SYSTEMATIC REVIEW
`
`IIE9 THE INTERNATIONALJOURNAL OF
`
`CLINICAL PRACTICE
`
`Flexible dosing with fesoterodine 4 and 8 mg: a
`systematic review of data from clinical trials
`
`J. J. Wyndaele,‘ T. Schneider? S. MacDiarmid,3 D. Scholfieldf‘ D. Arumi5
`
`‘Department of Urology,
`Universileit en Unlversitair
`Ziekenhuis Antwerpen,
`Antwerp, Belgium
`’Praxisklinik Urologie Rhein-
`Fluhr, Mulhelm, Germany
`3A||lance Urology Specialists,
`Greensboro, NC, USA
`‘Pfizer Ltd, Walton Oaks, UK
`5Pfizer Europe, Madrid, Spain
`
`Correspondence to:
`Jean-Jacques Wyndaele, MD,
`DSci, PhD, Department of
`Urology, Wilrijkstraat 10,
`Edegem, Antwerp B-2650,
`Belgium
`Tel: 3238213511
`Fax: 3235214479
`Email: jean-jacques.wyndae|e@
`ua.ac.be
`
`Disclosures
`JJW: None; TS: None;
`SM: Pflzen‘A||ergen.'Aste||as.'
`Uroplasty: consultantrspeaker,
`DS: Pfizer Ltd: employee;
`DA: Pfizer Europe: employee.
`
`SUMMARY
`
`Aims: To systematically review dose-escalation data from flexible-dose studies of
`fesoterodine and summarise factors associated with dose-escalation decisions.
`
`Methods: A Publl/led search was conducted using the terms (fesoterodine AND
`flexible dose), with no limits. Articles were included if they contained fesoterodine
`dose-escalation data for efficacy or safety outcomes or factors associated with
`dose-escalation decisions. Results: Of 13 articles identified by the search, 10 arti-
`cles (six clinical studies) met
`inclusion criteria.
`In flexible-dose trials of fesotero-
`dine, 51-63% of subjects initially receiving fesoterodine 4 mg opted for dose
`escalation to fesoterodine 8 mg, Escalators generally reported significantly more
`severe overactive bladder
`(OAB) symptoms, greater OAB symptom bother and
`worse health-related quality of
`life at baseline than non-escalators. Escalators
`demonstrated less treatment benefit with fesoterodine 4 mg than non-escalators.
`Non—escalators generally had a higher rate of dry mouth and constipation with
`fesoterodine 4 mg than escalators. The decision to escalate appeared to be deter-
`mined by the efficacyftolerability responses; fesoterodine escalators demonstrated
`a lower sensitivity (less efficacy and fewer adverse events) before their decision to
`escalate. By study end (Hi weeks after escalation decision), the efficacy and tol-
`erability profiles were similar in escalators and non-escalators. Conclusions: Data
`from flexible-dose studies provide strong evidence that fesoterodine provides treat-
`ment benefit to individual subjects with OAB because of its true dose—response
`effect.
`In clinical practice,
`it can be worthwhile to escalate to fesoterodine 8 mg
`in individual subjects who require additional efficacy benefit.
`
`Review criteria
`A PubMed search of the literature on flexible-dose
`fesoterodine was conducted. We summarised the
`dose—escalation data for efficacy and safety outcomes
`and factors associated with dose-escalation
`decisions.
`
`including elderly patients.
`
`Message for the clinic
`The results from clinical trials of flexibledose
`fesoterodine (4 and 8 mg) are consistent with the
`idea that the dose—response curve differs between
`individual patients. The dose—response effect of
`fesoterodine in the treatment of OAB symptoms
`provides clinicians with valuable information for
`achieving the optimal balance between efficacy and
`tolerability with a flexible-dose regimen in individual
`patients,
`
`Introduction
`
`Overactive bladder (OAB) is defined by the Interna-
`tional Continence Society as urgency, with or with-
`out urgency urinary incontinence (UUI). usually
`with daytime frequency and nocturia (1-2). OAB
`symptoms can have a marked negative impact on
`patient-reported
`health-related
`quality
`of
`life
`(HRQL) (3-5). The primary goals of phannacologic
`therapy for OAB are to relieve OAB symptoms and
`to improve HRQL (6).
