Clinical trial NCT02518971
Conditions: Postoperative Urinary Retention
Sponsor: University of Michigan
Start date: 2015-08-01; Completion date: 2018-12-19
Enrollment: 176 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study aims to evaluate the efficacy of prophylactic tamsulosin in reducing the incidence of postoperative urinary retention in primary total knee and hip arthroplasty patients.

Detailed description:
Prophylactic administration of tamsulosin will be compared to a placebo to evaluate the effectiveness in reducing the incidence of postoperative urinary retention in total hip and knee arthroplasty patients.

Arms: arm 1: 0.4 mg daily for five days pre-op through post-op day one (seven total) arm 2: One capsule daily for five days pre-op through post-op day one (seven total)
Interventions: intervention 1: Tamsulosin intervention 2: Placebo
Intervention descriptions: intervention 1: 0.4 mg daily intervention 2: one capsule daily

Protocol documents:
Prot_SAP_000.pdf: 
HUM00087825 
________________________________________________________________________ 
 
PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF 
PROPHYLACTIC TAMSULOSIN FOR POSTOPERATIVE URINARY RETENTION IN PRIMARY TOTAL 
HIP AND KNEE ARTHROPLASTY PATIENTS 
 
 
NCT02518971 
IRB approved: 11/08/18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


HUM00087825 
________________________________________________________________________ 
 
PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF 
PROPHYLACTIC TAMSULOSIN FOR POSTOPERATIVE URINARY RETENTION IN PRIMARY TOTAL 
HIP AND KNEE ARTHROPLASTY PATIENTS 
 
 
Principal Investigator:  
Andrew Urquhart, MD 
University of Michigan, Department of Orthopaedic Surgery 
 
 
 
 
1500 E Medical Center Drive, Taubman Center SPC 5328 
 
 
 
 
734-936-5780  
 
 
 
 
andrewu@med.umich.edu 
 
 
Co-Investigator(s): 
 
Jared Thomas, MD 
 
 
 
 
University of Michigan, Department of Orthopaedic Surgery 
 
 
 
 
tjared@med.umich.edu 
 
 
 
 
 
Bahaa S. Malaeb, MD 
 
 
 
 
University of Michigan, Department of Urology 
 
 
 
 
bmalaeb@med.umich.edu 
 
 
 
 
 
 
 
 
 
 
 
Brian Hallstrom, MD 
University of Michigan, Department of Orthopaedic Surgery 
 
 
 
 
hallstro@med.umich.edu 
 
J. David Blaha, MD 
University of Michigan, Department of Orthopaedic Surgery 
 
 
 
 
jdblaha@med.umich.edu 
 
 
 
 
 
Joseph S. Maratt, MD 
University of Michigan, Department of Orthopaedic Surgery 
 
 
 
 
jmaratt@med.umich.edu 
 
Aidin Eslam-Pour, MD 
 
 
 
 
University of Michigan, Department of Orthopaedic Surgery 
aeslampo@med.umich.edu 
 
 
 
 
 
Manuel Schubert,  MD 
University of Michigan, Department of Orthopaedic Surgery 
 
 
 
Biostatistician: 
 
Joel Gagnier ND, MSc, PhD 
University of Michigan, Department of Orthopaedic Surgery, Department 
of Epidemiology 
24 Frank Lloyd Wright Drive 
Ann Arbor, MI 48106-0391 
 
Study Drug/Study Device: 
Tamsulosin 
 
Funding Source:  
Approved RAC grant ($15,000)  
 
Approved OREF Grant ($5,000) 
 
 
Clinical Trial Number: 


HUM00087825 
________________________________________________________________________ 
 
 
NCT02518971 
 
 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ...........................................................................................1 
STUDY SCHEMA .............................................................................................................2 
STUDY SUMMARY ..........................................................................................................2 
BACKGROUND AND RATIONALE .............................................................................3 
Disease Background .................................................................................................................... 3 
Study Agent(s)/Devices Background and Associated Known Toxicities ...................................... 3 
Rationale ...................................................................................................................................... 3 
STUDY OBJECTIVES ......................................................................................................4 
Primary Objectives ....................................................................................................................... 4 
Secondary Objectives .................................................................................................................. 4 
Endpoints/Measurements ............................................................................................................. 4 
PATIENT ELIGIBILITY .................................................................................................5 
Inclusion Criteria ........................................................................................................................... 5 
Exclusion Criteria .......................................................................................................................... 5 
TREATMENT PLAN ........................................................................................................6 
Treatment Dosage and Administration ......................................................................................... 6 
Toxicities and Dosing Delays/Dose Modifications ........................................................................ 6 
Concomitant Medications/Treatments .......................................................................................... 6 
Duration of Therapy ...................................................................................................................... 7 
Duration of Follow Up ................................................................................................................... 7 
Removal of Patients from Protocol Therapy................................................................................. 7 


