Clinical trial NCT01741454
Conditions: Ureteral Obstruction
Keywords: Tolterodine Tamsulosin Ureteral Obstruction
Sponsor: University of Wisconsin, Madison
Start date: 2012-11-01; Completion date: 2018-03-30
Enrollment: 181 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether combination therapy with Tolterodine ER and Tamsulosin is more effective than monotherapy with tamsulosin alone in reducing stent symptoms. The second purpose is to determine if people have less stent discomfort if they take these medications starting 2 weeks before the stent is placed

The investigators hope to show that the addition of Tolterodine ER to Tamsulosin will provide added benefits in reducing stent symptoms in patients who have had unilateral placement of a ureteral stent.

Detailed description:
The investigators aim to show that the addition of Tolterodine ER to Tamsulosin will provide added benefits in ameliorating stent-related symptoms in participants who have had unilateral placement of a ureteral stent for urolithiasis. This objective will be assessed by determining the mean difference in the urinary symptom index domain of the Urinary Stent Symptom Questionnaire, which is a validated tool used to assess stent symptoms. The investigators suggest that a 15% further decrease in the index score in the experimental group, compared to the control group would represent a clinically significant improvement in urinary symptoms, based on the prior studies evaluating lower urinary tract symptoms in patients with stents. The investigators hypothesize that combination therapy with Tamsulosin and Tolterodine ER will yield greater symptom relief than tamsulosin alone.

Initially, a 7-day design (medical starts 7 days before stent insertion) was conducted to determine whether combination therapy with Tolterodine ER and Tamsulosin is more effective than monotherapy with tamsulosin alone in reducing stent symptoms.

Previous studies showed that tolterodine ER therapy significantly reduces urinary symptoms by week 4 of medication therapy. Given the evidence that tolterodine ER requires a longer duration to have maximum benefit, in the second phase, investigators increased the duration of medication to start 2 weeks prior to surgery and continued for 7 days after surgery, for a total of 21 days of medication, to test whether combination therapy is more effective than monotherapy in reducing stent symptoms

Arms: arm 1: Tamsulosin is a selective α1a-blocker (FlomaxTM), generic since 2009. It is an antagonist of α1-mediated contraction of prostate, bladder and proximal urethral smooth muscle, and as such, reduces urethral pressure and resistance, bladder outlet resistance, bladder hyperactivity, and consequently lower urinary tract symptoms. arm 2: Tamsulosin is a selective α1a-blocker (FlomaxTM), generic since 2009. It is an antagonist of α1-mediated contraction of prostate, bladder and proximal urethral smooth muscle, and as such, reduces urethral pressure and resistance, bladder outlet resistance, bladder hyperactivity, and consequently lower urinary tract symptoms.

Tolterodine ER is an anticholinergic agent, which is used as one of the first line agents for detrusor overactivity. arm 3: Tamsulosin is a selective α1a-blocker (FlomaxTM), generic since 2009. It is an antagonist of α1-mediated contraction of prostate, bladder and proximal urethral smooth muscle, and as such, reduces urethral pressure and resistance, bladder outlet resistance, bladder hyperactivity, and consequently lower urinary tract symptoms. arm 4: Tamsulosin is a selective α1a-blocker (FlomaxTM), generic since 2009. It is an antagonist of α1-mediated contraction of prostate, bladder and proximal urethral smooth muscle, and as such, reduces urethral pressure and resistance, bladder outlet resistance, bladder hyperactivity, and consequently lower urinary tract symptoms.

Tolterodine ER is an anticholinergic agent, which is used as one of the first line agents for detrusor overactivity.
Interventions: intervention 1: Tamsulosin intervention 2: Tolterodine ER
Intervention descriptions: intervention 1: 0.4 mg by mouth once per day. intervention 2: 4 mg by mouth once a day.