`Fesoterodine, an antimuscarinic for the treatment
`
`of OAB symptoms. including UUI, urgency and fre-
`quency, was developed in two once-daily doses, 4
`and 8 mg, which provides dose flexibility for treat-
`ment
`individualisation (7-10). The recommended
`
`starting dose of fesoterodine is 4 mg once daily, but
`the dose may be increased to 8 mg once daily based
`on individual response and tolerability (11). With
`these two available doses, the fesoterodine dose can
`
`be adjusted to achieve the optimal therapeutic bal-
`ance between efficacy and tolerability based on each
`subject’s clinical response.
`trials, subjects with OAB
`In two phase 3 pivotal
`treated with fixed-dose fesoterodine 4 or 8 mg dem-
`onstrated significant improvement in OAB symptoms
`and HRQL compared with subjects treated with pla-
`cebo (9,10,12). A dose—response relationship was
`suggested by the generally greater efficacy of fesotero-
`dine 8 mg over fesoterodine 4 mg. A post hon: analy-
`sis of pooled phase
`3 data demonstrated that
`fesoterodine significantly decreased OAB symptoms,
`including UUI episodes, in a dose-dependent fashion,
`with fesoterodine 8 mg providing significant addi-
`tional benefit compared with fesoterodine 4 mg (13).
`Another post hoc analysis of pooled phase 3 data
`demonstrated that subjects with greater UUI severity
`at baseline had a significantly greater improvement
`with
`fesoterodine
`8 mg
`vs.
`fesoterodine
`4 mg,
`whereas the improvement
`in UUI between those
`
`(5) 2014 John Wiley Sr Sons Ltd
`l'ntJ Clfn Pract, July 2014, 63, 7, 830-840, doi: 10.1111rijcp,12425
`
`830
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2086 - 0001
`
`

`
`Flexible dosing with iesoterodine in OAB
`
`831
`
`receiving the 4-mg and 8—mg dose was not significant
`in subjects with less severe UUI severity at baseline
`(14).
`
`randomised, double-blind, placebo-
`A 12-week,
`(Evaluation of urinary urgency
`controlled trial
`Incontinence in patients Given fesoterodine 8 mg vs.
`fesoterodine 4 mg in a Head-to-head efficacy Trial;
`EIGHT) prospectively confirmed that fixed-dose feso-
`terodine 8 mg demonstrates significantly greater effi-
`cacy than fesoterodine 4 mg for
`reducing UUI
`episodes and other OAB symptoms (15). Significantly
`greater patient-reported improvements in symptom
`bother and HRQL with fesoterodine 8 mg vs. fesote-
`rodine 4 mg indicated that this difference in efficacy
`is clinically meaningful to patients with OAB (15).
`Although fixed-dose studies are valuable in defin-
`ing the dose—response effect of a drug, studies with a
`f1exible—dose design better reflect clinical practice (i.e.
`dosing decision based on the individual’s clinical
`response rather than prespecified dosing protocol)
`and the benefit/risk profile a treating clinician can
`expect for an individual patient. The purpose of this
`article is to systematically review dose-escalation data
`from flexible-dose studies of fesoterodine and sum-
`
`marise baseline characteristics and therapy response
`phenotypes of patients who may benefit
`from a
`higher dose of OAB medication.
`
`Methods
`
`This systematic review followed the recommenda-
`tions of the PRISMA statement
`(16). A PubMed
`search was conducted on 26 November 2013, using
`the terms (fesoterodine AND flexible dose), with no
`limits. The references cited in the retrieved articles
`also were scanned for additional articles. Articles
`
`were included if they contained fesoterodine dose-
`escalation data for efficacy or safety outcomes or fac-
`
`tors associated with dose-escalation decisions. Of the
`
`13 articles identified by the PubMed search, 10 arti-
`cles (six clinical studies) met inclusion criteria (Fig-
`ure 1).
