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Keywords:

  • antimuscarinic;
  • lower urinary tract symptoms;
  • micturition;
  • muscarinic antagonists;
  • urinary incontinence

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Aims

To assess the long-term safety, tolerability, and efficacy of flexible-dose fesoterodine in elderly patients with OAB.

Methods

Patients aged ≥65 years who completed a 12-week, randomized, double-blind, placebo-controlled trial were eligible for the 12-week, open-label (OL) extension phase. Patients who received double-blind placebo started on fesoterodine 4 mg and could increase to 8 mg after 4 or 8 weeks of OL treatment, while fesoterodine-treated patients continued on their double-blind dose; only one dose escalation or de-escalation was permitted. Discontinuations and adverse events (AEs) were monitored, and patients completed 3-day bladder diaries and patient-reported outcomes at the beginning and end of the 12-week OL phase.

Results

Six hundred fifty-four patients entered the 12-week OL extension (mean age 72 years; 52% women). AEs were reported by 30.7% and 48.1% of patients who had received double-blind fesoterodine and placebo, respectively; 1.9% and 9.4%, discontinued due to AEs, respectively. Patients who received double-blind fesoterodine maintained their efficacy response. After 12 weeks of OL treatment, efficacy outcomes in patients who received double-blind placebo were similar to those who had received double-blind fesoterodine. On average, the efficacy response was maintained for the duration of the study.

Conclusions

Fesoterodine was well tolerated and improvements in OAB symptoms and quality of life measures were not diminished with longer-term treatment of patients aged ≥65 years. Neurourol. Urodynam. 33:106–114, 2014. © 2013 Wiley Periodicals, Inc.


Abbreviations
AEs

adverse events

DB

double-blind

HRQL

health-related quality of life

OAB

overactive bladder

OAB-q

overactive bladder questionnaire

OAB-S

overactive bladder satisfaction questionnaire

OL

open label

PPBC

patient perception of bladder condition

PROs

patient-reported outcomes

SOFIA

study of fesoterodine in an aging population

TBS

treatment benefit scale

UPS

urgency perception scale

USS

urinary sensation scale

UUI

urgency urinary incontinence

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

The prevalence of overactive bladder (OAB) increases with age,[1-3] as does bother associated with OAB symptoms.[4] In older individuals, OAB symptoms are associated with reduced health-related quality of life (HRQL), impairment in activities of daily living, depression, urinary tract infections, falls and fractures, and perhaps institutionalization and mortality.[5-8]

Treatment of OAB in older patients with antimuscarinics, the first-line pharmacological treatment for OAB symptoms, may be limited by concerns regarding safety and tolerability.[9] Few studies have prospectively examined the response of elderly patients to antimuscarinic therapy; much of the data on OAB treatment in the elderly derives from post hoc analyses of pooled data from clinical trials. Most available data are therefore from relatively healthy individuals aged ≥65 years, without further age stratification, and thus may be of limited relevance to the elderly patients of greatest concern in clinical practice.[9] Additionally, to date there is only one report in which the efficacy and tolerability of antimuscarinics in elderly patients has been assessed for longer than 12 weeks.[10]

The Study of Fesoterodine in an Aging population (SOFIA) trial was a randomized, double-blind, placebo-controlled, prospective trial of flexible-dose fesoterodine 4 and 8 mg in 794 patients aged ≥65 years conducted at 61 sites in 15 countries.[11] The study had an enrolment target of approximately 30% of patients aged >75 years, and randomization to fesoterodine or placebo was stratified by age (≤75 and >75 years). Approximately one-third of the patients in the SOFIA trial were aged >75 years, and nearly one-half were men. Significant improvements versus placebo in primary (urgency) and secondary (severe urgency, micturitions, nocturnal micturitions, incontinence pad use) diary endpoints and patient-reported outcomes (PROs) measuring symptom bother and HRQL were observed in the fesoterodine-treated group, and response rates on measures of treatment benefit and satisfaction were significantly higher with fesoterodine.[11] Assessment of patients stratified by age showed that improvements in most diary variables and PROs were greater with fesoterodine versus placebo in both patients aged ≤75 and >75 years, and similar rates of adverse events and discontinuations were observed in both age groups. There were no changes in Mini-Mental State Examination score and very few adverse cognitive events were reported in either the fesoterodine or placebo groups.[11]

Here we report the results from a 12-week open-label phase that followed the double-blind treatment phase of the SOFIA trial.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Study Design and Patients