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Patient Replacement .................................................................................................................... 7 
PROCEDURES ..................................................................................................................7 
Screening/Baseline Procedures ................................................................................................... 7 
Procedures During Treatment ...................................................................................................... 8 
Follow-up Procedures................................................................................................................... 8 
Time and Events Table................................................................................................................. 9 
Removal of Subjects from Study ................................................................................................ 10 
RESPONSE CRITERIA…………..……………………………...…………………….10 
Safety/Tolerability ....................................................................................................................... 10 
ADVERSE EVENTS…………..……………………………………………………….10 
Experimental Therapy ................................................................................................................ 10 
Adverse Event Monitoring .......................................................................................................... 12 
Definitions ................................................................................................................................... 13 
Steps to Determine If an Adverse Event Requires Expedited Reporting ................................... 14 
Reporting Requirements for Adverse Events ............................................................................. 14 
Unblinding Procedures ............................................................................................................... 15 
Stopping Rules  .......................................................................................................................... 14 
DRUG/DEVICE INFORMATION ................................................................................15 
Tamsulosin  ................................................................................................................................ 15 
CORRELATIVES/SPECIAL STUDIES .......................................................................16 
STATISTICAL CONSIDERATIONS ...........................................................................16 
Study Design/Study Endpoints ................................................................................................... 16 
Sample Size and Accrual ........................................................................................................... 16 
Data Analyses Plans .................................................................................................................. 16 
STUDY MANAGEMENT ...............................................................................................16 
Conflict of Interest ....................................................................................................................... 16 


HUM00087825 
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Institutional Review Board (IRB) Approval and Consent  ........................................................... 16 
Registration Procedures ............................................................................................................. 17 
Data Management and Monitoring/Auditing ............................................................................... 17 
Adherence to the Protocol .......................................................................................................... 17 
Amendments to the Protocol ...................................................................................................... 18 
Record Retention ........................................................................................................................ 18 
Obligations of Investigators ........................................................................................................ 18 
REFERENCES .................................................................................................................18 
APPENDICES ..................................................................................................................19 
    AUA Symptom Index…………………………………………………………………………………..20 
    Toxicity Assessment Survey………………………………………………………………………….21 
Patient Pain Medication Prescription Log……………………………….……………………………….22 
PI Oversight Meeting Log………………………………………………………………………………….23 


HUM00087825 
 
1 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
AUA 
American Urological Association 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
H&P 
History & Physical Exam 
ISC 
Intermittent straight catheterization 
MTD 
Maximum Tolerated Dose 
ORR 
Overall Response Rate 
p.o. 
per os/by mouth/orally 
POUR 
Postoperative urinary retention 
PVR 
Estimated post-void residual 
SAE 
Serious Adverse Event 
WBC 
White Blood Cells 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY SCHEMA 
 
STUDY SUMMARY 
Title 
Prospective, randomized, double-blind, placebo-controlled trial of 
prophylactic tamsulosin for postoperative urinary retention in primary total 
hip and knee arthroplasty patients 
Short Title 
Prophylactic tamsulosin for postoperative urinary retention in hip and 
knee arthroplasty 
Phase 
Phase 3 
Methodology 
Prospective, randomized, double-blind, placebo-controlled 
Study Duration 
1.5 - 3 years until a prior calculated sample size reached (see above) 
Study Center(s) 
Single-center 
Objectives 
Determine if prophylactic tamsulosin given beginning five days prior to 
surgery through post-op day one reduces the incidence of postoperative 
urinary retention in total hip and knee arthroplasty patients 
Number of Subjects 
456 screened with a 50% accrual rate (182 total subjects needed with 
20% dropout for a total of 228 patients enrolled) 


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Control Group 
91 patients undergoing primary total hip or knee arthroplasty who are on 
an α1-adrenoceptor blocker at the time of surgery 
Diagnosis and Main 
Inclusion Criteria 
Postoperative urinary retention in primary total knee and hip arthroplasty 
patients 
Study Product(s), Dose, 
Route, Regimen 
Tamsulosin 0.4 mg p.o. daily 
Duration of administration 
Five days prior to operation until post-op day one (seven days total) 
Reference therapy 
Placebo 
Statistical Methodology 
Two-tailed t-test for primary outcome, (80% power, α = 0.05) 
 
1. 
BACKGROUND AND RATIONALE 
1.1       Disease Background 
Postoperative urinary retention (POUR) following total hip and knee arthroplasty is a 
common complication with a reported mean incidence of 24-32% and a range of 0-75% 
(1). POUR is usually treated with intermittent or indwelling urinary catheterization which 
have been associated with postoperative urinary tract infections, can add to the cost of 
postoperative care, and make the postoperative experience uncomfortable. Tamsulosin 
has been used off-label to treat POUR and has been shown to reduce POUR following 
radical prostatectomy (2, 3), prostate brachytherapy (4), and inguinal herniorrhaphy (5). 
Tamsulosin is a selective alpha-1 adrenergic receptor blocker that works by relaxing the 
smooth muscles within the bladder neck and prostate. In addition, there is a clinical trial 
being performed at the Mayo Clinic investigating the prophylactic use of tamsulosin for 
POUR incidence reduction following spine surgery (clinicaltrials.gov). 
1.2       Study Agent(s)/Devices Background and Associated Known Toxicities 
Tamsulosin has been shown to reduce POUR following radical prostatectomy (2, 3), 
prostate brachytherapy (4), and inguinal herniorrhaphy (5) and can increase ureteral 
calculi expulsion rate and speed (6, 7).  
 
