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Prospective Randomized Controlled Trial of Extended-Release Oxybutynin Chloride and Tolterodine Tartrate in the Treatment of Overactive Bladder: Results of the OBJECT Study
Mayo Clin Proc, April 2001, Vol 76
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Original Article
Prospective Randomized Controlled Trial of Extended-Release Oxybutynin Chloride and Tolterodine Tartrate in the Treatment of Overactive Bladder: Results of the OBJECT Study RODNEY A. APPELL, MD; PETER SAND, MD; ROGER DMOCHOWSKI, MD; RODNEY ANDERSON, MD; NORMAN ZINNER, MD; DANIEL LAMA, MD; MARTHA ROACH, MD; JOHN MIKLOS, MD; DANIEL SALTZSTEIN, MD; TIMOTHY BOONE, MD; DAVID R. STASKIN, MD; AND DETLEF ALBRECHT, MD, FOR THE OBJECT STUDY GROUP
• Objective: To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder. • Subjects and Methods: The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallelgroup study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline. • Results: A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective
than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups. • Conclusions: Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events. Mayo Clin Proc. 2001;76:358-363
O
veractive bladder, a condition with symptoms of urinary urge incontinence, urgency, and frequency, affects more than 17 million people in the United States,1 making it more prevalent than asthma (15 million),2 osteoporosis (10 million),3 diabetes mellitus (7 million),4 or Alzheimer disease (4 million).5 The cost of treating overactive bladder is considerable for patients, families, and third-
party payers. In 1995, the estimated cost of urinary incontinence in patients older than 65 years was $26.3 billion.6 Until recently, specialists often treated overactive bladder, but general and family practitioners now write the majority of prescriptions for overactive bladder treatments.7 For editorial comment, see page 353. Although behavioral and surgical interventions may be used to treat overactive bladder, antimuscarinic therapy with immediate-release oxybutynin chloride has been the mainstay of treatment for overactive bladder for almost 30 years.8-10 Efficacy has been satisfactory, but high discontinuation rates due to anticholinergic adverse effects, such as dry mouth, have reduced patient compliance.9 Recently, 2 medications intended to improve tolerability and patient acceptance of antimuscarinic therapy for overactive bladder have become available. Tolterodine tartrate demonstrated efficacy in the reduction of urinary frequency as the primary clinical end point, and extended-release oxybutynin chloride has shown efficacy in the reduction of urge incontinence episodes as the primary clinical end point, as well as efficacy in reduction of urgency and frequency.11-13
From Cleveland Clinic Foundation, Cleveland, Ohio (R.A.A.); Evanston Continence Center, Evanston, Ill (P.S.); Urology Associates of North Texas, Arlington (R.D.); Stanford University, Stanford, Calif (R.A.); Western Clinical Research, Inc, Torrance, Calif (N.Z.); San Bernardino Urologic Associates, San Bernardino, Calif (D.L.); Martha B. Roach, LLC, Atlanta, Ga (M.R.); Urogynecology, PC, Alpharetta, Ga (J.M.); Urology Antonio Research, San Antonio, Tex (D.S.); Baylor College of Medicine, Houston, Tex (T.B.); Beth-Israel Deaconess Medical Center, Boston, Mass (D.R.S.); and ALZA Corporation, Mountain View, Calif (D.A.). Dr Appell is now at Baylor College of Medicine, Houston, Tex. Authors’ financial disclosures and a complete list of participants in the OBJECT Study Group appear at the end of this article. This study was funded by ALZA Corporation, Mountain View, Calif. Address reprint requests and correspondence to Rodney A. Appell, MD, Baylor College of Medicine, 6560 Fannin St, Suite 2100, Houston, TX 77030 (e-mail: [email protected]). Mayo Clin Proc. 2001;76:358-363
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© 2001 Mayo Foundation for Medical Education and Research
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Mayo Clin Proc, April 2001, Vol 76
Both oxybutynin chloride and tolterodine tartrate are muscarinic receptor antagonists that suppress involuntary bladder contractions; oxybutynin also has musculotropic properties.9 In 2 phase 3 trials, mean urge incontinence episodes with extended-release oxybutynin were reduced from 27.4 per week at baseline to 4.8 per week at the end of the study11 and from 18.6 to 2.9 per week.13 With tolterodine, mean urge incontinence episodes were reduced from 20.3 per week at baseline to 9.1 per week at end of study14 and from 23.3 to 10.6 per week.15 Both compounds may produce anticholinergic adverse effects, including central nervous system (CNS) effects. Dry mouth is the most frequently reported adverse effect and is dose related with both medications.13,16 Extended-release oxybutynin doses are normally titrated to levels that achieve an optimal balance of tolerability and efficacy, and previous studies have assessed multiple dose strengths (5-30 mg).11-13 Conversely, tolterodine is normally prescribed as a fixed 4-mg dose (2 mg twice daily) and has been studied in fixed-dose regimens.15 The design of the OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study used a fixed-dose regimen to allow benchmark comparison between extendedrelease oxybutynin and tolterodine, and to our knowledge, it is the first study to compare the efficacy and tolerability of these drugs in patients with overactive bladder. SUBJECTS AND METHODS Objectives This study compared the effect of 12 weeks of treatment with extended-release oxybutynin or tolterodine on episodes of urge incontinence, total incontinence, and micturition frequency episodes, and it evaluated the tolerability of extended-release oxybutynin and tolterodine in participants with overactive bladder. Participants Participants with overactive bladder who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids per 24 hours were included. Those with mixed stress and urge incontinence were eligible if the majority of the leakage accidents were related to urge incontinence. Participants with other causes of incontinence (eg, urinary tract infection, prostatitis, interstitial cystitis, urinary tract obstruction, urethral diverticulum, bladder tumor, bladder stone, prostate cancer) were excluded, as were those who had delivered a baby or undergone pelvic, vaginal, bladder, or prostate surgery less than 6 months before study enrollment. Participants with a postvoid residual urine volume of more than 150 mL at the time of screening and those at considerable risk of developing complete urinary retention if placed on an antimuscarinic agent were also excluded. In
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addition, those with clinically important medical problems or other organ abnormalities or pathologies for whom administration of extended-release oxybutynin or tolterodine would present undue risk (medically uncontrolled cardiovascular, pulmonary, gastrointestinal, renal, endocrine, neurological, autoimmune, hematological, urological, or psychiatric disorders; severely reduced hepatic function or renal impairment) were excluded. Also excluded were subjects with hematuria or a positive urine culture and those with uncontrolled narrow-angle glaucoma, obstructive uropathy, myasthenia gravis, pelvic organ prolapse to the hymenal ring, or gastrointestinal conditions such as partial or complete obstruction, preexisting severe gastrointestinal narrowing (pathologic or iatrogenic), decreased gastrointestinal motility (paralytic ileus, intestinal atony, chronic and severe constipation), or risk of gastric retention. Any medications used for the treatment of overactive bladder or medications with anticholinergic activity used to treat other conditions had to be discontinued at screening. Patients were recruited regardless of whether they had received prior treatment and irrespective of any previous response to anticholinergic therapy. Participants who had taken an investigational drug within the previous month or had known allergies or hypersensitivities to oxybutynin chloride, tolterodine tartrate, or components of the respective tablets were excluded. Participants with current alcohol or other drug abuse, women who were pregnant or breast-feeding, and participants who were not capable of following the study schedule or directions were excluded. Those who were not able to swallow the medication without chewing, crushing, biting, dividing, or dissolving the capsule were also excluded. Intervention After urogenital, pelvic, and rectal examinations, eligible participants were randomized to receive 1 of 2 treatments: 10 mg/d of extended-release oxybutynin chloride or 4 mg/d (2 mg twice daily) of tolterodine tartrate. To help ensure a similar distribution of baseline urge incontinence, a stratified randomization based on the severity of urge incontinence at baseline was used. Stratum 1 (mild incontinence) included participants with up to 21 weekly urge incontinence episodes at baseline. Stratum 2 (moderate or severe incontinence) included those with more than 21 episodes of weekly urge incontinence episodes at baseline. Within each stratum, participants were randomized to receive either extended-release oxybutynin or tolterodine. Study medications were administered in a double-blind and double-dummy fashion. All medications were encased in identical gelatin capsules. Each subject received 3 capsules per day, 2 in the morning and 1 in the evening. In the oxybutynin group, participants were given capsules containing 1 extended-release oxybutynin tablet and 1 placebo