Protocol documents:
Prot_SAP_000.pdf: 
1 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
 
 
 
 
COMBINATION VERSUS MONOTHERAPY WITH ALPHA-BLOCKERS AND 
ANTICHOLINERGICS FOR THE RELIEF OF URINARY STENT SYMPTOMS – A 
RANDOMIZED CONTROL TRIAL 
 
 
Principal Investigator: Stephen Nakada, MD 
Co-Investigator: Viacheslav Iremashvili; Shuang Li; Kristina Penniston 
University of Wisconsin-Madison, School of Medicine and Public Health, Department of Urology  


2 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
 
BACKGROUND AND SIGNIFICANCE 
Ureteral stents are used to relieve acute or chronic obstruction of the upper urinary 
tract, or used as a prophylactic measure following instrumentation or surgery involving the 
ureter.   Ureteral stents work by re-establishing or maintaining patency of the ureter in 
conditions of obstruction or injury.  Stents passively dilate the ureter, allowing urine to flow 
both through and around the stent, and are indicated when there is ureteral obstruction with 
or without renal insufficiency, secondary to nephrolithiasis, malignancy, or other pathologic 
processes.  Additionally, they can be used as a prophylactic measure after endoscopic 
procedures involving the ureter, or surgical repair of the ureter such as in ureteral 
anastomoses.   
Unfortunately, despite their use since the late 60’s, stent related symptoms are 
common in patients after stent insertion and continue to be a challenge to manage.  Overall 
quality of life is impaired in 45% - 80% of patients with ureteral stents in place 1.   Stent 
related symptoms occur in up to 80% of patients following stent insertion.  These include: 
storage urinary symptoms such as urinary frequency, urgency, nocturia, dysuria, hematuria, 
stent colic (flank/SP pain), and incomplete emptying or urinary incontinence.   To date, 
various methods have been investigated and employed in an effort to alleviate these 
symptoms, from various stent designs to pharmacotherapy.  With respect to pharmacologic 
management of stent symptoms, various agents have been investigated, including 
intravesical pharmacologic therapy 2, periureteral injection of botox 3, selective alpha-1 
blockers 4,  and anticholinergic agents 5. 


3 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
 There are several studies documenting the evidence supporting the use of alpha-
blockers to reduce stent discomfort, including two recent meta-analyses 4,6.  These analyses 
demonstrated a significant benefit for using either tamsulosin or alfusozin in relieving 
symptoms.  However, only a few studies have assessed the efficacy of anticholinergic agents 
in this context, despite the theoretical and anecdotal benefits of this class of drugs.  The 
available literature on anticholinergic therapy for stent symptom relief do show benefits, e.g. 
in one study, tolterodine ER showed symptom improvement over placebo 7.    Data on 
combination therapy with both agents is even more limited and show mixed results, from no 
advantage to modest benefits in the combination arm 8,9.  There is also evidence that suggests 
tolterodine ER does not achieve maximum benefit upon initiation of the medication. Kaplan 
et al. found no difference in urinary symptoms between placebo and tolterodine ER at 1 
week, however by week 4 of medication therapy tolterodine ER was significantly better than 
placebo at improving urinary symptoms.10  There is no available literature on the effect of 
starting tolterodine ER prior to surgery to give maximum benefit of the medication prior to 
placement of a ureteral stent.  
We plan to design our study in a manner that will address some of the methodological 
weaknesses of the aforementioned studies, and use the most commonly used alpha-blocking 
and anticholinergic agents and dosing: tamsulosin 0.4mg PO OD and tolterodine ER 4mg PO 
OD, respectively.   
OBJECTIVES AND HYPOTHESIS: 