The safety of tamsulosin is well known given its selectivity for the genitourinary tract, 
versus blood vessels (8). Reported adverse reactions include drug allergy (contains 
sulfa) and floppy iris syndrome (9). Common side effects include orthostatic hypotension, 
dizziness, fainting, vertigo, headache, nasal congestion and palpitations. 
1.3       Rationale 
This study aims to evaluate the efficacy of prophylactic tamsulosin in reducing the 
incidence of POUR in primary total knee and hip arthroplasty patients. By reducing the 
incidence of POUR, it may be possible to reduce catheter-associated urinary tract 
infections, postoperative discomfort, and thus patient satisfaction, as well as the cost of 
care for arthroplasty patients.  
 
 


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2. 
STUDY OBJECTIVES 
2.1         Primary Objectives 
 
2.1.1 
To compare prophylactic administration of tamsulosin to that of placebo in 
reducing the incidence of POUR in total hip and knee arthroplasty patients. 
POUR will be defined as any of the following: 1) Estimated post-void residual 
(PVR) volume of urine greater than or equal to 200 mL; 2) Estimated retention 
urine volume of greater than or equal to 200 mL in patients unable to void for 6 
hours; 3) Patients experiencing discomfort or distension and unable to void with 
residual urine volume less than 200 ml. 
 
All patients will fill out the American Urological Association (AUA) Symptom Index 
(form is attached), preoperatively, and at two-weeks, postoperatively. The scores 
will be used to compare the results of tamsulosin administration between the two 
groups by assessing if postoperative scores have returned to preoperative 
(baseline) scores. Patients will also be asked to document their usage of opioid 
pain medications, using a medication log, from their time of discharge until their 
two week follow up appointment.  
2.2        Secondary Objectives  
 
2.2.1 
To determine if prophylactic administration of tamsulosin reduces hospital stay or 
likelihood of discharge to a skilled nursing facility  
 
2.2.2 
To determine if prophylactic administration of tamsulosin reduces surgical site 
infection over two weeks, postoperatively 
 
2.2.3 
To determine if prophylactic administration of tamsulosin reduces acute 
postoperative pain medication requirements 
 
2.2.4 
To determine if prophylactic administration of tamsulosin reduces postoperative 
complications (deep venous thrombosis, pulmonary embolism, cardiovascular 
event, pneumonia, fevers, urinary tract infection) 
2.3       Endpoints/Measurements 
Primary endpoint of the study is the development of POUR. POUR is defined as any of 
the following: 1) any estimated post-void residual (PVR) volume of urine greater than or 
equal to 200 mL per bladder scan; 2) estimated urine volume retention of greater than or 
equal to 200 mL in patients unable to void within six hours after indwelling urinary 
catheter removal; 3) patients experiencing bladder discomfort or distention and unable to 
void with residual urine volume less than 200 mL; 4) requirement of intermittent straight 
catheterization (ISC) during hospitalization; 5) administration of tamsulosin outside of the 
study medication during the postoperative hospitalization. The development of POUR will 
be determined based on recorded values in the electronic medical record of bladder 
scans, the need for ISC, initiation of tamsulosin in the medication administration record, 
and mention of urinary retention in daily progress notes or in the discharge summary. If a 
patient is asymptomatic with regards to urinary symptoms and does not require 
intermittent urinary catheterization, but does not have any PVR volumes recorded in the 
medical record, then the patient is clinically deemed to not have developed POUR. 
 
In keeping with our standard of care for arthroplasty patients who develop POUR, as 
defined in section 2.1.1, after the Foley catheter is discontinued, will be given a trial of 
intermittent straight catheterization (ISC) for 24 hours. If, after 24 hours of ISC, the 
patient has not resumed spontaneous voids with a residual volume of less than 200 mL, 


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management will be continued based on routine protocol for urinary retention after 
surgery (post-void bladder scan, straight urinary catheterization, possible Foley catheter 
placement, and possible urology consult). 
 
Secondary measures are: length of hospital stay, incidence of discharge to a skilled 
nursing facility, surgical site infection, acute postoperative pain medication requirements, 
and other postoperative complications (deep venous thrombosis, pulmonary embolism, 
cardiovascular event, pneumonia, fevers, or urinary tract infection). 
 
3. 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria requirements to be registered to the 
study. Study treatment may not begin until a subject is registered. 
3.1          Inclusion Criteria 
1. 
Men age ≥ 35 years 
 
2. 
Primary total hip and knee arthroplasty patients (general, spinal, or epidural 
anesthesia) 
 
3. 
No current use (>one month) of alpha blockers 
 
4. 
Community ambulator  
 
5. 
Adequate organ and marrow function as defined below: 
- leukocytes 
 
≥ 3,000/µL 
- absolute neutrophil count ≥ 1,500/µL 
- platelets  
 
≥ 100,000/µL 
- creatinine  
 
within normal institutional limits 
 
 
6. 
Ability to understand, and the willingness to sign, a written informed consent 
7. 
Use of intraoperative foley. 
3.2         Exclusion Criteria 
 
