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Female Urology – Incontinence Differential Effects of the Antimuscarinic Agents Darifenacin and Oxybutynin ER on Memory in Older Subjects Gary Kay Thomas Crook , Ludmyla Rekeda Raul Lima , Ursula Ebinger Miguel Arguinzoniz Michael Steel Washington Neuropsychological Institute, Washington, DC, USA Psychologix, Inc, Fort Lauderdale, FL, USA Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Novartis Pharma AG, Basel, Switzerland Objectives: To investigate the effects of darifenacin controlled-release (CR) Accepted March 13, 2006 and oxybutynin extended-release (ER) on cognitive function (particularly, Published online ahead of memory) in older subjects.
Methods: Healthy subjects (n = 150) 60 years were randomised to darifena-cin, oxybutynin ER or placebo in a multicentre, double-blind, double- dummy, parallel-group, 3-week study. Doses were administered according Cognitive function to US labels: oxybutynin ER 10 mg once daily (od), increasing to 15 mg od then 20 mg od by week 3; darifenacin 7.5 mg od in weeks 1 and 2, then 15 mg od in week 3. The primary end point was accuracy on the Name–Face Association Test (delayed recall) at week 3.
Results: Results of the Name–Face Association Test at week 3 (mean differ-ence, 0.06, p = 0.908) showed no significant difference between darifenacinand placebo on delayed recall. In contrast, oxybutynin ER resulted in memoryimpairment, with significantly lower scores than placebo and darifenacin(mean differences, 1.30, p = 0.011 and 1.24, p = 0.022, respectively) fordelayed recall on the Name–Face Association Test at week 3. Additional testsof delayed recall indicated significant memory impairment with oxybutyninER versus placebo at certain time points, whereas darifenacin was similar toplacebo. No between-treatment differences were detected in self-rated mem-ory, demonstrating that subjects were unaware of memory deterioration.
Conclusions: While darifenacin had no significant effects on memory versusplacebo, oxybutynin ER caused significant memory deterioration (magnitudeof effect comparable to brain aging of 10 years). The results also demonstrate UNCORRECTED PROOF that subjects may not recognize/report memory deterioration.
# 2006 Published by Elsevier B.V.
* Corresponding author. Department of Neurology, Georgetown University School of Med-icine, Washington, DC 20008 USA. Tel. +1 202 686 7520; Fax: +1 202 686 8802.
E-mail address: (G. Kay).
0302-2838/$ – see back matter # 2006 Published by Elsevier B.V. doi:
opioids, benzodiazepines or sedating antihistamines), or drugs that are substrates or inhibitors of cytochrome P450 Overactive bladder (OAB) is a widespread condition, (CYP) 2D6 or CYP 3A4. Subjects were excluded if they suffered the prevalence of which rises with increasing age from conditions for which anticholinergic use is contra- As bladder contractions are mediated primarily by indicated (e.g., uncontrolled narrow angle glaucoma, urinaryretention), if they suffered from dementia or scored 27 on the cholinergic activation of muscarinic M3 receptors Mini-Mental State Exam (MMSE) or if they displayed evidence antimuscarinics are used widely as first-line OAB of depression (score 9 on Geriatric Depression Scale).
treatments Some agents may, however, be Subjects entered a 2-week screening period, during which associated with safety concerns, including effects eligibility was assessed, and cognitive tests were administered on the central nervous system (CNS); (e.g., memory for familiarisation with procedures. Subjects were rando- impairment) . The potential for CNS safety issues mised (1:1:1 ratio) to receive once-daily (od) treatment with is of particular concern in older patients, who are oxybutynin ER, darifenacin or placebo (The 3-week more vulnerable because of age-related memory duration allowed titration of oxybutynin ER in accordance decline reduced brain muscarinic receptor with US prescribing information treatment for 1 week at density and comorbidities . Furthermore, each dose allowed steady-state cerebrospinal fluid concentra- clinical studies have demonstrated increased sensi- tions to be reached. Thus, the oxybutynin ER group received10 mg od in week 1, 15 mg od in week 2, and 20 mg od in week tivity of older subjects to antimuscarinics, including 3. The darifenacin group received 7.5 mg od in weeks 1 and 2 effects on memory . Consequently, selecting an (with a sham dose increase after 1 week), then 15 mg od during appropriate antimuscarinic for OAB requires balan- week 3 (in line with US prescribing information) . The third cing efficacy with possible effects on memory.
group received placebo throughout, with sham dose increases An important differentiator between antimuscari- after 1 and 2 weeks. Blinding was maintained by using the nics is activity at muscarinic receptor subtypes (M1– double-dummy technique. Dosing was supervised during M5). While oxybutynin binds preferentially to M3 and week 3 to ensure compliance.
