Clinical trial NCT02355886
Conditions: Bladder Carcinoma
Sponsor: University of Washington
Start date: 2015-04-22; Completion date: 2019-02-28
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II/III trial studies gabapentin in reducing the need for pain medication in patients with bladder cancer undergoing surgery to remove the bladder and nearby tissue and organs. Gabapentin may reduce the amount of pain medicine required after surgery, improve pain after surgery, and/or reduce the length of hospital stay after surgery.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess if perioperative gabapentin will decrease post-operative analgesic requirements within the first 48 hours after radical cystectomy (RC) in patients undergoing RC as measured morphine equivalents.

SECONDARY OBJECTIVES:

I. To assess patient self-assessment of postoperative pain on Numeric Pain Scale (NPS) at 24 and 48 hours.

II. To assess time to return of bowel function (ROBF).

III. To assess length of stay (LOS) following RC.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive gabapentin orally (PO) thrice daily (TID) for 48 hours after surgery.

ARM II: Patients receive placebo PO TID for 48 hours after surgery.

Arms: arm 1: Patients receive gabapentin PO TID for 48 hours after surgery. arm 2: Patients receive placebo PO TID for 48 hours after surgery.
Interventions: intervention 1: Gabapentin intervention 2: Placebo intervention 3: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
9274           NCT02355886     February 20, 2017 
1 
Current Version: 2/2017 
Research Study Protocol 
Title: Randomized placebo control trial of perioperative gabapentin to reduce total analgesic 
requirements in patients undergoing radical cystectomy  
Principal Investigator: Jonathan L. Wright, MD 
Co-Investigators: George R. Schade, MD, Brian Winters, MD, Franklin Lee, MD, Christopher 
Kent, MD, Sarah Holt, PhD 
Study Coordinator: Brian Winters, MD 
Research team and contact information: grschade@uw.edu 
Study Site: University of Washington Medical Center 
Background and Significance: Approximately 73,000 patients will be diagnosed with bladder 
cancer in the US in 2013. Of these, 30% will have muscle-invasive1 for which surgical therapy 
via a radical cystectomy (RC) with urinary diversion is the standard of care. Despite advances in 
surgical and anesthetic techniques and improvement in post-operative care, RC remains 
extremely morbid with rates of complications, readmissions, and 90-day perioperative mortality 
approaching 50%, 30%, and 7% respectively.2,3 Thus strategies to reduce RC patients’ morbidity 
and suffering are needed. 
One such potential strategy is to improve patients’ post-operative pain management.  Not only 
does post-operative pain contribute to patient suffering, pain (and lack of pain control) may also 
contribute to perioperative morbidity. For example, pain decreases patient ambulation following 
surgery, which in turn is associated with a number of post-operative complications, including 
thromboembolic events, for which the incidence (3.7%) in the RC population is the highest 
among surgical patients. 4 Additionally, the perception of pain 5 and excessive use of narcotic 
pain medications are major contributors to the development of prolonged post-operative ileus, 
which effects nearly 20% of RC patients 6 and is a major cause of prolonged hospitalization. 
Consequently, strategies aimed at improving pain control and reducing narcotic requirements 
could be beneficial in reducing both patient discomfort and the development of complications. 
Recently, the use of perioperative gabapentin has been evaluated in a number of surgical 
populations as a strategy to improve patient pain control and reduce total analgesic requirements. 
7 For example, a recent placebo controlled randomized trial demonstrated that 1,200 mg 
gabapentin given in the pre-operative suite prior to hysterectomy was associated with improved 
patient perception of pain on visual analog scale for 24 hours and an approximately 35% 
decrease in narcotic use over the first 24 hours post-operatively. 8 Similarly, in another study, 
patients receiving preoperative gabapentin prior to open cholecystectomy had an approximately 
25% relative reduction in analgesic requirements, as well as significantly decreased 
postoperative pain and nausea/vomiting compared to those receiving placebo. 9 Based on these 
encouraging data, we propose a double blind placebo controlled randomized trial evaluating the 
use of perioperative gabapentin in patients undergoing RC.   
Study Population: We will include 44 adult patients with a diagnosis of bladder cancer 
undergoing radical cystectomy with urinary diversion (ileal conduit ororthotopic neobladder, etc) 


