EUROPEAN UROLOGY 54 (zoos) 543-562
`
`available at www.sciencedirect.com
`
`journal homepage: www.europeanuroIogy.com
`
`$1
`
`European Association of Urology
`
`Review — Neuro-urology
`
`
`
`The Effects of Antimuscarinic Treatments in Overactive
`
`Bladder: An Update of a Systematic Review and Meta-Analysis
`
`Christopher R. Chapple “”", Vile Khullar b, Zahava Gabriel C, Dominic Mustori C,
`Caty Ebel Bitouri ‘l, David Weiristeind
`
`"Sheffield Teaching Hospital NHS Trust, Royal Hollomshire Hospital, Urology Research, Sheffield, UK
`blmpericil College, St. Mary’s Hospital, London, UK
`‘Heron Evidence Development Ltd., UK
`“Pfizer, France
`
`Article info
`
`Abstract
`
`Article history;
`Accepted June 11, 2003
`Published online ahead of
`print on June 20, 2008
`
`Keywords:
`Antirnuscarinic
`Overactive bladder
`
`Detrusor Overactlvlty
`Incontlnence
`Mel3a‘3na1Y515
`Systematic review
`
`Context: Antimuscarinic agents are currently the first-line pharmacotherapy for overactive
`bladder-
`Objectives: A systematic review published in 2005 was updated, including data on a newly
`licensed antimuscarinic (fesoterodine). The primary aim of this study was to systematically
`review evidence on the efficacy of licensed administration of antimuscarinic treatments in
`overactive bladder from randomised controlled trials. Secondary aims were to review
`evidence on tolerability and safety and healtlrrelated quality of life (HRQL).
`Evidence acquisition: All relevant data sources from randomised controlled trials were
`searched, and two independent reviewers considered publications for inclusion and
`extracted relevant data. Meta—ana1ysis was used to pool efficacy, tolerability, safety, and
`HRQL outcomes by treatment. Efficacy was measured by continent days, mean voided
`volume, urgency episodes, and micturition frequency. Tolerability and safety were mea-
`sured by means of adverse event and withdrawal rates. HRQL was measured by various
`instruments.
`Evidence synthesis: Ari additional 1118 references were retrieved with data on 83 studies
`extracted. Antimuscarinics were found to be more effective than placebo. Tolerability was
`good; few of the antimuscarinics were found to have significantly higher withdrawal rates in
`comparison to placebo. No serious adverse event for any product was statistically significant
`compared to placebo. Dry mouth (mild, moderate, severe) was the most commonly reported
`adverse event (29.6% on treatment vs 7.9% on placebo), followed by pruritus (15.4% on
`treatment vs 5.2% on placebo). Improvements were seen in HRQL with treatment by
`darifenacin, fesoterodine, oxybutyniri transdermal delivery system, propiverine extended
`release (ER), solifenacin, tolterodine ER and immediate release, and trospium. Limitations of
`the study include restrictions on the types of patients typically included in overactive
`bladder trials and topics that have not been adequately addressed in the current antimus-
`carinic literature.
`Conclusions: Antimuscarinics are efficacious, safe, and well-tolerated treatments that
`improve HRQL. Profiles of each drug and dosage differ and should be considered in making
`treatment choices.
`
`-l_'' 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
`
`‘ Corresponding author. Sheffield Teaching Hospital, Glossop Road, Sheffield S10 21K,
`United Kingdom. Tel. +44 114 271 2559; Fax: +44 114- 279 7841.
`E-mail address: c.r.chapp1e@shef.ac.uk (C.R. Chapple).
`0302-2838/$- see back matter i 2008 European Association of Urology. Published by Elsevier E.V. All rights reserved.
`
`doi:‘10.‘l016/j.eu1'uro.2008.05.04?
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2066 - 0001
`
`

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`54-4
`
`EUROPEAN UROLOGY 54(2oo8)543—562
`
`1.
