Clinical trial NCT04122196
Conditions: Kidney Stone Pain, Postoperative Addiction Opioid Use
Sponsor: University of Missouri-Columbia
Start date: 2020-06-01; Completion date: 2024-07-01
Enrollment: 118 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, placebo-controlled, double-blinded study examining the use of perioperative pregabalin in ureteroscopy with stent placement. Ureteroscopy is typically performed for kidney or ureteral stones, but may be performed for other reasons such as for the diagnosis and possible treatment of certain kinds of cancers. As part of the same surgery, a ureteral stent is often placed. The surgery and the stent can cause discomfort, and patients may receive narcotic pain medicine. In other surgeries, a single dose of pregabalin, around one hour before surgery has been shown to decrease the need for pain medication after the surgery. This work will test whether this is true in ureteroscopy by giving eligible patients who agree to participate either pregabalin or a placebo shortly before surgery then examining how much pain medication they use after surgery. A placebo is an inactive medication. Neither the study participant nor the study staff will know who received pregabalin and who received placebo until after the study is over. For completing surveys, patients will receive compensation for their time in the form of gift certificates.

Detailed description:
The prevalence of urolithiasis is greater than 8% and increasing in the United States. For those who require surgery, ureteroscopic treatment is common, representing \>120,000 procedures yearly in the United States. This does not include ureteroscopy for other, including diagnosis of structural anomaly and diagnosis and management of ureteral and renal pelvic tumors. Frequently, a ureteral stent is placed intraoperatively. There is post-operative pain in around 80% of patients, and 12% of those undergoing ureteroscopy will have an emergency department visit in the first 30 post-operative days, typically for stent related symptoms or post procedural pain. Aside from the short-term repercussions of ureteroscopy with stent placement there are long-term issues related to pain and the treatment thereof. Recent evidence suggests that approximately 6% of opioid naïve patients who undergo ureteroscopy will become new persistent opioid users.

A single perioperative dose of pregabalin has been shown in many surgical contexts to have analgesic, anxiolytic, and opioid sparing effects. A common regimen employed in the literature is a single preoperative dose of 300mg PO pregabalin 1hr before induction of anesthesia. Pregabalin is a well-tolerated gabapentinoid medication with temporary cognition/coordination changes being the most common side effects. There is currently no standard of care for the use of perioperative gabapentinoid medication in ureteroscopy. A pilot was performed looking at such use that demonstrated the safety of this use and the feasibility of studying this at our institution.

In this work, the efficacy and safety of perioperative pregabalin in ureteroscopy with stent placement will be evaluated by executing a prospective, double blind, randomized, placebo-controlled trial for the use of perioperative pregabalin in the management of post-ureteroscopy symptoms, with the hypothesis that this treatment is safe and efficacious. Emphasis will be placed on patient-centered outcomes, especially those related to opioid sparing effects, mainly within the first 30 days after the surgery and extending out to one year.

The study will be powered with an 80% probability to detect a 10% difference in the primary outcomes. It will also assume a loss to follow up rate of 50%. This will require approximately 200 total subjects with a planned 1:1 placebo to active treatment enrollment ratio. The necessary enrollment can be accomplished in 11 months, allowing for 30 days of follow up within the funding period.

The final goal of this project will be at least one paper in a top urology journal. This will contribute to the literature by helping to inform urologists and anesthesiologists on the efficacy and safety of perioperative pregabalin for ureteroscopy with stent placement and will provide data regarding opioid sparing management after ureteroscopy. Opioid related issues abound nationwide and are evident in Missouri. This study has the potential to influence opioid use both in this state and nationwide as it relates to this frequently performed procedure.

Arms: arm 1: Patient will receive a compounded version of 300mg pregabalin PO approximately one hour before surgery. arm 2: Patient will receive a compounded version of inactive placebo PO approximately one hour before surgery.
Interventions: intervention 1: Pregabalin 300mg intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: Patient will receive a compounded version of 300mg pregabalin PO approximately one hour before surgery. intervention 2: Patient will receive a compounded version of inactive placebo PO approximately one hour before surgery.