9274 
2 
Current Version: 2/2017 
Study Design: The proposed study is a randomized double-blind placebo controlled trial 
studying the use of perioperative oral gabapentin (1,200 mg (4 X 300 mg caps) one hour before 
surgery plus 300 mg 3x’s daily for 48 hours) as an adjunct pain medication in the RC population. 
Following IRB approval and with informed consent, we plan to recruit 44 patients undergoing 
RC at UWMC to achieve a power of 0.8 at α <0.05 in order to detect a 30% difference in 
analgesic requirement over 48 hrs. Patients will be randomized 1:1 into receiving gabapentin as 
outlined above or a placebo designed to look like 300 mg caps with the same dosing. Patients 
will be stratified by urinary diversion type. Study medications will be administered by nurses in 
the pre-operative suite and on the floor.  The surgical and anesthesia/pain service team will be 
blinded to the group assignment. Following RC, all patients will receive our standard post-
operative pain management regiment, including scheduled acetaminophen (every 6 hours) and 
ketorolac (every 8 hours) and morphine patient-controlled analgesia, and will be transitioned to 
oral narcotics as clinically indicated, generally at 48 hours post-op. Patients’ postoperative pain 
will be assessed on a verbally administered numerical pain scale (NPS) (0-10 scale) at time 0 
(arrival in the recovery room) and at 1 ± 0.25, 4 ± 0.25, 12 ± 0.25, 24 ± 0.25  and 48 ± 0.25 hours 
post-RC by the patients’ nurse and prospectively recorded in the patients’ chart and abstracted by 
the study coordinator. A NPS was chosen because of their ease of use compared to visual analog 
scales, particularly for elderly patients.10 Each patient’s total analgesic use for the first 48 hours 
post-op will be recorded, as will time to first flatus and bowel movement, LOS, and adverse 
events. 
 
Study Procedure Chart: 
 
Pre-
Enrollment 
Pre-op 
Day 
of 
Surgery 
POD1 
POD2 
Recruitment 
X 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
Surgery 
 
 
X 
 
 
Medications 
Study Drug or 
Placebo 
 
 
Once 
3x’s Daily 
3x’s Daily 
Tylenol 
(acetaminophen) 
 
 
 
4x’s Daily 
4x’s Daily 
Toradol 
(ketorolac) 
 
 
 
3x’s Daily 
3x’s Daily 
Morphine  
(patient 
controlled 
analgesia) 
 
 
 
X* 
X* 
Pain Assessment 
Numeric 
Pain 
Scale (NPS) 
 
 
X 
X 
X** 
POD = post-operative day 
* will be adjusted per usual clinical care to meet patient pain requirements 
** Pain will continue to be assessed following the 48 hour time period per usual clinical care 


9274 
3 
Current Version: 2/2017 
 
Sample Size: Based on a power calculation, to achieve a power of 0.8 at α <0.05 in order to 
detect a 30% difference in 48 hour with mean morphine equivalents, with population mean of 
100 ± 50 mg we plan to enroll a total of 44 patients undergoing RC for a diagnosis of bladder 
cancer, including 22 patients in each arm. 
 
Study Duration: Based on an annual RC volume of 100 cases/year, we anticipate approximately 
7-10 patients will be eligible for our study per month. Assuming a 50% acceptance rate for 
enrollment in a clinical trial, we believe that accrual will take approximately 12 months. 
 