`
`Introduction
`
`Overactive bladder (OAB) refers to the common and
`bothersome group of storage lower urinary tract
`symptoms (LUTS). The International Continence
`Society (ICS) defines OAB syndrome as urgency with
`or without urge urinary incontinence (UUI), usually
`with frequency and nocturia [1]. Prevalence rates for
`OAB are estimated to be approximately 12% in North
`America and Europe [2]. Both men and women are
`equally affected by OAB, and the incidence rate
`increases with age [2]. This condition has a serious
`impact on individuals as well as on society as a
`whole [3,4]; to illustrate, the annual cost of OAB has
`been estimated as to be as high as €3.98 billion in
`Germany alone [5]. OAB can be managed with
`bladder and behavioural
`training, biofeedback,
`electrical stimulation, pharmacologic treatments,
`or with a combination of therapies [6]. Antimus—
`carinic agents are the first—line pharmacotherapy for
`OAB treatment [7].
`A systematic review of the tolerability, safety, and
`efficacy of licensed antimuscarinic treatments in
`OAB was published in October 2005 [8]. This review
`represented an update to that published in 2003 by
`Herbison et al
`[9]. Since then,
`there have been
`considerable changes to the evidence base. A large
`number of new trials with existing agents have been
`published, particularly for solifenacin and darifena—
`cin. Some of these new trials are head-to-head trials,
`
`an area identified as a research priority in the 2005
`review. Additionally,
`there are data on a newly
`developed antimuscarinic, fesoterodine [10]. Peso-
`terodine is rapidly and extensively hydrolyzed by
`nonspecific ubiquitous esterases to S—hydroxy—
`methyl
`tolterodine (5—HMT), which is also the
`active metabolite of tolterodine and is responsible
`for all of the antimuscarinic activity of fesoterodine
`[11—13]. Fesoterodine has two active doses, 4 and
`8 mg [14,15], and clinical studies have shown
`that plasma concentrations are close proportional
`[16].
`This meta-analysis was conducted to update the
`2005 data. The primary aim of this study was to
`review all of the evidence on the efficacy of licensed
`antimuscarinic therapy for OAB available from
`randomised controlled trials. The efficacy outcomes
`of interest were the changes in the number of
`micturitions, urgency and incontinence episodes
`per day, volume voided per micturition, and both the
`proportion of patients returning to continence or
`undergoing global improvements in their storage
`LUTS. Secondary aims were to review evidence on
`tolerability, safety, and effects of treatment on
`health-related quality of life (HRQL).
`
`2.
`
`Methods
`
`2.1.
`
`Publication searches
`
`The review undertook a comprehensive search of all major
`literature databases and the abstractbooks from several major
`conferences: American Urological Association, ICS, European
`Association of Urology, International Urogynaecological Asso-
`ciation,
`International Consultation of
`Incontinence, and
`Societe Internationale d’Urologie. As with the 2005 review,
`there were no restrictions on the inclusion of publications by
`language; publications in languages other than English were
`translated into English.
`The literature database search for the previous 2005 review
`was carried out on August 31, 2004, for publications published
`since 1966 in the MEDLINE, EMBASE, Cochrane Controlled
`Trials Register, and Cumulative Index to Nursing and Allied
`Health Literature databases. The literature database search for
`
`this review was carried out on October 18, 2007, and included
`all publications published in 2004- or later in the same
`databases. Conference proceedings had previously been
`searched to the end of 2004. For the review update, we added
`evidence from further proceedings of each conference up to
`October 2007. The overlap in date ranges for the searches led to
`duplication in retrieved publications but was designed to
`ensure that no evidence was missed.
`
`2.2.
`
`Study procedures
`
`The same rigorous processes were followed in this review as
`in the last. This review was conducted and reported according
`to QUORUM guidelines [17]. A team of reviewers indepen-
`dently determined the eligibility of each publication by
`applying a set of criteria (Table 1). Two different reviewers
`considered each publication,
`and discrepancies were
`resolved through discussion. Cited references from included
`trials and reviews of similar trials were also searched. Many
`studies were reported in more than one publication, and all
`studies that met the inclusion criteria were included in the
`
`review. However, only one extraction dataset per study was
`compiled from all publications relating to that study, so as to
`avoid the error of double-counting patients in subsequent
`analyses. Two independent reviewers extracted study char-
`acteristics and placed the baseline and outcomes data,
`including publications in parallel, into a Microsoft Access
`database (Microsoft Corporation, Redmond, WA, USA). The
`methodological quality of publications was assessed as
`previously reported [8]. A third reviewer checked the resulting
`extractions and resolved any discrepancies. Safety and
`tolerability outcome data were extracted from all studies;
`efficacy outcome data were extracted only from studies
`reporting that patients and investigators had been blinded to
`treatment allocation. Table 2 provides a list of outcomes
`extracted.