This was an open-label extension of a 12-week, double-blind, placebo controlled, parallel group, multicentre study (ClinicalTrials.Gov ID NCT00798434). Details of the double-blind study have been described.[11] Briefly, adults aged ≥65 years with self-reported OAB symptoms for ≥3 months, a mean of ≥8 micturitions and ≥3 urgency episodes/24 hr on a 3-day bladder diary, at least “some moderate problems” on the Patient Perception of Bladder Condition (PPBC), and a Mini-Mental State Examination score ≥20 at double-blind baseline were randomized to double-blind fesoterodine or placebo for 12 weeks, with equal stratification by age (>75 years/≤75 years) and dosing time (morning/evening). Patients randomized to fesoterodine started on 4 mg and could increase to 8 mg at weeks 4 or 8 and de-escalate to 4 mg at week 8, with sham escalation for patients randomized to placebo. Patients who completed the double-blind phase were eligible to receive open-label treatment.

Upon entry into the open-label phase, patients who had received double-blind placebo (DB placebo/OL fesoterodine) received fesoterodine 4 mg with an option to increase to 8 mg after 4 or 8 weeks of open-label treatment (i.e., weeks 16 or 20 of the trial), while patients who had received double-blind fesoterodine (DB fesoterodine/OL fesoterodine) continued on the same dose during the open-label phase. Only one dose increase to the 8-mg dose and one decrease back to 4 mg after escalation to the 8-mg dose were permitted.

The study protocol was approved by the appropriate ethics committees, with patients providing written informed consent prior to their participation, and was conducted in accordance with the International Conference on Harmonisation guidelines on Good Clinical Practice, the Declaration of Helsinki, and local regulations.

Outcome Measures

Safety and tolerability were assessed by the incidence, severity, and relatedness to treatment of all reported and treatment-emergent adverse events (AEs); trial withdrawals due to AEs; and vital signs. Efficacy was assessed by 3-day bladder diaries, in which patients recorded all micturitions and rated the sensation associated with each micturition using the 5-point Urinary Sensation Scale (USS; 1 = no urgency; 2 = mild urgency; 3 = moderate urgency; 4 = severe urgency; 5 = urgency urinary incontinence [UUI]).[12] Patients also completed the Treatment Benefit Scale (TBS), PPBC, Urgency Perception Scale (UPS), eight items from the Overactive Bladder Satisfaction Questionnaire (OAB-S; question 5 from the medication expectations subscale and questions 9, 10a–10d, and 11a–11b from the satisfaction with OAB control subscale), and Overactive Bladder Questionnaire (OAB-q). The TBS is a single-item instrument on which patients rate their condition as “greatly improved,” “improved,” “not changed,” or “worsened” during treatment.[13] The PPBC is a single-item, six-point scale where patients rate the severity of their bladder-related problems from “no problems at all” to “many severe problems.”[14] The UPS is a single-item scale patients use to rate the sensation typically associated with micturitions; response options include “I am usually not able to hold urine”; “I am usually able to hold urine until I reach the toilet if I go immediately,” and “I am usually able to finish what I am doing before going to the toilet.”[15] The OAB-S items administered measure, on five-point scales, the degree to which medication met patients' expectations (from “greatly exceeds” to “does not meet” expectations) and to which patients were satisfied with OAB treatment (from “very satisfied to “very dissatisfied”).[16] Lastly, the OAB-q is comprised of an 8-item Symptom Bother scale and 25-item HRQL scale, with four HRQL domains (Coping, Concern, Sleep and Social Interaction).[17] Patients in the 12-week open-label phase completed bladder diaries and patient-reported outcomes at the beginning (i.e., week 12 of the trial) and end (i.e., week 24 of the trial) of open-label treatment.

Statistics

Descriptive statistics were used to analyse all endpoints, and no formal statistical tests were performed, as all patients were on open-label fesoterodine and there were no statistical hypotheses to test. The safety analysis set was comprised of all those who took ≥1 dose of open-label fesoterodine. Efficacy was assessed in the full analysis set, which consisted of all patients that took ≥1 dose of open-label fesoterodine and had ≥1 efficacy measurement. Patients using concomitant antimuscarinics in violation of the protocol (n = 12/654; 2%) were not excluded, since they met OAB randomization criteria and full analysis set inclusion criteria.

