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Keywords:

  • elderly;
  • overactive bladder syndrome;
  • trospium chloride

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Study Type – Therapy (data synthesis from RCTs) Level of Evidence 1c

What’s known on the subject? and What does the study add?

Treatment of overactive bladder syndrome (OAB) in elderly individuals presents several potential clinical challenges, which include alterations in sleep and cognition, multiple co-morbidities, polypharmacy, and frailty syndrome. A broad consensus of clinical opinion exists that the addition of an overactive bladder medication may amplify these clinical challenges via the antimuscarinic effects on cognition and the potential for drug-drug interactions.

The quaternary amine structure of trospium chloride provides protection against penetration of the blood-brain barrier, and minimizes the potential for metabolic drug-drug interactions. This study globally supports the efficacy and safety of Sanctura XR (extended release trospium chloride) in a population of elderly patients (75 years or older) with overactive bladder syndrome and multiple co-morbidities at risk for drug-drug interactions, impaired cognition and frailty syndrome.

OBJECTIVE

  • • 
    To evaluate the safety and efficacy of once-daily trospium chloride extended release (ER) in overactive bladder syndrome (OAB) in subjects aged ≥75 years.

SUBJECTS AND METHODS

  • • 
    The analysis included subjects ≥75 years of age with OAB.
  • • 
    A subgroup analysis of pooled data was performed for subjects aged ≥75 years from two randomized, double-blind, multicenter studies of subjects with OAB receiving once-daily trospium 60 mg extended release (ER) or placebo for 12 weeks, followed by 9-month open-label extension periods during which all subjects received trospium ER. A total of 143 of the 1165 subjects from two phase III registration trials who were aged ≥75 years (85 trospium ER, 58 placebo; mean age 79 years and ranging up to 90 years; 73% female) were evaluated.
  • • 
    Dual primary efficacy variables were the changes from baseline in the average number of toilet voids per day and urge urinary incontinence episodes per day.

RESULTS

  • • 
    At week 12 of the double-blind period, trospium ER produced greater improvements from baseline than placebo in voiding diary parameters, OAB Patient Global Assessment, and quality of life.
  • • 
    Efficacy and tolerability persisted among subjects receiving open-label trospium ER for up to 1 year.

CONCLUSIONS

  • • 
    Once-daily trospium chloride 60 mg ER demonstrated efficacy vs placebo and was tolerated in subjects aged ≥75 years with OAB.
  • • 
    For subjects who continued into the open-label treatment period, efficacy and tolerability were observed for up to 1 year.

Abbreviations
AE

adverse event

ER

extended release

KHQ

King’s Health Questionnaire

OAB

overactive bladder

OAB-q

Overactive Bladder Questionnaire

OAB-PGA

Overactive Bladder Patient Global Assessment

QOL

Quality of life

TEAE

treatment-emergent adverse event

UUI

urge urinary incontinence

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

The objective of this analysis was to evaluate the safety and efficacy of once-daily trospium chloride extended release (ER) in overactive bladder syndrome (OAB) in subjects aged ≥75 years. There appears to be only one other study reported in the literature on the use of an ER OAB antimuscarinic in the treatment of subjects with OAB specifically aged ≥75 years; the analysis focused on tolerability, and showed that the tolerability profile of tolterodine ER during 8–12 weeks of treatment in subjects aged ≥75 years was no worse than that in younger subjects [1]. In studies of subjects aged ≥65 years, ER antimuscarinics were effective in the treatment of OAB [2–4]. Yet, antimuscarinics may be underutilized in elderly patients owing to clinical concerns about the potential for CNS effects, drug–drug interactions, and other anticholinergic adverse events (AEs) such as dry mouth and constipation.

Treatment of OAB in the elderly presents several potential challenges. Past clinical trials have often either excluded or failed to recruit older participants, which makes generalization of results to this population more difficult. Older adults with OAB are more likely to receive concomitant medications for conditions that are more prevalent in the elderly, such as congestive heart failure [5,6], which could result in metabolic drug–drug interactions with antimuscarinics. Patients taking six different drugs have an 80% chance of experiencing at least one drug–drug interaction [7]. In addition, cumulative anticholinergic exposure (‘anticholinergic burden’) from multiple medications can increase the risk of anticholinergic AEs [8]. Older adults, including those with urinary incontinence, may also be susceptible to the frailty syndrome and potential accompanying cognitive impairment [9–11]. Advanced age can also result in changes in blood–brain barrier permeability [12–15]. Specific AEs, such as cognitive impairment and sleep disturbances, associated with many anticholinergics, may be of particular concern for elderly patients [15]. The current trial did not exclude subjects based on concomitant medication use, gender or age.