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Mayo Clin Proc, April 2001, Vol 76
Treatment of Overactive Bladder
Table 1. Demographics and Disposition of Patients Enrolled at Baseline
Characteristics Age (y) Mean ± SD Range Sex, No. (%) Female Male Race, No. (%) White African American Hispanic Asian Other Received antimuscarinic medication before study, No. (%) Yes No Unknown
Extended-release oxybutynin Tolterodine P (n=185) (n=193) value 58.6±13.4 26-87
59.6±13.2 21-85
.44*
152 (82.2) 33 (17.8)
163 (84.5) 30 (15.5)
.58†
162 (87.6) 10 (5.4) 7 (3.8) 4 (2.2) 2 (1.1)
166 (86.0) 13 (6.7) 10 (5.2) 3 (1.6) 1 (0.5)
.87†
75 (40.5) 109 (58.9) 1 (0.5)
73 (37.8) 119 (61.7) 1 (0.5)
.80†
*Analysis of variance. †Fisher exact test.
tablet in the morning; in the evening, a second placebo was given. In the tolterodine group, participants received capsules containing 1 tolterodine tablet and 1 placebo tablet in the morning; a second encapsulated tolterodine tablet was given in the evening. The institutional review board of each participating study center approved the study, and each subject signed an institutional review board–approved consent form. The study was conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practices and the Declaration of Helsinki. Safety Monitoring Standard clinical chemistry and hematologic tests, urinalyses, postvoid residual urine volume by pelvic ultrasonography, and electrocardiography were performed at screening and repeated at the end of the study. Participants were asked at each study visit (at weeks 2, 4, 8, and 12) to describe any unusual symptoms or adverse events that had occurred during the previous dosing interval. Efficacy Assessments The primary outcome measure was the number of urge incontinence episodes at 12 weeks adjusted for baseline as determined from 7-day urinary diaries (modified from those used by Wyman and colleagues17). All participants kept 24-hour urinary diaries for 7 days during each evalua-
360
tion period. The diaries documented the number of micturitions and incontinence episodes, as well as the nature (urge or other) of incontinence episodes during 7-day periods at baseline and at the study follow-up visits during weeks 2, 4, 8, and 12. Nocturnal voids and nocturnal incontinence episodes were included in these data but were not evaluated separately. Other outcome measures included the number of total incontinence episodes and micturition frequency episodes at 12 weeks adjusted for baseline. Statistical Analyses As specified in the protocol, the principal statistical analyses (SAS 6.12) were performed on the end-of-study (week 12) results. All statistical tests were 2-sided and performed with a significance level of 5%. The main outcome measures—urge incontinence, total incontinence, and micturition frequency—were analyzed using a 2-factor analysis of covariance model, with the baseline value as a covariate, and with treatment and stratum as the factors. When there are dropouts in clinical trials, an analysis of only study completers raises the possibility of introducing bias. To address this, additional analyses were performed by using the efficacy results obtained at all time points (weeks 2, 4, 8, and 12). All patients who completed diaries at least once while on treatment were included in these analyses. For each of the main outcome measures, a longitudinal repeated measures analysis was conducted for all efficacy time points together using a model with baseline as a covariate and including the measurement week, treatment, and stratum in the model. These analyses did not differ materially from the principal analyses; hence, only the significance levels are reported. A 2-sided Fisher exact test was used for comparisons of the incidence of the most frequent adverse events between the 2 treatment groups. A Wilcoxon rank sum test was used to determine differences in baseline comparability of efficacy end points. RESULTS A total of 37 study centers across the United States randomized 378 participants (315 women, 63 men) into the 2 treatment groups; 332 participants (276 women, 56 men) completed the study, and 46 discontinued early. Baseline characteristics were similar between the 2 treatment groups (Table 1); the majority of participants were white (87%) and were naïve to antimuscarinic therapy (60%). Baseline urinary symptoms were also comparable between the 2 groups (Table 2). Reasons for discontinuation were similar between the 2 treatment groups and are described in Table 3. Adverse events were the most frequent cause of discontinuation. There were 29 participants (14 in the extended-release oxybutynin group and 15 in the tolterodine
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Mayo Clin Proc, April 2001, Vol 76
group) who discontinued treatment because of adverse events. Overall, these participants reported a total of 35 different adverse events. The specific event resulting in each individual’s discontinuation was not uniquely identified. One hundred sixty participants in the extended-release oxybutynin group and 172 in the tolterodine group had urinary diary data at baseline and at 12 weeks and were included in the efficacy analyses. All participants who received study drugs were included in the safety analyses. Efficacy At 12 weeks (end of study), extended-release oxybutynin was significantly more effective than tolterodine in the primary outcome measure, which was the mean number of weekly urge incontinence episodes (P=.03). Extendedrelease oxybutynin was also significantly more effective than tolterodine in end-of-study total incontinence episodes (P=.02) and micturition frequency episodes (P=.02) (Table 4). Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Overall, 96.2% and 95.3% of the participants using extended-release oxybutynin and tolterodine, respectively, had fewer incontinence episodes at the end of the study compared with number of episodes at baseline. Although the overall discontinuation rate was relatively low (12%), analyses restricted to those participants completing 12 weeks of therapy could potentially contain bias. Consequently, additional analyses on all participants with at least 1 efficacy measurement were conducted using a longitudinal repeated measures approach. The results were consistent with those of the main analyses, with extended-release oxybutynin significantly more effective than tolterodine in number of episodes of urge incontinence (P=.04), total incontinence (P=.03), and micturition frequency (P=.02). Safety The incidence of dry mouth was similar in the extendedrelease oxybutynin group (28.1%) and the tolterodine group (33.2%) (P=.32) (Table 5). Moderate to severe dry mouth was reported by comparable numbers of participants receiving extended-release oxybutynin and tolterodine (10.2% vs 10.9%, respectively [P=.87]). All adverse events, including events related to the CNS, such as asthenia, blurred vision, dizziness, insomnia, nervousness, and somnolence, occurred at low rates and with similar frequency between the 2 treatment groups and across all age groups. Constipation was reported by 7.0% or less of all participants. Overall, the discontinuation rates for adverse events were 7.6% in the extended-release oxybutynin group and 7.8% in the tolterodine group (P=.99).