Protocol documents:
Prot_001.pdf: 
1 
 
 
BIOMEDICAL RESEARCH PROTOCOL 
UNIVERSITY OF MISSOURI 
 
Project Title: Perioperative pregabalin as part of a multimodal treatment plan for pain after ureteroscopy 
with stent placement: a randomized, controlled trial 
 
IRB Number: 2017676 
Version Number: 1.2 
Version Date: 07/22/2020 
Principal Investigator: Katie Murray, DO 
Funding Source: Departmental   
Clinical Trial Phase: Not Phased  
Clinicaltrials.gov Number: NCT04122196 
Study Drug/Study Device: Pregabalin  
 
 
Principal Investigator 
Katie Murray, DO 
Department of Surgery Urology 
Division 
Co-Investigator 
Geoffrey Rosen, MD 
Department of Surgery Urology 
Division 
Consenting Professional(s) 
Department 
Department of Surgery-Urology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
University of Missouri University Hospital 
Department of Surgery Urology Division 
1 Hospital Drive 
Columbia, MO 65212 
 
 


2 
 
 
Table of Contents 
PROTOCOL SUMMARY AND/OR SCHEMA .............................................................................................. 4 
OBJECTIVES AND SCIENTIFIC AIMS ....................................................................................................... 4 
Primary Hypothesis ................................................................................................................ 4 
Secondary Hypotheses .......................................................................................................... 4 
Primary Endpoints .................................................................................................................. 4 
Secondary Endpoints: ............................................................................................................ 4 
BACKGROUND AND STUDY DESIGN/INTERVENTION ........................................................................... 4 
CRITERIA FOR SUBJECT ELIGIBILITY .................................................................................................... 5 
Subject Population ................................................................................................................. 5 
Subject Inclusion .................................................................................................................... 5 
Subject Exclusion ................................................................................................................... 5 
OVERVIEW OF STUDY DESIGNATION ..................................................................................................... 6 
Design ...................................................................................................................................... 6 
Pre-op standardized care ....................................................................................................... 6 
Post-op standardized care ..................................................................................................... 6 
THERAPEUTIC AND DIAGNOSTIC AGENTS ............................................................................................ 6 
RECRUITMENT PLAN ................................................................................................................................. 6 
PRETREATMENT EVALUATION ................................................................................................................ 6 
SURGICAL PLAN ........................................................................................................................................ 7 
EVALUATION DURING TREATMENT/INTERVENTION ............................................................................ 7 
Not part of usual care ............................................................................................................. 7 
Usual care ................................................................................................................................ 7 
TOXICITIES/SIDE EFFECTS ....................................................................................................................... 8 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ............................................... 8 
CRITERIA FOR REMOVAL FROM STUDY ................................................................................................ 8 
BIOSTATISTICS .......................................................................................................................................... 8 
Sample Size ............................................................................................................................. 8 
Analysis ................................................................................................................................... 8 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ......................... 9 
Research Participant Registration ........................................................................................ 9 
Participant randomization ...................................................................................................... 9 
DATA MANAGEMENT ISSUES .................................................................................................................. 9 
Quality Assurance .................................................................................................................. 9 
Data and Safety Monitoring ................................................................................................... 9 
PROTECTION OF HUMAN SUBJECTS ..................................................................................................... 9 
Benefits and Risks .................................................................................................................. 9 
Toxicities and side effects ................................................................................................... 10 
Alternatives / Therapeutic options ...................................................................................... 10 
Financial Costs and Burdens .............................................................................................. 10 
Patient incentives ................................................................................................................. 10 
Privacy and Confidentiality .................................................................................................. 10 
Volunteering Nature of the Study ........................................................................................ 10 
Serious Adverse Event (SAE) Reporting ............................................................................ 10 


3 
 
 
INFORMED CONSENT PROCEDURES ................................................................................................... 10 
REFERENCES ........................................................................................................................................... 12 
APPENDICES ............................................................................................................................................ 14 
Appendix 1 – REDCap instruments ..................................................................................... 14 
Appendix 2 – Watson clock drawing form .......................................................................... 15 
Appendix 3 – Instructions for Watson clock drawing test ................................................ 16 
Appendix 4 – Visual analog scale ....................................................................................... 17 
Appendix 5 – Post-op study specific instruction ............................................................... 18 
Appendix 6 – Written consent and HIPAA authorization .................................................. 19 
Appendix 7 – E-consent ....................................................................................................... 20 
 
 
 
 


4 
 
 
PROTOCOL SUMMARY AND/OR SCHEMA 
We propose a clinical trial examining the use of perioperative pregabalin to decrease opioid usage after 
ureteroscopy with stent placement. Patients undergoing ureteroscopy with stent placement will receive 
either a single dose of 300 mg pregabalin PO or an identical placebo in the preoperative area. We will 
assess patient centered outcomes, specifically examining possible side effects as well as short- and long-
term opioid sparing effects.  
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Hypothesis 
The use of perioperative pregabalin in ureteroscopy with stent placement will decrease the amount of 
perioperative pain experienced by the patient. 
 