Potentially favorable properties of trospium chloride in elderly patients with OAB include a low likelihood of penetration into the CNS secondary to its molecular structure (hydrophilic, polar, relatively large quaternary amine compound), a low likelihood of drug–drug interactions owing to minimal metabolism via hepatic cytochrome P450 and a low incidence of associated AEs. This post hoc subanalysis was conducted to evaluate data on the experiences of subjects aged ≥75 years who participated in trospium ER phase III trials.

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

This subgroup analysis dataset included data pooled from two multicenter, parallel, randomized studies [16,17]. Both studies involved a 12-week double-blind period, followed by an optional 9-month open-label period. Data were analysed for subjects aged ≥75 years.

The study design and methods have been reported in detail elsewhere [16,17]. Male and female subjects experiencing OAB for ≥6 months who met the following criteria (based on a 3-day bladder diary) were enrolled: urinary frequency of ≥30 toilet voids in 3 days (i.e. mean ≥10 toilet voids per day); ≥1 ‘severe’ urgency severity rating in 3 days (according to the Indevus Urgency Severity Scale [18]); and pure urge urinary incontinence (UUI) or mixed urinary incontinence with predominant UUI, with ≥3 UUI episodes in 3 days (i.e. mean ≥1 UUI/day). Subjects were not excluded from participation based on concomitant medications or age. Subjects were randomized on a 1:1 basis to receive placebo or trospium chloride 60 mg ER once daily for 12 weeks during the double-blind period. The randomization schedule was stratified by average baseline number of toilet voids per day to ensure balance for this variable in the two treatment groups. Randomization was accomplished using an interactive voice response system (Kronos Communicated Data, Trenton, NJ, USA). Subjects subsequently had the option to continue into the 9-month open-label period, during which they received trospium chloride 60 mg ER once daily. Study medication was administered in the morning on an empty stomach.

Efficacy and safety assessments

Bladder diary data were collected over 3 days before the baseline, week 1, 4 and 12 visits of the double-blind period, and before the month 9 visit of the open-label period. Primary efficacy variables were the changes in the average number of toilet voids per day and the frequency of UUI episodes per day. Secondary efficacy parameters included urgency severity associated with toilet voids (as measured by the IUSS), volume voided per toilet void, frequency of nocturnal toilet voids (those occurring from bedtime to arising) and frequency of toilet voids associated with urgency (i.e. the number of toilet voids with an IUSS value of 1 (mild), 2 (moderate), or 3 (severe)). Quality of life (QOL) measures (Overactive Bladder Patient Global Assessment (OAB-PGA), King’s Health Questionnaire (KHQ) [19], and Overactive Bladder Questionnaire (OAB-q) [20]) were assessed at baseline, week 12 of the double-blind period and month 9 of the open-label period.

Safety and tolerability assessments included monitoring vital signs, physical examinations, clinical laboratory tests and recording of AEs. Adverse events were self-reported by study subjects without prompting by the investigator, which is standard in OAB trials.

Statistical analyses

The efficacy assessments were performed using the intention-to-treat subject sample. For the double-blind period, the intention-to-treat sample included all subjects who were randomized and dispensed study medication, and had at least one post-baseline evaluation. Within the open-label period, the diary and QOL data were collected only at month 9; thus, the intention-to-treat sample for the open-label efficacy analysis includes data only for subjects that remained in the study and provided data at month 9.

Efficacy analyses were performed using the last observation carried forward dataset, which comprised data recorded or carried forward separately within the double-blind period and within the open-label period, to account for any missing efficacy data. Descriptive statistics were used to present safety data. For demographic data, treatment groups were compared using an anova model with treatment, pooled investigator and their interaction for continuous variables, and a Cochran–Mantel–Haenszel procedure adjusting for pooled investigator for categorical variables. For efficacy data, rank anova with effects for treatment and pooled study center was used to compare treatment groups. P values ≤0.05 were considered statistically significant.

