British journal of Urology (1995). 75. 452--456
`
`Trospium chloride versus oxybutynin: a randomized, double-
`blind, multicentre trial in the treatment of detrusor hyper-
`reflexia
`
`H. MADBRSBACI-IER*. M. ST('3HRER*. R. RICHTER:]:. H. BURGD('j')RFER§. I-1.]. HACHEMI andG. MURTZ||
`‘Rehab-Centre. Bad Hdring, Austria, TBG Unfallklinik Murriau, Germany, i’/IKH Bremen. Germany. §BG Unfallklinik Hamburg
`Bergedorf. Germang,1]Centre Paraplegique Beau Sejour, Switzerland and M/ladnus AG. Cologne. Germany
`
`Objective To compare trospium chloride (TCIJ. a quat-
`ernary ammonium derivative with atropine-like eflects
`and predominantly
`antispasmodic
`activity. with
`oxybutynin (Oxy)
`in terms of efficacy and adverse
`effects.
`
`Patients and methods In a randomized. double-blind.
`multicentre trial. 95 patients with spinal cord injuries
`and detrusor hyper-reflexia were studied. Treatment
`consisted of three doses per day over a 2 week period,
`with either Oxy (5 mg three times daily) or with TCI
`(20 mg twice daily) with an additional placebo at
`midday. The results were evaluated with regard
`to changes in objective (urodynamic) data and sub-
`jective symptoms as well as the incidence/severity of
`adverse effects.
`
`Results With both drugs there was a significant increase
`in maximum bladder capacity. a significant decrease
`in maximum voiding detrusor pressure and a signifi-
`
`cant increase in compliance and residual urine: there
`were no statistically significant differences between
`the treatment groups. The percentage of patients who
`reported severe dryness of the mouth was considerably
`lower
`(4%)
`in those receiving TCI 2x20 mg/day
`than in those receiving Oxy (23%) 3)-<5mg/day.
`Withdrawal from treatment was also less frequent in
`those receiving TCI
`(6%)
`than in those receiving
`Oxy (16%).
`Conclusion Trospium chloride and oxybutynin. judged
`in terms of objective urodynamic parameters. are of
`substantially equal value as parasympathetic antagon-
`ists. However. assessment of tolerance in terms of
`
`adverse drug effects showed that TC} had certain
`advantages.
`therapy of detrusor
`Keywords Bladder hyper-reflexia,
`hyper-reflexia.
`trospium chloride.
`oxybutynin
`hydrochloride
`
`Introduction
`
`Detrusor hyper-reflexia is a common problem in patients
`with suprasacral spinal cord lesions. It is usually com-
`bined with detrusor striated sphincter dyssynergia (DSD).
`which may cause increased detrusor hyper-reflexia and
`low compliance. Untreated detrusor hyper—reflexia and
`DSD may destroy the kidneys.
`The
`combination
`of
`clean
`
`intermittent
`
`self-
`
`catheterization {ClC) and pharmacological relaxation of
`the detrusor is an established method of treating an
`unbalanced reflex bladder with reflex urinary inconti-
`nence. However. side-effects of the drugs used may limit
`their effects.
`
`is an antiparasyrnpathetic
`Trospium chloride (TCl)"'
`quaternary ammonium derivative with atropine—like
`
`Accepted for publication 28 November 1994
`‘The oral application of trospium chloride 20 mg lml. fspasmolyt.
`Madaus. Germany), is licensed in Germany and under consideration
`for licensing in several European countries.
`
`452
`
`effects as well as effects on ganglia and smooth muscle
`[1]. Its antispasmodic activity is predominant. TCI has
`hydrophilic properties and does not pass the blood—brain
`barrier in significant amounts [1,2]. In the 1980s it was
`used in low daily dosages of up to 15 mg for
`the
`treatment of
`the unstable bladder, with promising
`results [3.4].