1. 
History of radical prostatectomy 
 
2. 
Receiving any other investigational agents 
 
3. 
Revision hip and knee arthroplasty patients 
 
4. 
Severe liver or kidney disease 
 
5. 
Taking strong inhibitors of CYP3A4 (ketoconazole, itraconazole, clarithromycin, 
ritonavir, indinavir/ritonavir, lopinavir/ritonavir, or conivaptan) 
 
6. 
Being on alpha-blockers (alfuzosin, doxazosin, prazosin, terazosin, tamsulosin, 
phenoxybenzamine, or silodosin) 
 
7. 
Being on 5-alpha reductase inhibitors (finasteride, dutasteride) 
 
8. 
History of allergy or sensitivity to tamsulosin or other alpha-blockers (alfuzosin, 
doxazosin, prazosin, terazosin, or phenoxybenzamine) 
 


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9. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements 
 
10. 
Taking Sildenafil,Tadalafil, or Vardenafil 
 
4. 
TREATMENT PLAN 
4.1          Treatment Dosage and Administration 
 
4.1.1 
Patients will be randomized to receive either a placebo or tamsulosin 0.4 mg 
daily for five days prior to surgery, the morning of surgery, and the first day post-
op to be continued until all capsules are taken. Medication will be provided to 
patients at either their pre-operative appointment or mailed to them via UPS 
before their surgery date.  
 
4.1.2 
Patients will receive tamsulosin/placebo preoperatively on an outpatient basis.  
4.1.3 
All patients will have an indwelling Foley catheter placed intraoperatively, to be 
discontinued the morning of postoperative day one in keeping with existing 
protocol for all patients undergoing total hip or knee arthroplasty.  
 
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Tamsulosin None 
0.4 mg daily 
Oral  
5 days preop  
through 
postop day 1 
N/A 
Placebo 
None 
1 capsule daily 
Oral 
5 days preop 
through 
postop day 1 
α1-
adrenocept
or blocker 
None 
Prescribed dose Oral  
Continue 
current 
therapy 
throughout 
the 
perioperative 
period 
N/A 
 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluated for toxicity per the 
Toxicity Assessment Survey (attached). Each patient will be assessed for the 
development of toxicity per the Time and Events Table, and overall study cohort safety 
will be statistically compared at defined intervals (See Section 5.4).  


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7 
4.3 
Concomitant Medications/Treatments 
Medication contraindications include CYP3A4 inhibitors (ketoconazole, itraconazole, 
clarithromycin, ritonavir, indinavir/ritonavir, lopinavir/ritonavir, and conivaptan) and other 
medications that may have an interaction (amiodarone, dronedarone, boceprevir, 
chloramphenicol, clarithromycin, cobicistat, conivaptan, cyclosporine, delavirdine, 
doxazosin, fluvoxamine, fosamprenavir, imatinib, itraconazole, ketoconazole, 
lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, prazosin, rifampin/isoniazid, 
rifampin/isoniazid/pyrazinamide, ritonavir, telaprevir, telithromycin, terazosin, tipranavir, 
voriconazole), Sildenafil,Tadalafil, and Vardenafil .  
4.4 
Duration of Therapy 
End of protocol therapy occurs when 1) patient completes the seven-capsule regimen, 2) 
adverse reaction to tamsulosin occurs, 3) postoperative complication occurs; deemed 
prohibitive of further continuation of therapy, 4) patient decides to withdraw, 5) an 
indwelling catheter is placed for monitoring the fluid and electrolyte intake and output for 
medical purpose, 6) patient perishes. 
4.5 
Duration of Follow-Up 
Patients will be followed per usual protocol for primary hip and knee arthroplasty patients, 
including inpatient stay (1-4 days on average) and a two-week clinic follow-up 
appointment. After patient completes the AUA Symptom Index and the Toxicity 
Assessment Survey and submits their opioid pain medication log at the two-week follow-
up appointment, active participation in the study will conclude, however we will monitor 
their medical records for 30 post operatively 
 
During the inpatient stay, patients will continue to take tamsulosin or placebo until the 7-
capsule regimen is complete or until one of the end-of-protocol-therapy criteria listed in 
section 5.5 is met. If the patient goes on to treatment failure, he may be discharged on 
tamsulosin at the discresion of his physician. It will be noted if a patient is discharged on 
tamsulosin and appropriate follow-up will be arranged with either the patient’s primary 
care physician or urologist. 
4.6 
Removal of Patients from Protocol Therapy 
Patients will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
The Principal Investigator will be notified, and the reason for therapy removal and the 
date the patient was removed will be documented on the Case Report Form. The patient 
should be followed-up per protocol.  
4.7 
Patient Replacement 
Patients will not be required to be replaced as the study will continue until the minimal 
sample size, as determined by a prior sample size calculation, is reached. 
5. 
PROCEDURES 
5.1   Screening/Baseline Procedures 
Assessments performed for clinical indications (not exclusively to determine study 
eligibility) may be used for baseline values even if the assessments were done before 
informed consent was obtained. All screening procedures must be performed within 30 
days prior to registration unless otherwise stated. The screening procedures include: 