M1 receptors, darifenacin demonstrates 9.3-fold Written informed consent was obtained, and the study was selectivity for M performed in accordance with good clinical practice guidelines 3 over M1 receptors in-vitro . This observation may be important for effects on memory, following ethical approval by a local review board according to as the muscarinic M the ethical principles laid down in the Declaration of Helsinki.
1 receptor plays a role in memory/ cognition . Indeed, it has been proposed that M3 Assessment of cognitive function may confer benefits selectively, as non-M3-receptor– mediated CNS side effects may be avoided (or Cognitive function was assessed through the Psychologix/ reduced) Supporting evidence includes two Cogscreen (Psychologix Inc, Fort Lauderdale, FL, USA; Cogsc- studies of healthy subjects (one in subjects 65 reen, LLC, Washington, DC, USA) battery of computerised years), in which darifenacin had no effect versus cognitive function tests (CFTs) performed during clinic visits at placebo on cognition . In contrast, a small-scale baseline and following each week (prior to dose or sham dose clinical study showed that oxybutynin was asso- increase) shows the tests that were employed ciated with cognitive dysfunction (which have been demonstrated to be reliable and valid in To our knowledge, there are no reports of a single- numerous studies) tasks performed in each test and controlled study investigating the effects of two the sequence in which the tests were performed.
separate antimuscarinics on memory. We report a comparison of the effects of darifenacin and extended-release (ER) oxybutynin on memory in older subjects.
Subjects and study design Healthy male and female subjects aged UNCORRECTED PROOF 60 years with English as a first language (n = 150) were entered into a multicentre, trolled, parallel-group, 3-week study. Subjects had to be able to follow instructions and complete the computerised cogni- tive tests with valid responses. Medications prohibited from 2 weeks prior to screening included drugs with anticholinergic properties, drugs with known effects on cognition (e.g., Fig. 1 – Study design. ER = extended release.
Table 1 – Battery of tests used to assess memory and cognitive function Immediate memory recall Name–Face Association Subjects are presented with a series of 14 people (displayed on a video monitor) who introduce themselves individually bycommon first names. Subjects are then asked to recall nameswhen the 14 people reappear in a different sequence. Two separatetests performed (first and second acquisition).
First–Last Name Association Subjects are presented with four pairs of first and last names.
Subjects are then asked to recall corresponding first namesas each last name is presented. Two separate testsperformed (first and second acquisition).
Facial Recognition Subjects are presented with a single facial photograph and are required to touch the face on the screen. In each of 24subsequent trials, subjects are required to identify a new faceadded to the set (8-second delay between each trial). Resultsare analysed as ‘correct before first miss' and ‘total correct'.
Delayed memory recall Name–Face Association 30 minutes after completion of the immediate recall Name–Face Association Test (as described above), subjects are re-presentedwith each face and asked for the corresponding name.
First–Last Name Association 30 minutes after completion of the immediate recall First–Last Name Association Test (as described above), subjects are askedto recall corresponding first names as each last name isre-presented.
Misplaced Objects Subjects are presented with a 12-room house on a monitor and asked to place 20 objects within the house using a touchscreen (no more than 2 objects per room).
After a 30-minute delay subjects are asked to recall objectplacement. Correct recall at first attempt is assessed.
Visual attention and memory Matching to Sample Subjects are presented with a checkerboard (4 4) made up of purple and yellow squares. The checkerboard disappears and is replacedby one identical and one similar board. Subjects are asked toidentify the identical board. Response speed, accuracy and efficiencyare measured.
Visual Sequence Comparison Subjects are presented with two random strings of numbers and letters (4–8 items) simultaneously (shown on left andright hand sides of a monitor) and are asked to identify whetherthey are the same or different. For each pair of strings, differencesof up to two items are allowed. Speed, accuracy and efficiency(the number of problems correctly completed per minute) are measured.