`The efficacy and tolerance of high dose treatment with
`trospium chloride (20 mg twice daily p.o.) was demon-
`strated in a multicentre pilot study [5] and the results
`have been confirmed by Stohrer et al. [6].
`The tertiary amine oxybutynin (Oxy) is effective in the
`treatment of detrusor hyper-reflexia and is regarded as
`the therapeutic standard. The comparative pharmaco-
`logical properties of both drugs are summarized in
`Table 1.
`
`The aim of this study was to compare trospium
`chloride with oxybutynin hydrochloride to determine
`the efficacy and tolerance in a multicentre double—blind
`comparative clinical trial.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2034 - 0001
`
`

`
`TROSPIUM CHLORIDE VERSUS OXYBUTYNIN 453
`
`Table 1 Pharmacological characteristics of trospium chloride and oxybutynine
`
`Trospium chloride
`
`Oxybutynim:
`
`Chemistry
`Liquor penetration
`Dosage
`Galenics
`Half-life time
`Maximum serum level
`Elimination
`Metabolites
`
`'
`
`Quaternary ammonium compound
`No
`20 mg twice daily
`Sugar—coated tablets
`5-15 h
`4-6 h p.21.
`Kidney (unchanged)
`No
`
`Tertiary amine
`Yes
`2.5-5 mg two or three times daily
`‘Tablets
`2-3 h
`1 h p.a.
`Kidney
`Yes
`
`Patients and methods
`
`Participants in the study were suffering from detrusor
`hypcr—reflexia as defined by the International Continence
`Society [7]. Exclusion criteria were acute urinary tract
`infection. glaucoma. known allergy to atropine. Oxy or
`TC],
`tachycardia, renal. hepatic and/or cardiovascular
`insufiiciency, intake of other anticholinergic drugs, body
`weight over 90 kg or age below 18 years. Ninety-five
`spinal injury patients were enrolled in the trial. A total
`of 88 patients for whom urodynamic findings before and
`after treatment were available were included in the
`
`evaluation of efiicacy: 52 were treated with TCl 20 mg
`twice daily and 43 with Oxy 5 mg three times daily.
`Both groups were comparable for sex distribution. age.
`body weight, maximum cystometric bladder capacity.
`maximum detrusor pressure. bladder Compliance and
`residual urine (Table 2).
`The study design comprised a week without drugs and
`then 2 weeks’ treatment either with Oxy (5 mg three
`times daily) or TC) (20 mg twice daily). To maintain
`double-blind conditions the TCI group received a placebo
`
`Table 2 Demographic and urodynamic data
`
`at midday (double dummy technique) [8]. The evaluation
`before and after the treatment period comprised a urody-
`namic investigation with collection of data on maximum
`cystometric bladder capacity. maximum voiding detrusor
`pressure. compliance and residual urine. clinical symp-
`tomatology and adverse effects. Before the trial began
`patients were evaluated for any symptoms which might
`be regarded as adverse eflects.
`
`Results
`
`The primary indices of efficacy were maximum bladder
`capacity and maximum voiding detrusor pressure during
`micturition. Maximum bladder capacity in the TCI group
`increased significantly (P-6.0.001) by 96.6 mL (group
`mean before
`treatment 215.2 rnL:
`after
`treatment
`
`311.9 mL). In the Oxy group there was an increase from
`187.8 mL to 350.9 mL. amounting to _an average of
`163.0 mL (P<0.00l ). However. the difierence between
`the two treatment groups (P=0.057) was not statisti-
`cally significant at the 5% level (Fig. 1).