For the 12-week open-label phase, mean changes from double-blind baseline to week 24 and from week 12 to 24 in urgency episodes, severe urgency episodes, micturitions, nocturnal micturitions, UUI episodes, and number of incontinence pads used per 24 hr were determined for patients in the DB fesoterodine/OL fesoterodine and DB placebo/OL fesoterodine groups. For PROs, patients reporting that their condition was “improved” or “greatly improved” on the TBS, that OAB medication “met” or “somewhat” or “greatly exceeded my expectation” (question 5) or that they were “very” or “somewhat satisfied” (questions 9, 10a–10d, and 11a–11b) on the OAB-S, and who showed ≥1-point improvement on the PPBC or UPS were considered responders for those respective instruments. The proportion of responders on the TBS and OAB-S from week 0 (double-blind baseline) to week 24 (end of open-label treatment) and on the PPBC and UPS from week 12 (end of double-blind treatment) to week 24 (end of open-label treatment) were assessed, as were changes in scores on OAB-q scales and domains from week 12 to 24.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Patients

A total of 655 patients completed the double-blind phase, and of these, 654 and 581 patients entered and completed the 12-week open-label extension, respectively (Table I). Overall, men and women were equally represented (F, n = 343/654, 52.4%; M, n = 311/654, 47.6%), and nearly one third of subjects were aged >75 years. The mean entry age was 72.4 years (range 65–90 years). At double-blind baseline, concomitant medications were used by 93.6% and 90.3% of patients randomized to fesoterodine and placebo, respectively. Types of concomitant medications were typical for an elderly subject population, with use of renin-angiotensin system modifiers, analgesics, antithrombotics, and serum lipid reducers each in approximately 30% or more of the patients (Table II).

Table I. Subject Disposition and Incidence of Treatment-Emergent Adverse Events
 OverallWomenMen65–75 Years>75 Years
DB PBO/OL FESO (n = 341)DB FESO/OL FESO (n = 313)DB PBO/OL FESO (n = 174)DB FESO/OL FESO (n = 169)DB PBO/OL FESO (n = 167)DB FESO/OL FESO (n = 144)DB PBO/OL FESO (n = 233)DB FESO/OL FESO (n = 213)DB PBO/OL FESO (n = 108)DB FESO/OL FESO (n = 100)
  • DB, double-blind; FAS, full analysis set; FESO, fesoterodine; OL, open-label; PBO, placebo; TEAE, treatment-emergent adverse event.

  • a

    All-causality TEAEs reported by ≥2% of patients in either treatment group (overall) during the 12-week open-label phase.

Enrolled, n341313174169167144233213108100
Treated, n341313174169167144233213108100
Safety population, n341313174169167144233213108100
FAS population, n33330517116516214023121010295
Discontinued, n, %42 (12.3)31 (9.9)16 (9.2)14 (8.3)26 (15.6)17 (11.8)24 (10.3)19 (8.9)18 (16.7)12 (12.0)
AEs33 (9.7)11 (3.5)12 (6.9)7 (4.2)21 (12.6)4 (2.8)18 (7.7)9 (4.2)15 (13.9)2 (2.0)
Withdrawn consent2 (0.6)7 (2.2)1 (0.6)1 (0.6)1 (0.6)6 (4.2)02 (0.9)2 (1.9)5 (5.0)
Lack of efficacy5 (1.5)11 (3.5)3 (1.7)6 (3.6)2 (1.2)5 (3.5)5 (2.1)8 (3.8)03 (3.0)
Protocol violation1 (0.3)0001 (0.6)01 (0.4)000
Lost to follow-up0000000000
Other1 (0.3)2 (0.6)001 (0.6)2 (1.4)001(0.9)2 (2.0)
Completed, n (%)299 (87.7)282 (90.1)158 (90.8)155 (91.7)141 (84.4)127 (88.2)209 (89.7)194 (91.1)90 (83.3)88 (88.0)
Patients with AEs, n (%)
All causalities164 (48.1)96 (30.7)90 (51.7)59 (34.9)74 (44.3)37 (25.7)105 (45.1)70 (32.9)59 (54.6)26 (26.0)
Treatment-related138 (40.5)42 (13.4)81 (46.6)30 (17.8)57 (34.1)12 (8.3)93 (39.9)34 (16.0)45 (41.7)8 (8.0)
Patients with serious AEs, n (%)
All causalities7 (2.1)11 (3.5)3 (1.7)7 (4.1)4 (2.4)4 (2.8)3 (1.3)7 (3.3)4 (3.7)4 (4.0)
Treatment-related3 (0.9)01 (0.6)02 (1.2)01 (0.4)02 (1.9)0
Patients with severe AEs, n (%)
All causalities14 (4.1)13 (4.2)7 (4.0)9 (5.3)7 (4.2)4 (2.8)8 (3.4)9 (4.2)6 (5.6)4 (4.0)
Treatment-related12 (3.5)4 (1.3)6 (3.4)3 (1.8)6 (3.6)1 (0.7)7 (3.0)3 (1.4)5 (4.6)1 (1.0)
Most common TEAEs, n (%)a
Dry mouth95 (27.9)21 (6.7)66 (37.9)15 (8.9)29 (17.4)6 (4.2)63 (27.0)16 (7.5)32 (29.6)5 (5.0)
Constipation21 (6.2)5 (1.6)11 (6.3)2 (1.2)10 (6.0)3 (2.1)15 (6.4)4 (1.9)6 (5.6)1 (1.0)
Urinary tract infection4 (1.2)14 (4.5)3 (1.7)12 (7.1)1 (0.6)2 (1.4)4 (1.7)8 (3.8)06 (6.0)
Hypertension7 (2.1)2 (0.6)6 (3.4)01 (0.6)2 (1.4)5 (2.1)2 (0.9)2 (1.9)0
Headache7 (2.1)04 (2.3)03 (1.8)07 (3.0)000
Table II. Baseline Demographics and Concomitant Medications
 DB PBO/OL FESO (n = 341)DB FESO/OL FESO (n = 313)
  • CI, confidence interval; DB, double-blind; OL, open-label.