`
`Results
`
`Randomised, double-blind, placebo-controlled
`trials
`
`CIim'calTriaI5.gov ID: NCT00536484
`A 12-week, double-blind, placebo-controlled trial
`evaluated the effects of flexible-dose fesoterodine in
`
`subjects aged 218 years who reported OAB symp-
`toms (17). Eligible subjects were randomised to feso-
`terodine 4 mg or placebo once daily. At the end of
`week 2, in consultation with the investigator, subjects
`could continue on fesoterodine 4 mg or increase the
`dose to 8 mg for the remaining 10 weeks (sham dose
`escalation for placebo). Of 883 subjects (fesoterodine,
`i“.! : 438; placebo, rt : 445) who received 3 1 dose of
`study medication, 87% completed the trial. At week
`2, 63% of the fesoterodine group and 73% of the
`placebo group chose dose escalation. At week 12,
`fesoterodine significantly decreased micturitions (pri-
`mary end—point), UUI episodes and urgency episodes
`per 24 h compared with placebo (all p < 0.05);
`decreases in nocturnal micturitions and nocturnal
`
`urgency episodes were not significant. Scores for all
`OAB Questionnaire
`(OAB—q)
`scales
`(Symptom
`Bother and total HRQL) and HRQL domains (Con-
`
`Interaction) were
`cern, Coping, Sleep and Social
`significantly improved with fesoterodine vs. placebo
`at week 12 (all p < 0.01). Fesoterodine treatment was
`generally well tolerated, with dry mouth and consti-
`pation the most common adverse events (Table 1).
`This flexible-dose trial was not designed to com-
`pare fesoterodine 4 mg and 8 mg, so post hoc analy-
`
`Additional records identified
`Records identified through
`
`database search
`through other sources
`(0 =13)
`(n =0)
`
`
`
`
`
`
`Records after duplicates removed
`(n =1 3)
`
`
`
`
`Full-text articles assessed
`
`for eligibility
`(n =13)
`
`Articles excluded (:1 = 3):
`No dose-escalation outcome
`
`Articles included in
`qualitative synthesis
`(n=10)
`
`
`
`
`
`
`
`
`Figure 1 PRISMA flow diagram
`
`© 2014 John Wiley St Sons Ltd
`i'ntJ Cfin Pract, July 20M, 58, 7, 830-840
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2086 - 0002
`
`

`
`B32
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`© 2014 John Wiley 8: Sons Ltd
`Int} Cfin Pratt, July 2014, 68
`
`7
`
`. 830-840
`
`Patent Owner, UCB Pharma GmbH — Exhi
`
`it 2086 - 0004
`
`

`
`B34
`
`Flexible dosing with fesoterodine in OAB
`
`ses were conducted to compare outcomes in subjects
`who chose to increase their
`fesoterodine dose to
`
`those who remained on 4 mg
`8 mg (escalators) vs.
`(non-escalators) (18). Baseline demographical charac-
`teristics were similar between escalators and non-
`
`escalators. Baseline disease severity appeared greater
`among escalators, with micturitions and urgency epi-
`sodes per 24 h in the fesoterodine group significantly
`higher among escalators vs. non—escalators. At week
`2, before the dose—escalation decision, subjects who
`subsequently chose fesoterodine dose escalation had
`significantly less improvement from baseline in mic-
`turitions and urgency episodes vs. non—escalators
`(both p < 0.001; Table 1). Improvement in UUI epi-
`sodes did not differ between fesoterodine escalators
`
`and non—escalators, whereas the diary-dry rate (i.e.
`proportion of subjects with 2 l UUI episode at base-
`line who report no UUI episodes at subsequent time
`point) was significantly lower among escalators at
`week 2 (p : 0.008). At week 2, the rate of adverse
`events was generally greater for
`fesoterodine non-
`escalators than escalators. At week 12, improvements
`in micturitions, UUI episodes, and diary-dry rate
`were comparable for
`fesoterodine escalators and
`non—escalators, whereas improvement in urgency epi-
`sodes was significantly greater among non—escalators
`vs. escalators (p = 0.002). At week 12, the rates of
`the most common adverse events (dry mouth, con-
`stipation, headache) were similar
`for
`fesoterodine
`escalators and non—escalators (Table 1).