Ethics

The two studies included in this analysis were performed according to the principles of the Declaration of Helsinki and its amendments, and the principles of Good Clinical Practice. Subjects provided written informed consent before participation in the study. The clinical study protocols, protocol amendments, informed consent documents and other appropriate study-related documents were reviewed and approved by central and local Institutional Review Boards.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Of the 1165 subjects randomized, 143 were aged ≥75 years (trospium ER, 85; placebo, 58; Fig. 1). The ages of subjects in each treatment group ranged up to 90 years, and the mean age was 79 years. There were no significant between-group differences in baseline demographic characteristics (Table 1). In this specific (age ≥75 years) subgroup analysis, baseline OAB disease severity was greater in the patients who received trospium ER than in those who received placebo: the mean number of nocturnal toilet voids per day was significantly higher; the mean number of UUI episodes per day and mean urgency severity associated with toilet voids were numerically higher and approached significance; and the median number of UUI episodes per week was numerically higher, although not statistically significant (Table 1).

image

Figure 1. Disposition of subjects. ER, extended release.

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Table 1.  Baseline subject characteristics
CharacteristicPlacebo (n= 58)Trospium chloride ER (n= 85)P
  1. ER, extended release; OAB, overactive bladder; UUI, urge urinary incontinence.

Gender, n (%)  0.60
 Female45 (77.6)60 (70.6) 
 Male13 (22.4)25 (29.4) 
Mean age ± SE, years78.7 ± 0.4479.2 ± 0.360.85
Race, n (%)  0.47
 White55 (94.8)83 (97.6) 
 Black 1 (1.7) 1 (1.2) 
 Hispanic 1 (1.7) 0 (0.0) 
 Asian 1 (1.7) 0 (0.0) 
 Other 0 (0.0) 1 (1.2) 
Previous anticholinergic use for OAB, n (%)  0.17
 Naïve28 (48.3)34 (40.0) 
 Non-naive30 (51.7)51 (60.0) 
Baseline efficacy parametersn= 57n= 82 
Mean toilet voids per day ± SE  11.96 ± 0.24 12.14 ± 0.230.74
 Mean nocturnal toilet voids per day ± SE  2.29 ± 0.15  2.76 ± 0.150.02
Mean UUI episodes per day ± SE  3.66 ± 0.37  3.89 ± 0.290.09
Median UUI episodes per week 16.33 22.170.85
Mean urgency severity associated with toilet voids ± SE  1.61 ± 0.06  1.72 ± 0.050.07
Mean volume voided per toilet void ± SE136.11 ± 5.89139.96 ± 4.860.42
Mean daily frequency of toilet voids associated with urgency ± SE 10.27 ± 0.30 10.73 ± 0.310.36

The discontinuation rate in the double-blind period was not significantly different between placebo and the active drug. Five trospium ER recipients and three placebo recipients discontinued study participation because of an AE. Among these, the AE resulting in discontinuation was considered at least possibly related to the study medication in four trospium ER recipients (one subject each with constipation, renal pain, urinary retention and dry throat) and two placebo recipients (one subject each with flatulence and dizziness).

A total of 112 subjects entered into the 9-month open-label period. The overall discontinuation rate from the open-label period was 42.9%. The main reasons for discontinuation were AEs and patient withdrawal of consent. Twenty-one subjects discontinued from the open-label period because of AEs. Of these, 14 subjects discontinued because of AEs considered at least possibly related to the study medication. In 10 of these subjects, the AEs leading to discontinuation were related to the gastrointestinal system (constipation, dry mouth, stomach discomfort, abdominal discomfort and abdominal distension, nausea); the other AEs leading to discontinuation were first-degree atrioventricular block, vertigo, urinary incontinence and urinary retention (one subject each).

Almost every subject aged ≥75 years (approximately 98% for placebo and trospium ER) was taking ≥1 concomitant medication, including over-the-counter medications (mean = 7) during both the double-blind and open-label periods. These medications included but were not limited to mineral supplements and vitamins, antithrombotic agents (e.g. aspirin, clopidogrel), lipid-lowering agents (e.g. atorvastatin, simvastatin) and beta-blockers (e.g. atenolol). The most commonly used concomitant medication was aspirin during both the double-blind period (placebo, 39.7%; trospium ER, 35.3%) and the open-label period (38.4%).