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Table 2. Baseline Urinary Symptoms*
Symptom Urge incontinence episodes/wk Total incontinence episodes/wk Micturition frequency episodes/wk
Extended-release oxybutynin Tolterodine (n=185) (n=193)
P value†
25.5±14.6
24.6±15.1
.36
28.4±17.8
28.0±18.3
.62
92.9±23.0
91.8±20.0
.77
*Values are mean ± SD for all patients enrolled at baseline. †Wilcoxon rank sum test.
DISCUSSION The OBJECT trial reports the first use of extended-release oxybutynin in a fixed-dose regimen, and the study design compared 2 antimuscarinic agents used in the treatment of overactive bladder. A placebo arm was not included, as both products were approved by the Food and Drug Administration on the basis of placebo-controlled trials. The double-blind, randomized design of this study limits the potential for treatment selection bias. The tolerability profile of both drugs in the present study was excellent, with rates of discontinuation and adverse events that were similar between groups. Tolerability results for tolterodine in this trial included a 7.8% discontinuation rate for adverse events and a 33.2% incidence of dry mouth and are similar to those reported in a previous trial of tolterodine.15 In the extended-release oxybutynin group, the 7.6% discontinuation rate seen in this trial was also comparable to rates in past studies,11-13 but the incidence of dry mouth (28.1%) was lower than previously reported. The lower rate of dry mouth is not surprising given the higher average doses studied in past trials.11-13 In the OBJECT trial, low rates of CNS adverse events were seen in participants across all age groups in both treatment groups. Adverse events that led to withdrawal from the study and are typically related to anticholinergic therapy Table 3. Reasons for Discontinuation* Reason for discontinuation Adverse event/ intercurrent illness Protocol violation Personal reason Lack of efficacy Lost to follow-up Withdrawal of consent
Extended-release oxybutynin Tolterodine (n=185) (n=193) 14 (7.6) 0 (0) 3 (1.6) 3 (1.6) 3 (1.6) 2 (1.1)
15 (7.8) 2 (1.0) 1 (0.5) 1 (0.5) 3 (1.6) 0 (0)
P value† >.99 .50 .36 .36 >.99 .24
*Values are number (percentage) for all subjects enrolled at baseline. †Fisher exact test.
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Mayo Clin Proc, April 2001, Vol 76
Treatment of Overactive Bladder
Table 4. Efficacy Parameters*
Parameter Urge incontinence episodes/wk Baseline End of study (95% CI) Total incontinence episodes/wk Baseline End of study (95% CI) Micturition frequency episodes/wk Baseline End of study (95% CI)
Extended-release oxybutynin (n=160)
Tolterodine (n=172)
Table 5. Adverse Events* P value
25.6±14.7 6.1±9.7 (4.4-7.3)
24.1±14.5 7.8±11.1 (6.7-9.5)
.24† .03‡
28.6±17.9 7.1±12.0 (5.2-8.6)
27.0±17.0 9.3±13.4 (8.0-11.3)
.34† .02‡
91.8±22.6 67.1±22.1 (64.6-70.0)
91.6±20.2 71.5±20.5 (69.1-74.2)
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.86† .02‡
*Actual end-of-study (12 week) mean (±SD) values are reported based on the number of subjects who completed the study. Baseline mean ± SD values include only those patients who completed the study. CI = confidence interval. †Wilcoxon rank sum test. ‡Testing and CI construction were done on the values adjusted for baseline and stratum in an analysis of covariance model.
were dry mouth (3 patients on tolterodine), dizziness (2 patients on tolterodine, 1 patient on extended-release oxybutynin), and urinary retention (1 patient on each drug). Based on the results of other trials, both extended-release oxybutynin11-13 and tolterodine14,18 are better tolerated than immediate-release oxybutynin chloride and represent an advance in the treatment of overactive bladder. In animal studies, tolterodine has shown selectivity for the urinary bladder compared with the salivary glands.19 While the importance of these results in humans is unknown, they may be linked to the drug’s clinical tolerability profile.20 Extended-release oxybutynin is formulated with use of a delivery system that minimizes drug peaks and troughs21,22 and may reduce exposure to oxybutynin chloride’s active metabolite. The metabolite levels are thought to influence the severity of dry mouth more than does the parent drug concentration.22,23 When compared with efficacy results in earlier trials,14,15,24 the outcome of tolterodine use in this trial showed greater improvement in urge and total incontinence episodes than in other tolterodine trials,14,15,24 although micturition frequency episodes were similar to those in the previous trials.14,15,24 With extended-release oxybutynin, the urge and total incontinence efficacy in this study was similar to that in past studies,11-13 and micturition frequency efficacy was better than that seen in the earlier trials.11-13
Events Anticholinergic Dry mouth Total Moderate to severe Constipation Impaired urination/ urinary retention Blurred vision Central nervous system Dizziness Somnolence Asthenia Insomnia Nervousness Other Headache Dyspepsia Nausea Vomiting
Extended-release oxybutynin Tolterodine P (n=185) (n=193) value†
52 (28.1)
64 (33.2)
.32
19 (10.2) 13 (7.0)
21 (10.9) 12 (6.2)
.87 .84
6 (3.2) 4 (2.2)
6 (3.1) 2 (1.0)
>.99 .44
9 (4.9) 8 (4.3) 3 (1.6) 1 (0.5) 0 (0)
8 (4.1) 3 (1.6) 7 (3.6) 3 (1.6) 2 (1.0)
.81 .13 .34 .62 .50
15 (8.1) 11 (5.9) 6 (3.2) 3 (1.6)
17 (8.8) 10 (5.2) 3 (1.6) 3 (1.6)
.86 .82 .33 >.99
*Values are number (percentage) for all subjects enrolled at baseline. †Fisher exact test.