Objectives:  
 Primary Objectives:  
1) To assess if perioperative gabapentin will decrease post-operative analgesic 
requirements within the first 48 hours after RC in patients undergoing RC as 
measured morphine equivalents 
 Secondary Objectives:  
1) To assess patient self-assessment of postoperative pain on NPS at 24 and 48 hours 
2) To assess time to return of bowel function (ROBF) 
3) To assess length of stay (LOS) following RC 
 
Recruitment: Recruitment will be done for patients who are consenting to undergo a radical 
cystectomy with urinary diversion for a diagnosis of bladder cancer. Prior to initiation of 
recruitment, all clinic staff will undergo a briefing by Dr. Wright and the study team describing 
the study, its goals, and methodology. At the first clinic visit in which radical cystectomy is 
discussed with the patients for their diagnosis of bladder cancer, possible participants will be 
screened for enrollment in the study.  Possible participants will then for their diagnosis of 
bladder cancer, the patient will have the study described to them. If the patient expresses interest, 
informed consent will be obtained. Participants will be provided with a copy of the study design, 
IRB approval and Study Procedure Chart. Following informed consent, the patient will be 
scheduled for RC per routine care. Participants will be under no obligation to participate in the 
study and the decision whether or not to perform surgery will not be affected based on patient 
participation. All enrolled patients PHI will be stored in a locked office and all electronic PHI 
will be stored on password protected/encrypted computers and/or drives within the UW 
Department of Urology. 
 
Inclusion/Exclusion Criteria: 
 
Inclusion: 
1) Age ≥ 18 years old 
2) Diagnosis of bladder cancer 
3) Anticipated radical cystectomy with ileal conduit or orthotopic neobladder 
 
 
Exclusion: 
1) Age less than 18 years, Age > 75 years 
2) Presence of spinal cord injury including any form of paraplegia or quadriplegia 
3) Allergy to gabapentin 


9274 
4 
Current Version: 2/2017 
4) Active alcohol dependence, defined as 2 or more positive questions on the CAGE 
alcoholism questionnaire12 
5) Illicit drug use (excluding recreational marijuana) 
6) Chronic kidney disease with glomerular filtration rate <30 ml/min 
7) Pregnancy: All female patients <55 yo will be administered a urine pregnancy test 
prior to enrollment 
8) Non-English speaking patients 
9) Chronic gabapentin, or the similar drug pregabalin, use 
10) Chronic narcotic use (daily or near daily use for >90 days) 
 
Study Procedures:  
 
After consent is obtained during the clinic visit, the participant will be scheduled for RC per 
standard procedure. Participants will then undergo randomization, stratified by patient sex to 
ensure equal randomization (50% chance of receiving gabapentin) for both male and female 
patients. A third party member not involved in the study design or write-up will place participant 
study arm randomization status within a sealed envelope. On the date of surgery, the sealed 
envelope will be opened by Investigational Drug Services and the appropriate study drug 
(gabapentin or placebo) will be assigned and dispensed to the participant as described.  
 
Participants will be administered an oral dose of gabapentin (1,200 mg (4 X 300 mg caps) or an 
identical placebo (4 caps) one hour before surgery in the preoperative suite by the participants 
nurse. They will then undergo the planned procedure. Following RC, participants will be 
administered gabapentin 300 mg 3x’s daily by mouth for 48 hours or an identical placebo by the 
acute care nurse. The surgical and anesthesia/pain service team will be blinded to the group 
assignment. Following RC, all patients will receive standard post-operative pain management, 
including acetaminophen, morphine patient-controlled analgesia per the acute pain service, 
toradol and will be transitioned to oral narcotics as clinically indicated. Patients’ postoperative 
pain will be assessed on NPS (0-10 scale) at time 0 (arrival in the recovery room) and at 1 ± 
0.25, 4 ± 0.25, 12 ± 0.25, 24 ± 0.25 and 48 ± 0.25 hours post-RC. Each patient’s total analgesic 
use for the first 48 hours post-op will be recorded and converted to total morphine equivalents 
using the Agency Medical Director's Group of Washington morphine equivalents calculator 
(http://www.agencymeddirectors.wa.gov/opioiddosing.asp), as will time to first flatus and bowel 
movement, total LOS, and adverse events. Discharge from the hospital following RC will mark 
the end of each participant’s participation in the study. Subsequent follow-up and care will be per 
routine care for RC. 
 