Psychomotor/reaction time and information processing Divided Attention Subjects watch a cursor (indicator) move vertically within a circle (Visual Monitoring Alone) divided into central, upper and lower sections. When the cursorcrosses into upper or lower sections, subjects are required topress a box marked ‘CENTRE' with a light pen. Indicator speedis measured as the median time the cursor spent outside thecentral section of the circle before the subject presses ‘CENTRE'.
Premature responses also are assessed.
Divided Attention In the second component of the Divided Attention Test, the (Visual Sequence Comparison and Visual Sequence Comparison task (as described above) is Visual Monitoring, Dual Condition) UNCORRECTED PROOF performed simultaneously with the Divided Attention IndicatorAlone Task (as described above). Response speed is measuredfor both tasks and accuracy and efficiency (number of itemscompleted) are measured for the Visual Sequence ComparisonTask in the Dual Condition (i.e., when performed with the DividedAttention Visual Monitoring Task). When the two tasks are presentedsimultaneously, the test assesses divided attention, working memory,and visual-motor and visual-perceptual speed. In addition,comparison of performance under single and dual task conditionsyields information regarding the subject's capacity for multitasking.
* Order in which tests were performed.
The primary end point was the effect of each antimus- oxybutynin ER having an effect size, versus placebo, approxi- carinic at week 3, versus placebo, on recent (delayed) memory mately one third of that seen with scopolamine in older as measured by accuracy on the delayed recall Name–Face patients Allowing for a dropout rate of 30%, we continued Association Test . This test measures an ability that enrollment until at least 150 subjects (50% female) were declines markedly with advancing age and has shown some recruited. Thus, a 1:1:1 randomisation schedule gave approxi- limited changes in response to drugs Name-recall is the mately 50 subjects per group. Analysis of the primary end most frequent memory complaint at all ages across multiple point was based on a modified intent-to-treat (ITT) population cultures This parameter is therefore relevant to the (subjects taking at least one dose of study medication with daily activities of older patients with OAB, making it complete baseline and week 3 scores for the primary end appropriate for analysis. The most important secondary end point). For secondary end points, the modified ITT population points were delayed recall on the First-Last Name Association comprised subjects with scores for at least one test at baseline Test and the Misplaced Objects Test both of which and any post-baseline time point. Scores for active treatments measure memory abilities relevant to daily life, and on which were compared with placebo using an analysis of covariance performance declines with advancing age. Also included as (ANCOVA) model with baseline score, age and gender as secondary measures were delayed recall scores at weeks 1 and covariates. This was a two-sided test at the 5% significance 2, and effects on immediate memory, visual attention, level. For exploratory purposes, comparisons between dar- information processing and psychomotor/reaction time.
ifenacin and oxybutynin ER were derived from an identical Subjective memory loss was assessed as a tertiary end ANCOVA model.
point, using a validated self-reporting instrument, the Memory Assessment Clinics Self Rating Scale (MAC-S) .
The MAC-S is a test in pencil/paper format, in which each subject is asked to rate their abilities on 10 specific memory tasks and two global items. Subjects were asked to rate how their memory had changed since the beginning of the study.
One hundred fifty subjects (darifenacin n = 49, oxy- Assessment of safety and tolerability butynin ER n = 50, placebo n = 51) were randomised and comprised the safety population. Of these, 134 Adverse events (AEs) (graded by severity and relationship to completed the study and formed the modified ITT study drug as assessed by investigators), including serious AEs population for the primary analysis ). Of the (SAEs), were documented. Results of laboratory tests and vital nine subjects who discontinued in the darifenacin signs were recorded.
group, six had partial data and were included in secondary analyses. There were six discontinuations Statistical analyses in the oxybutynin ER group, of which partial data A sample size of 35 subjects per group was considered available for five subjects were included in secondary sufficient to detect an effect size of 0.867 for active treatment analyses. One subject in the placebo group discon- versus placebo at week 3. This decision was based on tinued, for whom partial data were not available for UNCORRECTED PROOF Fig. 2 – Patient flow through the 3-week study.