Secondary Hypotheses 
We hypothesize that the use of the perioperative pregabalin in ureteroscopy with stent placement will:  
- 
Have secondary benefits in the immediate post-operative period 
- 
Decrease the proportion of patients receiving opioid prescription in the first 30 post-operative 
days 
- 
Not decrease patient satisfaction with their procedure 
- 
Not significantly increase the risk of adverse outcomes 
- 
Decrease the risk of new persistent opioid use at 3, 6, and 12 months after surgery 
 
Primary Endpoints 
The primary endpoint will be the value on the visual analog scale of pain score supplied by the patient 
approximately one hour after reaching the post-operative area.  
 
Secondary Endpoints: 
Secondary endpoints include the following: 
- 
Reported post anesthesia care unit (PACU) symptoms experienced 
- 
Score on clock drawing test 
- 
Number of unplanned contacts between the patient and the healthcare system within 30 days 
- 
Reported satisfaction at 7- and 30-days post procedure 
- 
Proportion of patients with new persistent opioid use at 3, 6, and 12 months after surgery 
BACKGROUND AND STUDY DESIGN/INTERVENTION 
 
The prevalence of urolithiasis is greater than 8% and increasing in the United States (US) [1]. There are 
several treatment options, including ureteroscopy (with or without laser lithotripsy), extracorporeal shock 
wave lithotripsy, and percutaneous nephrolithotomy. A recent study in California demonstrated that 
ureteroscopic treatment was employed in more than 40% of interventions [2], with some nationwide 
estimates up to 59% [3]. At least 300,000 stone interventions are performed yearly in the US on working 
age adults [4], thereby, there are at least 120,000 ureteroscopies. There are several other indications for 
ureteroscopy, including diagnosis of structural anomaly and diagnosis and management of ureteral and 
renal pelvic tumors. 
 
Depending on the specifics of the procedure, it may be advisable to place a ureteral stent intraoperatively 
[5]. The most commonly used variety of stent is the double J stent [6], which has long been known to 
cause post-operative pain in around 80% of patients, as well as irritative symptoms in a sizeable portion 
[7, 8]. Approximately 12% of those undergoing ureteroscopy will have an emergency department (ED) 
visit in the first 30 post-operative days [9], typically for stent related symptoms or post procedural pain 
[10]. Aside from the short-term repercussions of ureteroscopy with stent placement (such as ED visits), 
there are long-term issues related to pain or the treatment thereof. Recent evidence suggests that 
approximately 6% of opioid naïve patients who undergo ureteroscopy will become new persistent opioid 
users [11].   
 


5 
 
 
Alpha-blockers decrease ureteral stent discomfort when compared to placebo [12, 13]. Anti-muscarinic 
medications have also been shown to be helpful with stent related discomfort independently, or in 
addition to alpha blockade [14], though the evidence is mixed [15]. A recent systematic review failed to 
find any studies of other medications for stent related discomfort that met inclusion criteria [16]. 
Subsequently, a well-designed study demonstrated the utility of mirabegron for indwelling stent symptoms 
[17]. 
 
Recent guidelines recommend the use of multimodal treatment strategies in the management of 
postoperative pain [18]. In several contexts, gabapentin or pregabalin have been shown to be a beneficial 
part of such a strategy. For example, in percutaneous nephrolithotomy, a randomized, placebo-controlled, 
double-blind study demonstrated that a single dose of 600mg of oral gabapentin 1 hour before surgery 
significantly decreased catheter-related bladder discomfort, number of patients requiring opioid pain relief, 
and amount of opioid pain relief when used [19]. Similarly, outside urology, several well-designed trials 
demonstrate the positive effects of perioperative pregabalin or gabapentin in the elective, outpatient 
surgery setting [20-22]. Several reviews and meta-analyses have also supported the use of perioperative 
gabapentin or pregabalin in various settings [23-26]. The principal side effects of pregabalin are 
temporary cognition/coordination changes, with a very low risk of serious side effects [27]. No well-
constructed studies to date have examined the perioperative use of gabapentinoids in post-ureteroscopy 
ureteral stent related symptoms.  
 