  • a

    At double-blind study baseline; UUI data presented as medians.

  • b

    Includes only patients with >0 UUI episodes or incontinence pad use at baseline.

  • c

    Includes medications used by ≥5% of patients in either treatment group in the 12-week open label phase.

  • d

    Included anastrozole, oestradiol, oestrogens, and tamoxifen.

  • e

    Included bromocriptine mesilate, ibuprofen, methotrexate, misoprostol, and naproxen.

  • f

    Included kliogest “novo industri,” oestradiol, oestranorm, oestriol, oestrogens, prempak, progesterone, promestriene, testosterone, and tibolone.

  • g

    Included 5-α reductase inhibitors, α blockers, herbals, minerals, muscarinic receptor antagonists, phosphodiesterase type 5 inhibitors, and vasodilators. Patients using muscarinic antagonists (n = 12/654) were included in the analysis.

Mean (SD) age, years72.7 (5.6)72.3 (5.7)
≤75 years, n (%)233 (68.3)213 (68.1)
>75 years, n (%)108 (31.7)100 (31.9)
Gender, n (%)
Male167 (49.0)144 (46.0)
Female174 (51.0)169 (54.0)
Race, n (%)
White340 (99.7)312 (99.7)
Black1 (0.3)0
Other01 (0.3)
OAB symptoms at baseline, mean (95% CI)a
Urgency episodes/24 hr8.8 (8.4, 9.2)8.5 (8.1, 8.9)
Severe urgency episodes/24 hr4.1 (3.7, 4.5)3.5 (3.2, 3.9)
Micturitions/24 hr12.1 (11.8, 12.4)11.9 (11.6, 12.2)
Nocturnal micturitions/24 hr2.9 (2.8, 3.1)2.8 (2.7, 2.9)
UUI episodes/24 hr (median)b1.71.3
Incontinence pad use/24 hrb3.3 (2.8, 3.8)2.8 (2.5, 3.2)
Concomitant medicationsc
Renin-angiotensin system agents128 (37.5)119 (38.0)
Analgesics112 (32.8)105 (33.5)
Antibacterials for systemic use31 (9.1)43 (13.7)
Antidiarrheals, intestinal anti-inflammatory/antiinfective agents28 (8.2)23 (7.3)
Antiepileptics11 (3.2)9 (2.9)
Antihypertensives21 (6.2)20 (6.4)
Anti-inflammatory and anti-rheumatic products39 (11.4)41 (13.1)
Antithrombotic agents118 (34.6)97 (31.0)
Beta blocking agents75 (22.0)78 (24.9)
Calcium channel blockers64 (18.8)67 (21.4)
Cardiac therapy46 (13.5)24 (7.7)
Corticosteroids for systemic use20 (5.9)15 (4.8)
Corticosteroids, dermatological preparations26 (7.6)22 (7.0)
Diuretics40 (11.7)37 (11.8)
Drugs for acid-related disorders71 (20.8)75 (24)
Drugs for functional gastrointestinal disorders9 (2.6)10 (3.2)
Drugs for obstructive airway diseases36 (10.6)29 (9.3)
Drugs for treatment of bone diseases22 (6.5)22 (7.0)
Drugs used in diabetes37 (10.9)38 (12.1)
Endocrine therapyd9 (2.6)22 (7.0)
Laxatives11 (3.2)18 (5.8)
Mineral supplements30 (8.8)33 (10.5)
Nasal preparations27 (7.9)21 (6.7)
Ophthalmological and otological preparations7 (2.1)19 (6.1)
Ophthalmologicals45 (13.2)59 (18.8)
Other gynaecologicalse18 (5.3)14 (4.5)
Psychoanaleptics36 (10.6)37 (11.8)
Psycholeptics35 (10.3)38 (12.1)
Serum lipid reducing agents95 (27.9)101 (32.3)
Sex hormones and modulators of the genital systemf24 (7.0)33 (10.5)
Stomatological preparations91 (26.7)82 (26.2)
Thyroid therapy36 (10.6)27 (8.6)
Topical products for joint and muscular pain27 (7.9)27 (8.6)
Urologicalsg55 (16.1)51 (16.3)
Vasoprotectives20 (5.9)21 (6.7)