The study design used had several limitations. While 12 weeks is a standard length for clinical trials of these types of antimuscarinic medications, the results may not reflect those seen in long-term treatment of a chronic condition such as overactive bladder. In addition, the racial distribution in this trial is not representative of the US population as a whole, and specialists, rather than primary care physicians, enrolled participants in this trial. Evaluation of efficacy with the primary outcome measure—urge incontinence episodes at 12 weeks—indicates extended-release oxybutynin was statistically significantly more effective than tolterodine, also yielding fewer episodes of total incontinence and micturition frequency. Participants taking tolterodine averaged 28% more urge incontinence episodes than those taking extended-release oxybutynin, the relative difference (7.8 vs 6.1 episodes, respectively) between the number of urge incontinence episodes at study week 12. Financial Disclosure.—Dr Appell is an adviser, investigator, and speaker for ALZA Corporation and a speaker and investigator for Pharmacia Corporation. Dr Sand is an adviser, investigator, and speaker for ALZA Corporation and an investigator for Pharmacia Corporation. Dr Dmochowski is an adviser, investigator, and speaker for ALZA Corporation and an investigator for Pharmacia Corporation. Dr Anderson is an adviser, investigator, speaker, and stockholder for ALZA Corporation and an investiga-
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Mayo Clin Proc, April 2001, Vol 76
tor and speaker for Pharmacia Corporation. Dr Zinner is an adviser, investigator, and speaker for ALZA Corporation and an investigator for Pharmacia Corporation. Dr Lama is an investigator for ALZA Corporation and Pharmacia Corporation. Dr Roach is an adviser, investigator, and speaker for ALZA Corporation and an adviser and investigator for Pharmacia Corporation. Dr Miklos is an adviser, investigator, and speaker for ALZA Corporation. Dr Saltzstein is an investigator for ALZA Corporation. Dr Boone is an adviser, investigator, and speaker for ALZA Corporation and a speaker for Pharmacia Corporation. Dr Staskin is an adviser, investigator, speaker, and stockholder for ALZA Corporation and an adviser and speaker for Pharmacia Corporation. Dr Albrecht is an employee and stockholder of ALZA Corporation. OBJECT Study Group.—Members of the OBJECT Study Group (*protocol design responsibility): Rodney Anderson,* Stanford University, Stanford, Calif; Joseph Antoci,* Connecticut Clinical Research Center, Waterbury, Conn; Rodney A. Appell,* Cleveland Clinic Foundation, Cleveland, Ohio; Yitzhak Berger, Associates in Urology, West Orange, NJ; Jay R. Bishop, Jr, Urologic Associates of Southwestern New Mexico, Silver City; Timothy Boone,* Baylor College of Medicine, Houston, Tex; Rodney Brown, Gulf Port Urology Clinic, Gulf Port, Miss; Stacy Childs, Wyoming Research Foundation, Cheyenne; Anurag A. Das, Albany Medical Center, Albany, NY; Rodney Dennis, Urology Center of Alabama, Birmingham; Roger Dmochowski,* Urology Associates of North Texas, Arlington; Eugene Dula, West Coast Clinical Research, Van Nuys, Calif; Alan D. Garely, North Shore University Hospital-LIJ, Great Neck, NY; Marc Gittelman, South Florida Medical Research, Adventura; James E. Gottesman, Seattle Urological Associates, Seattle, Wash; Chester F. Graham, Urology Specialists & Associates, Dallas, Tex; Paul G. Hagood, Ponca City, Okla; Richard Harris, RMD Clinical Institute, LLC, Melrose Park, Ill; Mickey Karram, Seton Center, Cincinnati, Ohio; Daniel J. Lama, San Bernardino Urologic Associates, San Bernardino, Calif; James G. McMurray, Medical Affiliated Research Center, Huntsville, Ala; John Miklos, Urogynecology, PC, Alpharetta, Ga; David R. Munoz, Internal Medicine Northwest, Tacoma, Wash; Ajay Nehra,* Mayo Clinic, Rochester, Minn; Kenneth M. Peters, William Beaumont Hospital, Royal Oak, Mich; Henry Ritter, Peninsula Urology Medical Center, Atherton, Calif; Martha Roach,* Atlanta, Ga; Daniel Saltzstein, Urology Antonio Research, San Antonio, Tex; Peter Sand,* Evanston Continence Center, Evanston, Ill; Paul Sieber, Urology Associates of Lancaster, Lancaster, Pa; Jeffery Snyder, Genitourinary Surgical Consultants, PC, Denver, Colo; David Spellberg, Center for Clinical Research, Naples, Fla; John Tuttle, Network Trials, Inc, Lexington, Ky; David R. Staskin,* Beth-Israel Deaconess Medical Center, Boston, Mass; Mark A. Wainstein, Genito-Urinary Surgeons, Inc, Toledo, Ohio; Charles White, Coast Clinical Research, Mobile, Ala; and Norm Zinner, Western Clinical Research, Inc, Torrance, Calif. Acknowledgment.—The authors wish to acknowledge Denise Desmond, BS, for clinical trial data collection, Martin O’Connell, PhD, for statistical support, and Jennifer Wright, BS, for assistance with medical writing.
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24.
