ELSEVIER
`
`CLINICAL EFFICACY AND SAFETY OF TOLTERODINE
`IN THE TREATMENT OF OVERACTIVE BLADDER:
`A POOLED ANALYSIS
`
`RODNEY
`
`A. APPELL
`
`double-blind,
`
`in four randomized,
`
`ABSTRACT
`the safety, efficacy, and tolerability of tolterodine
`examine
`ObjectivesTo
`parallel, multicenter,
`12-week studies of patients with overactive bladder.
`times
`(5 mg three
`MethodsTwo
`of the four studies compared
`tolterodine
`(2 mg twice daily) to oxybutynin
`daily) and placebo, one study compared
`tolterodine
`(2 mg twice daily) to oxybutynin
`(5 mg three times daily),
`and one study compared
`two dosages of tolterodine
`(1 and 2 mg twice daily)
`to placebo. Efficacy was
`determined
`from micturition diaries and patient perception of their bladder condition. Safety and tolerability
`were assessed
`from adverse events and laboratory measures.
`Resu1ts.A
`total of 1,120 patients were
`randomized
`and treated at 134 centers. For the primary efficacy
`variable,
`the number of micturitions/24
`hours, pooled
`results showed a significant decrease
`from baseline for
`the 1 mg tolterodine
`(P <O.OOl), 2 mg tolterodine
`(P co.00 1). and 5 mg oxybutynin
`(P ~0.01) groups,
`compared
`to placebo. Both
`tolterodine
`doses and oxybutynin
`significantly decreased
`incontinence
`epi-
`sodes/24 hours and significantly
`increased volume voided/micturition,
`compared
`to placebo. Tolterodine at
`a dose of 2 mg twice daily and 5 mg oxybutynin
`twice daily were significantly more effective
`in improving
`patient perception
`of bladder condition
`than placebo. Tolterodine
`at a dose of 2 mg and 5 mg oxybutynin
`were equivalent
`in their effectiveness. Tolterodine
`at doses of 1 mg and 2 mg were
`tolerated
`significantly
`better
`than oxybutynin when adverse events, dry mouth
`(both frequency and intensity], dose reductions, and
`patient withdrawals were considered.
`is limited by systemic side effects that
`its clinical utility
`Conclusions.Although
`oxybutynin
`is highly effective,
`lead to frequent
`discontinuation
`of treatment
`or dose reductions. Patients
`receiving
`tolterodine
`should not
`experience
`these
`limitations
`and
`instead will get safe and
`long-term
`effective
`treatment
`for
`their
`condition.
`UROLOGY 50 (Suppl 6A): 90-96,
`1997. 0 1997, Elsevier Science Inc. All rights reserved.
`
`ymptoms of the overactive bladder are urgency,
`frequency, and urge incontinence
`caused by in-
`S
`voluntary contractions of the detrusor muscle during
`bladder
`filling. As the detrusor contractions
`are me-
`diated by cholinergic muscarinic
`receptor stimula-
`tion, antimuscarinic
`drugs have been used for
`the
`treatment
`of this conditi0n.l
`The most commonly
`used antimuscarinic
`agent for treatment of overactive
`bladder
`is oxybutynin, which has been shown
`to be
`effective
`in controlled clinical studies.2 However,
`the
`clinical usefulness of oxybutynin
`is limited by sys-
`temic side effects, particularly
`dry mouth,3,4 which
`
`the Section of Voiding Dysfunction and Female Urology,
`From
`The Cleveland Clinic Foundation, Cleveland, Ohio
`Reprint
`Rodney A. Appell, MD, FACS, Head, Section
`requests:
`of Voiding Dysfunction
`and Female Urology,
`The Cleveland
`Clinic Foundation, 9500 Euclid Avenue, Desk A-l 00, Cleveland,
`OH 44195
`
`may be of sufficient severity to result in poor compli-
`ance or even discontinuation
`of treatment.l.5
`Tolterodine
`is a new, potent, competitive musca-
`rinic
`receptor antagonist
`developed
`for treatment
`of the overactive bladder. This compound was se-
`lected
`for development
`with
`the objective
`of
`achieving a separation of the antimuscarinic
`effects
`on the urinary bladder and salivary glands. Differ-
`ences between
`tolterodine
`and oxybutynin
`have
`been demonstrated
`in a number of preclinical
`stud-
`ies, including
`pharmacologic
`in vitro and in vivo
`studies.6
`It has been demonstrated
`that
`the
`two
`compounds
`are equipotent
`at bladder muscarinic
`receptors,
`as shown by radioligand
`binding
`and
`functional
`data.6 However,
`radioligand
`binding
`data show
`that tolterodine
`has 8 times less potency
`than oxybutynin
`at the muscarinic
`receptors
`in the
`parotid gland.6
`
`0 1997, ELSEVIER SCIENCE
`ALL RIGHTS RESERVED
`
`INC.