Safety and Tolerability

Duration of exposure

The overall median duration of exposure to placebo and/or fesoterodine from baseline to week 24 was 168 days for both open-label treatment groups in the 12-week open-label extension study. During the open-label phase, the median duration of exposure to fesoterodine was 84 days.

Of the patients previously treated with fesoterodine during the double-blind phase, 60.1% were receiving 8 mg/day at the start of the 12-week open-label phase. At 4 weeks of open-label treatment (week 16), 50.9% of patients in the DB placebo/OL fesoterodine group opted to receive 8 mg/day. After 8 weeks of open-label treatment (week 20) a similar proportion of patients in both treatment groups chose to receive 8 mg/day (DB placebo/OL fesoterodine, 50.8%: DB fesoterodine/OL fesoterodine, 52.7%).

Treatment discontinuations

Discontinuation rates in the DB placebo/OL fesoterodine group (n = 42/341, 12.3%) were slightly higher than in the DB fesoterodine/OL fesoterodine group (n = 31/313, 9.9%) during the 12-week open-label study, particularly among men and among patients aged >75 years (Table I). The majority of discontinuations were due to AEs, insufficient clinical response, and withdrawn consent (Table I).

Adverse events

The overall proportion of patients experiencing AEs in the 12-week open-label phase (260/654, 39.8%) was similar to that of patients receiving placebo in the double-blind phase (142/393, 36.1%).[11] Patients in the DB placebo/OL fesoterodine group reported more all-causality and treatment-related AEs, although the proportions of patients with serious or severe AEs were approximately equal in both treatment groups (Table I). The most frequent all-causality treatment emergent AEs in the DB placebo/OL fesoterodine group were dry mouth (n = 95/341, 27.9%) and constipation (n = 21/341, 6.2%), while dry mouth was most prevalent in the DB fesoterodine/OL fesoterodine group (n = 21/313, 6.7%). The most common treatment emergent AEs reported during the 12-week open-label phase occurred with greater frequency in the DB placebo/OL fesoterodine group, except for urinary tract infection (Table I). Women tended to report higher rates of AEs than men, but overall AE rates did not appear to differ by age. Most treatment emergent AEs were of mild or moderate intensity, and dry mouth was the most frequent severe treatment emergent AE (DB placebo/OL fesoterodine group, n = 4/341; DB fesoterodine/OL fesoterodine, n = 3/313).

The proportion of patients who withdrew due to all-causality treatment emergent AEs was higher in the DB placebo/OL fesoterodine group (n = 32/341, 9.4%) than the DB fesoterodine/OL fesoterodine group (n = 6/313, 1.9%). The majority of these AEs were treatment-related (DB placebo/OL fesoterodine group, n = 31/341, 9.1%; DB fesoterodine/OL fesoterodine group, n = 4/313, 1.3%). Dry mouth was the most frequent AE leading to discontinuation (DB placebo/OL fesoterodine group, n = 7/341, 2.1%; DB fesoterodine/OL fesoterodine group, n = 3/313, 1.0%). Other AEs leading to discontinuation in two or more patients in either treatment group were constipation (n = 3/341, 0.9%), decreased urinary flow (n = 3/341, 0.9%), and urinary hesitation (n = 2/341, 0.6%), all of which were observed only in the DB placebo/OL fesoterodine group. Additionally, 3 (0.9%) patients (all men) in the DB placebo/OL fesoterodine group discontinued due to urinary retention: a 73-year-old male receiving fesoterodine 4 mg who was not catheterized, a 73-year-old male with a history of catheterization receiving fesoterodine 4 mg who was catheterized, and a 70-year-old male receiving fesoterodine 8 mg who was catheterized. There were two patients with urinary retention who did not discontinue treatment. One was a 67-year-old male in the DB fesoterodine/OL fesoterodine group with benign prostatic hyperplasia receiving fesoterodine 8 mg; this subject's dose was reduced to 4 mg. The other subject was a 66-year-old male in the DB placebo/OL fesoterodine group with benign prostatic hyperplasia receiving fesoterodine 8 mg.