Efficacy

At week 12, trospium ER produced significantly greater mean reductions from baseline than placebo in mean number of daily toilet voids (−2.15 (SE 0.29) vs −0.37 (SE 0.33); P= 0.0008), daily UUI episodes (−1.77 (SE 0.35) vs −0.54 (SE 0.42); P= 0.003), and daily frequency of toilet voids associated with urgency (−2.53 (SE 0.33) vs −0.61 (SE 0.49); P= 0.004) (Fig. 2). Significant differences between trospium ER and placebo were seen as early as week 1 for daily UUI episodes and week 4 for daily toilet voids and urge frequency (Fig. 2).

image

Figure 2. Change from baseline in mean (a) number of toilet voids per day, (b) number of urge urinary incontinence (UUI) episodes per day and (c) frequency of toilet voids associated with urgency per day (rank analysis of variance of intent-to-treat last observation carried forward data). Error bars indicate standard error values. Weekly data (weeks 1, 4 and 12) are average findings across 3 days of bladder diary data. ER, extended release. *P < 0.01, †P < 0.001 vs placebo.

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Despite the significantly higher mean number of nocturnal toilet voids (those occurring from bedtime to arising) at baseline in the trospium ER group, nocturnal toilet voids per day were reduced to a significantly greater degree from baseline with trospium ER compared with placebo (−0.76 (SE 0.21) vs −0.08 (SE 0.16); P < 0.01) at week 12 (Fig. 3). A significant difference between trospium ER and placebo was seen from week 4 onwards (Fig. 3).

image

Figure 3. Change from baseline in mean number of nocturnal toilet voids/day (rank analysis of variance of intent-to-treat last observation carried forward data). Error bars indicate standard error values. Weekly data (weeks 1, 4, and 12) are average findings across 3 days of bladder diary data. ER, extended release. *P < 0.01; †P < 0.001.

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The median per cent change in weekly UUI episodes was significantly greater with trospium ER vs placebo at week 12 (−69.9% vs −25.0%; P= 0.04). The mean increase in volume voided per toilet void (a secondary outcome measure) achieved with trospium ER was also significantly greater than with placebo (plus;30.73 (SE 5.69) mL vs +3.10 (SE 4.80) mL; P= 0.001). Although numerically better, there was no significant difference between the trospium ER and placebo groups in the change from baseline in average urgency severity associated with toilet voids (−0.28 (SE 0.06) vs −0.20 (SE0.08); P= 0.33).

Among the 112 subjects who went on to receive open-label trospium ER, beneficial effects of trospium ER treatment were seen at month 9 both in those who received trospium ER during both study periods and in those who received placebo during the double-blind period and switched to trospium ER during the open-label period. These beneficial effects were reflected in changes from baseline in mean number of daily toilet voids (−2.35 (SE 0.43) and −1.52 (SE 0.61), respectively), number of daily UUI episodes (−2.19 (SE 0.45) and −1.63 (SE 0.50), respectively), daily frequency of toilet voids associated with urgency (−2.77 (SE 0.50) and −1.49 (SE 0.76), respectively) and volume voided per toilet void (+40.50 (SE 5.83) mL and +32.86 (12.88) mL, respectively), and median per cent change from baseline in weekly UUI episodes (−75.0% and −70.0%, respectively).

Patient-reported outcomes

At week 12, patient-reported outcomes in OAB symptoms were significantly better with trospium ER than with placebo for each of the four items of the OAB-PGA (Table 2). A greater proportion of subjects receiving trospium ER than receiving placebo considered their outcome to be very much or much improved with regard to frequency of toilet voids (38.3% vs 22.4%), accidental urge leaks (37.0% vs 24.1%), urge to urinate (38.3% vs 19.0%) and overall OAB condition (42.0% vs 25.9%).

Table 2.  Overactive Bladder Patient Global Assessment (OAB-PGA) responses in subjects aged ≥75 years at week 12 of the double-blind period and month 9 of the open-label period
Response to questionDouble-blind, n (%)Open-label, n (%)
Placebo (n= 58)Trospium chloride ER (n= 81)P*Placebo-to-trospium (n= 36)Trospium-to-trospium (n= 61)
  • *

    P value from a Cochran–Mantel–Haenszel test (with effect for treatment and adjusting for pooled study center) that the row mean scores differ between the treatment groups.