`Overall,
`flexible-dose fesoterodine improved key
`OAB symptoms and patient-reported outcomes and
`was generally well tolerated. The decision to escalate
`to fesoterodine 8 mg appeared to be determined by
`the efficacy and tolerability responses, with fesotero-
`dine escalators demonstrating a lower sensitivity (less
`efficacy and fewer adverse events) before their deci-
`sion to dose escalate.
`
`ClinicalTrials.gov ID: NCT00911937
`This 12-week, double-blind, placebo—controlled, mul-
`ticenter study evaluated the effects of flexible-dose
`fesoterodine
`in subjects with self-reported OAB
`symptoms
`for 3 3 months,
`including 3 8 micturi-
`tions, 2 3 urgency episodes and Z 2 but 5 8 noctur-
`nal urgency episodes per 24 h (19). Eligible subjects
`were randomised to fesoterodine 4 mg or placebo
`once daily within 4 h of bedtime for 4 weeks. At
`week 4, the fesoterodine dose could be increased to
`8 mg once daily, based on patient treatment response
`and tolerability (sham dose escalation for placebo).
`After week 4, no further dose adjustments were per-
`mitted. Of 937 subjects (fesoterodine,
`11! = 463; pla-
`cebo,
`n = 474) who
`took 2 1
`dose
`of
`study
`
`medication, 781 completed the study. At week 4,
`61% of subjects treated with fesoterodine and 67%
`of those treated with placebo chose dose escalation.
`At week 12,
`fesoterodine significantly decreased
`nocturnal urgency episodes (p = 0.003; primary end-
`point), micturitions (p = 0.001), nocturnal micturi-
`tions (p = 0.011) and urgency episodes (p < 0.001)
`per 24 h vs. placebo; the decrease in UUI episodes
`with fesoterodine was not significant vs. placebo at
`week 12
`(Table 1). Fesoterodine also significantly
`improved all OAB-q scale and domain scores vs. pla-
`cebo at week 12 (all p < 0.05). Dry mouth, constipa-
`tion and headache were the most common adverse
`
`events in each treatment group (Table 1).
`flexible
`The results of this study indicated that
`doses of fesoterodine were well tolerated and signifi-
`cantly decreased nocturnal urgency episodes and
`nocturnal micturitions vs. placebo in subjects with
`OAB symptoms, including nocturnal urgency.
`
`ClinicalTrials.gov ID: NCT00798434
`In the 24-week, multicenter, SOFIA (Study of Feso-
`terodine In an Aged population) trial, which con-
`sisted of
`a
`12-week,
`randomised, double-blind,
`placebo—controlled, flexible—dose phase (20) followed
`by a 12-week, open—1abel phase (21) (see Open—label
`trials section below), fesoterodine was evaluated in
`
`elderly (aged 2 65 years) subjects with OAB symp-
`toms. During the double-blind phase (20), subjects
`were randomised to fesoterodine 4 mg or placebo
`once daily. At weeks 4 and 8, subjects could increase
`the fesoterodine dose to 8 mg based on treatment
`response and tolerability; subjects who increased the
`dose at week 4 could decrease at week 8 (sham dose
`
`increaseldecrease for placebo). During double-blind
`treatment, 392 subjects received fesoterodine and 393
`received placebo, with 52% and 66%,
`respectively,
`opting for dose escalation at week 4 (Table 1). At
`week 8, 16% and 9% of subjects in the fesoterodine
`and placebo groups,
`respectively, opted for close
`escalation, and 4% and 3% de-escalated.
`At week 12,
`fesoterodine significantly decreased
`urgency episodes (primary end-point), micturitions
`and night-time micturitions per 24 h compared with
`placebo
`(all p < 0.01; Table 1);
`among subjects
`with 2 1 UUI episode at baseline (46% of subjects),
`the decrease in UUI episodes was not significant vs.