`
`Treatment dosing
`2.2.1.
`There were seven drugs included in this review {darifenacin,
`fesoterodine, oxybutynin, propiverine, solifenacin, toltero-
`dine. and trospium). each of which could be delivered
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2066 - 0002
`
`

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`sunorsnn UROLOGY 54 (zoos) 543-562
`
`545
`
`Table 1 — Study inclusion and exclusion criteria for the review
`Criterion
`Included
`
`Population
`
`Perspective of study
`
`Type of study
`
`Language
`Trial Length
`Sample Size
`Intervention!‘
`treatments
`
`Age: 218 yr
`Race: any
`Gender: male or female
`Qualifying event/disease/factors:
`Idiopathic OAB/DO/Ul (including UUI)
`550% of patients with DO consequent
`upon neurogenic pathology
`UUI
`MUI (urge—predominant incontinence)
`550% of patients with BOO/BPH/BPO/benign
`prostatic enlargement or previous LUTD surgery
`Any severity of disease at baseline
`Prospective (concurrent)
`Comparative
`
`RCT (Blinded RCTs only for clinical efficacy data,
`open—label RCTs and blinded RCTS for
`safety and tolerability data)
`Crossover trials with a washout
`period between treatments
`
`All
`32 wk
`Any
`Oral and TDS monotherapy with antimuscarinics; UK licensed doses:
`
`0 Darifenacin (Enablexfi): all doses
`- Oxybutynin 1R (Cystrln"', Ditropan "): 2.5-5 mg bid, tid, 5 mg qid
`- Oxybutynin ER (Ditropan XL"): 5 mg od, 10 mg od, 15 mg od, 20 mg od
`o Oxybutynin TDS (Kentera", Oxytrol"): 3.9 mg od
`- Propiverine LR {Detrunorrn" ): 15 mg od, bid, tid. qid
`o Propiverine ER (Detrunorm XL“): all doses
`0 Solifenacin ('Vesicare"'): all doses
`o Tolterodine IR (Detrusitol SR“, Detrol"): 1 mg bid, 2 mg bid
`a Tolterodine ER (Detrusitol XL “', Detrol LA“ , Detrusitol Neo " ,
`Dereustiol Retard"): 2 mg od, 4-mg od
`u Trospium {Regurin ” )2 20 mg bid
`0 Fesoterodine ('I'oviaz“): all doses.
`
`Control intervention/
`ireatments
`
`Combination therapy with one of the included
`drugs and a nonpharmacological treatment if all the
`treatment arms receive the same nonpharrnacological treatment
`Placebo or any of the included drugs, including a
`different formulation of the same drug
`
`Included trial outcomes
`
`A11)’
`
`Excluded
`
`Age: <18 yr
`Qualifying eventfdiseaselfactors:
`>50% of patients with DC
`consequent upon neurogenic
`pathology
`SUI
`
`MUI (stress—predominant
`incontinence)
`>50% of patients with BOO/
`BPH/BPO/benign prostatic
`enlargement or previous
`LUTD surgery
`Retrospective (nonconcurrent,
`historical)
`Noncomparative
`Nonrandomised CCT
`Open—label follow—up of RCT
`Cohort
`Observational
`Case—control
`Case study
`Crossover trials without a
`wash-out period between
`treatments
`None
`<2 wk’
`None
`
`Oral monotherapy with
`antimuscarinicsz Flavoxate (Urispas"')
`Propantheline (Pro-Banthine i‘)
`
`All intravesical antimuscarinic
`formulations
`
`Combinafion therapy with
`antimuscarinics, and an a-blocker
`
`Combination therapy with
`one of the included drugs
`and a nonpharrnacological
`treatment when not all the
`treatment arms receive the
`same nonpharmacological treatrnent
`
`Nonpharmacological
`treatment (bladder training,
`electronic stimulation, physiotherapy)
`Usual care
`No intervention
`None
`
`Abbreviations: BOO. bladder outlet obstruction; HP!-1, benign prostatic hyperplasia; BPO, benign prostatic obstruction; CCT. controlled clinical
`trial; DO, detrusor overactivity; ER, extended release; IR, immediate release; LA, extended release; LUTD, lower urinary tract disease; MUI,
`mixed urinary incontinence; GAB, overactive bladder; RCT, randomised controlled trial; SUI, stress urinary incontinence; TDS, transdermal
`system; UI, urinary incontinence; UUI, urge urinary incontinence; XL, extended release.