Frequency of toilet voids     
 Very much improved 3 (5.2)12 (14.8)0.004 5 (13.9) 8 (13.1)
 Much improved10 (17.2)19 (23.5) 10 (27.8)20 (32.8)
 Minimally improved15 (25.9)26 (32.1)  9 (25.0)22 (36.1)
 No change23 (39.7)20 (24.7)  9 (25.0) 8 (13.1)
 Minimally worse 5 (8.6) 0  0 2 (3.3)
 Much worse 1 (1.7) 3 (3.7)  2 (5.6) 1 (1.6)
 Very much worse 1 (1.7) 1 (1.2)  1 (2.8) 0
Accidental urge leaks     
 Very much improved 6 (10.3)18 (22.2)0.032 7 (19.4) 7 (11.5)
 Much improved 8 (13.8)12 (14.8)  8 (22.2)18 (29.5)
 Minimally improved14 (24.1)24 (29.6)  8 (22.2)21 (34.4)
 No change24 (41.4)22 (27.2) 10 (27.8)10 (16.4)
 Minimally worse 5 (8.6) 1 (1.2)  2 (5.6) 3 (4.9)
 Much worse 0 4 (4.9)  0 2 (3.3)
 Very much worse 1 (1.7) 0  1 (2.8) 0
Urge to urinate     
 Very much improved 2 (3.4) 9 (11.1)0.012 5 (13.9) 4 (6.6)
 Much improved 9 (15.5)22 (27.2)  8 (22.2)23 (37.7)
 Minimally improved13 (22.4)22 (27.2)  11 (30.6)16 (26.2)
 No change29 (50.0)24 (29.6) 10 (27.8)14 (23.0)
 Minimally worse 3 (5.2) 0  0 2 (3.3)
 Much worse 1 (1.7) 4 (4.9)  2 (5.6) 2 (3.3)
 Very much worse 1 (1.7) 0  0 0
Overall overactive bladder condition     
 Very much improved 4 (6.9)12 (14.8)0.027 8 (22.2) 8 (13.1)
 Much improved 11 (19.0)22 (27.2)  7 (19.4)20 (32.8)
 Minimally improved12 (20.7)21(25.9)  8 (22.2)21 (34.4)
 No change25 (43.1)20 (24.7) 10 (27.8) 9 (14.8)
 Minimally worse 4 (6.9) 2 (2.5)  2 (5.6) 0
 Much worse 1 (1.7) 3 (3.7)  1 (2.8) 3 (4.9)
 Very much worse 1 (1.7) 1 (1.2)  0 0

At month 9 of the open-label period, subject-perceived improvements in OAB, according to the OAB-PGA, persisted: the proportion of subjects in the placebo-to-trospium and trospium-to-trospium groups reporting their outcome to be very much or much improved with regard to frequency of toilet voids (41.7% and 45.9%, respectively), accidental urge leaks (41.7% and 41.0%, respectively), urge to urinate (36.1% and 44.3%, respectively) and overall OAB condition (41.7% and 45.9%, respectively) was similar to that in the trospium ER group at week 12.

Quality of life

Reductions from baseline in KHQ scores (indicating improvement in QOL) at Week 12 were numerically greater in subjects who received trospium ER than in subjects who received placebo on most domains, although the difference was only significant for average change in Severity Measures. On the Severity Measures domain, the changes from baseline in both the trospium ER and placebo groups were ≥5, which is considered the minimal important difference for KHQ domains [21] (trospium ER −8.08 (SE 1.03) vs placebo −5.63 (1.31); P= 0.03). During the open-label period, the placebo-to-trospium and trospium-to-trospium groups had reductions from baseline in KHQ scores on all domains at month 9.