`placebo at week 12. Treatment with fesoterodine also
`significantly improved all OAB-q scale and domain
`scores Compared with placebo at week 12
`(all
`p<0.05). No clinically meaningful change from
`baseline was observed in the Mini-Mental State
`
`for cognitive
`a test
`score,
`Examination (MMSE)
`impairment, in either treatment group after 12 weeks
`
`(5) 2014 John Wiley & Sons Ltd
`Int} Cfin Pratt, July 2014, 68, 7, 830-840
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2086 - 0005
`
`

`
`Flexible dosing with fesoterodine in OAB
`
`835
`
`of double—blind treatment. Dry mouth and constipa-
`tion were the most common adverse events for sub-
`
`jects treated with fesoterodine (Table 1).
`significantly
`Flexible
`doses
`of
`fesoterodine
`decreased key OAB symptoms, improved HRQL and
`were well tolerated in elderly subjects with OAB. No
`new safety concerns were observed with flexible-dose
`fesoterodine treatment in this elderly population.
`
`CIinica[TriaIs.gov ID: NCT00928070
`A 12-week. randomised, double-blind, p1acebo-con-
`trolled, flexible-dose, multicenter trial was conducted
`in vulnerable elderly subjects (22), defined as those
`aged 2 65 years with a score of2 3 on the 13-item
`Vulnerable Elders Survey (VES-13) (24). The VES-13
`is a validated measure on which individuals self-rate
`
`function and
`limitations in physical
`their health,
`disabilities.
`Subjects with
`VES—13
`functional
`scores 2 3 have a fourfold greater risk of death or
`functional decline over a 2-year period compared
`with subjects with scores < 3 (23). Eligible subjects
`had self-reported OAB symptoms
`for 2 3 months
`before screening,
`including 2 2 and 5 15 UUI epi-
`sodes and 2 8 micturitions per 24 h. Subjects with
`moderate to very severe cognitive impairment
`(an
`MMSE score < 20 (24)) were excluded. Subjects were
`randomised to fesoterodine 4 mg or placebo once
`daily for the first 4 weeks, after which,
`in consulta-
`tion with the investigator,
`the fesoterodine dose
`could be
`increased to 8 mg for
`the
`remaining
`8 weeks (sham dose escalation for placebo). During
`the last 8 weeks of the study. the fesoterodine close
`could be decreased to 4 mg at any time.
`Of the 562 subjects (fesoterodine, n = 281; pla-
`cebo : 281; mean age, 75 years) who received 2 1
`dose of study medication, most (fesoterodine, 53%;
`placebo, 64%) opted to increase their dose at week 4.
`At week 12, 45% of subjects receiving fesoterodine
`and 57% of those receiving placebo remained on the
`higher dose. At 12 weeks of treatment, the decreases
`from baseline in the mean number of UUI episodes
`(primary end-point), micturitions and urgency epi-
`sodes per 24 h were significantly greater with fesoter-
`odine vs. placebo (Table 1).
`Improvements from
`baseline to week 12 in scores on the OAB-q Symp-
`tom Bother and total HRQL scales and the Concern
`
`and Coping domains were significantly greater with
`fesoterodine than placebo (all p 3 0.02). Dry mouth
`and constipation were the most common adverse
`events, with most cases mild or moderate in nature.
`
`At week 12, no significant change from baseline was
`demonstrated in cognitive function, as assessed with
`the MMSE.
`These results indicated that a flexible-dose fesotero-
`
`dine regimen significantly improved UUI episodes,
`
`© 2014 John Wiley & Sons Ltd
`intJ Cfin Pract. July 2014, E8, 7, 830-840
`
`other OAB symptoms and HRQL compared with pla-
`Cebo and was generally well tolerated in vulnerable
`elderly subjects with OAB. No new safety concerns
`were identified in this vulnerable elderly population.
`
`Open-label trials
`
`CIim'calTriaIs.gov ID: NCT00425100
`the
`study,
`In a 12-week, open—label, multicenter
`effects of flexible-dose fesoterodine were investigated
`in subjects aged 2 18 years who were at least some-
`what dissatisfied with tolterodine immediate release
`or tolterodine extended release treatment within the
`
`previous 2 years (25). Eligible subjects reported OAB
`symptoms
`for 2 3 months.