HUM00087825 
 
8 
5.1.1 
Informed consent 
5.1.2 
Medical history 
Complete medical and surgical history, history of urinary retention, 
benign prostatic hypertrophy, urogenital procedures 
5.1.3 
Demographics 
Age, gender, race, ethnicity 
5.1.4 
Review of subject eligibility criteria 
5.1.5 
Review of previous and concomitant medications 
5.1.6 
Physical exam including vital signs, height and weight (Standard of Care) 
Vital signs (temperature, pulse, respirations, blood pressure), height, 
weight 
5.1.7 
Adverse event and efficacy assessment 
Baseline adverse events will be assessed. Efficacy will be assessed 
periodically as well. Adverse events and efficacy will be considered in 
continuation of the study at enrollment intervals (See Section 5.4). See 
Section 7 for adverse event monitoring and reporting.  
5.1.8 
Hematology-(Standard of Care) 
CBC with differential 
5.1.9 
Serum chemistries (Standard of Care) 
Basic metabolic panel (BMP) to include: BUN, creatinine, electrolytes 
(sodium, potassium, calcium, chloride, bicarbonate), and glucose 
5.2  Procedures During Treatment 
            5.2.1        Preoperative 
• Physical exam, vital signs (Standard of Care) 
• Hematology (Standard of Care) 
• Serum chemistries (Standard of Care) 
• Completion of the AUA Symptom Index by the patient 
• Completion of the Toxicity Assessment Survey by the patient 
• Patient to be given seven capsules of 0.4 mg tamsulosin, with one to be taken daily for 
the five days before surgery, one on the morning of surgery, and one on the day after 
surgery. Pills should be administered approximately one half hour following the same 
meal each day. 
 
            5.2.2        Postoperative 
 
 Tamsulosin/placebo taken on postoperative day one 
 Completion of the Toxicity Assessment Survey by the patient on post-op day one 


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9 
            5.2.3        Post-discharge 
Patients that go on to treatment failure will be discharged with a plan of care dictated by 
urology (if consulted), or the primary treatment team, which may include Foley catherter 
placement, tamsulosin, intermittent straight catheterization, outpatient follow-up with 
urologist or primary care physician, or some combination of the previously mentioned 
treatment options. 
5.3       Follow-up Procedures 
Completion of AUA Symptom Index,Toxicity Assessment Survey, and opioid pain 
medication log by the patient. 
 
5.4       Time and Events Table 
 
Event 
Pre-
operative 
Inpatient 
Stay 
2-wk 
Follow-up 
Informed Consent 
X 
 
 
History and PE 
X 
 
X 
Performance Status 
X 
 
 
Toxicity Evaluation 
X 
X 
X 
AUA retention score 
X 
 
X 
Opioid Pain Medication 
log 
 
 
X 
 


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5.5          Removal of Subjects from Study/Study Treatment 
 
5.5.1 
Patient voluntarily withdraws from treatment (follow-up permitted) 
5.5.2 
Patient withdraws consent (termination of treatment and follow-up) 
5.5.3 
Patient is unable to comply with protocol requirements 
5.5.4 
Patient experiences toxicity that makes continuation in the protocol unsafe 
5.5.5 
Treating physician judges continuation in the study would not be in the patient’s 
best interest 
6.0        Response Criteria 
 
6.1   Safety/Tolerability 
 
 
Analyses will be performed for all patients having received at least one dose of study drug.  
7.0        ADVERSE EVENTS 
7.1 Experimental Therapy 
            7.1.1      Contraindications 
History of allergy, sulfa allergy potential for cross sensitivity, poor cyp2d6 
metabolizers 


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            7.1.2      Special Warnings and Precautions for Use 
 
 
Floppy iris syndrome in patients undergoing cataract surgery while on Flomax 
            7.1.3      Interaction with other medications (per Epocrates): 
Amiodarone, dronedarone, boceprevir, chloramphenicol, clarithromycin, 
cobicistat, conivaptan, cyclosporine, delavirdine, doxazosin, fluvoxamine, 
fosamprenavir, imatinib, itraconazole, ketoconazole, lopinavir/ritonavir, 
nefazodone, nelfinavir, posaconazole, prazosin, rifampin/isoniazid, 
rifampin/isoniazid/pyrazinamide, ritonavir, telaprevir, telithromycin, terazosin, 
tipranavir, voriconazole 
7.1.4 
 Adverse Reactions 
 
 
All 
Drug related  
Any 
 
390 (76) 
132 (26) 
α1-adrenoceptor blocker-associated 
 
 
Dizziness 
44 (8.5) 
30 (5.8) 
Abnormal ejaculation 
25 (4.9) 
22 (4.3) 
Headache 
24 (4.7) 
7 (1.4) 
Asthenia 
20 (3.9) 
10 (1.9) 
Rhinitis 
18 (3.5) 
3 (0.6) 
Postural hypotension 
15 (2.9) 
14 (2.7) 


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Palpitation 
14 (2.7) 
7 (1.4) 
Dry mouth 
8 (1.6) 
6 (1.2) 
Syncope 
5 (1.0) 
0 
Somnolence 
4 (0.8) 
2 (0.4) 
Other 
 
 
Impotence 
28 (5.4) 
15 (2.9) 
Decreased libido 
6 (1.2) 
4 (0.8) 
Urinary retention 
23 (4.5) 
1 (0.2) 
Discontinued treatment 
86 (217) 
26(5) 
 
 
Others: allergic reaction, angioedema, Steven Johnson syndrome, arrhythmia, 
priapism (10) 
7.2          Adverse Event Monitoring 
A study coordinator will monitor for AEs with the use of the patient surveys, at the 2-week 
follow-up appointment, and with a chart review following the 30-day end-of-study-
treatment timepoint. Adverse events will be reported in compliance with the IRB standard 
reporting guidelines. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care. See steps 
7.4 and 7.5 for requirements for expedited reporting. 
 