4 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
We aim to show that the addition of Tolterodine ER to Tamsulosin will provide added 
benefits in ameliorating stent related symptoms in patients who have had unilateral 
placement of a ureteral stent for urolithiasis.  This objective will be assessed by determining 
the mean difference in the urinary symptom index domain of the USSQ (the Urinary Stent 
Symptom Questionnaire), which is a validated tool used to assess stent symptoms1.  We felt 
that a 15% further decrease in the index score in the experimental group, compared to the 
control group would represent a clinically significant improvement in urinary symptoms, 
based on the prior studies evaluating lower urinary tract symptoms in patients with stents. 
We hypothesize that combination therapy with Tamsulosin and Tolterodine ER will yield 
greater symptom relief than tamsulosin alone.  In addition, we hypothesize that a longer 
duration of treatment of Tolterodine ER, 2 weeks prior to insertion of the stent, will yield 
greater symptom relief than initiation of Tolterodine ER after stent placement or tamsulosin 
alone.   
RESEARCH DESIGN AND METHODS: 
This is a prospective, double blind, randomized control trial.    
STUDY SITE 
This study was originally planned to take place at UW Health, Meriter Health Sciences, 
Vista Medical Center East and University of Manitoba. Three of the sites were unable to 
recruit patients to the study and have dropped out of the study: Meriter Health Sciences, 
Vista Medical Center East and University of Manitoba. Thus, the study was amended in 2014 
to be a single site study conducted only at the UW Health. 


5 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
The study site will obtain an IRB approval prior to recruiting any patients.   
1. UW hospitals and clinics.  Department of Urology, Madison, WI.  
 Study coordinator – Dr. Sara Best, & Dr. Stephen Nakada 
 
STUDY ACTIVITIES 
Patients who will be undergoing urinary stent insertion during the management of 
renal or ureteral stones, or other conditions requiring endoscopy will be randomized into 
the combination or monotherapy arm, based on a computer generated randomization 
scheme, and will be enrolled into the study arm in a blinded manner.   The study is intended 
to be double-blinded.  The drug kit will linked to the randomization number and both the 
investigator and patient will thus be blinded to the treatment. All patients will be required 
to provide a signed informed consent, which outlines the differences in the two treatment 
arms and study objectives.   Patients will be provided the corresponding pills in pre-filled 
vials, based on their group assignment.  Initially, the study used a 7-day treatment regimen. 
Patients in the monotherapy arm were given a set of Tamsulosin and placebo pills, while the 
combination therapy arm were given a set of Tamsulosin and Tolderodine ER, with sufficient 
quantities for 7 days.  Pill counts were obtained at the end of the follow-up period to ensure 
compliance.  All patients enrolled into the study were asked to complete the USSQ prior to 
stent insertion to serve as a baseline assessment of urinary symptoms, and again at 24 hours, 
5 days after stent insertion and post stent removal. In the 7-day regimen, 80 patients were 
enrolled and completed the study (15 patients enrolled but withdrawn, 95 patients in total). 


6 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
The data analysis shows no benefit from being on combination therapy likely secondary to 
the short duration of therapy.  
In 2014, a change of protocol was approved that extended the study treatment to 21 
days.  Patients will start the study medication 2 weeks prior to their surgery date and 
continue for the 1 week duration of the stent. Patients in the monotherapy arm will be given 
a set of Tamsulosin and placebo pills, while the combination therapy arm will be given a set 
of Tamsulosin and Tolderodine ER, with sufficient quantities for 21 days.    Pill counts will be 
obtained at the end of the follow-up period to ensure compliance.  All patients enrolled into 
the study will complete the USSQ at baseline prior to starting medication to serve as a 
baseline assessment of urinary symptoms, prior to stent insertion, and again at 24 hours, 5 
days after stent insertion and post stent removal. The patients will have the stent removed 
in 7 days, which will conclude the study period.    If the stent needs to be removed sooner, it 
will be arranged as per current protocol.   Early termination is only relevant if the 5 day USSQ 
is not completed.  In the 21-day regimen, 106 patients are planned to be enrolled. Thus, a 
total of 201 patients, to see if there is a difference with the longer duration of medication 
treatment. Subjects have been enrolled on this 21-day regimen since 10/29/2014, and all 
new subjects use this regimen. 
STUDY POPULATION 
The key participants of this study will be male and female adult patients with kidney or 
ureteral stones, or other conditions, requiring unilateral or bilateral ureteral stent 
placement, either before or after a surgical intervention.  Specifically, the post-operative 