`including 2 3 urgency
`episodes and 2 8 micturitions per 24 h at baseline
`and at
`least moderate bladder problems on the
`Patient Perception of Bladder Condition (PPBC).
`After a 2-week washout period,
`subjects
`received
`fesoterodine 4 mg once daily for 4 weeks. At the end
`of week 4, based on subjective assessment of efficacy
`and tolerability by the subject and the investigator,
`subjects could remain on fesoterodine 4 mg or
`increase the dose to 8 mg. At week 4, approximately
`50% of 516 treated subjects opted for dose escalation
`to fesoterodine 8 mg.
`At week 12, significant decreases from baseline
`were demonstrated in the primary end-points (i.e.
`UUI episodes, micturitions and urgency episodes per
`24 h; all p < 0.0001 vs. baseline; Table 2). The per-
`centage of subjects who reported satisfaction with
`fesoterodine treatment on the single-item OAB Satis-
`faction Questionnaire (26) (primary end-point) was
`79.8% at week 12. Significant decreases from baseline
`also were observed in secondary end-points,
`includ-
`ing nocturnal micturitions and severe urgency epi-
`sodes per 24 h at week 12 (both p < 0.0001). Scores
`on the two OAB-q scales and all OAB-q HRQL
`domains showed significant
`(p < 0.0001) and clini-
`cally meaningful (2 10-point change) improvements
`by week 12. Dry mouth and constipation were the
`most commonly reported adverse events (Table 2).
`A post hoc analysis of data from this study evaluated
`the efficacy and tolerability of fesoterodine among
`subjects who chose to increase their fesoterodine dose
`(escalators) vs.
`those who remained on fesoterodine
`
`4 mg (non-escalators) (27). The age and gender of
`subjects at baseline were similar between the 255 esca-
`lators and 258 non-escalators in the safety-analysis set.
`Escalators self-reported significantly (p < 0.05) higher
`mean baseline levels of OAB symptoms (except UUI
`episodes) and worse OAB symptom bother and HRQL
`vs.
`non-escalators.
`Although
`significant
`(all
`p < 0.0001)
`improvements compared with baseline
`were demonstrated in all bladder diary variables at
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2086 - 0006
`
`

`
`B36
`
`Flexible dosing with fesoterodine in OAB
`
`week 4 (before dose—escalation decision) for both sub-
`sequent escalators and non-escalators, mean improve-
`ments in these end-points (except UUI episodes) and
`the diary-dry rate were significantly (all p < 0.05)
`greater for non-escalators vs. escalators at week 4
`(Table 2).
`At week 12, significant improvements vs. baseline
`were again observed for all bladder diary variables
`among escalators and non-escalators, but no signifi-
`cant differences were demonstrated between the
`
`in bladder diary variables
`improvements
`mean
`(except urgency episodes) and the diary-dry rate for
`escalators vs. non-escalators.
`Improvements
`from
`baseline at week 12 in scores for the OAB-q Symp-
`tom Bother scale and the Coping, Sleep and Social
`Interaction domains were similar for escalators and
`
`non-escalators, whereas OAB-q total HRQL and
`Concern domain scores were significantly better in
`non-escalators vs. escalators (all p < 0.05). Further-
`more, no significant difference was seen between
`escalators and non-escalators in the percentage of
`subjects reporting satisfaction with fesoterodine treat-
`ment at week 12 (escalators, 78%; non-escalators,
`82%). The most common adverse events in both
`escalators and non-escalators during the study were
`dry mouth and constipation (Table 2). The rate of
`study discontinuation was 14% for non-escalators vs.
`7% for escalators; no escalator discontinued because
`
`of lack of efficacy.
`These results indicated that
`
`treatment with flexi-
`
`ble-dose fesoterodine significantly improved OAB
`symptoms, patient-reported HRQL, and treatment
`satisfaction and was well
`tolerated in subjects who
`were dissatisfied with previous treatment with tolter—
`odine. Subjects who chose dose escalation at week 4
`achieved additional OAB symptom improvement
`after dose escalation. At week 12, OAB symptom
`improvement and the incidence of adverse events
`were similar among escalators and non-escalators.