 


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All patients experiencing an adverse event, regardless of its relationship to study 
drug/device, will be monitored until:  
➢ 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline,  
➢ 
any abnormal laboratory values have returned to baseline,  
➢ 
there is a satisfactory explanation other than the study drug for the changes 
observed, or 
➢ 
death. 
       7.3          Definitions 
             7.3.1      Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
experimental intervention, whether or not related to the intervention.  
             7.3.2      Severity of Adverse Events 
 
The severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities or 
significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
             
 7.3.3      Serious Adverse Events 
 
A serious adverse event is defined in regulatory terminology as any untoward medical 
occurrence that: 
                   7.3.3.1      results in death, 
If death results from (progression of) the disease, the disease should be reported as 
event (SAE) itself. 
                   7.3.3.2      is life-threatening, 
The patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
 
7.3.3.3      requires in-patient hospitalization or prolongation of existing hospitalization for                
                 ≥ 24 hours, 
 
7.3.3.4     results in persistent or significant disability or incapacity, 


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14 
7.3.3.5     is a congenital anomaly/birth defect, or 
                         7.3.3.6      is an important medical event. 
 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of “serious adverse event”.  
For example: allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, convulsions that may not result in hospitalization, or development of drug 
abuse or drug dependency. 
           7.4         Steps to Determine if an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event.   
 
Step 2: Grade the adverse event.  
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4:  Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol, 
• 
the drug package insert, or 
• 
the current Investigator’s Brochure 
7.5      Reporting Requirements for Adverse Events 
 All AEs will be reported in adherence to IRB standard reporting guidelines. 
7.5.1     Follow expedited reporting procedures when the AE meets any of the following 
criteria:  
1. Any serious event (injuries, side effects, deaths or other problems), 
which, in the opinion of the Principal Investigator, was unanticipated, 
involved risk to subjects or others, and was possibly related to the 
research procedures 
2. Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk 
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject 


HUM00087825 
 
15 
4. Any new information (e.g., publication, safety monitoring report), interim 
result, or other finding that indicates an unexpected change to the 
risk/benefit ratio for the research 
5. Any breach in confidentiality that may involve risk to the subject or 
others 
6. Any complaint of a subject that indicates an unanticipated risk, or that 
cannot be resolved by the Principal Investigator 
7.6        Unblinding Procedures 
Unblinding will occur when the safety of a patient requires this and will be up to the 
judgment of the treating physician. The investigators will be notified of such unblinding.         
 
Stopping Rules  
The study will be stopped when the adverse event rate exceeds that of the expected rate 
listed above or greater than two serious adverse events occur and are judged to be the 
direct result of the investigatory agent. 
8. 
DRUG/DEVICE INFORMATION 
8.1       Tamsulosin  
• 
Other names for the drug: Flomax™ 
 
• 
Classification: alpha-1 selective alpha blocker 
 
• 
Mode of action: selective α1 receptor blocker that has preferential selectivity for 
the α1A receptor in the prostate versus the α1B receptor in the blood vessels 
 
• 
Storage and stability: stable at room temperature 
 
• 
Preparation: 0.4 mg capsule 
 
• 
Route of administration for this study: oral 
 
• 
Incompatibilities (per Epocrates): amiodarone, dronedarone, boceprevir, 
chloramphenicol, clarithromycin, cobicistat, conivaptan, cyclosporine, delavirdine, 
doxazosin, fluvoxamine, fosamprenavir, imatinib, itraconazole, ketoconazole, 
lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, prazosin, 
rifampin/isoniazid, rifampin/isoniazid/pyrazinamide, ritonavir, telaprevir, 
telithromycin, terazosin, tipranavir, voriconazole 
 
• 
Availability: commercially available as a generic 
 
• 
Side effects: Of the more common drug-related side effects, dizziness, abnormal 
ejaculation, headache, asthenia, postural hypotension, palpitation, dry mouth and 
impotence per (10). Please refer to the package insert for a comprehensive list of 
adverse events. 
 
• 
Nursing implications: no additional duties will be required of Nursing that are not 
otherwise performed per postoperative protocol for total arthroplasty patients. 


HUM00087825 
 
16 
             8.2        Return and Retention of Study Drug/Device 
If the patient does not take all of the prescribed capsules, the remaining capsules will be 
destroyed per University policy. 
9. 
CORRELATIVES/SPECIAL STUDIES 
     No special correlative studies are planned. 
10. 
STATISTICAL CONSIDERATIONS 
10.1      Study Design/Study Endpoints 
Prospective, double blinded, randomized single-center study comparing the efficacy of 
tamsulosin in reducing POUR incidence in primary total hip and knee arthroplasty 
patients. 
 