Efficacy outcomes

Treatment responses were maintained for diary endpoints in the 12-week open-label phase for patients in the DB fesoterodine/OL fesoterodine group, while patients in the DB placebo/OL fesoterodine group exhibited noticeable improvements during the open-label phase; this was the case for all diary endpoints except for UUI episodes/24 hr (Fig. 1). Mean changes from double-blind baseline in diary variables were similar for both groups at week 24; this was observed in both men and women and in patients aged ≤75 and >75 years (Table III). A similar pattern of results was generally observed for PROs during the 12-week open-label extension. The percentage of responders at the end of 12-week open-label treatment with improvement on the TBS, and those with favorable responses on the OAB-S for meeting treatment expectations and overall satisfaction, was similar for both groups (Fig. 2). Improvements in PPBC and UPS scores from week 12 to 24 were greater for patients in the DB placebo/OL fesoterodine group, and noticeable improvements in OAB-q Symptom Bother and total HRQL scores and all HRQL domain scores occurred in the DB placebo/OL fesoterodine group during the open-label phase (Fig. 2).

image

Figure 1. Mean (95% CI) changes per 24 hr in 3-day diary variables from double-blind baseline to weeks 12 and 24 for (A) urgency episodes; (B) severe urgency episodes; (C) micturitions; (D) nocturnal micturitions; and (F) number of incontinence pads used and median changes in (E) UUI episodes. BL, baseline; CI, confidence interval; DB, double blind; OL, open-label.

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Table III. Week 24 Outcomes in Patients by Sex and Age
 WomenMen65–75 years>75 years
DB PBO/OL FESO (n = 171)DB FESO/OL FESO (n = 165)DB PBO/OL FESO (n = 162)DB FESO/OL FESO (n = 140)DB PBO/OL FESO (n = 231)DB FESO/OL FESO (n = 210)DB PBO/OL FESO (n = 102)DB FESO/OL FESO (n = 95)
  • Diary data presented as mean (95% CI) change from baseline to week 24 (except for UUI, presented as median); TBS data represent percentage of responders at week 24; PPBC and UPS data represent percentage of patients with improvement from week 12 to 24; OAB-q data represent mean (95% CI) change from week 12 to 24.

  • CI, confidence interval; FESO, fesoterodine; HRQL, health-related quality of life; OAB-q, overactive bladder questionnaire; PBO, placebo; PPBC, patient perception of bladder condition; TBS, treatment benefit scale; UPS, urgency perception scale; UUI, urgency urinary incontinence.

  • a

    Includes only subjects with >0 UUI episodes on baseline diary.

  • b

    Includes only subjects using incontinence pads at baseline.