`
`90
`
`0090-4295/97/$17.00
`PII soogo-4295(97)00599-2
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1017 - Page 1
`
`

`
`duration
`treatment
`TABLE 1. 12-Week
`Ill tolterodine
`studies
`Enrollment
`Objective
`(patients)
`
`phase
`
`Treatment
`Duration
`(weeks)
`
`Studies
`Placebo-controlled
`94-OATA-
`Placebo-
`and active-controlled
`94-OATA-
`94-OATA-O
`Active-controlled
`94-OATA-O
`
`10
`
`15
`
`250
`
`250
`250
`
`200
`
`12
`
`12
`12
`
`12
`
`program
`clinical development
`tolterodine
`The
`was the largest such program ever undertaken with
`a medication
`for the treatment
`of overactive blad-
`der. To date, a total of 29 studies
`(17 phase
`I, 4
`phase
`II, and 8 phase
`III studies) have been con-
`ducted
`in 15 countries. More
`than 1,800 patients
`have been treated with
`tolterodine
`in clinical
`trials.
`A total of eight phase III studies were undertaken
`to examine
`the safety, efficacy, and
`tolerability
`of
`tolerodine
`in patients with overactive bladder and
`symptoms
`of frequency
`and urge
`incontinence
`or
`urgency. The duration
`of treatment was 4 weeks in
`four of the studies and 12 weeks
`in the other
`four
`studies.
`the efficacy, safety, and
`This article will detail
`tolerability
`results
`from
`the four studies
`that used a
`12-week
`treatment
`duration.
`
`AND METHODS
`MATERIALS
`12-
`randomized,
`double-blind,
`parallel, multicenter,
`Four
`week
`treatment
`studies were conducted
`in nine countries.
`Two of the studies compared 2 mg tolterodine
`twice daily
`to 5
`mg oxybutynin
`three
`times daily and placebo, one study com-
`pared 2 mg tolterodine
`twice daily
`to 5 mg oxybutynin
`three
`times daily, and one study compared
`two dosages of toltero-
`dine
`(1 and 2 mg twice daily)
`to placebo
`(Table
`I). Patients
`completed a 2-week washout/run-in
`period before randomiza-
`tion
`to treatment. Patients were seen at entry (visit 1 at - 1 or
`-2 weeks), at baseline
`(visit 2, day l), and after 2,4,8, and 12
`weeks of treatment
`(visits 3,4, 5, and 6, respectively).
`In the
`studies comparing
`tolterodine
`and oxybutynin,
`dose reduc-
`tion was permitted within
`the first 2 weeks of treatment
`in the
`case of intolerance
`to the study medication
`and only as an
`alternative
`to withdrawal.
`In these studies, no upper age limit was set, no concomitant
`medications
`(except drugs with anticholinergic
`effects and
`drugs
`for urge
`incontinence)
`were excluded, and electrocar-
`diograms
`(ECGs) were performed
`only at the end of treatment
`for patients
`in one study. This was due
`to the finding
`of an
`excellent safety profile
`for tolterodine
`in phase 1 and II studies.
`Common
`inclusion
`criteria
`in the studies were 1) patients
`who understood
`and gave signed
`informed
`consent; 2) male
`and female patients 2 18 years of age; 3) evidence of detrusor
`overactivity
`(phasic detrusor contraction with an amplitude
`2
`10 cm H,O);
`and 4) urinary
`frequency
`(an average of 28
`micturitions/24
`hours) and urge incontinence
`(an average of
`2 1 incontinence
`episode/24 hours) or urinary
`frequency.
`Common exclusion
`criteria
`in the studies were 1) clinically
`
`UROLOGY
`
`50 (Supplement 6A), December 1997
`
`2) hepatic or renal disease; 3)
`stress incontinence;
`significant
`urinary
`tract infections
`(UTIs); 4) interstitial
`cysti-
`recurrent
`tis; 5) uninvestigated
`hematuria
`or hematuria
`secondary
`to
`malignant
`disease; 6) indwelling
`catheter or intermittent
`cath-
`eterization;
`7) treatment with any investigational
`drug
`in the 2
`months prior
`to entry; 8) previous
`treatment with
`tolterodine;
`9) electrostimulation
`therapy or bladder
`training within
`14
`days prior
`to entry or initiation
`during
`the study; 10)
`treat-
`ment with any anticholinergic
`drug or any drug
`for urinary
`urge incontinence within
`14 days prior
`to the baseline visit or
`initiation
`during
`the study; 11) unstable dosage of any treat-
`ment with anticholinergic
`side effects or
`initiation
`of such
`treatment during
`the study; 12) previously
`demonstrated
`se-
`rious side effects on oxybutynin;
`13) an average
`total voided
`volume >3,000 mU24 h; and 14) clinically
`significant
`voiding
`difficulty with
`risk of urinary
`retention.