Table 2 – Subject demographics and baseline characteristics Darifenacin (n = 49) Oxybutynin ER (n = 50) Mean age (yr) (range) Mean BMI (kg/m2) (range) Mean baseline score for delayed recall on Name–Face Association First–Last Name Association Testy BMI = body mass index.
* Modified intent-to-treat population (primary): darifenacin n = 40, oxybutynin ER n = 44, placebo n = 50.
y Modified intent-to-treat population (secondary): darifenacin n = 46, oxybutynin ER n = 49, placebo n = 50.
inclusion in secondary analyses (). Demo- (For oxybutynin ER, scores at week 2 graphics and baseline characteristics were similar were significantly lower than for placebo or dar- across treatment groups ().
ifenacin (mean differences, 0.99, p = 0.022 and 1.23, p = 0.007, respectively), showing that the Assessment of memory—delayed recall memory impairment at week 3 also was evident at week 2 There were no significant There was no significant difference between the between–treatment differences at week 1, when darifenacin and placebo groups with respect to the lowest doses were administered.
primary end point, delayed recall on the Name–Face For darifenacin and placebo, there was a trend for Association Test at week 3 (mean difference, 0.06, improvement during the study reflecting a p = 0.908). In contrast, scores for delayed recall on learning effect whereby subjects improve through the Name–Face Association Test were significantly practise. Thus, by week 3, mean scores for delayed lower in the oxybutynin ER group than the placebo recall on the Name–Face Association Test had group (mean difference, 1.30, p = 0.011) or darife- increased by 0.9 and 1.0 in the placebo and nacin group (mean difference, 1.24, = 0.022), indi- darifenacin groups, respectively. In the oxybutynin cating memory deterioration ( ER group, in whom a similar learning effect was Results from the Name–Face Association Test at expected, a decrease in performance by 0.8 was week 2 were consistent with those at week 3, when there also was no significant difference between In delayed recall on the First–Last Name Associa- darifenacin and placebo groups for delayed recall tion Test, oxybutynin ER resulted in significant impairment versus placebo ( p < 0.05) at weeks 1 and 2 (). In contrast, no significant differences were observed between darifenacin and placebo at any time point ).
In the Misplaced Objects Test, oxybutynin ER resulted in significantly lower scores than placebo at weeks 2 and 3 for correct recall at first attempt (suggesting a decline in performance, whereas darifenacin was not significantly different UNCORRECTED PROOF from placebo at any time point.
Assessment of memory—immediate recall Oxybutynin ER reduced accuracy scores for immedi- ate recall on the First–Last Name Association Test at Fig. 3 – Effects of darifenacin, oxybutynin ER and placebo onaccuracy of delayed recall on the Name–Face Association second acquisition (attempt) versus placebo (mean Test at each time point. ER = extended release; differences, 0.28, 0.55 and 0.32 at weeks 1, 2 and ANCOVA = analysis of covariance.
3, respectively), with significant effect at week Table 3 – Accuracy of delayed recall on the Name–Face Association Test over Estimated LSM difference Darifenacin 7.5 mg od Oxybutynin ER 10 mg od Oxybutynin ER 10 mg od Darifenacin 7.5 mg od Oxybutynin ER 15 mg od Oxybutynin ER 15 mg od Darifenacin 15 mg od Oxybutynin ER 20 mg od Oxybutynin ER 20 mg od ER = extended release; LSM = least square mean; od = once daily.
* Analysis of covariance model adjusted for baseline score, age and gender. Negative differences indicate relatively worse scores.
2 ( p = 0.029; No significant difference was accuracy. Similarly in the Visual Sequence Compar- detected between darifenacin and placebo on this ison Test, there was no significant difference in test ). No significant between–treatment scores over time among treatment groups for differences were noted for this test at first acquisi- efficiency or accuracy.
tion (data not shown).
No significant difference was observed among Information processing speed treatment groups for other assessments of immedi- ate recall: accuracy on Name–Face Association Test (first or second acquisition) or accuracy on Facial slower response times than placebo at week 3 for Recognition Test (correct before first miss and total sequence comparison speed in the Divided Atten- tion Test (mean difference, 0.3 seconds, p = 0.012; ). There was no significant difference among treatments in scores over time for sequence com- parison efficiency or accuracy, and median reaction No significant differences were observed between to correct response in the Visual Sequence Compar- treatment groups at any time point in the Matching ison Test ().
to Sample Test for efficiency (speed or At week 2, darifenacin had a significantly higher score than oxybutynin ER for Single Task Premature Hits (mean difference, 0.56, p = 0.046; but was not significantly different from placebo. No significant difference was observed among treat- ment groups over time for Dual Task Reaction Time or Dual Task Premature Hits.
