months.

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

Criteria for evaluation (efficacy, safety):
Efficacy: This study was not intended to assess the efficacy of the study drug. The following primary and secondary efficacy variables were evaluated to assess the treatment regimens (monthly Bonviva with a PSP versus monthly Bonviva with BM):
Primary Endpoint: Persistence on treatment with monthly Bonviva with a PSP versus persistence on treatment with monthly Bonviva with BM.
Secondary Endpoint: Patient discontinuation and the reasons for discontinuation; patient adherence: the number of patients on medication at the end of the trial.
Safety: Adverse Events (AEs) and Serious Adverse Events (SAEs).

Statistical methods:
Persistence analysis: For the evaluation of persistence, statistical significance was declared at the 5% level (2-sided). The analysis was performed using Version 9.1 of the SAS® package. Continuous variables were summarized by mean, standard deviation (SD), standard error of the mean (SEM), median, minimum and maximum (range) and number of patients. Categorical variables were summarized by frequency and percentage. Kaplan-Meier methods were used to compare persistence on treatment at various time-points.
Safety: Safety evaluations consisted of monitoring and recording of AEs (including SAEs) in an ongoing way throughout the duration of the study.

Summary (efficacy, safety, other results):
This study had a large number of protocol violators (255 of 685 patients). Protocol violations were more frequent in treatment Group B and concerned non compliance with the protocol on measuring and feedback of results for uNTX. The majority of these were recruited at one center (no. 7). 247 patients were treated at this center, of which 117 violated the protocol during the treatment period, with the majority of these violations occurring in Group B (111/129 patients).
Intention to Treat (ITT) and Per Protocol (PP) Populations were analysed. Due to the large number of protocol violators in one center, two variants of the PP Population were also defined. The PP Eligibility Population comprised those patients in the ITT population who met the inclusion and exclusion criteria irrespective of whether they subsequently were classified as protocol violators. The PP Population Excluding Center 7 Patients was adopted because when the protocol violators were excluded in the traditional PP analysis it led to an imbalance in the two treatment groups thus not allowing any meaningful analyses.

Primary Endpoint: A statistically significant difference was found between the two treatment groups for the primary endpoint of time on therapy during the six months of the trial (according to both log-rank and Cox proportional hazard models) in favour of Group A (patients enrolled into the PSP) for the ITT, PP and PP Eligibility Populations (P=0.0002, 0.0038 and 0.0008 respectively according to the log-rank test). However, patients enrolled at center no. 7 into Group B (BM) failed to persist much earlier than patients enrolled at other centers.
When persistence on treatment during the six months of the trial was analysed for the PP Eligibility Population Excluding Center 7’s patients, there was only a slight difference between the two groups (75% versus 73% and 75% versus 71% respectively) and this difference did not reach statistical significance (P=0.7295 and 0.4452 respectively according to the log-rank test).
Hence the statistically significant difference in persistence between the two groups found for the ITT, PP and PP Eligibility Populations was probably due to a bias introduced by the inclusion of patients from center 7, and if center 7 is excluded the present study does not show any significant difference between the two groups. As persistence on treatment was good in both groups it can be concluded that both methods of monitoring were efficient in improving patient’s compliance.

Secondary Endpoints: The main reason for study discontinuation was ‘adverse events’ (41 patients in Group A and 35 in Group B for the ITT Population). Of the patients who discontinued the study, the proportion of patients discontinuing due to an AE was similar for both treatment groups across all populations. Patient adherence was also similar for both groups for PP Eligibility and PP Populations when center 7’s patients were excluded.

Safety: There was no marked difference in AEs or SAEs between the treatment groups. Most of the AEs were mild (51%) or moderate (43%) in intensity and most of them were unrelated to the study drug (63%). Four patients experienced SAEs leading to death; only one of these patients had SAEs considered to be possibly related to the study medication (thromboembolism in arm, and pulmonary embolism). The most common treatment emergent AEs (TEAEs) were gastrointestinal disorders (14.3%) musculoskeletal and connective tissue disorders (12.3%), infections and infestations (11.6%) and general disorders and administration site conditions (6%). TEAEs reported during this study were similar to those reported in previous studies with Bonviva.

Conclusions:
Persistence on treatment was similar for patients who received monthly Bonviva over a six month period and patient support or bone turnover marker feedback. Persistence on treatment and adherence were good in both groups. This suggests that, when appropriately conducted, both methods of monitoring were efficient in improving patient’s compliance.
In this trial in the Primary Care setting, collecting and giving feedback on uNTX proved technically difficult for investigators to manage. The support programme, which depends on a third party, was a more reliable way of encouraging patients to stay on therapy.

Click here for the protocol registry listing of this trial.