Outcome Assessment:  The primary endpoint will be patient total equivalent analgesic 
requirement (morphine equivalents) for the first 48 hours post-RC. Secondary endpoints will 
include patient self-assessed pain on NPS, the time to ROBF will be determined by time to first 
flatus and bowel movement and LOS following RC as calculated from the date of surgery to the 
date of discharge. 
 
Statistical Analysis: Assessment of the primary outcome will be by total morphine-equivalents 
required over the first 48 hours after RC. The two study groups will be compared using the t-test 
with p<0.05 considered statistically significant. The secondary endpoints pain on NPS, time to 


9274 
5 
Current Version: 2/2017 
ROBF and LOS will be evaluated similarly.  All outcomes will be analyzed in an intention to 
treat analysis. Regression analysis will be used to determine patient and clinical factors that 
predict response to gabapentin, with adjustment for age, sex, ethnicity, analgesic use at the time 
of RC, pathologic stage, estimated blood loss, and operative time.   Data analysis will be 
performed using Stata 12.1. Based on a power calculation to achieve a power of 0.8 at α <0.05 in 
order to detect a 30% difference in analgesic requirement over 48 hrs we plan to recruit 40 
patients undergoing RC at UWMC to.  
 
Pharmaceutical Information: 
 
Gabapentin is a potent analgesic and anticonvulsant that illicits effects through unclear 
mechanisims. From an analgesic standpoint, gabapentin prevents allodynia (pain-related 
behavior in response to normally innocuous stimulus), hyperalgesia (exaggerated response to 
painful stimuli), pain-related responses in several models of neuropathic pain, and decreases 
pain-related responses after peripheral inflammation. Currently gabapentin is FDA approved as 
an anticonvulsant and for post-herpetic neuralgia and is widely used clinically for management 
of neuropathic pain, other chronic pain sources, and increasingly as an adjunct therapy for 
perioperative pain. 
 
The drug comes in many forms including 100 mg, 300 mg, 400 mg, 600 mg and 800 mg 
capsules or an oral solution. Main adverse effects are related to the principal active ingredient. 
Gabapentin may case dizziness, somnolence and other symptoms and signs of central nervous 
system depression. Additionally, gabapentin is included in an FDA warning of a possible 
association between anticonvulsant use and suicidal thoughts and behaviors. However, in a meta-
analysis including greater than 131,000 patients gabapentin was use was not associated with a 
suicide attempts (3.48/1000 person years prior to gabapentin use vs. 3.45/1000 person years after 
gabapentin prescription).13 
 
Contraindications to use include hypersensitivity to the drug or its ingredients.  
 
We will be utilizing UWMC Investigational Drug Services to provide both gabapentin (300 mg 
capsules) and placebo in identical capsules. Medications will be dispensed through UWMC 
Investigational Drug Services. 
 
Privacy and Confidentiality 
  
Human subject’s names will be kept on a password-protected database and will be linked with a 
study identification number for this study. All clinical data will be stored in a separate database 
using the study ID number without any patient identifiers. All data will be entered/stored on a 
password protected computer/drive. Written data will be stored in a locked office of the 
investigators and maintained for a maximum of three years after the completion of the study. 
 
Risk/Benefit 
 
Risk to Participants: The primary risk to participants during the study is adverse effects from the 
medication. Generally, however, gabapentin is well tolerated with the most common side effects 


9274 
6 
Current Version: 2/2017 
being dizziness and somnolence for which patients will be closely monitored. Since the 
medication will be given as part of the participants’ otherwise routine post-operative care, we do 
not anticipate other changes to their post-operative care 
 
Benefits: The study will provide level-1 evidence regarding the use of perioperative gabapentin 
in a patient population exposed to considerable perioperative pain and morbidity related to RC 
for management of bladder cancer. If efficacious, perioperative gabapentin could significantly 
reduce perioperative analgesic (narcotic) use while improving perioperative pain and 
convalescence in a high-risk patient population, thereby considerably improving their 
perioperative quality of life. 
 
