Roche trials database

Protocol number:

ML19334

Title of Study:

A randomized, double-blind, placebo-controlled study to determine time to onset of suppression of the bone resorption marker sCTX with once-monthly ibandronate in the treatment of postmenopausal osteoporosis.

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

Bonviva/Boniva

Generic name:

ibandronate

Therapeutic area:

• Post-Menopausal Osteoporosis

Clinical study summary:

This was a prospective, multicenter, randomized, double-blind, placebo-controlled study to investigate the time of onset of the bone resorption marker sCTX in post-menopausal women taking Boniva (ibandronate) 150mg po monthly for 6 months.

Study center(s):

9 centers in the United States.

Phase of development:

IV

Objectives:

Primary: To determine the rapidity of reduction (restoration of premenopausal values) of the bone resorption marker, serum C-terminal telopeptide of type 1 collagen (sCTX), in postmenopausal women with osteoporosis randomized to either once-monthly Boniva 150mg plus vitamin D and calcium supplementation or placebo plus vitamin D and calcium supplementation.
Secondary: To determine the pattern of reduction of sCTX in this patient population; to determine the effect of Boniva on the bone formation marker, bone specific alkaline phosphatase (BSAP), in this patient population; to determine the effect of Boniva on parathyroid hormone (PTH) levels.

Methodology:

Eligible patients were stratified by screening sCTX value prior to study entry. Within each stratum, patients were randomized at baseline to Boniva (Group 1) or placebo (Group 2) in a 2:1 ratio. Group 1 patients received oral Boniva 150mg once-monthly. Group 2 patients received oral Boniva placebo once-monthly. Patients were to take their Boniva or placebo on the same calendar day of each month. All patients took a combination vitamin D and calcium supplement twice daily for the duration of the study.
A follow-up telephone call to the patient was scheduled 15 days after the final visit to collect information about ongoing or new adverse events and concomitant treatments.

Number of patients (planned/analyzed):

Planned: 63. Treated: 66.

Diagnosis and main criteria for inclusion:

Postmenopausal women 65 years and older, diagnosed with postmenopausal osteoporosis, for whom treatment with Boniva was deemed appropriate based on the physician's judgment, and naive to bisphosphonate therapy or exposed to daily or weekly bisphosphonates for a maximum of 3 months at least 5 years before screening.

Test product, dose and mode of administration or test procedure:

Boniva (ibandronate sodium) 150mg / oral / once-monthly.

Duration of treatment:

6 months

Reference therapy, dose and mode of administration or reference procedure:

Placebo / oral / once-monthly.

Criteria for evaluation (efficacy, safety):

Efficacy: Primary: Relative change in sCTX concentration from baseline to day 3.
Secondary: Relative and absolute changes in sCTX concentration from baseline to each time point sampled; relative and absolute changes in BSAP concentration from baseline to each time point sampled; relative and absolute changes in PTH concentration from baseline to month 1 day 7 and to month 6 day 7; variation in sCTX concentration: difference between the minimum and maximum sCTX concentrations at the following 4 time points (days 7, 14, 21 and 28) in month 6 representing steady state; difference between the minimum and maximum relative changes in sCTX concentrations from baseline to the following 4 time points (days 7, 14, 21 and 28) in month 6 representing steady state.

Safety: Adverse events (AEs), including clinical vertebral and nonvertebral fractures and acute phase reaction AEs; safety laboratory tests (blood); vital signs and physical measurements.

Statistical methods:

Sample Size: The planned sample size of 57 patients (38 patients in Boniva group and 19 patients in placebo group) provided 90% power to detect a 40% difference between 2 treatment groups at a type I error of 5% using a 2-sample t-test with a common standard deviation of 40%. To adjust for a 10% dropout/non evaluable rate, a total of 63 patients (42 patients in the Boniva group and 21 patients in the placebo group) were to be randomized in this study.

Primary Analysis: The sCTX concentrations as well as the relative change and absolute change from baseline in the secondary efficacy endpoints did not follow a normal distribution therefore, nonparametric methods were used for the primary and secondary endpoint analyses. The Wilcoxon rank sum test was used for testing the difference in median value between the Boniva and placebo groups. A 95% bootstrap confidence interval for the difference in the median was calculated. The ITT population was the primary analysis population.

Secondary Analyses: Secondary and exploratory endpoints were summarized descriptively.

Summary (efficacy, safety, other results):

Efficacy: Primary Endpoint: In the ITT analysis, patients in the Boniva group achieved a greater median relative change in sCTX concentration from baseline to day 3 than patients in the placebo group (see below), suggesting that sCTX may be a relevant biochemical marker for predicting Boniva efficacy. The per-protocol analysis of the primary efficacy endpoint showed similar results.

	Boniva (N=49)	Placebo (N=17)	p value1	Difference [95% CI]²
n	46	16
Mean ± SD*	-59.16±35.027	-3.82 ± 20.832
SEM	5.164	5.208
Median [95% CI]³	-70.16 [-80.34, -57.64]	-5.96 [-20.79, 6.03]	<.0001	-64.20 [-80.28, -46.21]
Range	-96.0 – 69.6	-34.2 – 40.3

1. From Wilcoxon rank sum test
2. Difference in median and its 95% bootstrap confidence interval.
3. 95% bootstrap confidence interval
*p value for normality test <0.0001 for Boniva group and <0.0001 for placebo group by Shapiro-Wilk test, and <0.0100 for Boniva group and <0.0100 for placebo group by Kolmogorov-Smirnov test.

