Clinical trial NCT06120530
Conditions: Pelvic Organ Prolapse
Sponsor: Indiana University
Start date: 2023-08-16; Completion date: 2024-03-15
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effects of 30 mL intraperitoneal Bupivacaine without epinephrine 0.25% on postoperative pain control in patients undergoing pelvic organ prolapse repair. The investigators hypothesize that use of intraperitoneal Bupivacaine will decrease postoperative pain scores and opiate consumption in the postoperative period, following pelvic organ prolapse repair.

Detailed description:

Arms: arm 1: 30 mL of bupivacaine without epinephrine 0.25% arm 2: Saline
Interventions: intervention 1: Bupivacaine intervention 2: Saline
Intervention descriptions: intervention 1: Intraperitoneal Bupivicaine without epinephrine 30 mg administered following completion of pelvic organ prolapse repair. intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
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Effect of intraperitoneal Bupivacaine on 
postoperative pain control in patients undergoing 
pelvic organ prolapse repair 
NCT06120530 
 
Support Provided by: 
Indiana University School of Medicine 
 
 


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Table of Contents: 
Study Schema 
1.0 
Background & Rationale 
2.0 
Objective(s) 
2.1 
Primary Objective 
2.2 
Secondary Objective 
2.3 
Tertiary/Exploratory/Correlative Objectives 
3.0 
Outcome Measures 
3.1 
Primary Outcome Measures 
3.2 
Secondary Outcome Measures 
3.3 
Tertiary/ Exploratory/ Correlative Outcome Measures 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 
4.2 
Exclusion Criteria 
5.0 
Study Design 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Study Calendar 
9.0 
Reportable Events 
10.0 Data Safety Monitoring 
11.0 Study Withdrawal/Discontinuation 
12.0 Statistical Considerations 
13.0 Data Management 
14.0 Privacy/Confidentiality Issues 
15.0 Follow-up and Record Retention 
16.0 References 
Appendix


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Abbreviations 
This page is optional. The list below includes some common abbreviations. However, this list 
should be customized for each protocol (i.e., abbreviations not used should be removed and 
new abbreviations used should be added to this list). 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 


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1.0 
Background & Rationale 
First introduced in the 1990’s, enhanced recovery after surgery (ERAS) is a multimodal 
perioperative approach to surgical recovery, shown to lead to early recovery and improved 
outcomes (1). One of the primary objectives of ERAS programs is appropriate pain control with 
reduction of postoperative opiate consumption. The mainstay by which most ERAS programs 
accomplish this goal is an interplay between NSAID’s, acetaminophen and local anesthesia. For 
patients undergoing pelvic organ prolapse repair -following implementation of ERAS programs- 
it has been shown that patient post discharge recovery is greatly improved and that 
postoperative opiate consumption is significantly decreased (2,3). In one study of patients 
undergoing open gynecologic procedures, they were found to have a reduction of mean opioid 
consumption of 72% with 16% of the patients opioid free prior to discharge (4). Additionally, it 
has been well documented that patients who undergo gynecologic or pelvic reconstructive 
surgery are overprescribed opiates at the time of discharge (5). It is recommended that opiate 
naïve patients be discharged with no more than 15 doses of a given narcotic and that these 
patients be individualized, as many will require less (5,6). 
One of the more controversial and under-investigated aspects of postoperative pain control in 
the field of Female Pelvic Medicine and Reconstructive Surgery (FPMRS) is the use 
intraperitoneal local anesthesia. 
The two type of peritoneum in the human body are the parietal peritoneum (PP) and visceral 
peritoneum (VP). The PP is innervated by the somatic nervous system, leading to the 
perception of localized, sharp pain (7). The VP has sub-mesothelial tissue innervated by the 
autonomic nervous system, responding to traction, distension and pressure, leading poorly 
localized, dull pain (7). We also know that the peritoneum is a highly permeable membrane 
given its long-term use in peritoneal dialysis (8). Due to blockade of free afferent peritoneal 
nerve endings, it is plausible that intraperitoneal local anesthesia has a role in management of 
postoperative pain. 
It has been documented that infiltration of local anesthetics has been shown to effectively 
control postoperative pain for patients undergoing laparoscopic, open and vaginal gynecologic 
procedures (9, 10, 11), but data is still limited as to the role of intraperitoneal local anesthetic 
lavage during pelvic reconstructive surgery. Two studies looking at the use of intraperitoneal 
lidocaine lavage at the time of total abdominal hysterectomy found that this offered 
improvement of pain control for 12 to 24 hours following the procedure with no associated 
reduction in opiate consumption (12, 13). In contrast, an RCT performed looking at the 
effectiveness of intraperitoneal Bupivacaine following laparoscopic pelvic surgery, appreciated 
significant improvement in pain (as demonstrated on a visual analog scale) and a decrease in 
analgesic requirement (14). There is also literature demonstrating improvement in patients 
perceived intraoperative discomfort at the time of postpartum tubal ligation, who receive 
intraperitoneal lidocaine (15).  
While there are some studies in gynecologic literature, most studies are present in anesthesia, 
general surgery, colorectal surgery and bariatric surgery literature (9, 16-20). In a systematic 
review of 41 RCT’s, 13 trials were identified comparing intraperitoneal Bupivacaine vs Lidocaine 
vs saline for patients undergoing laparoscopic cholecystectomy (9). In that review, seven of the 
13 trials reported improved pain relief compared to placebo, with effects lasting between 2-24 
hours (9). A recent RCT from bariatric surgery literature evaluated the effects of intraperitoneal 


