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Title: YM905 appears effective and well tolerated in patients with symptomatic idiopathic detrusor overactivity in a european placebo- and tolterodinge-conrolled, phase-II, dose-finding study
Authors: Chapple, C.R. ×
Arano, P
Bosch, J.H.R.
De Ridder, Dirk
Kramer, G.
Ridder, A.M. #
Issue Date: Aug-2002
Publisher: Allen R. Liss
Host Document: Neurourology and urodynamics vol:21 issue:4 pages:381-382
Conference: ICS edition:32 location:Heidelburg, Germany date:28-30 August 2002
Article number: 75
Abstract: Aims of Study
YM905 is a bladder-selective, antimuscarinic agent being developed for the relief of symptoms of urinary
frequency, urinary urgency, and urinary urge incontinence associated with idiopathic detrusor overactivity.
The objectives of this European phase II study were to evaluate the dose-response relationship on efficacy,
safety, and tolerability of once daily dosing of YM905 in patients with symptomatic idiopathic detrusor
overactivity and to compare YM905 in terms of efficacy and tolerability with tolterodine 2 mg bid.
Methods
This was a multinational, multicenter, double-blind, randomized, parallel-group, placebo- and activecontrolled,
phase II, dose-finding study. Patients were enrolled into a single-blind, 2-week placebo run-in
period after which they were randomized to 4 weeks of double-blind treatment with placebo, tolterodine 2 mg
bid, or YM905 (2.5 mg, 5 mg, 10 mg, or 20 mg) once daily. Efficacy was evaluated on the basis of information
obtained from patients’ urinary diaries.
The primary efficacy variable was the change from baseline to endpoint in mean number of micturitions per
24 hours. The secondary efficacy parameters included mean number of incontinence episodes, urgency
episodes per 24 hours, and mean volume voided per micturition. Safety assessment was done by reporting
adverse events, clinical laboratory tests, vital signs, ECGs, and post-void residual volume (ultra-sonography).
For inclusion, urodynamic evidence of idiopathic detrusor overactivity (phasic contractions ≥ 10 cm H2O)
within 6 months before inclusion had to be demonstrated, patients had to experience frequency of micturition
on average ≥ 8 times per 24 hours, and they had to have at least 3 urinary incontinence or 3 urgency
episodes during a 3-day urinary diary period before randomization.
Results
Overall, 225 patients (22 to 83 years of age, mean age 57 years, 60% females) were randomized to
treatment.
Efficacy: The results for micturition frequency show that the YM905 5-mg dose can be considered the minimal
effective dose. The mean change in the tolterodine 2-mg bid group was within the mean changes of 2.5 and 5
mg YM905. A similar outcome was found for the mean change from baseline to endpoint in mean volume
voided per micturition. The mean change of the tolterodine 2-mg bid group was between the mean changes
of placebo and the YM905 2.5-mg group. No statistically significant differences to placebo were found for two
other secondary efficacy variables—mean change in incontinence and urgency episodes/24 hours. However,
the YM905 dose groups showed numerically better changes than placebo. The mean effect in the tolterodine
2-mg bid group was generally smaller compared with that of the YM905 dose groups for both parameters.
The lack of statistical significance might be explained by the study not being powered for these secondary
efficacy variables.
Safety: Because the 5-mg dose is considered to be the minimal effective dose of YM905, the 2.5-mg dose is
not addressed here.
The total incidence of treatment emergent adverse events (TEAEs) with the 5-mg dose of YM905 (43%) was
similar to that of the placebo group (47%). The total incidence compared with placebo was higher for YM905
10 mg (60%), 20 mg (65%), and also for tolterodine 2 mg bid (62%).
Dry mouth was the most common TEAE, reported in both the 5-mg and 10-mg YM905 dose groups by 14%
of patients and by 38% in the 20-mg dose group, compared with 2.6% in the placebo group and 24% in the
tolterodine group. None of the YM905 doses affected vital signs or any of the laboratory parameters in a
clinically relevant manner.
Table 1. Efficacy of YM905 in patients with symptomatic idiopathic detrusor overactivity.
Treatment Group
Placebo YM905 Tolterodine
2.5 mg 5 mg 10 mg 20 mg
Micturitions/24 h n=36 n=40 n=37 n=33 n=34 n=37
Baseline mean 11.1 11.9 11.5 11.4 11.7 12.1
Endpoint change from
baseline
-1.03 -1.45 -2.21* -2.47** -2.75** -1.79
Incontinence episodes/24 h n=26 n=31 n=24 n=22 n=24 n=25
Baseline mean 2.3 2.1 2.3 2.5 1.5 2.3
Endpoint change from
baseline
-0.46 -0.85 -1.32 -1.18 -0.90 -0.65
Urgency episodes/24 h n=36 n=40 n=37 n=33 n=34 n=37
Baseline mean 5.2 5.9 5.6 5.3 5.2 5.7
Endpoint change from
baseline
-1.03 -1.07 -2.35 -2.46 -2.24 -1.62
Volume voided n=35 n=40 n=37 n=33 n=34 n=37
Baseline mean (mL) 135 148 162 153 152 160
Endpoint change from
baseline
9.7 19.9 38.0** 43.2*** 64.7*** 14.7
*p<0.05; **p<0.01; ***p<0.001 in pairwise comparisons between treatment groups and placebo
Conclusions
This phase II dose-finding study shows that YM905 has an apparent dose-response relationship on the
primary efficacy variable (micturition frequency) and the most common TEAE (dry mouth). It can be
concluded that YM905 5 mg, 10 mg, and 20 mg once daily are effective doses for the management of
patients with symptomatic idiopathic detrusor overactivity. As the 5-mg and 10-mg doses appear to be better
tolerated than the 20-mg dose, especially with regard to the occurrence of dry mouth, YM905 5 mg and
10 mg once daily have been selected for further evaluation in large-scale phase III studies.
The favorable efficacy–tolerability ratio for these doses of YM905 may be due to a higher selectivity of YM905
for the bladder than for the salivary gland when compared with tolterodine.
ISSN: 0733-2467
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Urology Section (-)
× corresponding author
# (joint) last author

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