Secondary Endpoints: The assessment of median relative change in sCTX levels over the 6-month treatment period showed a cyclic pattern in the Boniva group, where the relative decrease in sCTX concentration reached a maximum level just after a dose of Boniva was taken and then decreased to a minimum level just before the next dose was taken. This effect diminished over time. A similar pattern was not observed in the placebo group. In the ITT analysis, the median relative decrease in sCTX concentration from baseline in the Boniva group was larger than that in the placebo group at all post-treatment time points (all values <0.01).
The median absolute decrease in the sCTX concentration from baseline in the Boniva group was larger than that in the placebo group at all post-treatment time points in the ITT analysis. The differences between treatment groups were statistically significant at all time points (p values <0.02), except month 5 day 28 (P=0.052).
The percentage of ITT patients with sCTX concentrations between 0.011 and 0.631 ng/mL (pre-menopausal normal range ±2SD) at baseline who achieved a decrease in sCTX concentration of at least 8% from baseline was higher in the Boniva group than in the placebo group at all time points on treatment (up to month 6 day 28). Rates ranged from 76.1% to 95.6% in the Boniva group and from 12.5% to 75.0% in the placebo group.
Median variation in sCTX concentrations (difference between the minimum and maximum) during month 6 in the ITT population was smaller in the Boniva group (0.0930ng/mL) than the placebo group (0.1330ng/mL) suggesting that sCTX concentrations may have been more stable in the Boniva groups than in the placebo group during month 6. Median variation in relative change in sCTX concentration during month 6 showed a similar pattern across treatment groups.
Median relative change from baseline in BSAP concentration showed a trend to decrease over time in the Boniva group. The difference between the 2 treatment groups was statistically significant beginning at month 3 day 7 through the end of the study (p values <0.05). The analysis of absolute change from baseline in BSAP concentration over time showed a pattern similar to that for relative change; however, the difference between treatment groups was not statistically significant at most post-treatment time points.
An increase in median relative change in PTH concentration from baseline to month 1 day 7 was observed in the Boniva group, whereas a decrease was observed in the placebo group. The difference between treatment groups was statistically significant (p=0.0147). There was a larger increase in the median relative change in PTH concentration from baseline to month 6 day 7 in the Boniva group than the placebo group, but the difference between treatment groups was not statistically significant (p=0.2652). The analysis of absolute change from baseline in PTH concentration showed a pattern similar to that for relative change.

Safety: Once-monthly Boniva 150mg was generally well tolerated in this study. The majority of patients (95.5%) received the planned regimen of 6 doses of trial medication.
The system organ class categories with the highest patient frequency of AEs were gastrointestinal disorders (Boniva group, 44.9%; placebo group 17.6%), musculoskeletal and connective tissue disorders (Boniva group 34.7%; placebo group 52.9%), and infections and infestations (Boniva group, 34.7%; placebo group 41.2%). The most common AEs were nasopharyngitis (Boniva group, 16.3%; placebo group, 29.4%), diarrhea (Boniva group, 14.3%; placebo group, 0%), and arthralgia (Boniva group, 10.2%; placebo group, 5.9%). Two patients in the Boniva group and 1 patient in the placebo group had fracture-related AEs. Eight (16.3%) patients in the Boniva group, and none in the placebo group, had acute phase reaction AEs.  Most AEs were judged by the investigator to be mild or moderate in intensity. No life-threatening AEs were reported during the study. The majority of AEs were judged by the investigator to be unrelated to trial medication.
There were no deaths during the study. One patient in the Boniva group and 2 patients in the placebo group each had 1 SAE. All 3 SAEs resolved without sequelae and were assessed by the investigator as unrelated to trial medication. One  patient in the placebo group was withdrawn from the study due to AEs (skin reactions); no patients in the Boniva group were withdrawn due to AEs.
The number of patients with shifts in laboratory parameters from normal at baseline to outside the normal reference range (low or high) at end of treatment was small (≤2 patients) for most parameters. Three patients in the Boniva group had a shift in blood urea nitrogen from normal at baseline to high at the final visit. Six patients had 1 or more marked laboratory abnormalities.

Conclusions:

Data obtained in this study suggest that sCTX may be a useful biochemical marker for predicting Boniva efficacy. Most patients responded to Boniva within 3 days of treatment and a cyclic pattern of sCTX suppression was observed over each month's cycle. Once-monthly Boniva 150mg was generally well tolerated. There were no unusual or unexpected adverse events.

Publications (references, if available):

Silverman S, Barrett-Connor E, Simonelli C et al. Oral monthly ibandronate is associated with rapid suppression of serum CTX within three days of treatment initiation. JBMR, September 2007:S455

Silverman S, Barrett-Connor E, Simonelli C et al. Rapid suppression of serum CTX within three days of treatment initiation with monthly oral ibandronate. Arthritis and Rheumatism, September 2007; Supplement

Date of report:

26.10.2007

Click here for the protocol registry listing of this trial.