7 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
stent patients will include those who have undergone ureteroscopy, percutaneous 
nephrolithomy or extracorporeal shock-wave lithotripsy. 
INCLUSION CRITERIA 
Patients with unilateral or bilateral ureteral stent placement for urolithiasis are 
candidates for enrollment.  These include: patients who have undergone ureteroscopy for 
renal or ureteral calculi, percutaneous nephrolithotomy (PCNL), shock-wave lithoripsy 
(SWL), or other conditions requiring stent placement post operatively, or for relief of pain 
or obstruction.  
EXCLUSION CRITERIA 
Candidates will be excluded from the study if ANY of the following apply: 
1. Pre-existing LUTS 
2. Active UTI 
3. Contraindication to anticholinergic medication 
a. Prior hypersensitivity or allergy to tolterodine 
b. Patients with severe hepatic impairment (Child-Pugh Class C) 
c. Patients with uncontrolled close (narrow) angle glaucoma 
d. Patients with urinary retention 
4. Current  anticholinergic use 
5. Chronic pelvic pain syndromes (e.g. acute/chronic prostatitis, interstitial cystitis) 
6. Females who are pregnant or nursing 
7. Under 18 years of age  
8. Any patients unable to provide informed consent 


8 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
 
PATIENT SCREENING AND RECRUITMENT 
Potential subjects will be identified by the surgeon or study coordinator either at the time 
ureteroscopy, PCNL or stent placement is scheduled.  These subjects will be screened for 
inclusion/exclusion criteria by reviewing their medical record. A waiver of patient screening 
is requested in the current application. If inclusion/exclusion criteria are met, the surgeon 
will ask the patient if he or she is interested in talking with a study team member for a study 
that he or she is eligible. One the patients’ permission is obtained, a member of the research 
team will approach the patient for enrollment. Subjects will be recruited by verbal 
communication by the principal or co-investigators, or by a research coordinator.  The 
patient must consent to participate as evidenced by the signed, study-specific, IRB-approved 
informed consent form before any study specific data may be collected and recorded.   
 
We have requested a waiver of patient screening. We believe that the screening 
process will not pose more than minimal risks to subjects or adversely affect the rights and 
welfare of the subjects. The screening process only consists of reviews pre-existing data. No 
patient care or outcomes are affected as a result of screening. The surgeon or study 
coordinator will only review the medical record that is relevant for inclusion/exclusion 
criteria. No data will be collected in this phase. The exclusion criteria for the current study 
include pre-exsiting LUTS, active UTI,  contraindication to anticholinergic medication, 
current anticholinergic use,  chronic pelvic pain syndromes, pregnant females, and under 18 
years of age. In the Urology clinic, a significant amount of patients who undergo stone 


9 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
surgeries may have LUTS, active UTI, or currently taking anticholinergic medication. Consent 
without pre-screening will create a significant dropout rate. Thus, the study could not 
practicably be carried out without the waiver of screening. 
Once appropriate informed consent has been obtained, a complete medical history 
including a detailed urologic history will be completed. The subject will be randomized to 
one of the two arms (tamsulosin + placebo versus tamsulosin + tolterodine) using a 
computerized randomization scheme.   
 
STUDY DRUG/INTERVENTION 
The study drugs of interest are Tamsulosin and Tolterodine ER, both of which are 
routinely used in urology.  The UW pharmacy will supply the study drugs and placebo.   Each 
of the study drugs and placebo will be provided in standard drug vials.  Under the original, 
7-day study treatment regimen, each vial contained 7 pills each.  In 2014, the study was 
amended to add a 21-day treatment regimen.  This replacement study will use only the 21-
day treatment regimen, and the drug vials will contain 21 pills each. The placebo capsule will 
be similar in color and appearance to the Tolterodine capsule, and will be provided by the 
UW pharmacy.  Patients may continue to use any prior medications concurrently with either 
of the study drugs, and no washout period is necessary. 
TAMSULOSIN  