Increases from baseline in OAB-q scores (indicating improvement in QOL) at Week 12 were numerically greater in recipients of trospium ER than in placebo recipients on all subscales, and the difference between the groups was significant (P= 0.02) for the Concern/Worry subscale. Similar improvements in health-related QOL, as assessed by OAB-q, were observed at Month 9 in subjects who received trospium ER during the open-label period of the study. The OAB-q was also used to assess subject-determined symptom bother. A significantly greater reduction from baseline in the total symptom bother/severity score was seen in the trospium ER vs placebo group (−23.70 vs −14.22; P= 0.02). Numerically greater reductions were seen with trospium ER on most items of the symptom-bother scale, and these were significantly (P < 0.05) greater than with placebo for frequent urination during daytime hours, night-time urination and urine loss associated with a strong desire to urinate. During open-label treatment with trospium ER, improvements in symptom bother similar to those during the double-blind period were observed.

Safety

During the 12-week double-blind period, 29 of 58 subjects (50.0%) in the placebo group and 42 of 85 subjects (49.4%) in the trospium ER group experienced ≥1 treatment-emergent AE (TEAE). Of these, 9 of 58 subjects in the placebo group and 22 of 85 subjects (25.9%) in the trospium ER group experienced ≥1 TEAE considered at least possibly related to the study medication (Table 3). The most common TEAEs considered at least possibly related to the study medication in the trospium ER group were dry mouth (trospium ER n= 9; placebo, n= 2) and constipation (trospium ER n= 9; placebo, n= 0; Table 3).

Table 3.  Incidence of treatment-emergent adverse events (TEAEs) Considered at least possibly related to study medication reported in at least two subjects from either group
Adverse eventNumber of subjects (%)
Placebo (n= 58)Trospium chloride ER (n= 85)
  1. ER, extended release.

Subjects with ≥1 TEAE considered at least possibly related to study medication9 (15.5)22 (25.9)
Constipation0 (0.0)9 (10.6)
Dry mouth2 (3.4)9 (10.6)
Flatulence1 (1.7)2 (2.4)
Urinary retention0 (0.0)2 (2.4)
Urinary tract infection0 (0.0)2 (2.4)
Diarrhea3 (5.2)0 (0.0)
Dizziness2 (3.4)0 (0.0)

During the 9-month open-label period with trospium ER, 73 of 112 subjects (65.2%) reported ≥1 TEAE, and 34 of 112 subjects (30.4%) experienced ≥1 TEAE considered at least possibly related to the study medication. Again, the most common of the TEAEs considered at least possibly related to the study medication were dry mouth (n= 9) and constipation (n= 9). Three subjects experienced urinary retention (determined by ultrasound post-void residual or urinary catheterization).

During the double-blind period, 2 of 58 subjects in the placebo group and none in the trospium ER group experienced ≥1 serious TEAE. During the open-label period, 10/112 subjects experienced ≥1 serious TEAE. None of the serious TEAEs was considered at least possibly related to the study medication.

There were no patient reports of CNS AEs such as dizziness, vertigo, confusion, somnolence, or visual disturbance in any patient receiving trospium ER during the 12-week double-blind period. The incidence of reported CNS AEs was no higher in subjects who received trospium ER than in those who received placebo. Two CNS AEs were reported as being at least possibly related to the study treatment during open-label treatment with trospium ER: one report each of dizziness and vertigo.

Mean changes from baseline to endpoint for double-blind laboratory outcomes (including liver enzymes, markers of renal function, erythropoiesis markers, and other important hematology and chemistry laboratory parameters) were minor and were similar for the placebo and trospium ER groups. A mean increase in heart rate was noted in subjects receiving trospium ER of 4.8 beats per minute (bpm) (SE 1.23) at the end of the double-blind period and 0.9 bpm (SE 1.01) at the end of the open-label period.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

The objective of this study was to evaluate, in a post hoc analysis, the safety, efficacy, and tolerability of trospium ER for the treatment of OAB in subjects aged ≥75 years. Trospium ER reduced daily toilet voids and UUI episodes in the elderly. During the 12-week double-blind period, elderly subjects treated with trospium ER demonstrated greater improvements from baseline vs placebo, with an onset of effect sometimes within the first week of treatment. Also improved were secondary parameters including urgency frequency, daily volume voided/toilet void, and UUI episodes per week.