UNCORRECTED PROOF No significant difference was observed among treatment groups in response speed to the Visual Monitoring Task alone.
Memory assessment clinics self-rating scale Fig. 4 – Effects of darifenacin, oxybutynin ER and placebo onaccuracy of delayed recall on the First–Last Name In contrast with objective memory tests, there was Association Test at each time point. ER = extended release; no significant difference between groups in self- ANCOVA = analysis of covariance.
rated memory, as assessed by MAC-S scores at any Table 4 – in additional tests of memory and cognitive function over time Estimated LSM difference Immediate memory recall Name-Face Association (accuracy, second acquisition) First–Last Name Association (accuracy, second acquisition) Facial Recognition (accuracy, correct before first miss) Delayed memory recall First–Last Name Association (accuracy) Misplaced Objects (correct recall at first attempt) Matching to Sample (efficiency) Visual Sequence Comparison (efficiency) Divided Attention (Sequence Comparison Speed, Dual Condition) (s) Divided Attention (Sequence Comparison Efficiency) (s) Divided Attention (Sequence Comparison Accuracy) (s) Visual Sequence Comparison (median reaction to correct response) Divided Attention (Single Task Premature Hits) (s) Divided Attention (Task Reaction Time, Dual Condition) (s) Divided Attention (Premature Hits, Dual Condition) (s) UNCORRECTED PROOF Divided Attention (Response Speed to Visual Monitoring Task Alone) (s) *Modified intent-to-treat population. ER = extended release; LSM = least square mean.
* p < 0.05.
y p < 0.01 (analysis of covariance [adjusted for baseline score, age and gender]).
Table 5 – Adverse event incidence (safety population) Darifenacin (n = 49) Oxybutynin ER (n = 50) Subjects with any adverse event (n) Severe adverse events Serious adverse events Most common all-causality adverse events (n) All-causality nervous system events (n) time point. At week 3, the mean MAC-S scores were tests of delayed recall indicated significant memory 40.2, 41.8 and 40.2 for darifenacin, oxybutynin ER impairment with oxybutynin ER versus placebo and placebo, respectively, which were similar to (Name–Face Association at week 2, First–Last Name baseline (40.7, 40.0 and 39.1, respectively).
Association at weeks 1 and 2, and Misplaced Objects at weeks 2 and 3), while darifenacin was not significantly different from placebo in delayed recall at any time point.
The incidence of all-causality AEs is shown in The delayed recall tests were selected on the basis The most frequently reported AEs, as of their relevance to daily activities. Recalling the expected for this class, were dry mouth and name of someone to whom one is introduced is the constipation. Dry mouth occurred more frequently most problematic memory task faced on a daily during oxybutynin ER than darifenacin treatment basis in many cultures, and performance declines (40.0% vs 26.5%). One patient in each of the markedly over the adult life-span . For exam- oxybutynin ER and darifenacin groups discontinued ple, performance on the Name–Face Association because of dry mouth. The incidence of constipation Test declines by >65% between age 25 and 75 was higher in the darifenacin than oxybutynin ER years This ‘normal' decline may be exaggerated group ). Only one patient (in the darifenacin by drugs and the combined effect would be group) discontinued because of constipation. The expected to be of clear clinical significance. In a total incidence of all-causality nervous system similar manner, performance declines with age on events was similarly low in all groups, with only the First–Last Name Association and Misplaced two severe cases, both in the oxybutynin ER group Objects Tests ; this effect also can be exaggerated ). There was one serious AE (hip fracture by drugs . Thus, the deleterious effects of following an accident at home in a subject given oxybutynin ER on these tests suggests that this oxybutynin ER), which was not considered to be agent, at the dosage tested, may be associated with related to the study drug. There were no clinically diminished performance on important tasks of daily significant findings from assessments of laboratory life that depend on delayed recall.
values or vital signs.