10 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
Tamsulosin is a selective α1a-blocker (FlomaxTM), generic since 2009. It is an 
antagonist of α1-mediated contraction of prostate, bladder and proximal urethral smooth 
muscle, and as such, reduces urethral pressure and resistance, bladder outlet resistance, 
bladder hyperactivity, and consequently LUTS.  Its adverse effects include headache, 
dizziness, asthenia, nasal congestion, retrograde ejaculation, and a rare reversible condition 
known as floppy iris syndrome, which is only relevant if patients are undergoing cataract 
surgery. 
TOLTERODINE ER 
 
Toleterodine ER is an anticholinergic (antimuscurinic) agent, which is used as one of 
the first line agents for detrusor overactivity.  It is given as once-daily dosing for overactive 
bladder symptoms, and even used in BPH patients exhibiting bladder symptoms.  Its side-
effects include xerostomia, xeropthalmia, gastroparesis, constipation, drowsiness, acute 
urinary retention, but unlike other drugs of this class, e.g. oxybutynin, tolterodine ER causes 
little to no cognitive impairment due to its larger molecular weight which precludes crossing 
of the BBB. 
SAFETY AND MONITORING 
Regular inquiries of study flow, pertaining to patient recruitment, randomization, 
patient compliance (with medication and completing questionnaires) and adverse events 
will be scheduled to occur after the first week and subsequently every two weeks during the 
active patient enlistment phase.  Any adverse events/side effects will be monitored as per 


11 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
standard protocol in clinical use.  Patients will be instructed to report any untoward 
reactions to the study drugs to the urology clinic or on-call urology staff.   
No significant adverse events are anticipated with either of the study drugs, as they 
are routinely used in everyday urology practice.  The patient will report side effects if and 
when they occur; the drug will be stopped if continuation is deemed inappropriate.  Any 
adverse events or unanticipated problems will be recorded and the offending drug will be 
stopped, and the patient counseled accordingly.  If a patient has side effects that precludes 
their ongoing participation in the study, they will be withdrawn and considered a study 
drop-out.   All measures will be in effect to prevent breaches of confidentiality and/or 
emotional upset. 
Patients are instructed to contact their treating surgeon if they have symptoms that 
may require placing the stent or having surgery sooner than expected.  The surgeons who 
perform these procedures are also members of the study team, and will ensure that all 
patients’ clinical care will not be influenced due to study participation. We confirm that study 
participation will not delay needed clinical care in the event that an enrolled subject requires 
stent placement sooner than anticipated. We will only include patients whose stent 
placement will not be delayed as a result of study participation.  If the patient has the stent 
placed in the interim or has discontinued medications, he or she will be excluded from the 
study. 
 
 


12 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
STATISTICAL ANALYSIS & POWER CALCULATIONS: 
In 2014, a change of protocol was approved that extended the study treatment to 21 
days. Our sample size calculation in the 21-day regimen was based on the recommended 
sample size calculations by the original developers of the USSQ 1.  The authors’ calculations 
were based on the results of their validation studies that compared mean domain score and 
standard deviation differences between stented and control patients, using a 2-tailed test 
(p<0.05).  The percentage change (15%) translates to an absolute change in score by 4 
points.  Additionally, we extrapolated data from a recent meta-analysis evaluating the 
efficacy of tamsulosin to relieve stent related symptoms, which showed a mean standard 
deviation of 6.5 points between the tamsulosin and placebo arm 4 to confirm the previous 
authors’ sample size.  With an expected decrease of 4 points with the combination therapy, 
and an assumption of similar standard deviation (6.5),  a two-tailed t-test (p=0.05) and 
power of 0.80, our calculation yielded 43 patients per arm.  Given the relatively similar 
numbers from the two calculations, we opted to use the more conservative sample size of 53 
patients per arm as the data collection endpoint.   
We are assessing for both an absolute and relative change in the USSQ scores. 
1. We will be assessing for a relative change of 4 actual points (which translates to a 15% 
change, as per Joshi et al’s validation study) within each group from immediately post stent 
insertion at 24 hours compared to day 5.  
2. We will also assess for a change in scores between groups, i.e. comparing the mean intra-
group score change as described in 1 (i.e., immediately post stent insertion at 24 hours 
compared to day 5).   