Subjects originally assigned to placebo during the double-blind period and then treated with open-label trospium ER demonstrated improvements during the 9-month open-label period. Among subjects who received trospium ER throughout both study periods, improvements achieved by the end of the double-blind period persisted to the end of the open-label period. It should be noted that following entry into the open-label period, follow-up efficacy assessments were not conducted until month 9; thus, only subjects who completed the open-label period had efficacy data available for this period. The rate of discontinuation from the open-label period was 42.9% in patients aged ≥75 years, and approximately 30% in the overall study population [22], which is comparable to several other 1- to 2-year open-label studies of OAB antimuscarinics [23,24], and higher than in one other 1-year study [25]. Differences in discontinuation rates between studies may relate to the extent of prior exposure of subjects to antimuscarinics, and to the innate symptom variability noted in OAB. The discontinuation rates in the double-blind period were consistent with those seen in another analysis of subjects aged ≥75 years who received tolterodine ER or placebo for 8–12 weeks [1]. That analysis found that discontinuation rates were slightly higher in subjects aged ≥75 years, compared with younger subjects, regardless of treatment assignment.

As this was a post-hoc subgroup analysis with fewer subjects than in the overall study population, there was a greater likelihood of imbalance in baseline characteristics between the treatment groups. Differences were observed on some efficacy measures at baseline (Table 1), all representing greater baseline severity in the trospium ER group. The difference was significant for nocturnal toilet voids, and approached significance for severity of urgency associated with toilet voids and UUI episodes per day. A non-significant numerical difference was also observed for the median number of UUI episodes per week. These differences, together with the fact that this was a post-hoc exploration of efficacy in subjects aged ≥75 years and thus the original studies were not powered for this analysis, makes it notable that significant differences favoring trospium ER were observed for several endpoints.

Others have studied clinical outcomes in elderly patients with OAB. In a meta-analysis of three clinical trials involving adults aged ≥65 years (mean age not reported) who received ER oxybutynin (5–30 mg once daily), there was an 81% decrease from baseline in the number of UUI episodes [26]. With ER tolterodine (4 mg once daily) in subjects aged ≥65 years (mean age 74 years), there was significantly greater improvement in incontinence, volume voided/micturition and urgency compared with placebo [4]. Subjects aged ≥65 years also demonstrated significantly greater improvements from baseline compared with placebo in incontinence, frequency and urgency with darifenacin (7.5 or 15 mg once daily; mean age 71–72 years) [2] and solifenacin (5 or 10 mg once daily; mean age 72 years) [27] in pooled analyses. The analysis reported herein is the first specific assessment of efficacy in OAB restricting the study population to those aged ≥75 years.

Improvements in OAB symptoms as self-reported on the OAB-PGA were significantly better in subjects receiving trospium ER than placebo. These improvements continued through the open-label period. Measures of QOL showed numerically greater improvement on most subscales/domains with trospium ER vs placebo; however, with the reduced statistical power of this subanalysis population, not all comparisons were significant.

The results of this analysis also support the tolerability of trospium ER in elderly subjects. During the double-blind period, 25.9% of trospium ER recipients and nine placebo recipients experienced ≥1 TEAE considered at least possibly related to the study medication. The most common of these were dry mouth (trospium ER n= 9; placebo n= 2) and constipation (trospium ER, 10.6%; placebo, 0%). During the 9-month open-label period, 30.4% of subjects experienced ≥1 TEAE considered at least possibly related to the study medication. The corresponding proportion of subjects in the overall study population of all ages was 20.9%[28]. Again, the most common of these TEAEs in subjects aged ≥75 years were dry mouth (n= 9) and constipation (n= 9), which occurred at a similar incidence to that reported during double-blind treatment. Notably, although these subjects aged ≥75 years were taking a mean of seven concomitant medications during both study periods, TEAE rates were relatively low. In a separate multivariate logistic regression analysis (which included age), the risk of TEAEs in the entire study population (data not shown) was 2.8-fold increased for multiple medication use over randomization to trospium ER or placebo. This finding suggests that concomitant drugs contribute more to TEAEs than trospium ER or patient age [29]. Trospium ER recipients had a mean increase in heart rate of 4.8 bpm at the end of the double-blind period and 0.9 bpm at the end of the open-label period. This is not unexpected, as non-subtype specific antimuscarinics used in the treatment of OAB are known to increase resting heart rate via blockade of muscarinic M2 receptors [30]. However, a recent study showed that despite the known potential cardiovascular effects of some OAB drugs, there was no difference in the prevalence of cardiovascular comorbidities between treated and untreated patients with OAB (39.4% vs 38.3%; P= 0.326) [31].

