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Effect of Voluntary Dose Escalation on Placebo Effects in a Trial of Antimuscarinic Treatment for Overactive Bladder
DAVID R. STASKIN, MD1, MARTIN C. MICHEL, PhD2.
1Tufts University School of Medicine, Boston, MA, USA, 2University of Amsterdam, Amsterdam, Netherlands.

Background: Although substantial placebo (PBO) responses are common in trials of antimuscarinics in subjects with overactive bladder (OAB), the effect of more complex PBO responses on outcomes of trials evaluating voluntary dose escalation is unclear. In this post hoc analysis, we compared baseline values, initial responses, and complex dual PBO responses in subjects who chose dose escalation vs those who did not in a large flexible-dose trial.
Methods: In a randomized, double blind, 12-wk study, subjects with OAB symptoms were randomized to fesoterodine 4 mg or PBO once daily.1 At wk 2, subjects chose to maintain dose or escalate to 8 mg (sham escalation for PBO). Subjects completed 3-d bladder diaries, the Patient Perception of Bladder Condition (PPBC), and Urgency Perception Scale (UPS) at baseline and wks 2, 6, and 12, and the Overactive Bladder Questionnaire (OAB-q) at baseline and wk 12.
Results: PBO escalators (PBO+E; n=325 [73%]) had marginally more severe OAB symptoms and worse OAB symptom bother and health-related quality of life at baseline than PBO nonescalators (PBO-NE; n=120 [27%]; Table). During the 2 wk before dose escalation, median % improvement in diary variables were about twice as large in PBO-NE vs PBO+E, and a greater proportion of PBO-NE showed improvement on the PPBC and UPS. There was little additional improvement in diary variables in PBO-NE after 2 wk, while improvement in most variables doubled in PBO+E after sham dose escalation. The percentage of subjects reporting improvement on the PPBC and UPS after wk 2 was similar between groups. Overall improvements in diary variables and patient-reported outcomes (PROs) were generally larger in PBO-NE at wk 12. Rates of dry mouth (10% vs 7%), constipation (8% vs 5%), and study discontinuation (27% vs 9%) were higher in PBO-NE.
Conclusions: The majority of PBO subjects opted for dose escalation. Diary variable and PRO responses were generally greater in PBO subjects content with their response at 2 wk compared with PBO subjects who opted to escalate and received “more” PBO. These results should be accounted for when designing placebo-controlled antimuscarinic trials evaluating voluntary dose escalation.
1Staskin et al. Neurourol Urodyn. 2009;28(2):145.

Table. Bladder Diary and PRO Results in Placebo Nonescalators (n=120) and Escalators (n=325)*
Baseline MeanChange at Week 2Change at Week 6Change at Week 12
PBO-NEPBO+EPBO-NEPBO+EPBO-NEPBO+EPBO-NEPBO_E
Micturitions/24 h13.013.0-2.3
(-19.4)
-0.9
(-6.5)
-2.2
(-17.9)
-1.9
(-13.9)
-2.4
(-22.0)
-2.0
(-12.5)
UUI episodes/24 h2.02.3-1.2
(-100.0)
-0.8
(-50.0)
-1.1
(-100.0)
-1.2
(-81.8)
-1.3
(-100.0)
-1.2
(-77.8)
Urgency episodes/24 h9.19.2-3.6
(-42.1)
-1.1
(-10.3)
-4.2
(-48.3)
-2.5
(-21.4)
-4.4
(-50.0)
-2.5
(-24.2)
Nocturnal micturitions/24 h2.72.7-0.9
(-33.3)
-0.3
(-14.3)
-0.9
(-33.3)
-0.6
(-25.0)
-1.0
(-40.0)
-0.6
(-20.0)
Severe urgency episodes/24 h†‡4.34.8-2.6
(-70.5)
-1.2
(-30.2)
-2.4
(-80.0)
-2.1
(-60.0)
-2.7
(-63.3)
-2.0
(-53.8)
PPBC--63.842.366.956.873.755.2
UPS--28.221.032.829.336.129.0
OAB-q Symptom Bother§56.159.2-----29.2-17.1
OAB-q HRQL§57.453.9----27.216.3
HRQL = health-related quality of life; UUI = urinary urgency incontinence.
*Diary variable data represent least squares mean change (median % change) from baseline; PPBC and UPS data represent % of subjects with improvement from baseline; OAB-q data represent least squares mean change from baseline.
Includes only subjects reporting the symptom at baseline.
Defined by a rating of ≥4 on the Urinary Sensation Scale.
§Lower Symptom Bother scores indicate less symptom bother, higher HRQL scores indicate better HRQL.

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