Differential outcomes between darifenacin and oxybutynin ER may arise from differences in either CNS penetration or muscarinic receptor–binding profiles. Darifenacin exhibits limited CNS penetra- tion in preclinical studies, which may result from its This study demonstrated that the M3 selective moderate lipophilicity, relatively large molecular receptor antagonist darifenacin had no significant size, polarity and active efflux across the blood- effect on memory in older UNCORRECTED PROOF subjects. In contrast, brain barrier via the P-glycoprotein pump Once oxybutynin ER resulted in significant memory in the CNS, muscarinic-binding profiles play a role.
deterioration, as measured by delayed recall on Whereas darifenacin shows marked M3 selectivity, the Name–Face Association Test at week 3. Compar- oxybutynin demonstrates high affinity for M3 and ing these results with normative data for this test M1 subtypes The latter subtype is abundant in indicates that the degree of memory change seen the neocortex, hippocampus and neostriatum, in with oxybutynin ER (baseline to week 3) was contrast with low levels of M3 receptors in the brain comparable to a decline that occurs over the course and M1 receptors are known to be particularly of 10 years in the normal aging process. Additional hypothesis is supported by the low incidence of mon in older patients in clinical practice . In the nervous system AEs with darifenacin, both here and study reported here, in patients who were not in longer-term clinical trials. A pooled analysis of receiving anticholinergic co-medication and had three 12-week, fixed-dose studies with darifenacin no cognitive impairment at baseline, the lowest showed a profile of nervous system events that was oxybutynin ER dose (10 mg od) did not cause comparable with placebo, both overall and in memory impairment. In clinical practice, however, patients 65 years In contrast, results from when patients may be receiving concomitant antic- four clinical studies of 4 months showed that the holinergics or have existing memory impairment, it incidence of somnolence and dizziness with oxybu- is possible that this dose of oxybutynin ER may have tynin ER 5–30 mg/day was 12% and 6%, respectively a greater impact.
This study also measured immediate recall, for which oxybutynin ER showed some impairment versus placebo, while darifenacin and placebo were not significantly different. Major changes were not The results of this study add considerably to our expected here, as muscarinic receptor activation is knowledge regarding the differential effects of two thought to be involved primarily in memory con- antimuscarinics, darifenacin and oxybutynin ER, on solidation (i.e., how recent recollections are memory. The finding that darifenacin does not crystallised into memory). Similarly, significant impair memory is consistent with earlier studies effects were not expected in attention tests, and and the observation assumes clinical sig- no effects were observed across multiple tests.
nificance in light of the clear demonstration of Within the Divided Attention Test, however, dar- memory impairment during oxybutynin ER treat- ifenacin was significantly worse than placebo for ment. These findings highlight a need for further sequence comparison speed (mean difference, studies to fully establish the effects of all OAB 0.3 seconds) but did not differ from placebo in antimuscarinics on memory/cognition.
accuracy. Darifenacin scored worse than oxybuty- nin ER in the number of premature hits on a reaction Conflicts of interest time measure at week 2 (but not week 3) and did not Preparation of this manuscript was supported by differ significantly from placebo. Given that subjects an educational grant from Novartis Pharma AG, and receiving darifenacin showed no detriment on editorial and project management services were multiple other tests of attention, we did not consider provided by ACUMED1.
these isolated findings clinically relevant. In con- trast, findings with oxybutynin ER on memory were replicated across multiple tests at different time points, and are supported by earlier studies and an identifiable mechanism of action.
We are grateful for the support of our co-investiga- Interestingly, there were no reported differences tors, J. Diaz, FL, USA; L. Gilderman, FL, USA; J. Miller, in self-rated memory between treatments. This FL, USA; J. Nardandrea, FL, USA; B. Rankin, FL, USA; finding is particularly important as it indicates that M. Sabbagh, AZ, USA; L. Schmidt, AZ, USA, and to the memory changes may go unnoticed. This low level staff of Network Neurometrics, Inc, and Advanced of awareness may account for the low rate of Research Corporation who conducted the study.
reporting of memory impairment with antimuscari- nic therapies in clinical practice. In addition, disease- or treatment-related memory/cognitive impairment may be difficult to recognise, and memory decline may be attributed wrongly to aging.
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