Data Safety Monitoring: An independent safety monitoring board will meet every 6 months to 
monitor for adverse events. Any unexpected severe adverse event (SAE) identified will be 
reported to the FDA within 7 days. 
 
Severe Adverse Events: According to the FDA, SAE are defined as “Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect.” Additionally, “Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.” All patients will be 
monitored for AEs throughout their hospital stay. Any event determined to be a SAE by the data 
safety monitoring board will be reviewed and if determined to be unexpected will be reported to the 
FDA in accordance with (21 CFR 312.32(c)(1)(i)). 
 
Publications/Presentations: Data produced from this study will be presented at academic 
meetings/forums and will be submitted for publication in pertinent scientific journals (ie., 
Journal of Urology)  
 
Funding: This study will be funded in part by the University of Washington House-staff 
Association grant “Randomized placebo control trial of perioperative gabapentin to reduce total 
analgesic requirements in patients undergoing radical cystectomy” awarded to Drs. Wright and 
Schade. 
 
 
References 
1. 
Vaidya A, Soloway MS, Hawke C, Tiguert R, Civantos F. De novo muscle invasive bladder cancer: 
is there a change in trend? J Urol. 2001;165(1):47-50; discussion 50. 
2. 
Stimson CJ, Chang SS, Barocas DA, et al. Early and late perioperative outcomes following radical 
cystectomy: 90-day readmissions, morbidity and mortality in a contemporary series. J Urol. 
2010;184(4):1296-1300. 
3. 
Porter MP, Gore JL, Wright JL. Hospital volume and 90-day mortality risk after radical 
cystectomy: a population-based cohort study. World J Urol. 2011;29(1):73-77. 
4. 
Rice KR, Brassell SA, McLeod DG. Venous thromboembolism in urologic surgery: prophylaxis, 
diagnosis, and treatment. Rev Urol. 2010;12(2-3):e111-124. 


9274 
7 
Current Version: 2/2017 
5. 
Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg. 2000;87(11):1480-1493. 
6. 
Maffezzini M, Campodonico F, Canepa G, Gerbi G, Parodi D. Current perioperative management 
of radical cystectomy with intestinal urinary reconstruction for muscle-invasive bladder cancer 
and reduction of the incidence of postoperative ileus. Surg Oncol. 2008;17(1):41-48. 
7. 
Yan PZ, Butler PM, Kurowski D, Perloff MD. Beyond neuropathic pain: gabapentin use in cancer 
pain and perioperative pain. The Clinical Journal of Pain. 
8. 
Turan A, Karamanlioğlu B, Memiş D, Usar P, Pamukçu Z, Türe M. The analgesic effects of 
gabapentin after total abdominal hysterectomy. Anesth Analg. 2004;98(5):1370-1373, table of 
contents. 
9. 
Khademi S, Ghaffarpasand F, Heiran HR, Asefi A. Effects of preoperative gabapentin on 
postoperative nausea and vomiting after open cholecystectomy: a prospective randomized 
double-blind placebo-controlled study. Med Princ Pract. 2010;19(1):57-60. 
10. 
Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: 
IMMPACT recommendations. Pain. 2005;113(1-2):9-19. 
11. 
Ewing JA. Detecting alcoholism. The CAGE questionnaire. JAMA. 1984;252(14):1905-1907. 
12. 
Gibbons RD, Hur K, Brown CH, Mann JJ. Gabapentin and suicide attempts. Pharmacoepidemiol 
Drug Saf. 2010;19(12):1241-1247. 
 
Disclosures: The PI and all study investigators have no relevant financial relationships related to 
this study.