In preparation for this work, we performed a pilot study looking at perioperative pregabalin use in 
ureteroscopy at our institution. We obtained IRB approval for a prospective feasibility study. We enrolled 
10 patients undergoing ureteroscopy with stent placement at our institution. They all received 300mg 
pregabalin before surgery, along with a standardized regimen of post-operative and discharge 
medications. Patient centered outcomes were measured. Despite pre-operative counseling about pain 
control and stent discomfort, 20% expected to need opioid pain control. The only adverse effect reported 
more than once was dry mouth. All patients went home on the day of surgery, as is typical. No patient 
was prescribed opioid at discharge. One patient went to the emergency room in the first 30 post-operative 
days for a procedural pain related reason. Interestingly, it was actually immediately after stent removal. 
This patient was prescribed 90 oral morphine equivalents of tramadol. This rate of return is in line with 
contemporary reports [9].  
 
We learned a great deal from this pilot study. First, we saw that it was feasible to enroll patients at a 
relatively high rate. We approached 12 eligible patients to enroll 10. A surprisingly high number 
(approximately 1/3) of patients undergoing eligible procedures were not eligible for enrollment, typically 
due to chronic kidney disease or chronic opioid use. We were successfully able to administer the study 
medication and track outcomes. The number of surveys were quite burdensome – to participants, nurses, 
and study staff. Insurance companies regularly required prior authorization for the recommended 
discharge medications (but would approve relatively similar medications). We have modified the design of 
this study in several ways due to the lessons learned in the pilot study.  
CRITERIA FOR SUBJECT ELIGIBILITY 
Subject Population 
Undergoing elective ureteroscopy with stent placement at University of Missouri Hospital and affiliated 
facilities 
 
Subject Inclusion 
- 
Age ³ 18 years 
- 
Undergoing ureteroscopy with plan for stent placement 
 
Subject Exclusion 
- 
Renal insufficiency (eGFR < 50 mL/minute/1.73 m2) 
- 
Ureteral stent in place >30 days 
- 
Chronic opioid use 
- 
History of opioid abuse 


6 
 
 
- 
Chronic gabapentinoid use 
- 
History of gabapentinoid abuse 
- 
Plan for inpatient hospitalization either leading up to or after treatment 
- 
Pregnancy 
- 
Inability of the patient to consent for themselves in English 
- 
Allergy to gabapentinoid 
- 
Liver failure or hepatic dysfunction 
- 
No email address that is regularly checked 
OVERVIEW OF STUDY DESIGNATION 
Design 
This is a randomized, controlled clinical trial on the use of perioperative pregabalin in order to decrease 
ureteral stent related symptoms and decrease opioid usage after ureteroscopy with stent placement. 
Patients undergoing ureteroscopy with stent placement will receive a single dose of 300 mg pregabalin 
PO or an identical appearing placebo in the preoperative area.  
 
Pre-op standardized care 
After obtaining electronic written informed consent, patients will be enrolled.  
 
Subsequently, all patients will be given a single dose of pregabalin 300 mg PO or an identical appearing 
placebo with a sip of water approximately one hour before surgery. This will be administered per standard 
intuitional practice. It will not be recorded in the regular medical chart of the patient. 
 
Post-op standardized care 
Perioperative care, surgery, and anesthesia for all subjects will be per standard hospital protocol. 
 
To qualify for discharge from the PACU, per standard protocol, all patients will have had to have 
ambulated, voided, tolerated PO intake, and have pain subjectively adequately controlled.  
THERAPEUTIC AND DIAGNOSTIC AGENTS 
Pregabalin is an oral agent approved for use in fibromyalgia and neuropathic pain. A single dose of 
compounded 300mg PO will be given to all patients.  
 
A standard inactive placebo will be used. 
 