13 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
 
The questionnaire responses will be analyzed using cross tabulations and descriptive statistics to assess 
differences between groups. Paired t-tests will be used to assess within-group change in scores from the 
USSQ (comparison between post-op, i.e. at 48 hours, and day 5) and other discriminant properties.   T-
tests will be used to assess inter-group score changes. 
The intent-to-treat principle will be employed in the event subjects have to withdraw from their 
assigned group, although this is not expected given that both treatment medications are used 
extensively in urology, and both treatment regimens are occasionally employed based on anecdotal 
physician experience.   
 
 
DATA SECURITY: 
All information obtained from the medical record and questionnaires will be kept secure and 
only accessible by the defined study personnel.  Data collected will be stored into a 
Microsoft® Excel database by the research coordinator at the UW Hospitals site.  All 
information will be de-identified and coded prior to database entry.  The key for the code 
will be stored on a different computer for safety. 
 


14 
University of Wisconsin-Madison  
Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
REFERENCES 
1. 
Joshi HB, Newns N, Stainthorpe A, MacDonagh RP, Keeley FX, Timoney AG. Ureteral 
stent symptom questionnaire: development and validation of a multidimensional 
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2. 
Beiko DT, Watterson JD, Knudsen BE, et al. Double-blind randomized controlled trial 
assessing the safety and efficacy of intravesical agents for ureteral stent symptoms 
after extracorporeal shockwave lithotripsy. J Endourol. Oct 2004;18(8):723-730. 
3. 
Gupta M, Patel T, Xavier K, et al. Prospective randomized evaluation of periureteral 
botulinum toxin type A injection for ureteral stent pain reduction. J Urol. Feb 
2010;183(2):598-602. 
4. 
Yakoubi R, Lemdani M, Monga M, Villers A, Koenig P. Is there a role for α-blockers in 
ureteral stent related symptoms? A systematic review and meta-analysis. J Urol. Sep 
2011;186(3):928-934. 
5. 
Norris RD, Sur RL, Springhart WP, et al. A prospective, randomized, double-blinded 
placebo-controlled 
comparison 
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extended 
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oxybutynin 
versus 
phenazopyridine for the management of postoperative ureteral stent discomfort. 
Urology. May 2008;71(5):792-795. 
6. 
Lamb AD, Vowler SL, Johnston R, Dunn N, Wiseman OJ. Meta-analysis showing the 
beneficial effect of α-blockers on ureteric stent discomfort. BJU Int. Dec 
2011;108(11):1894-1902. 


15 
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Study #: 2017-0755  
IRB Approval Date: 7/17/2017 
7. 
Park SC, Jung SW, Lee JW, Rim JS. The effects of tolterodine extended release and 
alfuzosin for the treatment of double-j stent-related symptoms. J Endourol. Nov 
2009;23(11):1913-1917. 
8. 
Lee SJ, Yoo C, Oh CY, et al. Stent Position Is More Important than α-Blockers or 
Anticholinergics 
for Stent-Related Lower Urinary Tract 
Symptoms after 
Ureteroscopic Ureterolithotomy: A Prospective Randomized Study. Korean J Urol. Sep 
2010;51(9):636-641. 
9. 
Lim KT, Kim YT, Lee TY, Park SY. Effects of tamsulosin, solifenacin, and combination 
therapy for the treatment of ureteral stent related discomforts. Korean J Urol. Jul 
2011;52(7):485-488. 
10. 
Kaplan SA, Schneider T, Foote JE, et al. Superior efficacy of fesoterodine over 
tolterodine extended release with rapid onset: a prospective, head-to-head, placebo-
controlled trial, BJUI 107: 1432-1440.