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National Center for Health Statistics. Fast stats A to Z: asthma. Available at: www.cdc.gov/nchs/fastats/asthma.htm. Accessibility verified February 8, 2001. National Institutes of Health. Osteoporosis and Related Bone Diseases: National Resource Center Web site. Available at: www.osteo .org/osteo.html. Accessibility verified February 8, 2001. National Center for Health Statistics. Fast stats A to Z: diabetes. Available at: www.cdc.gov/nchs/fastats/diabetes.htm. Accessibility verified February 8, 2001. National Institute on Aging. Progress report on Alzheimer’s disease 1999. Available at: www.alzheimers.org/pubs/prog99.htm. Accessibility verified February 8, 2001. Wagner TH, Hu TW. Economic costs of urinary incontinence in 1995. Urology. 1998;51:355-361. IMS America. National Prescription Audit Plus Database 2000. Plymouth Meeting, Pa. Diokno AC, Lapides J. Oxybutynin: a new drug with analgesic and anticholinergic properties. J Urol. 1972;108:307-309. Yarker YE, Goa KL, Fitton A. Oxybutynin: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging. 1995;6:243-262. Fantl JA, Newman DK, Colling J, et al. Urinary Incontinence in Adults: Acute and Chronic Management. Rockville, Md: Agency for Health Care Policy and Research, Public Health Service; March 1996. Clinical Practice Guideline No. 2, 1996 Update. AHCPR publication 96-0682. Anderson RU, Mobley D, Blank B, Saltzstein D, Susset J, Brown JS. Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. J Urol. 1999;161:1809-1812. Gleason DM, Susset J, White C, Munoz DR, Sand PK. Evaluation of a new once-daily formulation of oxybutynin for the treatment of urinary urge incontinence. Urology. 1999;54:420-423. Versi E, Appell R, Mobley D, Patton W, Saltzstein D, Ditropan XL Study Group. Dry mouth with conventional and controlled-release oxybutynin in urinary incontinence. Obstet Gynecol. 2000;95:718-721. Abrams P, Freeman R, Anderstrom C, Mattiasson A. Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol. 1998; 81:801-810. Chancellor M, Freedman S, Mitcheson HD, Antoci A, Primus G, Wein A. Tolterodine, an effective and well tolerated treatment for urge incontinence and other overactive bladder symptoms [published correction appears in Clin Drug Invest. 2000;19:391]. Clin Drug Invest. 2000;19:83-91. Rentzhog L, Stanton SL, Cardozo L, Nelson E, Fall M, Abrams P. Efficacy and safety of tolterodine in patients with detrusor instability: a dose-ranging study. Br J Urol. 1998;81:42-48. Wyman JF, Choi SC, Harkins SW, Wilson MS, Fantl JA. The urinary diary in evaluation of incontinent women: a test-retest analysis. Obstet Gynecol. 1988;71(6, pt 1):812-817. Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology. 1997; 50(6A, suppl):90-96. Nilvebrant L, Gillberg PG, Sparf B. Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine. Pharmacol Toxicol. 1997;81:169-172. Nilvebrant L, Hallen B, Larsson G. Tolterodine—a new bladder selective muscarinic receptor antagonist: preclinical pharmacological and clinical data. Life Sci. 1997;60:1129-1136. Bauer K, Rakusan S, Kaik G. Pulmonary effects of long-term beta 2-blockade in healthy subjects: comparative study of metoprolol OROS. Am Heart J. 1990;120:473-477. Gupta SK, Sathyan G. Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin. J Clin Pharmacol. 1999;39:289-296. Buyse G, Waldeck K, Verpoorten C, Bjork H, Casaer P, Andersson KE. Intravesical oxybutynin for neurogenic bladder dysfunction: less systemic side effects due to reduced first pass metabolism. J Urol. 1998;160(3, pt 1):892-896. Millard R, Tuttle J, Moore K, et al. Clinical efficacy and safety of tolterodine compared to placebo in detrusor overactivity. J Urol. 1999;161:1551-1555.
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Original Article
Prospective Randomized Controlled Trial of Extended-Release Oxybutynin Chloride and Tolterodine Tartrate in the Treatment of Overactive Bladder: Results of the OBJECT Study RODNEY A. APPELL, MD; PETER SAND, MD; ROGER DMOCHOWSKI, MD; RODNEY ANDERSON, MD; NORMAN ZINNER, MD; DANIEL LAMA, MD; MARTHA ROACH, MD; JOHN MIKLOS, MD; DANIEL SALTZSTEIN, MD; TIMOTHY BOONE, MD; DAVID R. STASKIN, MD; AND DETLEF ALBRECHT, MD, FOR THE OBJECT STUDY GROUP
• Objective: To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder. • Subjects and Methods: The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallelgroup study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline. • Results: A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective
than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups. • Conclusions: Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events. Mayo Clin Proc. 2001;76:358-363
O
veractive bladder, a condition with symptoms of urinary urge incontinence, urgency, and frequency, affects more than 17 million people in the United States,1 making it more prevalent than asthma (15 million),2 osteoporosis (10 million),3 diabetes mellitus (7 million),4 or Alzheimer disease (4 million).5 The cost of treating overactive bladder is considerable for patients, families, and third-
party payers. In 1995, the estimated cost of urinary incontinence in patients older than 65 years was $26.3 billion.6 Until recently, specialists often treated overactive bladder, but general and family practitioners now write the majority of prescriptions for overactive bladder treatments.7 For editorial comment, see page 353. Although behavioral and surgical interventions may be used to treat overactive bladder, antimuscarinic therapy with immediate-release oxybutynin chloride has been the mainstay of treatment for overactive bladder for almost 30 years.8-10 Efficacy has been satisfactory, but high discontinuation rates due to anticholinergic adverse effects, such as dry mouth, have reduced patient compliance.9 Recently, 2 medications intended to improve tolerability and patient acceptance of antimuscarinic therapy for overactive bladder have become available. Tolterodine tartrate demonstrated efficacy in the reduction of urinary frequency as the primary clinical end point, and extended-release oxybutynin chloride has shown efficacy in the reduction of urge incontinence episodes as the primary clinical end point, as well as efficacy in reduction of urgency and frequency.11-13
From Cleveland Clinic Foundation, Cleveland, Ohio (R.A.A.); Evanston Continence Center, Evanston, Ill (P.S.); Urology Associates of North Texas, Arlington (R.D.); Stanford University, Stanford, Calif (R.A.); Western Clinical Research, Inc, Torrance, Calif (N.Z.); San Bernardino Urologic Associates, San Bernardino, Calif (D.L.); Martha B. Roach, LLC, Atlanta, Ga (M.R.); Urogynecology, PC, Alpharetta, Ga (J.M.); Urology Antonio Research, San Antonio, Tex (D.S.); Baylor College of Medicine, Houston, Tex (T.B.); Beth-Israel Deaconess Medical Center, Boston, Mass (D.R.S.); and ALZA Corporation, Mountain View, Calif (D.A.). Dr Appell is now at Baylor College of Medicine, Houston, Tex. Authors’ financial disclosures and a complete list of participants in the OBJECT Study Group appear at the end of this article. This study was funded by ALZA Corporation, Mountain View, Calif. Address reprint requests and correspondence to Rodney A. Appell, MD, Baylor College of Medicine, 6560 Fannin St, Suite 2100, Houston, TX 77030 (e-mail: [email protected]). Mayo Clin Proc. 2001;76:358-363
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© 2001 Mayo Foundation for Medical Education and Research