The medications will be compounded so as to have identical appearance. This will be performed by the 
investigational pharmacy at the University of Missouri. 
RECRUITMENT PLAN 
Patients will be recruited from the Division of Urology, Department of Surgery. The study will be 
introduced to every eligible patient scheduled for ureteroscopy with stent placement by the participating 
consenting physicians from the Department of Surgery-Urology Division and an electronic consent 
obtained prior to surgery by the consenting research personnel. Candidate subjects will be provided time 
to consider the study, to read the informed consent document at their convenience, and discuss the study 
with family and others, as desired. It will be clearly indicated that non-enrollment in the study will not 
negatively affect the patient’s care.  
PRETREATMENT EVALUATION 
This study does not require any additional pretreatment evaluations other than those which are part of 
current clinical care standards for a patient undergoing ureteroscopy with stent placement at University of 
Missouri. Preoperative evaluations typically include the following:  
- 
Routine history and physical examination to include documentation of any comorbidities, 
medications (including complementary and alternative medications), family history, social history 
(alcohol and tobacco usage), height, body weight 
- 
Past medical history including previous treatment for addiction 


7 
 
 
- 
Past surgical history including other uses of stents in the patient’s lifetime 
- 
Evaluation of renal function 
- 
Any woman of child bearing age who believes she may be pregnant receives a pregnancy test 
 
SURGICAL PLAN 
The technique of surgery will have been determined to be ureteroscopy with stent placement based on 
the discretion of the surgeon and patient. None of the techniques utilized in the study are considered 
experimental and all are considered standard therapeutic options for patients with indications for this 
procedure. Typical indications include nephroureterolithiasis and evaluation for malignancy.   
 
The operating team will consist of surgeons at University of Missouri Department of Surgery-Urology 
Division. The procedures are performed under standardized general anesthesia with standard 
intraoperative vital sign monitoring. 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Not part of usual care 
This protocol requires several evaluations outside those typically used. These are all questionnaires.  
 
Timing 
Questionnaire 
Respondent 
Before day of surgery OR on 
day of surgery 
Screening questionnaire 
Study staff 
 
Baseline questionnaire and 
demographic information 
Patient 
 
E-consent 
Patient 
 
Preop Watson clock drawing 
test and visual analog scale of 
pain 
Patient 
Day of surgery 
PACU 
Study staff 
 
Watson clock drawing test and 
visual analog scale of pain $ 
Patient 
3 days post op 
Early patient questionnaire 
Patient 
7 days post op 
Early patient questionnaire 
Patient 
30 days post op 
30 days post op chart review 
Study staff 
 
Early patient questionnaire $ 
Patient 
90 days post op 
Late patient questionnaire 
Patient 
6 months post op 
Late patient questionnaire 
Patient 
1-year post op 
Late patient questionnaire 
Patient 
 
1-year post op chart review 
Study staff 
Untimed 
Unanticipated contact 
Study staff/Treatment staff 
 
Evaluation of trial 
Patient 
$ indicates questionnaires for which compensation will be provided. Please see details of 
compensation. 
 
Usual care 
Routine evaluation and management for those undergoing ureteroscopy with stent placement include: 
ASA classification, assigned by the anesthesiologist  
Deep venous thrombosis prophylaxis per standardized pathway 
Estimated blood loss 
Use of intraoperative fluids (crystalloid, colloid, blood products) 
PACU medication 
Discharge medication 
Follow up plan 


8 
 
 
TOXICITIES/SIDE EFFECTS 
Various symptoms have been associated with the administration of pregabalin in the perioperative 
setting. The risk of serious adverse events in this use of pregabalin is low [27] and the potential benefits 
of this treatment may outweigh the risks. This will be recorded in the PACU questionnaire.   
 
Surgical complications will be assessed prospectively and retrospectively and reviewed using the 
institutional standard for complications reporting for all surgical patients as followed by the Department of 
Surgery. Standardized graded complications and adverse effects at UM utilize the five-point modified 
Clavien-Dindo system. Grade I include complications requiring monitoring but no intervention; Grade II 
requires bedside or medical treatment; Grade III constitute adverse events requiring surgical or 
procedural intervention with return to normal functioning; Grade IV includes disabling, life-threatening 
complications with resulting functional loss and grade V is death of the patient. This is a modification of 
the Clavien-Dindo system for reporting complications with defined, categorized and classified events that 
will be segregated into time periods of ≤30 days, 31-90 days and > 90 days after surgery and includes 
medication complications following NCI CTCAE version 5 guidelines. 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The intraoperative period is defined as the period from anesthesia induction to the extubation of the 
trachea. The surgical time is determined from the incision to the final skin closure. 
 