`from
`Efficacy of the different
`treatments was determined
`micturition
`diaries collected by the patient
`for 7 days prior
`to
`each visit. Efficacy was measured by comparing
`the values
`after 12 weeks of
`treatment
`to baseline. Efficacy measures
`included
`the number of micturitions/24
`hours
`(primary
`vari-
`able), number of incontinence
`episodes/24 hours, and mean
`urinary
`volume
`voided/micturition.
`Equivalence
`between 2
`mg tolterodine
`twice daily and 5 mg oxybutynin
`three
`times
`daily was evaluated with measurements
`of mean number
`of
`micturitions/24
`hours and mean number of incontinence
`ep-
`isodes/24 hours. Efficacy was also evaluated
`through patients’
`perceptions
`of their bladder condition.
`reported and
`Safety was determined
`through
`spontaneously
`observed adverse events, blood pressure measurements,
`rou-
`tine clinical chemistry, and hematology measurements.
`Appropriate
`parametric and nonparametric
`statistical meth-
`ods were used for analysis, and significance was set at the 5%
`level. The efficacy variables were analyzed using analysis sig-
`nificance was set at the 5% level. The efficacy variables were
`analyzed using analysis of variance with
`the factors of treat-
`ment, visit, and patient within
`treatment and a treatment-by-
`visit interaction
`in the model. Equivalence
`(for the mean num-
`ber of micturitions/24
`hours
`and
`the mean number
`of
`incontinence
`episodes/24 hours) within
`the individual
`studies
`between 2 mg tolterodine
`twice daily and 5 mg oxybutynin
`three
`times daily was analyzed with 95% confidence
`intervals
`corresponding
`to a “double
`l-sided
`a! test.” Mean
`relative
`changes
`in
`laboratory
`safety data were estimated using geo-
`metric means. Adverse events were summarized
`in frequency
`tables by treatment group, body system, preferred
`term, and
`intensity. The percentage of patients with at least one adverse
`event,
`the percentage with dry mouth,
`the percentage who
`reduced
`the dose, and
`the percentage
`of withdrawals
`were
`compared between groups using
`the chi-square
`test.
`
`RESULTS
`and
`A total of 1,120 patients were randomized
`treated
`in the four studies at a total of 134 study
`centers. Of these 1,120 patients, 121 were random-
`ized to 1 mg tolterodine,
`474 to 2 mg tolterodine,
`349
`to oxybutynin,
`and 176 to placebo. Of these
`patients, 181 withdrew
`before completion
`of treat-
`ment: 7 (6%)
`taking 1 mg
`tolterodine,
`63 (13%)
`taking 2 mg
`tolterodine,
`94 (27%)
`taking 5 mg
`oxybutynin,
`and 17 (10%)
`taking placebo. Signifi-
`cantly more patients
`treated with oxybutynin with-
`drew prior
`to study completion when compared
`to
`patients
`treated with
`1 mg
`tolterodine,
`2 mg
`tolterodine,
`or placebo
`(P <O.OOl
`for all compari-
`
`91
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1017 - Page 2
`
`

`
`in
`for early termination
`reason
`sons). The primary
`the 2 mg
`tolterodine,
`5 mg oxybutynin,
`and pla-
`cebo groups was the occurrence
`of adverse events.
`The treatment groups were well balanced. Analysis
`of baseline demographics,
`disease characterization,
`micturition
`charts, and urodynamic
`variables
`for
`each of the studies revealed no significant differences
`between
`the treatment groups. The mean age of pa-
`tients participating
`in these studies was 59.0 years
`and 75% of the patients were women.
`the number of
`For the primary efficacy variable,
`micturitions/24
`hours, pooled
`results showed
`a
`significant
`decrease
`from baseline
`for
`the 1 mg
`tolterodine
`(P <O.OOl),
`2 mg
`tolterodine
`(P
`<O.OOl), and 5 mg oxybutynin
`(P cO.01) groups,
`compared
`to the placebo group
`(Fig. 1). Each ac-
`tive treatment
`reduced
`the mean daily micturition
`frequency by approximately
`20% from
`the baseline
`mean. After 12 weeks of
`treatment,
`equivalence
`was observed between
`the groups
`receiving 2 mg
`tolterodine
`twice daily and 5 mg oxybutynin
`three
`times daily with
`regard
`to decreases in the number
`of micturitions/24
`hours
`in all three studies where
`oxybutynin
`was compared
`to tolterodine
`(Fig. 2).