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Both oxybutynin chloride and tolterodine tartrate are muscarinic receptor antagonists that suppress involuntary bladder contractions; oxybutynin also has musculotropic properties.9 In 2 phase 3 trials, mean urge incontinence episodes with extended-release oxybutynin were reduced from 27.4 per week at baseline to 4.8 per week at the end of the study11 and from 18.6 to 2.9 per week.13 With tolterodine, mean urge incontinence episodes were reduced from 20.3 per week at baseline to 9.1 per week at end of study14 and from 23.3 to 10.6 per week.15 Both compounds may produce anticholinergic adverse effects, including central nervous system (CNS) effects. Dry mouth is the most frequently reported adverse effect and is dose related with both medications.13,16 Extended-release oxybutynin doses are normally titrated to levels that achieve an optimal balance of tolerability and efficacy, and previous studies have assessed multiple dose strengths (5-30 mg).11-13 Conversely, tolterodine is normally prescribed as a fixed 4-mg dose (2 mg twice daily) and has been studied in fixed-dose regimens.15 The design of the OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study used a fixed-dose regimen to allow benchmark comparison between extendedrelease oxybutynin and tolterodine, and to our knowledge, it is the first study to compare the efficacy and tolerability of these drugs in patients with overactive bladder. SUBJECTS AND METHODS Objectives This study compared the effect of 12 weeks of treatment with extended-release oxybutynin or tolterodine on episodes of urge incontinence, total incontinence, and micturition frequency episodes, and it evaluated the tolerability of extended-release oxybutynin and tolterodine in participants with overactive bladder. Participants Participants with overactive bladder who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids per 24 hours were included. Those with mixed stress and urge incontinence were eligible if the majority of the leakage accidents were related to urge incontinence. Participants with other causes of incontinence (eg, urinary tract infection, prostatitis, interstitial cystitis, urinary tract obstruction, urethral diverticulum, bladder tumor, bladder stone, prostate cancer) were excluded, as were those who had delivered a baby or undergone pelvic, vaginal, bladder, or prostate surgery less than 6 months before study enrollment. Participants with a postvoid residual urine volume of more than 150 mL at the time of screening and those at considerable risk of developing complete urinary retention if placed on an antimuscarinic agent were also excluded. In
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addition, those with clinically important medical problems or other organ abnormalities or pathologies for whom administration of extended-release oxybutynin or tolterodine would present undue risk (medically uncontrolled cardiovascular, pulmonary, gastrointestinal, renal, endocrine, neurological, autoimmune, hematological, urological, or psychiatric disorders; severely reduced hepatic function or renal impairment) were excluded. Also excluded were subjects with hematuria or a positive urine culture and those with uncontrolled narrow-angle glaucoma, obstructive uropathy, myasthenia gravis, pelvic organ prolapse to the hymenal ring, or gastrointestinal conditions such as partial or complete obstruction, preexisting severe gastrointestinal narrowing (pathologic or iatrogenic), decreased gastrointestinal motility (paralytic ileus, intestinal atony, chronic and severe constipation), or risk of gastric retention. Any medications used for the treatment of overactive bladder or medications with anticholinergic activity used to treat other conditions had to be discontinued at screening. Patients were recruited regardless of whether they had received prior treatment and irrespective of any previous response to anticholinergic therapy. Participants who had taken an investigational drug within the previous month or had known allergies or hypersensitivities to oxybutynin chloride, tolterodine tartrate, or components of the respective tablets were excluded. Participants with current alcohol or other drug abuse, women who were pregnant or breast-feeding, and participants who were not capable of following the study schedule or directions were excluded. Those who were not able to swallow the medication without chewing, crushing, biting, dividing, or dissolving the capsule were also excluded. Intervention After urogenital, pelvic, and rectal examinations, eligible participants were randomized to receive 1 of 2 treatments: 10 mg/d of extended-release oxybutynin chloride or 4 mg/d (2 mg twice daily) of tolterodine tartrate. To help ensure a similar distribution of baseline urge incontinence, a stratified randomization based on the severity of urge incontinence at baseline was used. Stratum 1 (mild incontinence) included participants with up to 21 weekly urge incontinence episodes at baseline. Stratum 2 (moderate or severe incontinence) included those with more than 21 episodes of weekly urge incontinence episodes at baseline. Within each stratum, participants were randomized to receive either extended-release oxybutynin or tolterodine. Study medications were administered in a double-blind and double-dummy fashion. All medications were encased in identical gelatin capsules. Each subject received 3 capsules per day, 2 in the morning and 1 in the evening. In the oxybutynin group, participants were given capsules containing 1 extended-release oxybutynin tablet and 1 placebo
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Mayo Clin Proc, April 2001, Vol 76
Treatment of Overactive Bladder
Table 1. Demographics and Disposition of Patients Enrolled at Baseline
Characteristics Age (y) Mean ± SD Range Sex, No. (%) Female Male Race, No. (%) White African American Hispanic Asian Other Received antimuscarinic medication before study, No. (%) Yes No Unknown
Extended-release oxybutynin Tolterodine P (n=185) (n=193) value 58.6±13.4 26-87
59.6±13.2 21-85
.44*
152 (82.2) 33 (17.8)
163 (84.5) 30 (15.5)
.58†
162 (87.6) 10 (5.4) 7 (3.8) 4 (2.2) 2 (1.1)
166 (86.0) 13 (6.7) 10 (5.2) 3 (1.6) 1 (0.5)
.87†
75 (40.5) 109 (58.9) 1 (0.5)
73 (37.8) 119 (61.7) 1 (0.5)
.80†
*Analysis of variance. †Fisher exact test.
tablet in the morning; in the evening, a second placebo was given. In the tolterodine group, participants received capsules containing 1 tolterodine tablet and 1 placebo tablet in the morning; a second encapsulated tolterodine tablet was given in the evening. The institutional review board of each participating study center approved the study, and each subject signed an institutional review board–approved consent form. The study was conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practices and the Declaration of Helsinki. Safety Monitoring Standard clinical chemistry and hematologic tests, urinalyses, postvoid residual urine volume by pelvic ultrasonography, and electrocardiography were performed at screening and repeated at the end of the study. Participants were asked at each study visit (at weeks 2, 4, 8, and 12) to describe any unusual symptoms or adverse events that had occurred during the previous dosing interval. Efficacy Assessments The primary outcome measure was the number of urge incontinence episodes at 12 weeks adjusted for baseline as determined from 7-day urinary diaries (modified from those used by Wyman and colleagues17). All participants kept 24-hour urinary diaries for 7 days during each evalua-
360