Diary variable/24 hr
Urgency episodes, mean (95% CI)−4.4 (−5.2, −3.6)−4.0 (−4.6, −3.4)−4.1 (−4.7, −3.4)−4.2 (−4.9, −3.4)−4.6 (−5.1, −4.0)−4.1 (−4.7, −3.5)−3.6 (−4.5, −2.6)−4.0 (−4.7, −3.3)
Severe urgency episodes, mean (95% CI)−3.3 (−4.0, −2.5)−2.7 (−3.2, −2.2)−1.9 (−2.4, −1.3)−2.1 (−2.6, −1.6)−2.4 (−2.9, −2.0)−2.3 (−2.7, −1.9)−2.9 (−4.0, −1.8)−2.6 (−3.4, −1.9)
Micturitions, mean (95% CI)−2.4 (−2.8, −1.9)−2.3 (−2.7, −1.9)−2.2 (−2.6, −1.8)−2.4 (−2.9, −2.0)−2.4 (−2.8, −2.1)−2.3 (−2.7, −2.0)−2.0 (−2.5, −1.4)−2.4 (−2.9, −1.9)
Night-time micturitions, mean (95% CI)−0.6 (−0.8, −0.5)−0.6 (−0.8, −0.4)−0.6 (−0.8, −0.4)−0.7 (−0.9, −0.5)−0.6 (−0.8, −0.4)−0.6 (−0.7, −0.4)−0.7 (−0.9, −0.4)−0.9 (−1.1, −0.6)
UUI episodes, mediana−1.3−1.3−1.0−0.7−1.0−1.0−1.3−1.3
Incontinence pad use, mean (95% CI)b−1.4 (−1.9, −0.9)−0.9 (−1.2, −0.5)−0.2 (−2.4, −2.0)−1.2 (−2.0, −0.4)−1.3 (−2.1, −0.5)−1.1 (−1.4, −0.7)−1.0 (−1.6, −0.4)−0.7 (−1.3, −0.1)
TBS responder, n (%)134 (81.2)131 (80.9)117 (74.1)103 (75.2)177 (79.4)160 (77.7)74 (74.0)74 (79.6)
OAB-S responder, n (%)
question 5109 (63.7)115 (69.7)99 (61.1)85 (60.7)152 (65.8)129 (61.4)56 (54.9)71 (74.7)
questions 9, 10a–10d and 11a–11b77 (45.0)76 (46.1)66 (40.7)55 (39.3)101 (43.7)87 (41.4)42 (41.2)44 (46.3)
PPBC responder, n (%)100 (58.8)48 (29.1)49 (35.0)71 (43.8)118 (51.3)61 (29.0)53 (52.0)36 (37.9)
UPS responder, n (%)62 (36.7)36 (22.0)48 (29.6)22 (15.7)70 (30.4)40 (19.0)40 (39.6)18 (19.1)
OAB-q, mean (95% CI) change from week 12
Symptom Bother−13.9 (−17.2, −10.7)−3.1 (−6.6, −0.02)−6.9 (−9.4, −4.4)−0.8 (−3.5, 1.8)−9.5 (−12.1, −6.9)−1.4 (−3.6, 0.8)−12.8 (−16.4, −9.2)−3.5 (−8.0, 1.1)
HRQL total10.3 (7.6, 13.0)2.9 (0.6, 5.2)4.4 (2.3, 6.5)2.4 (0.1, 4.7)6.2 (4.3, 8.1)2.0 (0.2, 3.8)10.2 (6.4, 14.0)4.1 (0.8, 7.5)
Coping11.9 (8.7, 15.1)4.1 (1.5, 6.7)6.0 (3.3, 8.6)3.5 (0.7, 6.3)7.5 (5.2, 9.8)3.2 (1.1, 5.4)12.5 (8.1, 16.8)5.1 (1.2, 9.0)
Concern10.4 (7.2, 13.7)1.4 (−1.1, 3.8)5.1 (2.7, 7.4)2.1 (−0.5, 4.7)6.6 (4.4, 8.7)0.8 (−1.2, 2.9)10.7 (6.2, 15.2)3.5 (−0.0, 7.1)
Sleep10.6 (7.3, 13.9)3.6 (1.1, 6.2)3.8 (1.3, 6.3)2.8 (−0.2, 5.8)5.8 (3.5, 8.1)3.0 (0.8, 5.3)10.5 (6.1, 15.0)3.8 (−0.01, 7.6)
Social interaction6.9 (4.4, 9.4)2.4 (0.1, 4.8)1.5 (−0.7, 3.8)0.7 (−1.5, 2.8)3.8 (2.0, 5.6)0.7 (−1.1, 2.5)5.4 (1.6, 9.2)3.6 (0.2, 6.9)
image

Figure 2. Patient-reported outcomes for (A) response rates on the TBS, PPBC, UPS, and OAB-S (medication expectation and satisfaction with OAB control) instruments, and (B) mean (95% CI) changes in OAB-q Symptom Bother and HRQL scale and domain scores from the beginning to the end of open-label treatment in the SOFIA open-label extension phase. CI, confidence interval; HRQL, health-related quality of life; OAB, overactive bladder; OAB-q, overactive bladder questionnaire; OAB-S, overactive bladder satisfaction questionnaire; PPBC, patient perception of bladder condition; TBS, treatment benefit scale; UPS, urgency perception scale.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