`For
`the variable number
`of incontinence
`epi-
`sodes/24 hours, pooled
`results showed a signifi-
`cant decrease
`from baseline
`for both
`tolterodine
`doses and oxybutynin
`compared
`to placebo
`(P
`CO.05
`for all comparisons;
`see Fig. 1). Each active
`treatment
`reduced mean daily
`incontinence
`epi-
`sodes by 40% to 60% from
`the baseline mean. After
`12 weeks of treatment,
`equivalence was observed
`between
`the 2 mg tolterodine
`twice daily and 5 mg
`oxybutynin
`three
`times daily groups with
`regard
`to
`decreases
`in
`the number
`of
`incontinence
`epi-
`sodes/24 hours
`in all three studies where oxybuty-
`nin was compared
`to tolterodine
`(Fig. 3).
`For the efficacy variable, change
`in volume void-
`ed/micturition,
`pooled
`results showed a significant
`increase
`from baseline
`for both
`tolterodine
`doses
`and oxybutynin
`compared
`to placebo
`(P <O.OOl
`for all comparisons).
`Each active
`treatment
`in-
`creased
`the mean volume
`voided/micturition
`by
`18% to 28% when compared
`to baseline
`levels.
`Analysis of patients’ perceptions
`of their bladder
`condition
`revealed
`that 39% of patients who
`re-
`ceived placebo, 41% of those
`treated with 1 mg
`tolterodine,
`52% of those treated with 2 mg toltero-
`dine, and 50% of those treated with 5 mg oxybuty-
`nin perceived
`improvement
`in their condition
`after
`12 weeks of treatment
`compared
`to baseline. The
`percentage of patients
`reporting
`improvement
`was
`significantly
`higher
`in the 2 mg tolterodine
`group
`(P = 0.003) and the 5 mg oxybutynin
`group
`(P =
`0.017)
`than
`in the placebo group. Approximately
`10% of patients
`in each group perceived
`that their
`condition
`worsened
`after 12 weeks of treatment
`compared
`to baseline.
`
`92
`
`Incontinence
`Episodes
`
`(n)
`
`Micturitions
`ON
`
`-0.5
`
`F
`
`-1.0
`
`Ei
`2
`0
`
`-1.5
`
`-2.0
`
`-.-
`l P <o.Lx vs pbcebo.
`1. Change
`incontinence
`
`FIGURE
`tions and
`ment.
`
`0.0 -
`
`-0.5 -
`
`-1.0 -
`
`-1.5 -
`
`-2.0 -
`
`-2.5 -
`
`-3.0
`
`’
`
`5
`fi
`i
`0
`
`0 Placebo
`
`0 Tolteradine
`lmgbid
`q Toltemdine
`2 mg bid
`
`n z*d”i”
`
`of micturi-
`in number
`from baseline
`episodes
`after 12 weeks of treat-
`
`Study No.
`010
`
`015
`
`0 Toitemdine
`2 mg bii
`
`1
`
`I
`equivalent
`
`I L
`
`equivalent
`
`from baseline
`2. Change
`FIGURE
`tions after
`12 weeks of treatment
`and 015.
`
`in number
`in studies
`
`of micturi-
`008, 0 10,
`
`and oxy-
`the tolterodine
`between
`Comparisons
`revealed
`that 1 mg and 2
`butynin
`treatment
`groups
`mg tolterodine
`twice daily were
`tolerated
`signifi-
`cantly
`better
`than
`oxybutynin
`when
`adverse
`events, dry mouth,
`study withdrawal,
`and dose re-
`ductions were considered.
`Adverse events were reported by 78%, 74%, 75%,
`and 93% of patients
`treated with placebo,
`1 mg
`tolterodine
`twice daily, 2 mg
`tolterodine
`twice
`daily, and oxybutynin,
`respectively. The number of
`adverse events per patient was higher
`in the oxy-
`butynin
`group
`(2.9 per patient)
`than
`in
`the pla-
`cebo, 1 mg tolterodine
`twice daily, or 2 mg toltero-
`dine
`twice daily groups
`(2.0, 1.9, and 1.8 per
`patient,
`respectively).
`The most
`frequently
`re-
`ported
`adverse events were autonomic
`nervous
`system disorders
`(21%
`in the placebo group, 29%
`in the 1 mg
`tolterodine
`group, 43%
`in the 2 mg
`tolterodine
`group,
`and 81%
`in
`the oxybutynin
`group); gastrointestinal
`disorders
`(27% in the pla-
`cebo group, 22%
`in the 1 mg
`tolterodine
`group,
`
`UROLOGY
`
`50
`
`(Supplement
`
`6A), December
`
`1997
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1017 - Page 3
`
`

`
`Study No.
`010
`
`015
`
`I
`L---l
`equivalent
`
`-I L
`
`equivalent
`
`-2.5
`
`30 4
`
`B
`5
`‘2 25 -
`a
`
`20-
`
`15-
`
`io-
`
`B
`8
`8
`5
`0
`0
`C
`
`0 Toiterodlne
`2 mg bid
`
`I Oxybulynin
`5 mg tid
`
`in number
`from baseline
`Change
`3.