`'Studies in which patients received <2 wk of study treatment were excluded.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2066 - 0003
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`546
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`suaorsnu UROLOGY 54 (zoos) 543-562
`
`Table 2 — Efficacy, tolerability, safety, and HRQ1./PRO outcomes extracted from included studies
`
`Efficacy‘
`
`Tolerability
`
`Safety
`
`l-IRQL/PRO
`
`Change from baseline in the number of urgency episodes/24 1:
`Change from baseline in the number of incontinence episodes/24 h
`Change from baseline in the number of pads used per day
`Change from baseline in the number of daytime incontinence episodes/24 h
`Number of patients returned to continence at trial end point (recording no incontinence episodes
`on last voiding diary entry)
`Change from baseline in the number of nocturnal incontinence episodes/24-h
`Change from baseline in number of nocturnal awakenings related to overactive bladder/24h
`Number of patients achieving normal micturition frequency (37 or $8 micturitions/24 h) at trial end point
`Change from baseline in tlie volume of urine voided per micturition (ml)
`Change from baseline in tlie number of micturi1:'ions/24 h
`Change from baseline in maximum cystometric Capacity (ml)
`Total withdrawals
`Witlidrawals due to adverse events
`Wiflidrawals due to death
`Any adverse event
`Any serious adverse event
`Blurred vision, confusion, dizziness, palpitations. tremor, vertigo
`Constipation, diarrhoea, dry mouth (any severity), dry mouth (mild), dry mouth (moderate), dry mouth
`(severe), dry mouth (mild/moderate), dry mouth (moderate/severe), dyspepsia, nausea, vomiting
`Fatigue, headache, insomnia, somnolence, increased sweating, urinary retention, UTI, erythema, pruritus
`Generic: SF-36, SF-12
`Disease-specific: Incontinence Impact Questionnaire (IIQ), KHQ, UDI, OAB-q
`Number of patients reporting improvement in disease
`VAS scores of improvement in disease
`
`Abbreviations: l-IRQL, health-related quality of life; KHQ, King's Health Questionnaire; OAB-q, Overactive Bladder Questionnaire; PRO, patient-
`repoited outcome; UDI, Urogenital Distress Inventory; UT], urinary tract infection; VAS, visual analog scale; SI‘-‘-36, 5hort—form 36; 517-12, Short-
`form 12.
`
`‘Efficacy outcomes were extracted only from studies which reported that patients and investigators had been blinded to treatrnent allocation.
`
`through various formulations at various doses and frequen-
`cies. Data from arms of studies in which drug doses
`delivered to patients fell outside the European licensed
`range were not extracted (Table 1). Treatments were
`stratified according to whether the drug formulation was
`immediate release (IR), for which administration was oral
`and the dose frequency was generally more than once per
`day, or extended release (ER), for which administration was
`oral and the dose frequency was generally once per day. The
`only exception was in the case of oxybutynin administered
`via a transdermal system (TDS) patch_ freatments were
`stratified into categories according to the total daily dose at
`the start of the study and whether the study allowed flexible
`dosing.
`
`2.3.
`
`Statistical analysis
`
`Meta—ana1ysis was conducted where possible to pool results
`for each outcome of interest and for each combination of
`
`treatment by daily close category and formulation using the
`meta-analysis command METAN written for Stata v.9 (Stats-
`Corp LP. College Station, TX, USA) [18]. Dichotomous outcomes
`were summarised as risk ratios (RR) using the Mantel-
`Haenszel method; continuous outcomes were summarised
`as nonstandardised (aiso known as weighted) mean differ-
`ences using inverse variance weighting. Fixed rather than
`random effects models were used because the stratification
`
`was judged to largely remove the likelihood of substantial
`clinical or statistical heterogeneity [19].
`
`As with the previous review, trials with more than two
`treatment arms were analysed as if they were conducted as
`trials of each paired treatment comparison. For simplicity,
`consistency with the previous review [8] and consistency
`between trials, analyses of such trials were not adjusted for
`multiple comparisons (using Bonferonni correction methods
`or similar).
`
`3.
`
`Results
`
`3.1.