Adverse events will be monitored at intervals of 50 (25 in each group). If AEs in the trial 
group exceed those in the placebo group, and this difference is statistically significant 
and related to the active drug (tamsulosin), then the study will be terminated. Minor 
adverse events will be examined via statistical tests (chi-square) at each interval. If there 
are severe adverse events noted in the intervention group, the study may be halted until 
further review. 
10.2      Sample Size and Accrual 
POUR occurs in approximately 40% of patients following primary total hip or knee 
arthroplasty. Risk factors for POUR include male sex, total hip arthroplasty, intrathecal 
morphine and epidural anesthesia.  A sample size of 91 in each arm (tamsulosin versus 
placebo) is needed with continuity correction if a reduction of 50% (or a POUR incidence 
of 20%) is to be detected with a power of 80% at a significance level of α < 0.05. 114 
patients are need in each arm assuming an accrual rate of 80% for a total of 228 
patients. 
10.3 
Data Analyses Plans 
Chi-square test will be used to compare the primary outcome of the incidence of POUR 
between those taking and those not taking tamsulosin at the time of surgery, as well as 
the secondary measure of the incidence of discharge to a skilled nursing facility between 
the two groups. T-test will be used to compare the secondary measures of length of 
hospital stay and postoperative pain medication requirements (average daily dose) 
between the two groups. Regression analysis will be performed of other postoperative 
complications including surgical site infection, deep venous thrombosis, pulmonary 
embolism, urinary tract infection, pneumonia, cardiovascular event, fevers, and the 
duration of anesthesia between the two groups. Significance will be set at α = 0.05.  
11. 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
 
The investigators of this study have no financial, board or publishing conflicts of interest. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 


HUM00087825 
 
17 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment into this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA, 
and regional, state, and local regulations. Once this essential information has been 
provided to the patient, and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient, and by the person who conducted the 
informed consent discussion. 
11.3       Registration Procedures 
All patients must be registered before enrollment to study. Prior to registration, eligibility 
criteria must be confirmed with the study coordinator.  
11.4 
Data Management and Monitoring/Auditing 
Study coordinator will continually update an anonymized database of patients, their 
endpoints, secondary measures, adverse events. 
11.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
11.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
11.5.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB. According to the IRB, a protocol deviation is 
any unplanned variance from an IRB approved protocol that:  
• 
is generally noted or recognized after it occurs, 
• 
has no substantive effect on the risks to research participants, 
• 
has no substantive effect on the scientific integrity of the research plan or 
the value of the data collected, or 
• 
did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• 
has harmed or increased the risk of harm to one or more research 
participants, 
• 
has damaged the scientific integrity of the data collected for the study, 
• 
results from willful or knowing misconduct on the part of the investigator(s), 
or 
• 
demonstrates serious or continuing noncompliance with federal regulations, 
state laws, or University policies. 
 


HUM00087825 
 
18 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, please follow the guidelines below: 
 
Protocol Deviations: Personnel will report to any data and safety monitoring 
committee in accordance with their policies. Deviations should be summarized 
and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within one (1) 
week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report unanticipated problems.  
11.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
 
The written amendment, and, if required, the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. Study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
11.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to 
permit verification of proper entry of data. At the completion of the study, all Case Report 
Forms will be reviewed by the Principal Investigator and will require his/her final signature 
to verify the accuracy of the data. 
12. 
REFERENCES 
1. 
Balderi T, Carli F. Urinary retention after total hip and knee arthroplasty. Minerva 
anestesiologica. 2010;76(2):120-30. PubMed PMID: 20150853. 


HUM00087825 
 
19 
2. 
Jeong IG, You D, Yoon JH, Hong S, Lim JH, Hong JH, et al. Impact of tamsulosin on 
urinary retention following early catheter removal after robot-assisted laparoscopic radical 
prostatectomy: a prospective randomized controlled trial. International journal of urology : official 
journal of the Japanese Urological Association. 2014;21(2):164-8. doi: 10.1111/iju.12225. 
PubMed PMID: 23906190. 
3. 
Patel R, Fiske J, Lepor H. Tamsulosin reduces the incidence of acute urinary retention 
following early removal of the urinary catheter after radical retropubic prostatectomy. Urology. 
2003;62(2):287-91. PubMed PMID: 12893337. 
4. 
Merrick GS, Butler WM, Wallner KE, Lief JH, Galbreath RW. Prophylactic versus 
therapeutic alpha-blockers after permanent prostate brachytherapy. Urology. 2002;60(4):650-5. 
PubMed PMID: 12385927. 
5. 
Mohammadi-Fallah M, Hamedanchi S, Tayyebi-Azar A. Preventive effect of tamsulosin 
on postoperative urinary retention. Korean journal of urology. 2012;53(6):419-23. doi: 
10.4111/kju.2012.53.6.419. PubMed PMID: 22741052; PubMed Central PMCID: PMC3382693. 
6. 
Arrabal-Martin M, Valle-Diaz de la Guardia F, Arrabal-Polo MA, Palao-Yago F, Mijan-
Ortiz JL, Zuluaga-Gomez A. Treatment of ureteral lithiasis with tamsulosin: literature review and 
meta-analysis. Urologia internationalis. 2010;84(3):254-9. doi: 10.1159/000288224. PubMed 
PMID: 20389151. 
7. 
Lee SW, Woo SH, Yoo DS, Park J. Effect of tamsulosin on stone expulsion in proximal 
ureteral calculi: an open-label randomized controlled trial. International journal of clinical practice. 
2014;68(2):216-21. doi: 10.1111/ijcp.12271. PubMed PMID: 24372674. 
8. 
Yuan J, Liu Y, Yang Z, Qin X, Yang K, Mao C. The efficacy and safety of alpha-1 
blockers for benign prostatic hyperplasia: an overview of 15 systematic reviews. Current medical 
research and opinion. 2013;29(3):279-87. doi: 10.1185/03007995.2013.766594. PubMed PMID: 
23323875. 
9. 
Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin. 
Journal of cataract and refractive surgery. 2005;31(4):664-73. doi: 10.1016/j.jcrs.2005.02.027. 
PubMed PMID: 15899440. 
 