`
`CIinicalTriaI5.gov ID: NCT00806494
`The l2-week, open-label SAFINA (Study Assessing
`Flexible-dose fesoterodine IN Adults) study was con-
`ducted to determine the efficacy and safety of flexible
`doses of fesoterodine in subjects with OAB treated in
`the United Kingdom healthcare system (28). After
`12 weeks of flexible-dose treatment with fesoterodine,
`
`a 4-week period of no treatment was conducted to
`assess changes in efficacy outcomes after drug cessa-
`tion (30). Eligible subjects were aged 2 18 Years and
`had self-reported OAB symptoms for 2 3 months,
`including 2 8 micturitions and 2 3 urgency episodes
`per 24 h, and reported at least some moderate prob-
`lems on the PPBC. Subjects were treated with fesotero-
`dine 4 mg once daily for the first 4 weeks, after which
`
`they could opt to increase the dose to 8 mg after con-
`sultation with the investigator. No further dose adjust-
`ments were permitted after week 4.
`Of the 331 subjects who were treated with fesoter-
`odine, 195 (59%)
`increased the fesoterodine dose
`from 4 mg to 8 mg at week 4 (28). The most com-
`mon reason for escalating the fesoterodine dose was
`an insufficient
`treatment response (93%). At week
`12, clinically meaningful improvements from baseline
`were observed in micturitions (mean [95% CI]: -3.3
`[—3.6, -2.9]; primary end-point), urgency episodes
`(-5.1 [—5.6, —4.6]) and UUI episodes (-1.6 [—2.0,
`—1.3]) per 24 h with flexible-dose
`fesoterodine
`(Table 2). OAB-q Symptom Bother scale scores were
`improved from baseline and most subjects reported
`satisfaction (77%), much benefit (57%) and a will-
`ingness to continue (75%) with fesoterodine treat-
`ment at week 12. The most common adverse events
`
`were dry mouth (30%), constipation (9%) and diar-
`rhoea (9%). At week 16, 4 weeks after treatment ces-
`sation,
`the frequency of OAB symptoms increased
`and patient—reported outcomes deteriorated to week
`4 values or worse (29).
`
`A prespecified stepwise logistic regression analysis
`conducted to evaluate factors associated with fesotero-
`dine dose escalation at week 4 indicated that smaller
`
`improvement in micturitions and poorer response on
`the PPBC were significantly associated with close esca-
`lation (28). At week 12, improvements in most out-
`comes were similar in escalators and non-escalators.
`
`Flexible doses of fesoterodine in a clinical practice
`setting in the United Kingdom were efficacious and
`well tolerated, with most subjects reporting satisfac-
`tion and a willingness to continue fesoterodine treat-
`ment. Subjects who escalated the fesoterodine close at
`week 4 had a poorer clinical response at week 4 than
`subjects who did not escalate. However, at week 12,
`improvements in efficacy outcomes were comparable
`between dose escalators and non-escalators. OAB
`
`symptoms and HRQL deteriorated after 4 weeks of
`treatment cessation; subjects reporting the greatest
`perceived treatment benefit after 12 weeks of treat-
`ment with fesoterodine had the greatest deterioration.
`
`ClinicalTrials.gov ID: NCT00798434
`To assess the long-term efficacy and safety of flexi-
`ble-dose fesoterodine in elderly subjects with OAB,
`subjects who completed the 12-week,
`randomised,
`double-blind, placebo-controlled phase of the SOFIA
`trial
`(20) were eligible for
`a 12-week, open-label,
`extension phase (21). During the open-label phase of
`the trial, all subjects received treatment with fesoter-
`odine. Subjects who received fesoterodine during the
`double-blind treatment phase maintained their dose
`(4 or 8 mg) during the open-label phase. Subjects
`
`© 2014 John Wiley & Sons Ltd
`Int} Cfin Pratt, July 2014, 68, 7, 830-840
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2086 - 0007
`
`

`
`Flexible dosing with fesoterodine in OAB
`
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