tion period. The diaries documented the number of micturitions and incontinence episodes, as well as the nature (urge or other) of incontinence episodes during 7-day periods at baseline and at the study follow-up visits during weeks 2, 4, 8, and 12. Nocturnal voids and nocturnal incontinence episodes were included in these data but were not evaluated separately. Other outcome measures included the number of total incontinence episodes and micturition frequency episodes at 12 weeks adjusted for baseline. Statistical Analyses As specified in the protocol, the principal statistical analyses (SAS 6.12) were performed on the end-of-study (week 12) results. All statistical tests were 2-sided and performed with a significance level of 5%. The main outcome measures—urge incontinence, total incontinence, and micturition frequency—were analyzed using a 2-factor analysis of covariance model, with the baseline value as a covariate, and with treatment and stratum as the factors. When there are dropouts in clinical trials, an analysis of only study completers raises the possibility of introducing bias. To address this, additional analyses were performed by using the efficacy results obtained at all time points (weeks 2, 4, 8, and 12). All patients who completed diaries at least once while on treatment were included in these analyses. For each of the main outcome measures, a longitudinal repeated measures analysis was conducted for all efficacy time points together using a model with baseline as a covariate and including the measurement week, treatment, and stratum in the model. These analyses did not differ materially from the principal analyses; hence, only the significance levels are reported. A 2-sided Fisher exact test was used for comparisons of the incidence of the most frequent adverse events between the 2 treatment groups. A Wilcoxon rank sum test was used to determine differences in baseline comparability of efficacy end points. RESULTS A total of 37 study centers across the United States randomized 378 participants (315 women, 63 men) into the 2 treatment groups; 332 participants (276 women, 56 men) completed the study, and 46 discontinued early. Baseline characteristics were similar between the 2 treatment groups (Table 1); the majority of participants were white (87%) and were naïve to antimuscarinic therapy (60%). Baseline urinary symptoms were also comparable between the 2 groups (Table 2). Reasons for discontinuation were similar between the 2 treatment groups and are described in Table 3. Adverse events were the most frequent cause of discontinuation. There were 29 participants (14 in the extended-release oxybutynin group and 15 in the tolterodine
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Mayo Clin Proc, April 2001, Vol 76
group) who discontinued treatment because of adverse events. Overall, these participants reported a total of 35 different adverse events. The specific event resulting in each individual’s discontinuation was not uniquely identified. One hundred sixty participants in the extended-release oxybutynin group and 172 in the tolterodine group had urinary diary data at baseline and at 12 weeks and were included in the efficacy analyses. All participants who received study drugs were included in the safety analyses. Efficacy At 12 weeks (end of study), extended-release oxybutynin was significantly more effective than tolterodine in the primary outcome measure, which was the mean number of weekly urge incontinence episodes (P=.03). Extendedrelease oxybutynin was also significantly more effective than tolterodine in end-of-study total incontinence episodes (P=.02) and micturition frequency episodes (P=.02) (Table 4). Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Overall, 96.2% and 95.3% of the participants using extended-release oxybutynin and tolterodine, respectively, had fewer incontinence episodes at the end of the study compared with number of episodes at baseline. Although the overall discontinuation rate was relatively low (12%), analyses restricted to those participants completing 12 weeks of therapy could potentially contain bias. Consequently, additional analyses on all participants with at least 1 efficacy measurement were conducted using a longitudinal repeated measures approach. The results were consistent with those of the main analyses, with extended-release oxybutynin significantly more effective than tolterodine in number of episodes of urge incontinence (P=.04), total incontinence (P=.03), and micturition frequency (P=.02). Safety The incidence of dry mouth was similar in the extendedrelease oxybutynin group (28.1%) and the tolterodine group (33.2%) (P=.32) (Table 5). Moderate to severe dry mouth was reported by comparable numbers of participants receiving extended-release oxybutynin and tolterodine (10.2% vs 10.9%, respectively [P=.87]). All adverse events, including events related to the CNS, such as asthenia, blurred vision, dizziness, insomnia, nervousness, and somnolence, occurred at low rates and with similar frequency between the 2 treatment groups and across all age groups. Constipation was reported by 7.0% or less of all participants. Overall, the discontinuation rates for adverse events were 7.6% in the extended-release oxybutynin group and 7.8% in the tolterodine group (P=.99).
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Table 2. Baseline Urinary Symptoms*
Symptom Urge incontinence episodes/wk Total incontinence episodes/wk Micturition frequency episodes/wk
Extended-release oxybutynin Tolterodine (n=185) (n=193)
P value†
25.5±14.6
24.6±15.1
.36
28.4±17.8
28.0±18.3
.62
92.9±23.0
91.8±20.0
.77
*Values are mean ± SD for all patients enrolled at baseline. †Wilcoxon rank sum test.
DISCUSSION The OBJECT trial reports the first use of extended-release oxybutynin in a fixed-dose regimen, and the study design compared 2 antimuscarinic agents used in the treatment of overactive bladder. A placebo arm was not included, as both products were approved by the Food and Drug Administration on the basis of placebo-controlled trials. The double-blind, randomized design of this study limits the potential for treatment selection bias. The tolerability profile of both drugs in the present study was excellent, with rates of discontinuation and adverse events that were similar between groups. Tolerability results for tolterodine in this trial included a 7.8% discontinuation rate for adverse events and a 33.2% incidence of dry mouth and are similar to those reported in a previous trial of tolterodine.15 In the extended-release oxybutynin group, the 7.6% discontinuation rate seen in this trial was also comparable to rates in past studies,11-13 but the incidence of dry mouth (28.1%) was lower than previously reported. The lower rate of dry mouth is not surprising given the higher average doses studied in past trials.11-13 In the OBJECT trial, low rates of CNS adverse events were seen in participants across all age groups in both treatment groups. Adverse events that led to withdrawal from the study and are typically related to anticholinergic therapy Table 3. Reasons for Discontinuation* Reason for discontinuation Adverse event/ intercurrent illness Protocol violation Personal reason Lack of efficacy Lost to follow-up Withdrawal of consent
Extended-release oxybutynin Tolterodine (n=185) (n=193) 14 (7.6) 0 (0) 3 (1.6) 3 (1.6) 3 (1.6) 2 (1.1)
15 (7.8) 2 (1.0) 1 (0.5) 1 (0.5) 3 (1.6) 0 (0)
P value† >.99 .50 .36 .36 >.99 .24
*Values are number (percentage) for all subjects enrolled at baseline. †Fisher exact test.
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Treatment of Overactive Bladder
Table 4. Efficacy Parameters*
Parameter Urge incontinence episodes/wk Baseline End of study (95% CI) Total incontinence episodes/wk Baseline End of study (95% CI) Micturition frequency episodes/wk Baseline End of study (95% CI)
Extended-release oxybutynin (n=160)
Tolterodine (n=172)
Table 5. Adverse Events* P value
25.6±14.7 6.1±9.7 (4.4-7.3)
24.1±14.5 7.8±11.1 (6.7-9.5)
.24† .03‡
28.6±17.9 7.1±12.0 (5.2-8.6)
27.0±17.0 9.3±13.4 (8.0-11.3)
.34† .02‡
91.8±22.6 67.1±22.1 (64.6-70.0)
91.6±20.2 71.5±20.5 (69.1-74.2)
362
.86† .02‡
*Actual end-of-study (12 week) mean (±SD) values are reported based on the number of subjects who completed the study. Baseline mean ± SD values include only those patients who completed the study. CI = confidence interval. †Wilcoxon rank sum test. ‡Testing and CI construction were done on the values adjusted for baseline and stratum in an analysis of covariance model.