10. Narayan P., Rao Tunuguntla HSG. Long-Term Efficacy and Safety of Tamsulosin for Benign 
Prostatic Hyperplasia. Reviews in Urology Vol. 7 SUPPL. 4 2005:S42-S48 
 
 
 


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Appendix 1: AUA Symptom Index 
 
 American Urological Association (AUA) Symptom Score 
 
 
 
Patient ID:____________________________ Date: ________________ 
 
Have you noticed any of the following when you have gone to the 
bathroom to urinate over the past two weeks? 
Circle the correct answer for you and write your score in the right-hand column. 
 
Not at 
all 
Less 
than 1 
time in 
5 
Less 
than 
half 
the 
time 
About 
half 
the 
time 
More 
than 
half 
the 
time 
Almost 
always 
Your 
score 
Incomplete emptying – It does 
not feel like I empty my bladder 
all the way. 
0 
1 
2 
3 
4 
5 
 
Frequency – I have to go again 
less than two hours after I finish 
urinating. 
0 
1 
2 
3 
4 
5 
 
Intermittency – I stop and start 
again several times when I 
urinate. 
0 
1 
2 
3 
4 
5 
 
Weak stream – I have a weak 
urinary stream. 
0 
1 
2 
3 
4 
5 
 
Straining – I have to push or 
strain to begin urination. 
0 
1 
2 
3 
4 
5 
 
 
None 
1 time 
2 times 
3 times 
4 times 
5 times 
or 
more 
Your 
score 
Nocturia – I get up to urinate 
after I go to bed until the time I 
get up in the morning. 
0 
1 
2 
3 
4 
5 
 
Total AUA Symptom Score 
 
 
 
 


HUM00087825 
 
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Appendix 2: 
Toxicity Assessment Survey 
 
 
Patient ID:____________________________ Date: 
________________ 
 
Are you experiencing any of the following symptoms? 
1. Dizziness:  yes / no 
2. Headache:  yes / no 
3. Palpitations (a rapid, fluttering, or pounding heart):  yes / no 
4. Fainting:  yes / no 
5. Drowsiness:  yes / no 
 
 
 
 
 
 
 


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22 
 Patient Prescription Pain Medication Log 
 
 
Once you are discharged, you will be instructed to take a prescription pain medication 
according to your surgeon’s orders and pain levels. We would like to know how you are 
controlling your pain post-surgery from the day of your discharge up until your first 
follow up appointment. If you would please note how many pills of the prescription 
medication you take and how many times per day, it would be greatly appreciated. Then 
please bring this chart with you to your appointment and the research coordinator can get 
it from you. Thank you for your time and willingness to participate in our research. It is 
greatly appreciated. 
Wishes for a speedy recovery, 
The University of Michigan Orthopaedic Surgery Research Team 
 
Patient ID Number ________________ 
Prescription Medication Name: 
_____________________________Dosage:___________(mg) 
 
 
Pills 
taken 
 
 
 
 
 
EXAMPLE 
1 
0 
2 
0 
1 
1 
Day 1 
 
 
 
 
 
 
Day 2 
 
 
 
 
 
 
Day 3 
 
 
 
 
 
 
Day 4 
 
 
 
 
 
 
Day5 
 
 
 
 
 
 
Day 6 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
Day 8 
 
 
 
 
 
 
Day 9 
 
 
 
 
 
 
Day 10 
 
 
 
 
 
 
Day 11 
 
 
 
 
 
 
Day 12 
 
 
 
 
 
 
Day 13 
 
 
 
 
 
 
Day 14 
 
 
 
 
 
 
Day 15 
 
 
 
 
 
 
Day 16 
 
 
 
 
 
 
Day 17 
 
 
 
 
 
 
Day 18  
 
 
 
 
 
 
 


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23 
Principal Investigator (PI) Oversight Meeting Log 
PI:  
Study:  
Sponsor:  
Instructions: This log documents meetings held with the PI to review study status, enrollments, AEs, MAIs, lab results a
issues/deviations. 
Date of 
Discussion 
Patient#            
(if applicable) 
Topics Discussed 
Names of Attendees  
P
D