The postoperative period is defined as the period from the extubation to various study endpoints. 
 
Blood loss is defined as the estimate accounted from the suction device and absorptive sponges during 
the procedure, as described and agreed upon by the surgeon, anesthesiologist, circulating nurse, and 
surgical technician as covered by institutional guidelines. 
 
The patient’s pain will be evaluated with a visual analogue scale of pain [28]. This may either be done 
digitally or by paper [29]. 
 
Adverse events will be measured with an optional PACU questionnaire for nurses as well as by 
monitoring of unanticipated contact.  
 
Neurological changes will be measured using the Watson[30] clock drawing test. 
 
Satisfaction will be evaluated via questionnaires at subsequent time points.   
 
Need for opioid pain medication will be carefully tracked via patient questionnaire, chart review, and 
review of any available prescription database. 
CRITERIA FOR REMOVAL FROM STUDY 
Patients will be withdrawn from the study if they express a desire to do so or if it is determined to be in the 
patient’s best interest to do so.  
BIOSTATISTICS 
Sample Size 
The study will be powered with an 80% probability to detect a 10% difference in the primary outcomes. It 
will also assume a loss to follow up rate of 50%. This will require approximately 200 total subjects with a 
planned 1:1 placebo to active treatment enrollment ratio. We estimate at least 500 eligible procedures are 
conducted each year at our institution. Accounting for excluded patients and those who do not wish to 
participate, we estimate that full enrollment should be attainable within one year. 
 
Analysis 
A formal statistical analysis plan, crafted by the study team in partnership with the statistical consultants, 
will be finalized prior to data analysis.   


9 
 
 
 
The primary outcome will be the score on the visual analog scale of pain in the PACU.  
Secondary outcomes reported will be the amount of opioid prescribed (in oral morphine equivalents) in 
the first thirty post operative days. Also reported will be the proportion of patients requiring narcotic pain 
medication, a composite of unplanned healthcare interactions within the first 30 post-operative days, 
PACU length of stay, nausea/vomiting, changes in cognition or coordination, and a composite of serious 
adverse events (ICU admission or death) within the 30 post-operative days.  
 
Analyses will be performed in R. For the primary outcome, student’s t-test will be used to compare the 
amount of opioid prescribed. For the secondary outcomes, either chi-squared or student’s t-test will be 
performed to test for differences between those who received perioperative pregabalin and those who 
received placebo. For the secondary outcomes, multiple testing will be corrected using the Benjamini-
Hochberg method [31]. 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
Research Participant Registration 
We will confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility.  
 
We will obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
Participant randomization 
Randomization will be undertaken using the randomization module available in REDCap. Patients will be 
randomized to either “Group A” or “Group B”. Medications will be distributed via the investigational 
pharmacy according to patient allotment. No one outside the investigational pharmacy will have 
knowledge of which group receives active medication.   
DATA MANAGEMENT ISSUES 
The research team will be responsible for project compliance, data collection, abstraction and entry, data 
reporting, IRB correspondence, problem resolution and prioritization and coordination of the protocol 
study team activities. The data collected for this study will be entered into a secure departmental server or 
will be stored online in the university approved resource, REDCap [32]. Source documentation and 
regulatory binders will be stored in a locked filing cabinet within a locked department office space. These 
sites are exclusively used for research documents and only members of the research team will have 
access to files for this study.  
 
Quality Assurance 
Routine data quality reports will be generated to assess missing data and inconsistencies. Accrual rates, 
and extent and accuracy of evaluations will be monitored throughout the study period. Potential problems 
will be brought to the attention of the study team for discussion and action.  
 
Data and Safety Monitoring 
The MU Health Care Data and Safety Monitoring Plans can be found online.  
 
There are several different mechanisms by which clinical trials are monitored for data, safety and quality. 
There are institutional processes in place for quality assurance (e.g., protocol monitoring, compliance and 
data verification audits, therapeutic response and staff education on clinical research QA) and 
departmental procedures for quality control, plus institutional committees that are responsible for 
monitoring the activities of the clinical trials program.  
PROTECTION OF HUMAN SUBJECTS 
Benefits and Risks 
The experimental intervention (perioperative pregabalin administration) is currently used at University of 
Missouri Hospital through the ERAS protocol. Numerous studies have shown significant patient benefits 
in all fields, including Urology. Several reviews have demonstrated the efficacy and safety of perioperative 


10 
 
 
gabapentinoid administration. The principal side effects of pregabalin are temporary 
cognition/coordination changes, with a very low risk of serious side effects. Therefore, we do not believe 
that the therapeutic aspects of this trial pose any serious risk different from patients undergoing 
ureteroscopy with stent placement under standard procedures.  
  
Toxicities and side effects 
Adverse outcomes are not anticipated with the regimen of pregabalin used in this study. Patients are 
closely monitored during the perioperative period and any serious events will be immediately brought to 
the attention of the study staff. All potential side effects will be recorded in questionnaires.  
 
Alternatives / Therapeutic options 
The alternative to participation in the trial would be to undergo ureteroscopy with stent placement 
according to the surgeon’s standard practice and not to participate in the study.  The patient may or may 
not receive pregabalin in this case. No other aspect of patient care would differ. 
 
Financial Costs and Burdens 
The cost of study drug and study drug administration will be covered by the study and will not be billed to 
the patients.  
 
Patient incentives 
The patients will be offered the following compensation: 
 
Timing 
Amount 
Requirement 
Day of surgery 
$5.00 
Completion of day of surgery 
clock drawing test and visual 
analog scale 
30 days post-op 
$5.00 
Completion of early patient 
questionnaire 
We may extend this to later time points pending future funding.  
 
Monies will be supplied to patients in the form of e-gift certificates. 
 
Privacy and Confidentiality 
We will keep the study records confidential. No identifiers will be used in any reports or publications 
resulting from the study.  
 
Volunteering Nature of the Study 
Participation is entirely voluntary. All aspects of patient’s care and monitoring will be unaffected by 
whether the patient chooses to consent for the study. 
 
Serious Adverse Event (SAE) Reporting 
Any SAE will be reported to the IRB as soon as possible, but no later than 5 calendar days. The reporting 
procedure will be followed as outlined in the University of Missouri protocol found in the “Core Standard 
Operating Procedure for Event Reporting.”.  
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain full details of 
the protocol and study procedures as well as the risks involved to participants prior to their inclusion in the 
study. This may be performed by phone. Participants will also be informed that they are free to withdraw 
at any time. All participants will submit an electronically signed consent form. This consent form meets the 
requirements of the Code of Federal Regulations and the Institutional Review Board.  
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully explain 
the aspects of patient privacy concerning research specific information. In addition to signing the IRB 


11 
 
 
Informed consent, all patients must agree to the Research Authorization component of the informed 
consent form. 
 
Each participant will sign the electronic consent form. The participant will receive a copy of the informed 
consent form. A member of the study staff will also sign the electronic consent form.  
 
 
 


12 
 
 
REFERENCES 
 
 
1. 
Scales, C.D., et al., Prevalence of Kidney Stones in the United States. European Urology, 2012. 
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2. 
Raheem, O.A., et al., Contemporary Trends in the Ambulatory Surgical Treatment of Urolithiasis: 
Population-Based Analysis. Journal of Endourology, 2015. 29(10): p. 1189-1192. 
3. 
Oberlin, D.T., et al., Contemporary Surgical Trends in the Management of Upper Tract Calculi. 
Journal of Urology, 2015. 193(3): p. 880-884. 
4. 
Saigal, C.S., et al., Direct and indirect costs of nephrolithiasis in an employed population: 
Opportunity for disease management? Kidney International, 2005. 68(4): p. 1808-1814. 
5. 
Pais, V.M., Jr., et al., Does Omission of Ureteral Stents Increase Risk of Unplanned Return Visit? 
A Systematic Review and Meta-Analysis. J Urol, 2016. 196(5): p. 1458-1466. 
6. 
Finney, R.P., Experience with new double J ureteral catheter stent. J Urol, 1978. 120(6): p. 678-
81. 
7. 
Joshi, H.B., et al., Indwelling ureteral stents: evaluation of symptoms, quality of life and utility. J 
Urol, 2003. 169(3): p. 1065-9; discussion 1069. 
8. 
Bosio, A., et al., How bothersome double-J ureteral stents are after semirigid and flexible 
ureteroscopy: a prospective single-institution observational study. World J Urol, 2018. 
9. 
Carlos, E.C., et al., Psychiatric Diagnoses and Other Factors Associated with Emergency 
Department Return within 30 Days of Ureteroscopy. J Urol, 2019. 201(3): p. 556-562. 
10. 
Tan, H.J., et al., Immediate unplanned hospital admission after outpatient ureteroscopy for stone 
disease. J Urol, 2011. 185(6): p. 2181-5. 
11. 
Tam, C.A., et al., New Persistent Opioid Use after Outpatient Ureteroscopy for Upper Tract Stone 
Treatment. Urology, 2019. 
12. 
Kwon, J.K., et al., The beneficial effect of alpha-blockers for ureteral stent-related discomfort: 
systematic review and network meta-analysis for alfuzosin versus tamsulosin versus placebo. 
BMC Urol, 2015. 15: p. 55. 
13. 
Lamb, A.D., et al., Meta-analysis showing the beneficial effect of alpha-blockers on ureteric stent 
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14 
 
 
APPENDICES 
Appendix 1 – REDCap instruments 
 
See instruments_v1.0.pdf 
 
 
 


15 
 
 
Appendix 2 – Watson clock drawing form 
 
See Watson_v1.1.docx 
 
 
 


16 
 
 
Appendix 3 – Instructions for Watson clock drawing test 
 
See Watson_instructions_v1.0.pdf 
 
 


17 
 
 
Appendix 4 – Visual analog scale 
 
See VAS_v1.1.docx 
 
 


18 
 
 
Appendix 5 – Post-op study specific instruction 
 
See post-op_instructions_v1.0.pdf 
 
 


19 
 
 
Appendix 6 – Written consent and HIPAA authorization 
 
See consent_and_hipaa_v1.3.doc 
 
 
 


20 
 
 
Appendix 7 – E-consent 
 
See econsent_v1.0.pdf 
 
 
 
 

SAP_000.pdf: 
1 
 
 
Perioperative pregabalin as part of a multimodal treatment plan for pain after ureteroscopy with 
stent placement: a randomized, controlled trial 
 
Statistical analysis plan 
 
Version 1.0 
Version date: February 27, 2020 
 


2 
 
 
Statistical Analysis Plan  
 
Enrolled subjects’ characteristics will be summarized using mean ± SD for continuous variables and 
proportions for categorical variables. The primary outcome of interest, the value on the visual analog 
scale of pain score (VAS score), will be summarized overall and by treatment group, those who received 
perioperative pregabalin and those who received placebo.  To examine the research question, an 
independent sample t-test will be conducted to assess if differences exist on VAS scores by the treatment 
group. The assumptions of normality and homogeneity of variance will be assessed.  Normality of the 
scores will be assessed using the One-Sample Kolmogorov-Smirnov test.  Homogeneity of variance will 
be assessed using Levene’s Test for the Equality of Error Variances.  The t-test will be two- tailed with the 
probability of rejecting the null hypothesis when it is true set at p < 0.05.  If groups are unbalanced with 
respect to one or more patients’ characteristics, we will perform a stratified analysis of VAS scores based 
on that characteristics. 
For the secondary outcomes of interest, a two sample t-test or a Chi-square test of independency will be 
used to compare the treatment groups for continuous and categorical outcomes, respectively. 
In addition to univariate analysis, we will fit a generalized linear model or logistic regression model of 
outcome on treatment group controlling for possible confounding variables such as, gender, age, pre-
operation VAS score and pre-operation Watson clock drawing score, depending on type of outcome. 
 
 
Power Analysis  
 
Group sample sizes of 59 per group achieve 80% power to reject the null hypothesis of equal means 
when the population mean difference in VAS score is as little as 1 unit, assuming the standard deviations 
of 1 for group 1 (based on our pilot study) and 2.5 for group 2 (from literature), and with a significance 
level (alpha) of 0.05 using a two-sided two-sample unequal-variance t-test. Assumption about 40% 
dropout rate, it requires approximately 200 total subjects with a planned 1:1 placebo to active treatment 
enrollment ratio. We estimate at least 500 eligible procedures are conducted each year at our institution. 
Accounting for excluded patients and those who do not wish to participate, we estimate that full 
enrollment should be attainable within one year.