`FIGURE
`episodes
`after
`12 weeks of treatment
`tinence
`008, 010,
`and 015.
`
`of incon-
`in studies
`
`Placebo
`
`Toltercdine
`1 mg bid
`Percentage
`5.
`by severity.
`
`FIGURE
`mouth,
`
`Tolterodine
`2 mg bid
`of
`patients
`
`Oxybutynin
`5 mg tid
`reporting
`
`dry
`
`100
`
`80
`
`860
`
`8
`5
`e
`p
`
`40
`
`20
`
`0
`
`Gastrointestinal
`
`Autonomic
`Nervous System
`ofpatients
`Percentage
`4.
`FIGURE
`system,
`gastrointestinal,
`nervous
`tem adverse
`events.
`
`0 Placebo
`
`0 Toiterodine
`lmgbid
`
`I Tolterodlne
`2 mg bid
`
`I Oxybutynin
`5 mg tid
`
`General
`
`reporting
`or general
`
`autonomic
`body
`sys-
`
`group, and 40% in the
`26% in the 2 mg tolterodine
`oxybutynin
`group);
`and general body disorders
`(28%
`in
`the placebo
`group,
`25%
`in
`the 1 mg
`tolterodine
`group,
`30%
`in
`the 2 mg
`tolterodine
`group, and 27% in the oxybutynin
`group; Fig. 4).
`Dry mouth was the most frequently
`reported ad-
`verse event
`in each treatment
`group
`(reported
`by
`16% of the placebo group, 24% of the 1 mg toltero-
`dine group, 40% of the 2 mg tolterodine
`group, and
`78% of the oxybutynin
`group). The percentage of
`patients
`reporting
`dry mouth was significantly
`higher
`in the oxybutynin
`group
`than in the toltero-
`dine or placebo groups
`(P -CO.001 for all compari-
`sons).
`In addition,
`the percentage
`of patients
`re-
`porting
`moderate
`or severe dry mouth
`was
`significantly
`higher
`in the oxybutynin
`group
`(60%)
`compared
`to
`the 1 mg
`tolterodine
`(4%), 2 mg
`tolterodine
`(17%), and placebo
`(6%) groups
`(P
`CO.001
`for all comparisons;
`Fig. 5).
`
`UROLOGY
`
`50 (Supplement 6A), December 1997
`
`25
`
`20
`
`15
`
`g
`8
`5
`0 0 10
`E
`
`5
`
`0
`
`Placebo
`
`Tolterodine
`1 mg bid
`
`Tolterodine
`2 mg bid
`
`Oxybutynin
`5 mg tid
`
`FIGURE
`adverse
`
`Percentage
`6.
`events.
`
`of patients
`
`withdrawing
`
`due
`
`to
`
`reported adverse events included
`Other commonly
`headache, dyspepsia, dizziness, and UTI. Headache
`was reported by 10% of patients
`treated with 2 mg
`tolterodine and 7% of those treated with oxybutynin,
`whereas dyspepsia was
`reported
`by significantly
`more patients
`treated with oxybutynin
`(11%)
`than
`with 2 mg tolterodine
`(6%, P = 0.006). The propor-
`tion of patients
`reporting other events was generally
`consistent between
`treatments.
`the
`from
`A total of 34 patients were withdrawn
`studies because of adverse events: 5% in the pla-
`cebo group, 2% in the 1 mg tolterodine
`group, 8%
`in the 2 mg tolterodine
`group, and 20% in the oxy-
`butynin group
`(Fig. 6). The proportion
`of patients
`who withdrew
`because of adverse events was sig-
`nificantly
`higher
`in the oxybutynin
`group
`than
`in
`either of
`the
`tolterodine
`groups or
`the placebo
`group
`(P <O.OOl for all comparisons).
`Dose reduction was permitted
`in the tolterodine/
`
`93
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1017 - Page 4
`
`

`
`of the incidence of palpitations
`fluctuation
`random
`in this patient population.
`clinical
`Evaluations
`of blood pressure,
`istry, and hematologic
`values
`indicated
`ically significant
`differences
`between
`ment groups.
`
`chem-
`no clin-
`the
`treat-
`
`COMMENT
`these four phase III
`and collectively,
`Individually
`durations
`docu-
`studies with 12-week
`treatment
`of tolterodine
`ment
`the vastly greater
`tolerability
`compared
`to oxybutynin
`at equivalent
`doses. Pa-
`tients
`treated with
`tolterodine
`experienced
`signifi-
`cantly
`fewer occurrences of dry mouth
`(in terms of
`both
`frequency
`and
`severity),
`overall
`adverse
`events, study withdrawals,
`and dose
`reductions
`when compared
`to patients
`treated with oxybuty-
`nin. Patients
`treated with
`tolterodine
`were more
`compliant
`in taking
`their medication
`than were pa-
`tients
`treated with oxybutynin.
`The general safety of antimuscarinic medications
`for the treatment
`of overactive bladder was shown
`in these studies. The percentage
`of patients expe-
`riencing
`serious adverse events was comparable
`between
`the active treatment
`groups and placebo.
`Urinary
`retention
`and micturition
`disorders were
`reported
`only
`rarely, with a lower percentage
`of
`patients
`in the tolterodine
`groups
`reporting
`these
`events when compared with
`the placebo and oxy-
`butynin
`groups. Also, no differences were noted
`between
`the groups with
`regard
`to blood pressure,
`clinical chemistry,
`and hematologic
`values.
`No cardiovascular
`safety concerns
`(as measured
`from adverse events) were noted
`in either of the
`tolterodine
`treatment
`groups compared
`to placebo.
`Information
`on cardiac safety, determined
`from
`ECGs, was available
`from only one of the four stud-
`ies. Electrocardiograms
`were not performed
`after
`12 weeks of treatment
`in all the studies due to the
`fact that ECGs were extensively
`studied
`in phase I
`(five studies) and phase
`II (four studies). These
`showed
`that
`tolterodine
`had no effect on cardiac
`conduction
`in any patient
`groups,
`including
`the
`elderly. Electrocardiographic
`data after 12 weeks
`of treatment
`in the one study confirmed
`the results
`from
`the phase I and II studies.
`In addition,
`it was
`shown
`that
`tolterodine
`has no effect on cardiac
`conduction
`in patients
`taking concomitant
`diuret-
`ics (unpublished
`data).
`The efficacy parameters used in the studies were
`selected based on their
`relevance
`to patients with
`overactive bladder. The change
`in the number
`of
`micturitions/day
`was selected as the primary
`effi-
`cacy variable. The change
`in the number of incon-
`tinence episodes/day, while also of relevance
`to the
`patient, was selected only as a secondary efficacy
`variable because not all patients with overactive
`
`UROLOGY
`
`50 (Supplement 6A), December 1997
`
`I Tolterodine
`
`2 mg bid
`of patients
`
`Oxybutynin
`5 mg
`dose
`
`tid
`reduc-
`
`having
`
`FIGURE 7. Percentage
`tions.
`
`the first 2
`studies within
`comparative
`oxybutynin
`weeks of treatment
`in case of intolerance
`to the
`study medication
`and only as an alternative
`to
`study withdrawal.
`Dose reduction was reported
`for
`4%, 9%, and 32% of patients
`receiving placebo, 2
`mg tolterodine,
`and oxybutynin,
`respectively
`(Fig.
`7). The proportion
`of patients who had a reduction
`in
`the dose of
`the study drug was significantly
`higher
`in the oxybutynin
`group
`than
`in the 2 mg
`tolterodine
`(P <O.OOl)
`or placebo
`(P <O.OOl)
`groups.
`to
`in the 12-week studies
`Tolterodine was shown
`and placebo. Serious ad-
`be as safe as oxybutynin
`verse events were reported by 3% of patients
`in the
`placebo group, 4% in each tolterodine
`group, and
`4%
`in
`the oxybutynin
`group.
`Serious adverse
`events possibly
`indicating
`cardiac
`dysfunction
`were
`reported
`by 1.7% of patients
`in the placebo
`group, 0.8%
`in
`the 2 mg
`tolterodine
`group, and
`0.3% in the oxybutynin
`group. No serious cardiac
`adverse events were reported
`in the group
`receiv-
`ing 1 mg tolterodine
`twice daily.
`re-
`Overall, cardiovascular
`adverse events were
`ported most commonly
`in
`the 1 mg
`tolterodine
`group
`(12.4%), with
`lower percentages
`in the pla-
`cebo c&O%), 5 mg oxybutynin
`three
`times daily
`(6.3%), and 2 mg tolterodine
`(4.2%) groups. The
`cardiovascular
`adverse event
`that accounted
`for
`the difference between
`the 1 mg tolterodine
`group
`and
`the other
`treatment
`groups was palpitations,
`reported
`by 6.6% of patients
`receiving
`1 mg
`tolterodine
`twice daily, 2.4% of those receiving pla-
`cebo, 0.4% of
`those
`receiving
`2 mg
`tolterodine
`twice daily, and 2.3% of those receiving oxybuty-
`nin. The
`lack of a dose-response
`relationship
`for
`this.event
`suggests
`that
`these findings
`represent a
`
`94
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1017 - Page 5
`
`

`
`and historically
`incontinence,
`bladder experience
`antimuscarinic
`to demonstrate
`it has been difficult
`efficacy with
`this parameter.7-g Volume
`voided/
`micturition
`was selected as a secondary
`efficacy
`measure
`because an
`increase
`in
`this parameter
`would
`be essential
`to achieve
`the more patient-
`relevant measures. Urodynamic
`assessment was
`not selected
`in any of
`the
`four 12-week
`studies
`because
`it is a less patient-relevant
`measure.
`Urodynamic
`assessment as an efficacy parameter
`was evaluated
`in one of the phase
`III studies
`that
`had a 4-week
`treatment
`duration
`and was under-
`taken
`to confirm
`the findings
`of phase
`II studies
`with
`tolterodine.
`After 4 weeks of treatment,
`sig-
`nificant
`increases
`from baseline were noted
`in vol-
`ume at first contraction
`(63%
`increase, P = 0.30)
`and maximum
`cystometric
`capacity
`(20% increase,
`P <O.OOl)
`for 2 mg
`tolterodine
`twice daily com-
`pared
`to placebo. Although
`1 mg tolterodine
`twice
`daily was more effective
`than placebo with
`regard
`to these parameters,
`the differences
`did not reach
`statistical significance. Both doses of tolterodine
`(1
`mg twice daily and 2 mg twice daily)
`resulted
`in
`statistically
`significant
`greater
`increases in residual
`volume
`from baseline compared
`to placebo
`(P =
`0.034 and P = 0.042,
`respectively);
`however,
`the
`mean
`increases of 10 mL and 18 mL for 1 mg and 2
`mg tolterodine,
`respectively, were not considered
`clinically
`significant
`(Fig. 8). These
`results con-
`firmed
`the urodynamic
`results
`reported
`in
`the
`phase II studies of tolterodine.6
`An interesting
`finding
`in the 12-week studies was
`that clinical efficacy, as measured
`from
`the micturi-
`tion diaries for both
`tolterodine and oxybutynin,
`did
`not reach a maximum
`until 5 to 8 weeks after treat-
`ment was initiated. At 4 weeks after treatment
`initia-
`tion, 85% to 90% of the maximum
`effectiveness was
`noted. Although
`this discovery was initially surpris-
`ing, when
`the coping mechanisms by patients with
`this condition are considered,
`the delay to maximum
`response becomes understandable. Patients with
`this
`condition
`use habitual mechanisms
`to control
`their
`urgency and incontinence
`episodes. Many patients
`urinate according
`to a time schedule and at the first
`sensation of urgency. The study results suggest that it
`takes a period of time using medication
`for the pa-
`tient
`to trust
`the enhanced
`control
`that he or she
`begins to experience.
`in all four studies was a large
`A common
`feature
`placebo
`response
`for micturitions/24
`hours and in-
`continence
`episodes/24 hours. This placebo effect
`is believed
`to be due, at least in part,
`to a bladder-
`training
`effect
`that occurs as part of completing
`is
`micturition
`diaries. The presence of this effect
`supported
`by the 39% of placebo
`recipients who
`reported
`that
`their condition
`improved
`as the re-
`sult of treatment.
`Another
`possibility
`is that
`the
`patients
`taking placebo decreased
`their daily
`fluid
`
`UROLOGY
`
`50 (Supplement 6A), December 1997
`
`100
`
`,
`
`I
`
`Volume at
`First
`ContractiOn
`
`Madmum
`Cyslometric
`Capacity
`
`Residual
`Volume
`
`l
`
`P
`
`<O.M
`
`v8
`
`placsbo.
`
`FIGURE
`rameters
`
`from baseline
`8. Change
`after 4 weeks of treatment.
`
`in urodynamic
`
`pa-
`
`during
`urine production)
`(and subsequent
`intake
`the study
`to control
`their condition.
`This concept
`is supported
`by the decrease
`in micturitions/day
`and
`incontinence
`episodes/day
`without
`corre-
`sponding
`increases
`in volume voided/micturition.
`The effectiveness of 1 mg and 2 mg
`tolterodine
`twice daily was comparable
`in the studies, as mea-
`sured by the change
`in micturitions/day,
`inconti-
`nence episodes/day, and volume voided/micturition.
`These findings
`initially suggest that 1 mg tolterodine
`twice daily may be the most appropriate
`dosage for
`patient
`treatment because the efficacy is comparable
`and the tolerability
`is at the placebo
`level. However,
`the urodynamic
`results
`from
`the 4-week phase
`III
`study and patient perception scores do not support 1
`mg as the most appropriate dosage. Urodynamic
`re-
`sults revealed
`that 2 mg tolterodine,
`but not 1 mg
`tolterodine,
`is significantly more effective
`than pla-
`cebo in increasing maximum
`cystometric
`capacity
`and volume at first contraction. With
`regard
`to pa-
`tients’ perceptions of their bladder condition,
`the per-
`centage of patients
`reporting
`improvement was sig-
`nificantly higher with 2 mg
`tolterodine
`than with
`placebo, whereas
`the percentage
`reporting
`improve-
`ment with 1 mg tolterodine was at the placebo level.