Treating OAB in the elderly can be challenging. Elderly patients with OAB may be susceptible to cognitive impairment. While we had few reports of CNS AEs, elderly patients may not become aware of drug-induced memory changes and may mistakenly attribute memory difficulties to aging or comorbid conditions associated with aging [32]. Because some OAB medications have demonstrated a potential for adverse CNS effects [15], healthcare providers must be aware of the potential ‘anticholinergic burden’ on this sensitive population of patients with OAB. It has been shown in preclinical studies that the quaternary amine trospium has a low propensity to cross the blood–brain barrier [33] and that the multidrug resistance drug efflux transporter P-glycoprotein additionally plays a role in limiting blood–brain barrier penetration of trospium [34]. These findings may explain the favorable CNS AE rates observed with trospium ER compared with placebo in the current analysis.

A higher risk of accidental falls and injuries are associated with incontinence [35–37]. Falls can occur if a patient is rushing to the bathroom or at night when awakened from sleep. Falls are also associated with poor sleep patterns in the elderly [38,39]. In this analysis, there were significantly greater reductions in nocturnal toilet voids and numerical improvements in health-related QOL nocturnal domains with trospium ER than with placebo. No interventional studies specifically assessing the effect of OAB therapy on falls and associated injuries in elderly subjects have been conducted. However, it is possible that reductions in nocturnal events, such as those observed with trospium ER in our analysis, might be an important component in an overall strategy to reduce the risk of falls and fractures in elderly patients.

Our study had a number of potential limitations. First, a prospective study design would be preferable to a post-hoc analysis. As a post-hoc subgroup analysis, statistical power is reduced and, thus, not all numerical differences between groups are significant. As previously noted, there were also some between-group imbalances on baseline OAB parameters; however, in each case, the severity of disease was greater in the trospium ER group. As indicated in the methods, concomitant medication use was not an exclusion to study enrollment, and most patients were on one or more medications (mean seven) at the time of study entry. The groups were not matched for the number and type of medications being taken. Thus, it is not known if the ‘anticholinergic burden’ was similar between the groups. As is true with most OAB studies, we did not perform formal cognitive testing; however, a recent study reported that elderly subjects (aged ≥65 years; mean age 79 years) with Alzheimer’s disease and UUI receiving immediate-release trospium (45–60 mg/day) in combination with the cholinesterase inhibitor galantamine (up to 24 mg/day) for 6 months had no significant change in Mini-Mental State Examination scores [40]. In addition, these analyses do not necessarily address concerns about what the treatment experience is in the oldest-old and most frail patients. The mean age of subjects was 79 years in this analysis, with the oldest subjects being 90 years of age, yet no assessment of functional status or frailty was performed at enrollment. There are insufficient demographic and physical performance data available, for example, to discern how many of these subjects meet the criteria for the frailty syndrome [9]. It is possible that many do not, as the clinical trial participants here, while older, are often more highly functioning, community-dwelling elderly. As well, the majority of participants in the study had previously been on an antimuscarinic agent for OAB.

Conclusions

Once-daily trospium chloride 60 mg ER was effective and tolerated in subjects with OAB aged ≥75 years, suggesting that it is a suitable treatment option for advanced elderly patients with OAB.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

The authors thank Mark Harnett, LuAnn Sabounjian, and Bobby Sandage for their contribution to the development of this manuscript. M.K. Grandison, PhD, and Sushma Soni provided editorial assistance with financial support from Allergan, Inc.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Michael G. Oefelein is an employee of the sponsor; Pamela I. Ellsworth is a consultant speaker for Pfizer, a speaker for Novartis and is on the speaker bureau for Allergan; Eric S. Rovner is a paid consultant to Allergan and is a study investigator funded by Allergan; David R. Staskin is a speaker for Allergen, Astellas, Pfizer and Watson, and is a paid consultant to Allergen, Astellas and Pfizer; Peter K. Sand is a an advisor, investigator and speaker for Allergan, Watson, Pfizer, Astellas and GSK. Source of Funding: Allergan, Watson, Pfizer, Astellas and GSK.

Funding Sources: This work was supported by Allergan, Inc., and Endo Pharmaceuticals, Inc. (formerly Indevus Pharmaceuticals, Inc.).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES