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Keywords:

  • oxybutynin;
  • transdermal;
  • overactive bladder;
  • urinary incontinence;
  • quality of life;
  • MATRIX

Abstract

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

OBJECTIVE

To assess health-related quality-of-life (HRQoL) and safety with the oxybutynin transdermal system (OXY-TDS) (Oxytrol®, Watson Pharma, Corona, CA, USA) in the Multicentre Assessment of Transdermal Therapy in Overactive Bladder With Oxybutynin (MATRIX) study, as HRQoL measurements are increasingly important in evaluating pharmacotherapy for overactive bladder (OAB).

PATIENTS AND METHODS

This randomized, open-label, community-based study enrolled 2878 participants aged ≥18 years who had been given a diagnosis of OAB. The 327 study sites were representative of various practice types. All participants were treated with OXY-TDS 3.9 mg/day for ≤6 months. HRQoL was assessed using the King’s Health Questionnaire (KHQ); the primary endpoint was the change in KHQ scores from baseline to study end.

RESULTS

Most enrolees (2052/2625; 78.2%) had moderate to severe OAB at baseline (Patient Perception of Bladder Condition score ≥ 4 on a scale of 1–6), and most (1632/2859; 57.1%) had been given previous drug treatment for OAB. Of 2592 with evaluable baseline KHQ scores, 92.2% reported urgency and 88.2% reported urge urinary incontinence. The most impaired domains at baseline were Incontinence Impact (69.3), Symptom Severity (55.9), and Sleep/Energy (54.2). There were clinically meaningful and statistically significant improvements in nine of 10 domains at the study end; the greatest improvements were in Incontinence Impact (−13.5), Symptom Severity (−12.4), and Role Limitations (−13.3). The treatment was well tolerated, with low incidences of drug-related anticholinergic adverse effects such as dry mouth (75; 2.6%), constipation (44; 1.5%), and dizziness (21; 0.7%). There were drug-related application-site reactions, including pruritus, erythema, dermatitis and irritation, in 14.0% of participants.

CONCLUSIONS

OXY-TDS treatment was well tolerated in this diverse, community-based population, and resulted in clinically significant improvements in HRQoL, regardless of baseline characteristics.


Abbreviations
HRQoL

health-related quality of life

OAB

overactive bladder

(U)UI

(urge) urinary incontinence

KHQ

King’s Health Questionnaire

OXY-TDS

oxybutynin transdermal system

MATRIX

Multicentre Assessment of Transdermal Therapy in OAB With Oxybutynin

PPBC

Patient Perception of Bladder Condition

AE

adverse event

ITT

intent-to-treat

INTRODUCTION

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

As the population ages and life-expectancy increases, health-related quality of life (HRQoL) becomes increasingly important. Overactive bladder (OAB) is a chronic condition that affects ≈ 33 million adults in the USA, with an equal prevalence among men and women [1–3]. Lack of bladder control results in symptoms of urgency and/or urge urinary incontinence (UUI), often with increased frequency and nocturia [4]. Although these symptoms are not life-threatening, they result in an impairment of HRQoL that affects daily life and functioning in often otherwise healthy individuals [3,5–8]. The meaningful measurement of HRQoL is important from individual, medical and societal perspectives. One such tool for assessing HRQoL is the King’s Health Questionnaire (KHQ), a validated instrument for quantifying the subjective HRQoL issues experienced by patients with OAB.

OAB impairs HRQoL in ways that are often individual and not generalisable [5,6,8]. Symptoms adversely affect daily routines, and affected individuals must adjust their habits and lifestyle to accommodate their symptoms. Patients might be reluctant to travel, visit friends and family, or pursue leisure activities for fear of embarrassment [6,7]. Patients can institute new habits, such as ‘bathroom mapping’ and defensive voiding. Other coping strategies include wearing protective garments, using pads, and carrying a change of clothing. Interruption of activity due to urgency, frequency, or incontinent episodes, and fatigue resulting from nocturia, can impair work performance and reduce productivity [6,9]. Sexual relations and other interpersonal relations with a partner can be impaired by anxiety over the fear of urgency or urinary leakage [10,11]. Psychological morbidity, including clinical anxiety and depression, can result; depression has been shown to be more common among patients with OAB than in the general population [3,8].

Studies have shown that effective treatment of patients with OAB with antimuscarinic agents improves patient HRQoL [12–16], but long-term compliance with oral antimuscarinic therapies is limited, in part because of anticholinergic adverse effects [17,18].

The oxybutynin transdermal system (OXY-TDS; Oxytrol®, Watson Pharmaceuticals, Inc., Corona, CA, USA) has been shown to have similar efficacy to that of oxybutynin immediate release and extended-release tolterodine, but with the benefit of having an incidence of reported anticholinergic adverse effects not significantly different from placebo [16,19–21]. Phase III, randomized, placebo-controlled studies established the safety and efficacy of OXY-TDS in reducing the number of episodes of UUI, decreasing urinary frequency, and increasing voided volume in persons with OAB [16,20,21]. Secondary endpoints from those studies showed improvements in HRQoL for those treated with OXY-TDS, relative to placebo. However, additional studies are warranted to fully evaluate improvements in HRQoL as a primary outcome of OAB treatment.

The objective of this study, the Multicentre Assessment of Transdermal Therapy in OAB With Oxybutynin (MATRIX), was to evaluate changes in HRQoL in a large, community-dwelling adult population with OAB during treatment with OXY-TDS.

PATIENTS AND METHODS

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

This randomized, open-label, multicentre, community-based study (OXY0402; http://www.clinicaltrials.gov identifier NCT00224146) enrolled men and women in whom OAB had been diagnosed and who met study inclusion criteria: were ≥ 18 years old, had at least one symptom of OAB (UUI, urgency and/or frequency), were willing to discontinue all prescription and over-the-counter medications for OAB, and were capable of completing HRQoL questionnaires with no assistance. Women of child-bearing potential were required to have a negative pregnancy test result and to use a medically acceptable contraceptive during the study. Individuals were excluded only if they had contraindications to oxybutynin, had one or more treatable conditions that might cause OAB symptoms, had received treatment with OXY-TDS before the time of study participation, or resided in long-term care facilities or nursing homes. No exclusions were based on advanced age or other comorbid conditions, and no restrictions were placed on concomitant medication use (except for experimental drugs).

All participants received OXY-TDS (3.9 mg/day, twice-weekly patch application) for up to 6 months. Study sites were randomized 1 : 1, within the investigators’ medical speciality, to provide standard instructions or educational intervention that consisted of a packet of educational materials, with each month’s supply of OXY-TDS. The packet included an educational booklet, OAB newsletters, dosing reminders, calendar reminder stickers, and a bladder diary (not used for data collection). The protocol and supporting documents were approved by the institutional review board at each participating site, and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice regulations governing the protection of human subjects. All participants provided written informed consent before they participated in the study.

At the baseline visit, eligible participants had a limited physical examination and were asked a series of questions on demographics, medical history, occupation, previous OAB treatments and reason for discontinuation, and concomitant medication use. Participants also completed all baseline questionnaires (including the KHQ) and provided an overall assessment of OAB severity through the Patient Perception of Bladder Condition (PPBC), a validated, single-item measure that asks participants to rate their bladder condition on a scale from 1 (no problems at all) to 6 (many severe problems) [22]. The first OXY-TDS patch was applied at the research site or office, and participants were instructed to rotate the sites used for later applications.

Subsequent clinic visits were at 1, 3, and 6 months after the baseline visit. At the first month clinic visit, concomitant medications and adverse events (AEs) were reviewed with participants, and additional treatment for 2 months was supplied. At the 3-month and 6-month clinic visits, concomitant medications and AEs were again reviewed, questionnaires were administered, and, at the 3-month visit only, additional treatment for 3 months was supplied. For participants who withdrew early from the study, 6-month assessments were at the time of study discontinuation.

The primary outcome variable was the change in HRQoL as measured by the KHQ from baseline to study end (6 months or early withdrawal). Effects of educational intervention and participant age (<75 vs ≥ 75 years) on the change in KHQ scores were examined as secondary outcome variables. The KHQ, version 7, is a 27-item HRQoL assessment tool that was designed specifically for individuals with lower urinary tract conditions, including OAB [23,24]. The KHQ consists of questions that evaluate 10 domains of HRQoL: General Health Perception, Incontinence Impact, Symptom Severity, Role Limitations, Physical Limitations, Social Limitations, Personal Relationships, Emotions, Sleep/Energy, and Severity (Coping) Measures [24]. The General Health Perception domain asks individuals to rate their overall health as very good, good, fair, poor, or very poor. The multi-item Symptom Severity scale measures the severity of urinary symptoms. All other domains ask individuals to what degree (not at all, a little, moderately, or a lot) or how often (never, sometimes, often, or all the time) their bladder control symptoms affect the different aspects of their lives. The Incontinence Impact domain consists of a single item that asks individuals how much their problem affects their lives. The option of answering ‘not applicable’ is provided for questions that pertain to personal relationships or sexual activity. Each domain is scored on a scale of 0 (least impairment) to 100 (greatest impairment). A change from baseline of ≥ 5 points is considered clinically meaningful (minimally important difference) for all domains, except for the General Health Perception and Symptom Severity domains, for which a change in score of ≥ 3 points is considered clinically meaningful [24].

The safety of OXY-TDS was assessed over the 6-month period; AEs were assessed by investigators according to severity and relationship to the study drug.

A sample size of ≥ 2500 participants was targeted to obtain a significance level of 0.05 and 90% power for the primary endpoint, and capture sufficient information on safety and to provide an adequate number of participants for the pre-defined subgroup analyses, e.g. sex, age, ethnicity, previous OAB therapy; 10–20% of enrolees were to be aged ≥ 75 years.

Effectiveness was analysed using data from the intent-to-treat (ITT) population, which was defined as participants who received at least two doses of OXY-TDS and provided at least one assessment of effectiveness after baseline. The ‘last observation carried forward’ method was used for participants who did not complete the study. The safety population was defined as all participants who received at least one dose of OXY-TDS.

Baseline demographics and medical histories were summarized using descriptive statistics for continuous variables and distributions for categorical variables. Patient-reported outcome data were summarized using descriptive statistics for continuous variables and distributions for categorical variables at baseline, at study end (6 months or early withdrawal) and for the changes from baseline to study end. The statistical significance of the within-group change from baseline to study end was determined using a one-sample, two-tailed paired t-test for significance of the difference from zero for continuous variables, or the κ test for symmetry for categorical variables. For between-group differences in change from baseline in continuous variables, statistical significance was tested with an analysis of covariance model, which controlled for investigator speciality, baseline score, their interaction, and any unbalanced baseline characteristics, e.g. race, occupation, age, employment. For all analyses, P < 0.05 was considered to indicate statistical significance.

RESULTS

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

In all, 2888 participants were recruited for the study from 327 sites; various medical practice types, e.g. urology, 141; primary care, 96; obstetrics-gynaecology, 43; and geriatric medicine, 17, were represented. Of recruited participants, 2878 (99.7%) met the criteria for inclusion in the safety population, and 2593 (90.1%) met the criteria for inclusion in the ITT population. Among participants in the safety population, 1596 (55.5%) were enrolled at sites designated to provide enhanced educational materials that included information on behavioural modification. About half of the participants (1426; 49.5%) completed the maximum 6 months of treatment. Reasons for early discontinuation included AEs, regardless of relatedness to study drug (613; 21.3%), withdrawn consent (215; 7.5%), requirement for alternative therapy (212; 7.4%), loss to follow-up (208; 7.2%), non-compliance with study protocol (161; 5.6%), administrative decision (20; 0.7%), determination of ineligibility (11; 0.4%), and death (3; 0.1%). No reason for discontinuation was reported for nine individuals.

Most of the study population was Caucasian (83.6%) and female (87.2%), but because it was a large study, substantially many African Americans (285; 9.9%), Hispanic Americans (137; 4.8%), and men (369; 12.8%) were included (Table 1). The median (range) age of participants was 63 (18–100) years, with nearly a quarter of them aged ≥ 75 years (24.3%). About a third (1112; 38.6%) of participants were working. Many participants had comorbid conditions, most commonly cardiovascular disease (55.4%), musculoskeletal disease (54.7%) and gastrointestinal disease (44.1%), for which they were taking many concomitant medications (median 6, range 1–22).

Table 1.  The baseline demographics of the 2878 study participants
Characteristic (n sample)Value
  1. Not all participants responded to every question; the total number of participants responding is listed for each characteristic and was used to calculate percentages. *Participants could be counted in more than one category.

Age, years (2875)
 mean (sd)  62.5 (14.8)
 median (range)  63.0 (18–100)
 Participants ≥ 75 years, n (%) 699 (24.3)
Gender, n (%) (2877)
 Female2508 (87.2)
 Male 369 (12.8)
Race, n (%) (2877)
 White2406 (83.6)
 African American 285 (9.9)
 Hispanic 137 (4.8)
 Asian  34 (1.2)
 Other  15 (0.5)
Comorbid diseases, n (%)* (2878)
 Cardiovascular1593 (55.4)
 Musculoskeletal1575 (54.7)
 Gastrointestinal1269 (44.1)
 Neurological/psychiatric1048 (36.4)
 Endocrine1037 (36.0)
 Respiratory 666 (23.1)
 Renal 554 (19.2)
 Dermatological 429 (14.9)
 Haematological/lymphatic 255 (8.9)
 Other1596 (55.5)

Most participants had had symptoms of OAB for ≥2 years (69.4%), with 46.4% reporting a history of OAB symptoms for ≥ 4 years (Table 2). In addition, most participants (78.2%) reported their overall OAB severity on the PPBC at baseline as moderate or worse (score ≥ 4). More than half of all participants (57.1%) had taken previous oral drug treatment for OAB, about a third (31.6%) of whom had used more than one drug. The most common previous treatments for OAB included oral extended-release tolterodine (31.0%), oral extended-release oxybutynin (18.2%), oral immediate-release oxybutynin (13.1%), and oral immediate-release tolterodine (12.5%). Previous OAB treatment was most commonly discontinued because of ineffectiveness (53.2%) and adverse effects (22.3%).

Table 2.  The baseline disease characteristics of the 2878 participants
Characteristic (n sample)Value, n (%)
  1. Not all participants responded to every question; the total number of participants who responded is listed for each characteristic and was used to calculate percentages.

History of OAB symptoms, years (2876)
 <1 346 (12.0)
 1–<2 533 (18.5)
 2–<4 663 (23.1)
 ≥41334 (46.4)
Overall OAB severity (2626)
 1 – No problems  46 (1.8)
 2 – Very minor problems 120 (4.6)
 3 – Minor problems 407 (15.5)
 4 – Moderate problems 867 (33.0)
 5 – Severe problems 747 (28.4)
 6 – Many severe problems 438 (16.7)
History of previous OAB treatment (2859)
 Yes1632 (57.1)
 No1227 (42.9)
No. of previous OAB treatments (2878)
 01248 (43.4)
 11115 (38.7)
 2 376 (13.1)
 3  83 (2.9)
 4  56 (1.9)
Primary reason for stopping previous OAB treatment (2854)
 Ineffective1233 (53.2)
 AEs 516 (22.3)
 Compliance 178 (7.7)
 Unknown 352 (15.2)
 Other  37 (1.6)

In all, 2592 participants had evaluable baseline KHQ scores. At baseline, most participants (72.4%) rated their overall health as good or very good. Most participants (74.4%) reported that bladder control problems affected their lives (Incontinence Impact domain) moderately or a lot, with troublesome symptoms of frequency, nocturia, urgency, UUI, and stress UI. Nearly all (92.2%) reported urgency, and most (88.2%) reported UUI, as symptoms of OAB that bothered them a little to a lot. The mean domain scores were highest, reflecting greater impairment, for Incontinence Impact, followed by Symptom Severity, Sleep/Energy, Severity (Coping) Measures, Physical Limitations, and Role Limitations (Table 3). There were statistically significant improvements in all KHQ domains from baseline to study end and, except for the General Health Perception domain, these improvements were clinically meaningful, i.e. mean score changes met or exceeded the 3- or 5-point minimally important difference threshold (Table 3) [24]. KHQ domains with the greatest improvement at study end were those with the greatest impairment at baseline; the greatest improvements occurred in Incontinence Impact, Symptom Severity, Role and Physical Limitations, and Sleep/Energy (Table 3). The greatest proportionate changes, resulting in improvement of nearly 30% relative to baseline scores, were for the domains of Role Limitations (−29.5%), Emotions (−29.3%), and Personal Relationships (−29.1%) (Fig. 1).

Table 3.  The mean changes in KHQ scores from baseline to study end
KHQ domain, mean (sd) (n)BaselineStudy endChange, baseline to study endEffect size*
  • *

    Calculated as the change from baseline divided by the sd of the baseline value; an absolute value of effect size of ≥ 0.2 is considered clinically meaningful [24].

  • P = 0.001 vs baseline (one-sample, two-tailed paired t-test);

  • P < 0.001 vs baseline (one-sample, two-tailed paired t-test).

N259223362336 
General Health Perception  28.2 (19.8) (2584)  27.2 (20.4) (2333)  −1.2 (17.4) (2324)−0.06
Incontinence Impact  69.3 (27.4) (2574)  55.7 (29.4) (2324) −13.5 (29.5) (2307)−0.49
Symptom Severity  55.9 (20.5) (2166)  43.5 (24.5) (1883) −12.4 (24.8) (1698)−0.60
Role Limitations  45.1 (31.0) (2584)  31.7 (28.6) (2327) −13.3 (29.2) (2319)−0.43
Physical Limitations  46.7 (31.6) (2584)  34.9 (29.5) (2326)  −11.7 (29.9) (2319)−0.37
Social Limitations  25.6 (28.3) (2563)  18.8 (25.2) (2316)  −6.7 (23.7) (2289)−0.24
Emotions  30.0 (29.2) (2574)  21.0 (25.5) (2321)  −8.8 (25.4) (2305)−0.20
Personal Relationships  20.6 (29.5) (1706)  14.2 (25.4) (1607)  −6.0 (23.5) (1413)−0.30
Sleep/Energy  54.2 (27.3) (2582)  42.8 (25.6) (2326)  −11.2 (24.1) (2318)−0.41
Severity (Coping) Measures  47.9 (26.4) (2578)  39.3 (25.8) (2324)  −8.6 (21.3) (2313)−0.33
image

Figure 1. The percentage improvement in KHQ domain scores from baseline to the end of study. All P ≤ 0.001 (one-sample, two-tailed t-test).

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Results of the multi-item Symptom Severity domain are presented in Fig. 2. The rating for each of the symptom components is shown on a ‘spider’ graph in Fig. 3. This technique of depicting weighted averages allows an evaluation of the magnitude of changes across all symptoms. For all participants at baseline, values ranged from 0.36 for intercourse incontinence, indicating that relatively fewer participants had this symptom, to 2.48 for frequency, indicating that many participants had considerable difficulties. Symptoms that most often affected participants were frequency, urgency, UUI and nocturia. Results at the end of treatment are also shown in Fig. 3, with improvements indicated by rings that are closer to the centre of the graph. There were improvements across all areas of the Symptom Severity domain; the greatest changes were among the most bothersome symptoms, with > 40% of participants reporting improvements in frequency, nocturia, urgency and UUI (Fig. 2). In addition, a significantly (P < 0.001) greater proportion of participants reported improvement rather than worsening on all individual item responses for the remaining KHQ domains (Figures 4 and 5). The greatest proportions of participants reported an improvement on individual item responses in the domains of Role Limitations (household tasks, 41.5%; activities outside the home, 42.0%), Incontinence Impact (41.3%), Physical Limitations (physical activities, 39.2%; ability to travel, 39.0%), and Sleep/Energy (sleep, 38.4%; feeling tired, 34.4%).

image

Figure 2. Change from baseline to study end in individual item scores within the KHQ Symptom Severity domain. All P ≤ 0.001 (κ test of symmetry).

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image

Figure 3. A ‘spider’ graph showing the degree of improvement seen in specific symptoms of OAB from baseline to study completion. (‘Weighted average’ of individual item responses at baseline and at study end, i.e. the sum of all responses for an item [not applicable = 0, a little = 1, moderately = 2, a lot = 3], divided by the number of participants providing an answer to that item.)

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image

Figure 4. The percentage of participants with improvement or worsening from baseline to study end on individual items within the KHQ domains of Incontinence Impact, Role Limitations, Physical Limitations, and Social Limitations. Percentages of participants who reported no change are not shown (100%−[% improvement +% worsening]). *P < 0.001 (κ test of symmetry).

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image

Figure 5. The percentage of participants with improvement or worsening from baseline to study end on individual items within the KHQ domains of Personal Relationships, Emotions, Sleep/Energy, and Severity (Coping) Measures. Percentages of participants who reported no change are not shown (100%−[% improvement +% worsening]). *P < 0.001 (κ test of symmetry).

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For all KHQ domains, there were no significant differences in mean score improvements between participants who were randomly assigned to receive enhanced patient educational materials, which included information on behavioural modification, and those who were not. The mean improvement from baseline to study end for most KHQ domain scores was not substantially different between participants aged <75 and those ≥ 75 years. In General Health Perception (−1.3 vs − 0.6), Social Limitations (−7.4 vs − 4.7), Emotions (−9.9 vs. − 5.6), and Severity Coping Measures (−9.7 vs −5.7) domains, there were slightly greater improvements in participants aged <75 years (all < 0.05).

Of 2878 participants who received at least one dose of study drug, 863 (30.0%) had at least one drug-related AE. Most drug-related AEs were mild or moderate; 14.7% of participants had a mild AE, 11.3% a moderate AE, and 4.0% had a severe AE. Drug-related AEs in ≥2% of participants are shown in Table 4. Application-site reactions were slightly less frequent among participants aged ≥75 years (11.4%) than in those aged <75 years (14.8%). Except for dry mouth (2.6%), the following AEs associated with anticholinergic agents occurred among <2% of participants in the safety population: constipation (1.5%), nausea (0.9%), dizziness (0.7%), blurred vision (0.6%), dry eye (0.5%), somnolence (0.3%), dysuria (0.3%), abdominal pain (0.2%), palpitations (0.2%), and confusion (0.1%). In all, 475 participants (16.5%) discontinued the study because of drug-related AEs. Serious AEs occurred in 104 (3.6%) participants; relatedness to study drug could not be excluded in only one event (UTI).

Table 4.  Drug-related AEs occurring in ≥ 2% of 2878 participants
AEParticipants, %
  • *

    The sum of these individual application-site reactions does not equal the percentage of participants who had any application-site reaction (14.0%) because participants could have had more than one type of reaction.

Application-site reactions14.0
 Pruritus* 4.9
 Erythema* 4.6
 Dermatitis* 4.4
 Irritation* 3.2
 Other* 2.0
Rash 3.0
Dry mouth 2.6
Pruritus 2.6
Skin irritation 2.1

DISCUSSION

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

This multicentre, community-based study represents one of the largest efforts undertaken to evaluate the effects of treatment on HRQoL in persons with OAB, and might be the only such study to use HRQoL as a primary measure of the effectiveness of OAB treatment. Impaired HRQoL is a major reason why persons with OAB seek medical care; it seems logical to evaluate effectiveness by exploring how treatment alleviates patients’ initial concerns. Recommendations from the ICS and the Urodynamic Society state that validated HRQoL questionnaires are useful for measuring the impact of OAB or other urinary syndromes on a patient [4,25]. Relative to generic HRQoL assessment tools, the KHQ offers enhanced sensitivity and a greater ability to detect clinically relevant HRQoL changes [24,26]. It also offers advantages over other condition-specific questionnaires, in that it evaluates multi-dimensional aspects of HRQoL that might be affected by OAB, has been extensively validated and used in OAB intervention studies, is fast and simple enough for routine clinical use, and is available in many validated translations [12,14,15,27]. The KHQ has received a grade A recommendation from the International Consultation on Incontinence and will be included as a component of the new International Consultation on Incontinence modular questionnaires.

The MATRIX eligibility criteria were intentionally broad so that a diverse population reflecting clinical practice would be recruited. Comorbidities that are common among patients with OAB, such as diabetes or congestive heart failure, were also common in the MATRIX population [5]. At study entry, most enrolled participants (74.4%) reported that bladder control problems affected their lives ‘a lot.’ This description was consistent with baseline overall OAB severity as measured by the PPBC, on which most participants (78.1%) reported moderate, severe or many severe problems. Up to 6 months of treatment with OXY-TDS, with or without enhanced educational materials on behavioural modification, produced statistically significant and clinically relevant improvements in nine of 10 KHQ domains. A significant improvement was reported across all individual response items for each domain. Improvement in nocturia, within the Symptom Severity domain, also might have contributed to improvements in the Sleep/Energy domain and the Physical Limitations domain. The lack of a significant incremental effect produced by enhanced educational intervention might be explained by variations among control sites in the degree of behavioural and educational treatment provided as part of routine care.

The lack of clinical improvement in the General Health Perception domain is not surprising, in that it assesses overall health and is not condition-specific; thus, this domain could be affected by the large prevalence of comorbid illness observed in this population. Furthermore, many participants (72.4%) in the MATRIX study rated their general health as good or very good at baseline; this ceiling limited the potential for improvement. Similar proportions of respondents to a survey of elderly (≥65 years) Medicare beneficiaries, i.e. 65% of respondents with UI and 80% of those respondents with no UI, rated their general health as good or excellent [8]. Fewer patients (≈ 40%) in the original work by Kelleher et al.[23] on the KHQ (mean age 51.4 years) reported good or very good health, possibly because patients had been referred to a tertiary-care hospital setting and did not represent a strictly community-based sample, which might have been less burdened by comorbid disease.

In the present study, OXY-TDS was safe and well tolerated, with an incidence of dry mouth (2.6%) similar to that during placebo treatment in phase III studies (1.7–8.3%) [16,20,21]. Skin reactions at the application site, the most frequent drug-related AEs, were less common among MATRIX participants than in patients who participated in previous pivotal double-blind studies of OXY-TDS; this might be the result of explicit instructions to MATRIX participants that they should alternate the sites of application [20,21].

The open-label, community-based design of MATRIX enabled greater general applicability of the findings to clinical practice than was possible with rigorously controlled studies. Inclusion criteria for participants were based on the indications section of the package insert for Oxytrol, with the intent to enrol participants for whom this agent was indicated according to product labelling approved by the USA Food and Drug Administration. Thus, it is possible that a few participants did not have OAB according to the ICS definition. However, 94.4% of participants reported that they were bothered by urgency, and 89.9% by UUI, at baseline. In phase III studies of OXY-TDS, as in all phase III studies, rigorous patient selection criteria and protocol adherence requirements, although important for the firm establishment of pharmacological efficacy, excluded many individuals with OAB [20,21]. The phase III populations were relatively homogenous, making difficult the detection of differential treatment effects by gender, age, or racial subgroup. In addition, by design, the phase III studies could provide no safety data on rare AEs for those with potentially confounding concomitant medications or comorbid disease. By contrast, the MATRIX study provided data for a population that was more representative of clinical reality. As a result, drug–drug interactions or rare AEs were more likely to be detected. Because the pivotal phase III studies of OXY-TDS established its superiority over placebo, a placebo-controlled arm was not included in MATRIX. Moreover, evidence suggests that well-designed observational studies, such as that reported here, do not consistently overestimate therapeutic effectiveness; rather, they often produce results similar to those achieved with randomized, controlled studies [28,29].

Although MATRIX did not directly assess the efficacy of OXY-TDS in reducing OAB severity, the significant improvements in the domains of Symptom Severity and Severity (Coping) Measures suggest that OXY-TDS was indeed effective in treating patients with symptoms of OAB. A recently published study confirmed the relationship between treatment efficacy and HRQoL improvement in patients with OAB who were treated with OXY-TDS [26]. This randomized, double-blind, placebo-controlled, multicentre, dose-finding study of 637 Japanese patients with OAB was conducted to determine the minimal clinically important reduction in weekly incontinence episodes needed to improve HRQoL, as assessed by the KHQ. After 8 weeks of treatment, the mean incontinence frequency for patients treated with 3.9 mg/day OXY-TDS decreased from 20.8 to 6.3 episodes/week (decrease of 14.5), compared with a decrease of 10.1 episodes/week in the placebo group [26]. All KHQ domain scores decreased after treatment, with domains related to ‘limitation’ (Role, Physical, and Social Limitations) and ‘emotion’ (Emotion, Sleep/Energy) showing the greatest improvement; consistent with findings from our study, mean change in the General Health Perceptions domain was small [26]. The authors suggested that a 30% reduction in incontinence frequency was the minimal clinically meaningful change needed to produce improvements in HRQoL [26].

Previous studies of oral OAB treatments have shown improved HRQoL by including KHQ domain scores as secondary endpoints. In a randomized, double-blind, placebo-controlled, 12-week study of 975 patients with OAB, tolterodine extended-release treatment resulted in a statistically and clinically significant improvement in six of 10 domains [12]. In an open-label extension study of solifenacin (5 mg and 10 mg pooled), once-daily treatment in 1347 patients provided a statistically and clinically significant improvement in nine of 10 domains [13]. Chapple et al.[30] reported a statistically and clinically significant improvement in six of nine domains (Symptom Severity not reported) for darifenacin. Findings from MATRIX are consistent with these results and further showed the ability of OAB treatment to produce clinically meaningful improvements in HRQoL.

In summary, treatment with OXY-TDS for up to 6 months significantly improved HRQoL and was well tolerated in a community-based, diverse population of individuals with OAB. Forthcoming analyses will examine the effects of OXY-TDS treatment for OAB on work productivity and depression, differential treatment outcomes among participant subpopulations, and participant perceptions of OXY-TDS treatment.

ACKNOWLEDGEMENT

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

The authors acknowledge Thomson Scientific Connexions for providing editorial assistance in the preparation of this manuscript.

CONFLICT OF INTEREST

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

P. Sand is an advisor and investigator for Watson Pharma, Ortho Urology, Astellas–Glaxo Smith Kline, Indevus–Esprit and Pfizer; N. Zinner is a consultant/advisor for Lilly, Watson, Esprit, GSK and Allergan; a meeting participant/lecturer for Lilly, Watson, Novartis, Sanofi and Pfizer; and is involved in a scientific study/trial for GSK, Novartis, Sanofi, Pfizer, GTx and Ortho-McNeil; D. Newman is on the Advisory Board and is Research Support for Watson Pharma; and is part of the Speakers Bureau for Watson Pharma, Pfizer, GSK, Novartis and Astellas; V. Lucente is a paid consultant to sponsor and a study investigator funded by sponsor; R. Dmochowski is a consultant to Watson; C. Kelleher is a consultant for Novartis, USB, Watson and Astellas, has lectured for the above and for Pfizer and has an educational grant from Pfizer; N. Dahl is an employee of sponsor.

This work was supported by Watson Laboratories, Inc. The study sponsor designed the MATRIX protocol and supported the statistical analysis of study data. The sponsor participated in data interpretation and reviewed the manuscript before submission.

REFERENCES

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