`Maximum detrusor pressure during micturition was
`
`Variable
`
`Sex (13)
`Male
`Female
`Age (years) (mean. range)
`Body-weight (kg) (mean. range)
`Maximum cystometric
`bladder capacity (mL) (mean. range)
`Maximum voiding dctrusor pressure
`(cmHzO) (mean. range)
`Compliance
`(ml./cmH,O) (mean. range)
`Residual urine
`(m.L) (mean. range)
`
`British Journal of Urology (1995). 75
`
`'1“mspium chloride
`(n=52)
`
`28 (54%)
`24 (46%)
`32.8 (16-56)
`69.1 (47-91)
`
`215.5 (20-650)
`
`82.1 (25-150)
`
`74.6 (2—-480)
`
`49.2 (O-520)
`
`Oxybutynine
`(nu-.43)
`
`19 (44%)
`24 (55%)
`31.3 (18-54)
`62.1 (42-87)
`
`185.1 (20-450)
`
`82.1 (31-175)
`
`59.5 (3—37S)
`
`48.1 (O—360)
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2034 - 0002
`
`

`
`454 H. MADERSBACHER ct al.
`
`600 [-
`
`500 5
`
`3 30°
`200 L i
`
`132
`
`4001:
`weH 216
`
`0
`
`......_ .
`Post
`Pre
`l— TCI —l
`
`139
`
`400
`350
`300
`
`4 250
`E 200
`150
`100
`50
`
`
`
`Post
`Pre
`i— OXY--l
`
`
`
`Post
`Pre
`l"-"TCI —l
`
`Post
`Pre
`in OXY—4
`
`Pm. -: 0.001
`
`PTC|_Q)(y = 0.06
`
`PQXY < 0.001
`
`P-[cl <
`
`JDTCFOXV =
`
`Poxy <
`
`Fig.1. Trospium chloride vs oxybutynine. Maximal cystometric
`bladder capacity (arithmetic mean and so).
`
`Fig. 3. Trospium chloride vs oxybutynine. Residual urine (arith-
`metic mean and so).
`
`The frequency of hyper-reflexive waves tended to
`decrease in both groups as treatment progressed, but
`there were no statistically significant differences between
`the two drugs (P=O.16).
`As regards ‘vital signs‘ — heart rate, systolic and
`diastolic blood pressure — there were no conspicuous
`changes in either group.
`Analysis of tolerance was carried out on all 95
`patients. Subjective assessment of tolerance was based
`on the following target indices:
`Twenty ‘wellbeing items’ were the subject of direct
`questioning by the investigator before and at the end of
`the trial. Questions were asked about
`the following
`items in particular: dryness of mouth. blurred/double
`vision. palpitation. constipation. difficulty in swallowing.
`Severity was graded on the following scale: not present
`(0). slight (1), definite (2), severe (3). The overall rate of
`side—effects was almost comparable in both groups.
`Typical antiparasyrnpathetic side-effects — dryness of
`the mouth and constipation — were encountered in
`both groups. In the TCI group. 26 patients (54%) and
`in the Oxy group 22 patients (56%) complained of
`dryness of the month. However. the severity grading
`showed marked differences. For instance. dryness of the
`mouth deteriorated to ‘severe' in 4% in the TCI group.
`while the corresponding figure in the Oxy group was
`23% (Fig. 4).
`Withdrawal from the trial occurred more frequently
`in patients taking Oxy (n= 7, 16%) than in those taking
`TC] (in: 3. 6%). Furthermore, the Oxy patients withdrew
`earlier (after an average of 7.1 days)
`than the TCi
`patients (after an average of 14.3 days).
`To provide objective assessment of the tolerance and
`side-effects of the two drugs the following factors were
`checked before and after treatment: serum glutamic
`oxaloacetic transaminase, serum glutarnic pyruvic trans-
`arninase. serum alkaline phosphatase. urea. creatinine.
`leucocytes. erythrocytes. platelets. haemoglobin and
`packed cell volume.
`In neither group was there any
`tendency to change.
`
`British Journal of Urology (199 5}. 75
`
`comparable in both groups at the onset (TCI: x= 81.8 cm
`H20, Oxy:x=79.9 cmH,0). In the TCI group it fell by
`an average of 35.4 cmH;,O and in the Oxy group by
`38 cm H20. This primary target variable thus showed
`statistically significant differences within each treatment
`group (P < 0.001). Comparison of the two groups showed
`a slight trend towards greater pressure reduction in the
`Oxy group (Fig. 2). but this was not statistically signifi-
`cant [P=O.63).
`Bladder compliance showed an increase from an aver-
`age of 74.62 mL/cm to 92.75 mL/cm H20 in the TCI
`group. i.e. 16.96 rnL/cm H20 (P<0.001). A comparable
`improvement was seen in the Oxy group. where the
`mean initial reading of 59.49 ml./cm H20 increased by
`22.56 ml./cm H20 to 78.24 mL/cm I-I20. As P was 0.43.
`there were no clinically relevant differences in terms of
`
`bladder compliance between the two treatment groups.
`Residual urine increased significantly in both groups:
`in the TC! group from an average of 49.22—128.32 rnL
`(increase of 76.45 mL). and in the Oxy group from an
`average of 48.14—1S4.36 ml. (increase of 114.08 rnL].
`This secondary target index seemed to Show a trend
`towards a more pronounced increase in residual urine
`in the Oxy group.
`though this was not statistically
`significant (P=0.19) (Fig. 3}.
`‘.\
`\\ 120
`\ 100
`E
`O 0
`
`
`
`_
`
`.
`
`.
`
`20
`O
`
`I E
`
`‘i-R
`
`_
`
`Post
`Pre
`l— TCI —|
`HPTCI < Drool
`
`Prcmxv '-' 953
`
`Post
`Pre
`l‘ 0XY- 4
`Poxv < 9-001
`
`vs oxybutynine. Maximal voiding
`Fig. 2. Trnspiurn chloride
`detrusor pressure {arithmetic mean and 50).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2034 - 0003
`
`

`
`TROSPIUM CHLORIDE VERSUS OXYBUTYNIN 455
`
`
`
`L~TC| pre~
`
`LTCI post—J
`
`ROXY pre-J
`
`LOXY postJ
`
`01C
`
`Percent
`
`0
`
`Fig. -1-. Trospium chloride vs oxybutynine.
`Adverse efiect — dryness of the mouth.
`El. None. I, Mild. . Marked. E3. Severe.
`
`Discussion
`
`The increase in maximum bladder capacity together
`with the decrease in maximum dctrusor pressure during
`micturition with both agents demonstrated statistically
`significant and clinically relevant changes and provided
`objective evidence of relaxation of the dctrusor muscle.
`Furthermore.
`it can be assumed that TCI and Oxy are
`equal
`in their effects on detrusor hyperactivity. The
`inclusion criterion — only patients ‘with detrusor hyper-
`reflexia following spinal cord injury ~ excludes the
`possibility of placebo effects which might mask the actual
`drug effect. The improvement in bladder function was
`paralleled by the expected increase in residual urine.
`This is because although there is a decrease in detrusor
`contractility. dyssynergia of the striated muscle sphincter
`persists more or less unchanged.
`In addition to efficacy. tolerance is the second crucial
`parameter in the overall assessment of any drug. The
`20 ‘well-being items‘ related to typical anticholinergic
`symptoms and signs were the subject of targeted ques-
`tioning in both groups before and at the end of the
`treatment period. The high frequency of typical anticholi-
`nergic side—efl'ects associated with both drugs (e.g. dry-
`ness of the mouth: TCl 54%. Oxy 54%) occurred because
`the patients were specifically asked by the investigator
`whether they had dryness of the mouth or other symp-
`toms {12]. Studies in which side-elifects were recorded
`only when they were reported spontaneously by patients
`show a substantially lower rate [5.6.13.i4]. The most
`frequent side—efiect in this trial was dryness of the mouth;
`deterioration in the severity grading occurred more
`frequently during treatment with Uxy.
`Analysis of premature withdrawals from the trial (total
`11%) shows certain differences in favour of TCl. There
`were three withdrawals during treatment with TCl (6%)
`in contrast to seven during treatment with Oxy (16%).
`The lower incidence of withdrawals is related to the
`
`broad therapeutic range of TCI: Breuel reported that
`even single oral doses of 360 mg [factor 18 of a single
`
`British Journal of Urology (1995). 75
`
`therapeutic dose) were tolerated with only minor com—
`plaints [15}. Although several reasons were given by all
`10 patients who terminated the trial prematurely.
`it
`seems likely that in most cases typical anticholinergic
`drug eflects were the crucial factors and at least contrib-
`uted to premature withdrawal.
`One critical comment which must be made is that the
`
`less favourable results for tolerance of Oxy could be
`attributed to the fixed dose of 5 mg three times daily
`[10]. This dose conformed to the manufacturer's rec—
`ommendations when the trial was being planned.
`In patients who cannot tolerate oral administration of
`these drugs, alternative routes might be associated with
`better compliance. Intravesical instillation of Oxy has
`proved effective without causing the usual side-eflects.
`especially i.n patients who could not tolerate the drug
`orally [16.17]: the intravesical application of antichol.i-
`nergic drugs is logical, especially for patients already on
`CIC. as the drug could easily be instilled regularly at the
`end of catheterization without additional
`instrumen-
`
`tation. However, no solution of these drugs ready for
`instillation. preferably in a disposable package and with
`a suitable attachment
`to the catheter.
`is currently
`available.
`The results of this trial demonstrate that TCl has
`
`certain advantages over Oxy in terms of the severity of
`adverse drug reactions. underlined by the fact
`that
`patients receiving TCl withdrew from treatment less
`frequently than those receiving Oxy.
`Assessment of the efficacy and tolerance of trospium
`chloride in comparison with the internationally accepted
`standard drug — oxybutynin — demonstrates that the
`former is of equal value. The risk-benefit ratio of the
`beneficial effects versus the more severe anticholinergic
`side-effects supports the use of trospium chloride. Patients
`prone to dry mouth. e.g.
`the elderly. may therefore
`benefit from trospium chloride.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2034 - 0004
`
`

`
`456 H. MADERSBACHER at al.
`
`Conclusions
`
`The clinical efficacy and tolerance of trospium chloride
`and oxybutynin for the treatment of detrusor hyper-
`rellexia were compared in a controlled, double-blind,
`multicentre study. Of 95 patients with spinal cord injur-
`ics enrolled in the trial. 88 were suitable for statistical
`
`evaluation of efficacy. With both drugs there was a
`significant
`increase in maximum bladder capacity. a
`significant decrease in maximum voiding detrusor press-
`ure and a significant increase in compliance and residual
`urine. Maximum bladder capacity showed statistically
`significant
`increases
`(P<0.001) during the 2-week
`period of treatment with both drugs. There were no
`statistically significant differences between the treatment
`groups with regard to these parameters. Where tolerance
`is concerned, the percentage of patients who reported
`severe dryness of the mouth was considerably lower in
`those receiving trospium chloride (4%) 2 x 20 mL/day
`than in those receiving oxybutynin (23%) 3 x 5 mg/day.
`Withdrawal from treatment was also less frequent in
`those receiving trospium chloride (6%) than in those
`receiving oxybutynin (16%).
`This study shows that when objective urodynamic
`parameters are used to assess the clinical eflicacy of
`trospium chloride and oxybutynin. both drugs are of
`substantially equal value as parasympathetic antagon-
`ists. However, assessment of their tolerance in terms of
`
`adverse drug effects shows that trospium chloride has
`certain advantages.
`
`References
`
`1 Antweiler H, Lauterbach F. Lehmann HI), Uebel H. Vogel G.
`Zur Pharmalcologie und Toxikologie von Azonlaspir-
`anen in der Nortropin- bzw. Pseudonortropin-Reihe.
`Arzneimittcl-Forsch. Drug Res 1966; 16: 1581-92
`2 Amrnon HPT. A.rznelmlttelm3bcn- mm‘ Wechselwirkungen.
`Stuttgart: Wiss. Verlagsgesellschaft, 1991
`3 May P. Siikeland I, Valencic M. Kopf 1-I. Behandlung von
`Blasenfiinktionsstorungen mit Trospiumchlorid. Prakt Arzt
`1984:; 32: 2283-5
`4 Wolters A. Siikcland 1, Well W. Kopf H. Parasympahtoly-
`tische Therapie neurogener Blasenfunktionsstorungen.
`Dt med Wschr 1980: 39: 1344
`5 Madersbacher H. Stiihrer M. Richter R. Gianetti BM.
`
`G. Hochdosicrte Applikation Von Trospium-chlorid
`zur Therapie der Detrusorhyperreflexie. Urologe{A) 1991:
`30: 260-3
`
`6 Stiihrer M et al. Effect of trospium chloride on urodynamic
`"parameters in patients with dctrusor hyperreflexia due to
`spinal
`cord injuries:
`a. multicentre placebo-controlled
`double-blind trial. Ural Int 1991: 47: 138-43
`7 Abrams P et al. The standardisation of terminology of
`lower urinary tract function. Scand J Urol Nephr (Suppl)
`1983: 114: 149-53
`8 Spriet A. Simon P. Methodology of Clinical Drug Trials. Basel:
`Karger. 1985
`9 Riva D. Casolati E. Oxybutynine chloride in the treatment
`of female idiopathic bladder instability. Clin Exp Obstet
`Gynecol 1984: 11: 37412
`10 De Geeter P. Die Behandlung von Blasenfunktionsstiirungen
`mit Oxybutynin in der Urologischen Praxis — Ergebnisse
`einer Anwcndungsbeobachtung. Kontirlenz 1993; 1: 20141
`11 Baigrie R]. Kclleher
`IP. Fawcett DP. Pengelly AW.
`Oxybutyninz is it safe? Br] Urol 1988; 62: 319-32
`12 Wallander MA. Dirnenas E. Svardsudd K. Wildund j.
`Evaluation of three methods of symptom reporting in a
`clinical
`trial of lelodlpine. Eur I Clin Pharmacol 1991:
`4]: 187-96
`13 Madersbacher H. Stfihrer M. Miirtz G. Lauven G, Kuhn U.
`Trospiurnchlorid {spasmolytj e ]:‘.in wirksarnes Thera-
`peutikum beim Urge-/Reizblasen-Syndrom. Urology
`(B)
`1993; 33; 39-93
`'
`14 Th1'irofT]W, Bunke B. Ebner A et al. Randomized. double
`blind. multicenter trial on treatment of frequency. urgency
`and incontinence related to detrusor hyperactivity: oxybu-
`tynine versus propantheline versus placebo. J Urol 1991:
`145: 813-17
`
`15 Breuel H-P. Miirtz G. Bondy S. Horkulak J. Gianetti M.
`Safety and tolerance of trospium chloride in the high dose
`range. Arzneim-Forsch/Drug Res 1993: 43: 461-4
`
`Authors
`H. Madersbacher. Dr. med.. Professor and Head of the Neuro-
`Urological Unit.
`M. Stiihrer. Dr. med. habil. Consultant Urologist and Head of
`the Urological Department.
`L. Richter, Dr. med.. Consultant Urologist and Head of the
`Neuro-Urological Department.
`H. Burgdtirfer. Dr. med.. Urological Surgeon.
`H.]. Hachen. Dr. mcd.. Head of the Spinal Cord Injury Unit.
`G. Mtirtz. Dr. med.
`
`Correspondence: Prof. Dr H. Madersbacher. Univ.-Hospitals.
`Anichstrasse 35. A-6020 Innsbruck. Austria.
`
`British Journal of Urology (199 5}, 75
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2034 - 0005