`
`Trial flow
`
`This review retrieved 1118 references in addition to
`
`the 11 663 retrieved for the 2005 review. Of the newly
`retrieved references, 88 publications were included
`to add to the 123 included from the previous review
`for a total of 211 publications. There were on average
`2.5 publications per included trial,
`from these
`publications, data on 83 trials were extracted
`(Appendix A). Ten trials included for this review
`were excluded from this meta-analysis; eight were
`excluded because they contained no data relevant or
`suitable for meta-analysis [20—27}; one was excluded
`because the treatment dosing was mixed or unclear
`[28]; and one was excluded because randomisation
`was unclear [29]. Fig. 1 is a diagram of the study
`flow, showing the relationship between studies
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2066 - 0004
`
`

`
`sunopanu UROLOGY 54. (2008) 543-562
`
`547
`
`August 2005 review
`
`October 2007 update
`
`Fig. 1 — Trial flow.
`
`considered now and those considered at the 2005
`review.
`
`3.1.1.
`
`Trial characteristics
`
`Summaries of the patient and study design char-
`acteristics of the included trials are presented in
`Table 3. Twenty—four
`trials were published in
`abstract format only, and 59 trials were published
`as full publications. Forty-six trials
`(55%) had
`placebo arms. There was at least one placebo-
`controlled trial for all of the included antimuscarinic
`
`formulations, apart from the oxybutynin ER for-
`mulation.
`
`the
`trials were para11el—group studies,
`Most
`remaining ten trials being crossover in design. At
`least 72 of the trials were double-blind, five did not
`
`report blinding clearly, and the remaining six were
`single—blind or open—labe1 studies. Study lengths
`ranged from 2 to 52 wk, with 34 trials of 12—wk
`length. The number of patients in trials ranged from
`30 to 1593 patients, with five trials of >1000 patients
`
`[14-,30—33] and 20 trials with fewer than 100 patients.
`The mean age of patents included in the trials was
`58 yr (range: 40-75 yr).
`
`3.2.
`
`Efficacy
`
`Efficacy results are summarized in Table 4. Greater
`proportions of patients treated with antimuscari-
`nics than with placebo returned to continence, and
`these differences were statistically significant. The
`pooled RR varied between 1.3 and 3.5 across
`treatments and nominally were strongly statisti-
`cally significant (p<0.01) with the exception of
`fesoterodine, for which no data were available, and
`propiverine IR 45 mg/day, for which evidence was
`available from only one study [34]. There were no
`statistically significant differences among treat-
`ments in meta-analyses of active-controlled trials
`for this outcome.
`Active treatments were more effective than
`
`placebo in terms of the mean change in the number
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2066 - 0005
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`

`
`548
`
`EUROPEAN UROLOGY 54(2cIcI8} 543-562
`
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`chloride, which was not reported. Pooled differences
`in mean changes ranged from 0.5 to 1.3 episodes per
`day. There was some evidence from three trials
`[30,31,3S]
`favounng solifenacin 10 mg/day over
`tolterodine IR 4 mg/day (difference in mean change:
`.
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`0.73 95 A CI 0.19-1.27 micturitions per day 1:: = 0.01)
`and from four trials [36—39] favouring solifenacin
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`10 mg/day over solifenacin 5 mg/day (difference in
`mean change: 0.30; 95% CI, 0.04-0.55 micturitions
`per day; p = 0.02). Otherwise, there were no statis-
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`tically significant differences among active treat-
`.
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`ments.
`Fesoterodine, propivenne, solifenacin, and tolter-
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`reported The outcomes for oxYbutY1'1in arid tros
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`pium chloride were not suitable for meta-analysis.
`Pooled differences in mean changes varied between
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`-
`.
`.
`tolterodine IR 4 mg/day (difference in mean change:
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`propiverine IR 20 mg/day (difference in mean
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`.
`.
`.
`.
`p = 0.03), and evidence favouring solifenacin 5 mg/
`day over tolterodine IR4 mg/day (difference in mean
`change: 0.80; 95% CI, 0.17-1.43 episodes per day;
`p = 0.01). Otherwise,
`there were no statistically
`significant differences among active treatments.
`.
`.
`.
`.
`.
`Active treatments were all statistically signifi-
`cantly more effective than placebo in terms of the
`mean change in the volume voided per micturition
`(milliliter) where reported for each licensed drug
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2066 - 0008
`
`

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