This prospective, open-label extension study in the elderly reinforces the safety, tolerability, and efficacy of flexible-dose fesoterodine over an extended treatment period. Dry mouth and constipation were the most frequently observed AEs, and occurred in the DB placebo/OL fesoterodine group at rates similar to those in the DB fesoterodine/OL fesoterodine group during the double-blind phase of the SOFIA study (33.9% and 8.9%, respectively).[11] Although the types and rates of AEs observed most frequently (dry mouth, constipation, and urinary tract infection) were similar to those seen in other studies of fesoterodine in the elderly[10, 18-20] the rates of dry mouth and constipation were lower in patients treated with fesoterodine over the entire 24 weeks. This may suggest that tolerance to these AEs developed, that the option to adjust the dose mitigated the expression of these bothersome AEs, and/or that attrition of patients with these AEs occurred during the double-blind phase. Notably, the rate of urinary retention was low in the 12-week open-label phase, and all those who discontinued due to urinary retention (n = 3) had received placebo during the double-blind phase. These data are consistent with a retrospective database study in suggesting that when urinary retention occurs in men treated with antimuscarinics, it is most likely to occur within 14–30 days after initiation of treatment.[21] Similarly, a pooled post-hoc analysis of data from men in two fixed-dose studies of fesoterodine 4 (n = 120) and 8 (n = 114) mg showed that urinary retention occurred mainly in men ≥66 years of age receiving fesoterodine 8 mg, within 14 days of initiating treatment; only one subject was catheterized.[22]

Improvements in diary variables and PROs occurred in patients switched to fesoterodine, and were maintained in patients previously treated with fesoterodine, throughout the duration of the 12-week open-label phase. The lack of effect on UUI episodes is consistent with the data from the double-blind phase of the SOFIA study and is likely due to the lower rate of UUI episodes at baseline than in previous studies of fesoterodine in elderly patients.[10, 18, 19]

This study extends previous observations of the safety, tolerability, and efficacy of fesoterodine in elderly patients,[10, 11, 18-20] as this is the first study prospectively designed to assess antimuscarinic treatment in elderly patients for longer than 12 weeks. Additionally, the proportion of patients who were aged >75 years was higher than in previous studies. A pooled post-hoc analysis of data from two fixed-dose studies of fesoterodine 4 and 8 mg[23, 24] stratified by age found that treatment with 8 mg was required to obtain efficacy for diary and PROs in patients ≥75 years.[18] In open-label extensions of these two fixed-dose studies, patients received flexible-dose fesoterodine with efficacy measured for up to 2 years and safety/tolerability monitored for up to 3 years. A pooled analysis of data from these studies showed that significant improvements in diary variables were maintained with extended fesoterodine treatment (mean of 20 months) in different age groups, although the stratification of patients by age was conducted post hoc and there were relatively few patients aged ≥75 years.[10] Patients ≥75 years of age tended to select the higher 8-mg dose and were least likely to de-escalate to the 4-mg dose,[10, 18] suggesting that older patients may need higher doses of antimuscarinic agents to achieve symptom relief than younger patients. The majority (≥85%) of patients in the 65–74 years and ≥75 years age groups reported “good” or “excellent” treatment tolerance across time, and no age-based trends for treatment-related AEs was observed.[10]

The equal representation of men and women is a particular strength in the 12-week open-label extension phase, and is more typical of the epidemiological prevalence of OAB in the elderly.[2-4] Further, patients >75 years of age were well represented, with approximately one-third being >75 years of age. The design of the 12-week open-label extension allowed a within-study comparison of 12 versus 24 weeks of treatment with fesoterodine, since patients were immediately enrolled from the double-blind to the open-label phase. As expected in a clinical trial setting, persistence with drug was much higher than might occur in routine clinical practice where after 1 month, only approximately 50% of individuals remain on treatment. Older people, however, do appear to have higher persistence rates for bladder antimuscarinics.[25]

The study conclusions are potentially limited by the open-label trial design, so that direct evaluation of the placebo effect on treatment response is not possible. Although initial attrition in the 12-week open-label phase was minimized since patients moved directly from the double-blind to the open-label phase, completion of the double-blind phase was required for enrolment, suggesting that inclusion in the open-label assessment may have favoured those with better overall tolerability and response to fesoterodine.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Flexible-dose fesoterodine was well tolerated in elderly patients, and improvements in diary variables and patient-reported outcomes were achieved by the group previously treated with placebo and then maintained by both groups of older people. Long-term administration of flexible-dose fesoterodine is a safe and efficacious treatment option for management of OAB symptoms in the elderly.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Funding for this study was provided by Pfizer, Inc. Medical writing assistance was provided by Diane DeHaven-Hudkins, PhD and Colin Mitchell, PhD of Complete Healthcare Communications, Inc., and was funded by Pfizer, Inc.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES
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