`These facts, plus the excellent tolerability and safety of
`the 2 mg tolterodine dose, indicate that 2 mg tolterodine
`twice daily is the optimal
`treatment dosage.
`It is envisioned
`that
`the comparable efficacy and
`significantly
`better
`tolerability
`of tolterodine
`com-
`pared
`to oxybutynin would manifest
`itself
`in im-
`proved quality of life (QOL)
`for patients
`treated with
`tolterodine. Unfortunately,
`at this time, no disease-
`specific QOL tool has been developed
`for all patients
`with overactive bladder. Within one of the 12-week
`studies, a generic QOL
`tool (SF-36) was used to as-
`sess eight health concepts at baseline and after 12
`weeks of treatment.lO Baseline scores were found
`to
`be significantly
`lower
`than those of the age- and sex-
`matched
`general population,
`suggesting
`that
`the
`
`95
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1017 - Page 6
`
`

`
`impact
`has a negative
`overactive bladder condition
`on QOL. After 12 weeks of treatment,
`the results for
`the eight health concepts were not significantly
`dif-
`ferent between
`the groups; however, changes indicat-
`ing improvement were noted
`in six of eight concepts
`in the 2 mg
`tolterodine
`group compared
`to two of
`eight concepts in the oxybutynin
`and placebo groups.
`As the SF-36 is a generic instrument
`and is not spe-
`cifically
`targeted
`to patients with urge incontinence,
`and as most patients
`in this age group have three or
`more comorbidities,
`a significant
`change after 12
`weeks could probably not be expected. The results
`from
`this instrument
`indicate
`that
`tolterodine
`im-
`proves QOL to a greater extent
`than does oxybutynin
`or placebo.
`III studies were allowed
`in all phase
`Patients
`open-label
`treatment with
`tolterodine
`if
`long-term,
`they completed
`all visits in the double-blind
`study.
`Interim
`results
`from
`the open-label
`extension
`re-
`vealed
`that patients
`continue
`to receive effective
`treatment with
`tolterodine
`over long
`treatment du-
`rations. A total of 83% and 70% of patients contin-
`ued with
`tolterodine
`for 6 and 12 months,
`respec-
`tively. Efficacy was maintained
`over these periods.
`
`CONCLUSIONS
`of
`tolerability
`the excellent
`conclusion,
`In
`the management
`tolterodine
`has implications
`for
`in terms of both
`of patients with overactive bladder
`It is well doc-
`effective
`treatment
`and compliance.
`is a highly ef-
`umented
`that, although
`oxybutynin
`fective drug,
`its systemic side effects (particularly
`of
`dry mouth)
`lead
`to
`frequent
`discontinuation
`treatment
`or dosage reductions
`to levels that may
`be of minimal
`clinical benefit.l.5 Patients
`treated
`
`these limi-
`should not experience
`tolterodine
`with
`tations and, instead, will be able to receive safe and
`effective
`long-term
`treatment
`for their condition.
`
`REFERENCES
`in the treatment of
`1. Andersson K-E: Current
`concepts
`disorders of micturition.
`Drugs 35: 477-494;
`1988.
`2. Yarker YE, Goa KL, and Fitton A: Oxybutynin. A review of its
`pharmacodynamic and pharmacokinetic
`properties, and its thera-
`peutic use in denusor
`instability. Drugs Aging 6: 243-262; 1995.
`3. Thuroff
`J, Bunke B, Ebner A, Faber P, de Geeter P,
`Hannappel
`J, Heidler
`H, Madersbacher
`H, Melchior
`H,
`Schafter W, et al.: Randomized,
`double-blind, multicenter
`trial
`on treatment of frequency, urgency and incontinence
`related
`to detrusor hyperactivity.
`Oxybutynin
`versus propantheline
`versus placebo. J Urol 145: 813-817;
`1991.
`4. Ouslander
`JG, Blaustein J, Connor A, Orzeck S, and
`Yong CL: Pharmacokinetics
`and clinical effects of oxybutynin
`in geriatric patients. J Urol 140: 47-50; 1988.
`5. Kelleher CJ, Cardozo LD, Khullar V, Salvatore S, and
`Hill S: Anticholinergic
`therapy:
`the need for continued
`surveil-
`lance. Neurourol Urodyn 13: 432-433;
`1994.
`a
`6. Nilverbrant
`L, Hallen B, and Larsson G: Tolterodine:
`new bladder
`selective, muscarinic
`receptor antagonist:
`pre-
`clinical pharmacological
`and clinical data. Life Sci 60: 1129-
`1136; 1997.
`7. Zorzitto ML, Holliday PJ, Jewe