were dry mouth (3 patients on tolterodine), dizziness (2 patients on tolterodine, 1 patient on extended-release oxybutynin), and urinary retention (1 patient on each drug). Based on the results of other trials, both extended-release oxybutynin11-13 and tolterodine14,18 are better tolerated than immediate-release oxybutynin chloride and represent an advance in the treatment of overactive bladder. In animal studies, tolterodine has shown selectivity for the urinary bladder compared with the salivary glands.19 While the importance of these results in humans is unknown, they may be linked to the drug’s clinical tolerability profile.20 Extended-release oxybutynin is formulated with use of a delivery system that minimizes drug peaks and troughs21,22 and may reduce exposure to oxybutynin chloride’s active metabolite. The metabolite levels are thought to influence the severity of dry mouth more than does the parent drug concentration.22,23 When compared with efficacy results in earlier trials,14,15,24 the outcome of tolterodine use in this trial showed greater improvement in urge and total incontinence episodes than in other tolterodine trials,14,15,24 although micturition frequency episodes were similar to those in the previous trials.14,15,24 With extended-release oxybutynin, the urge and total incontinence efficacy in this study was similar to that in past studies,11-13 and micturition frequency efficacy was better than that seen in the earlier trials.11-13
Events Anticholinergic Dry mouth Total Moderate to severe Constipation Impaired urination/ urinary retention Blurred vision Central nervous system Dizziness Somnolence Asthenia Insomnia Nervousness Other Headache Dyspepsia Nausea Vomiting
Extended-release oxybutynin Tolterodine P (n=185) (n=193) value†
52 (28.1)
64 (33.2)
.32
19 (10.2) 13 (7.0)
21 (10.9) 12 (6.2)
.87 .84
6 (3.2) 4 (2.2)
6 (3.1) 2 (1.0)
>.99 .44
9 (4.9) 8 (4.3) 3 (1.6) 1 (0.5) 0 (0)
8 (4.1) 3 (1.6) 7 (3.6) 3 (1.6) 2 (1.0)
.81 .13 .34 .62 .50
15 (8.1) 11 (5.9) 6 (3.2) 3 (1.6)
17 (8.8) 10 (5.2) 3 (1.6) 3 (1.6)
.86 .82 .33 >.99
*Values are number (percentage) for all subjects enrolled at baseline. †Fisher exact test.
The study design used had several limitations. While 12 weeks is a standard length for clinical trials of these types of antimuscarinic medications, the results may not reflect those seen in long-term treatment of a chronic condition such as overactive bladder. In addition, the racial distribution in this trial is not representative of the US population as a whole, and specialists, rather than primary care physicians, enrolled participants in this trial. Evaluation of efficacy with the primary outcome measure—urge incontinence episodes at 12 weeks—indicates extended-release oxybutynin was statistically significantly more effective than tolterodine, also yielding fewer episodes of total incontinence and micturition frequency. Participants taking tolterodine averaged 28% more urge incontinence episodes than those taking extended-release oxybutynin, the relative difference (7.8 vs 6.1 episodes, respectively) between the number of urge incontinence episodes at study week 12. Financial Disclosure.—Dr Appell is an adviser, investigator, and speaker for ALZA Corporation and a speaker and investigator for Pharmacia Corporation. Dr Sand is an adviser, investigator, and speaker for ALZA Corporation and an investigator for Pharmacia Corporation. Dr Dmochowski is an adviser, investigator, and speaker for ALZA Corporation and an investigator for Pharmacia Corporation. Dr Anderson is an adviser, investigator, speaker, and stockholder for ALZA Corporation and an investiga-
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Mayo Clin Proc, April 2001, Vol 76
tor and speaker for Pharmacia Corporation. Dr Zinner is an adviser, investigator, and speaker for ALZA Corporation and an investigator for Pharmacia Corporation. Dr Lama is an investigator for ALZA Corporation and Pharmacia Corporation. Dr Roach is an adviser, investigator, and speaker for ALZA Corporation and an adviser and investigator for Pharmacia Corporation. Dr Miklos is an adviser, investigator, and speaker for ALZA Corporation. Dr Saltzstein is an investigator for ALZA Corporation. Dr Boone is an adviser, investigator, and speaker for ALZA Corporation and a speaker for Pharmacia Corporation. Dr Staskin is an adviser, investigator, speaker, and stockholder for ALZA Corporation and an adviser and speaker for Pharmacia Corporation. Dr Albrecht is an employee and stockholder of ALZA Corporation. OBJECT Study Group.—Members of the OBJECT Study Group (*protocol design responsibility): Rodney Anderson,* Stanford University, Stanford, Calif; Joseph Antoci,* Connecticut Clinical Research Center, Waterbury, Conn; Rodney A. Appell,* Cleveland Clinic Foundation, Cleveland, Ohio; Yitzhak Berger, Associates in Urology, West Orange, NJ; Jay R. Bishop, Jr, Urologic Associates of Southwestern New Mexico, Silver City; Timothy Boone,* Baylor College of Medicine, Houston, Tex; Rodney Brown, Gulf Port Urology Clinic, Gulf Port, Miss; Stacy Childs, Wyoming Research Foundation, Cheyenne; Anurag A. Das, Albany Medical Center, Albany, NY; Rodney Dennis, Urology Center of Alabama, Birmingham; Roger Dmochowski,* Urology Associates of North Texas, Arlington; Eugene Dula, West Coast Clinical Research, Van Nuys, Calif; Alan D. Garely, North Shore University Hospital-LIJ, Great Neck, NY; Marc Gittelman, South Florida Medical Research, Adventura; James E. Gottesman, Seattle Urological Associates, Seattle, Wash; Chester F. Graham, Urology Specialists & Associates, Dallas, Tex; Paul G. Hagood, Ponca City, Okla; Richard Harris, RMD Clinical Institute, LLC, Melrose Park, Ill; Mickey Karram, Seton Center, Cincinnati, Ohio; Daniel J. Lama, San Bernardino Urologic Associates, San Bernardino, Calif; James G. McMurray, Medical Affiliated Research Center, Huntsville, Ala; John Miklos, Urogynecology, PC, Alpharetta, Ga; David R. Munoz, Internal Medicine Northwest, Tacoma, Wash; Ajay Nehra,* Mayo Clinic, Rochester, Minn; Kenneth M. Peters, William Beaumont Hospital, Royal Oak, Mich; Henry Ritter, Peninsula Urology Medical Center, Atherton, Calif; Martha Roach,* Atlanta, Ga; Daniel Saltzstein, Urology Antonio Research, San Antonio, Tex; Peter Sand,* Evanston Continence Center, Evanston, Ill; Paul Sieber, Urology Associates of Lancaster, Lancaster, Pa; Jeffery Snyder, Genitourinary Surgical Consultants, PC, Denver, Colo; David Spellberg, Center for Clinical Research, Naples, Fla; John Tuttle, Network Trials, Inc, Lexington, Ky; David R. Staskin,* Beth-Israel Deaconess Medical Center, Boston, Mass; Mark A. Wainstein, Genito-Urinary Surgeons, Inc, Toledo, Ohio; Charles White, Coast Clinical Research, Mobile, Ala; and Norm Zinner, Western Clinical Research, Inc, Torrance, Calif. Acknowledgment.—The authors wish to acknowledge Denise Desmond, BS, for clinical trial data collection, Martin O’Connell, PhD, for statistical support, and Jennifer Wright, BS, for assistance with medical writing.
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2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12. 13. 14.
15.
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