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Bupivacaine vs placebo in patients undergoing bariatric surgical procedures. In this study, 106 
patients were assigned to receive intraperitoneal lavage with 50 mL of 0.2% Bupivacaine or the 
same volume of normal saline during the procedure. Using a VAS, patients postoperative pain 
was rated at 1, 4, 8 and 24 hours after surgery. This study found statistically significant 
decreased pain scores and opiate consumption among the Bupivacaine group for the first 24 
hours after surgery (19). Studies have also been performed evaluating the use of 
intraperitoneal Bupivacaine vs Tramadol for management of postoperative pain during same 
day laparoscopic surgery. In a randomized trial of 90 patients assigned to intraperitoneal 
Bupivacaine (20 mL at 0.25%), IV tramadol hydrochloride (2 mg/kg), intraperitoneal saline (20 
mL) or IV saline (2 mL) appreciated better analgesic outcomes among the Bupivacaine group 
(21). 
 
Of the local anesthetic options available, Bupivacaine is known to have a longer duration of 
action compared to its counterparts (22). The maximum dose of Bupivacaine that should be 
administered is 2.0 mg/kg without epinephrine and 2.5 mg/kg with epinephrine (22). Therefore, 
the maximum allowable dose of Bupivacaine without epinephrine 0.25% should not exceed 56 
mL in a 70 kg patient. While toxicity caused by local anesthesia can have CNS (nausea, 
vomiting, chills, pupil constriction, tinnitus, nervousness, dizziness, blurred vision, or tremors, 
followed by drowsiness, convulsions, unconsciousness, and possibly respiratory arrest as noted 
in the package insert) and CVS (depression of the myocardium, decreased cardiac output, 
heartblock, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia 
and ventricular fibrillation, and cardiac arrest as noted in the package insert when high doses or 
unintentional intravascular injection is administered) manifestations, these formulations have 
relatively wide safety margins and toxicity only occurs when these thresholds are exceeded (22, 
23). One systemic review set out to evaluate the safety profile and systemic levels of local 
anesthesia following intraperitoneal administration (23). In this review, 415 patients were 
included, 11 (2.7%) were found to have systemic levels close to or above threshold and no 
cases of clinical toxicity were observed (23).  
The purpose of this study is to evaluate the effects of 30 mL intraperitoneal Bupivacaine 
without epinephrine 0.25% on postoperative pain control in patients undergoing pelvic organ 
prolapse repair. We hypothesize that use of intraperitoneal Bupivacaine will decrease 
postoperative pain scores and opiate consumption in the postoperative period, following pelvic 
organ prolapse repair.   
 
2.0 
Objective(s) 
2.1 
Primary Objective 
2.2 
Secondary Objective 
 
2.1: To determine whether intraperitoneal Bupivacaine will decrease pain scores at 
approximately 4 hours, as determined by a numeric rating scale (NRS) in patients undergoing 
pelvic organ prolapse repair. 


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2.2: Pain scores as determined by NRS at approximately 8, 12 and 24 hours, total opiate 
consumption postoperatively while inpatient as determined by morphine milligram equivalents 
(MME), time to first narcotic dose during inpatient stay, and hospital length of stay. 
 
3.0 
Outcome Measures/Endpoints 
3.1 
Primary Outcome Measures 
3.2 
Secondary Outcome Measures 
3.1: Patient pain will be measured by means of a NRS at 4 hours after surgical pelvic organ 
prolapse repair. 
3.2: Patient pain will be measured by means of a NRS at 8, 12 and 24 hours after surgical pelvic 
organ prolapse repair. Total opiate consumption will be measured in MME, obtained from the 
electronic medical record. Time to first narcotic dose will be measured in hours and minutes. 
Hospital length of stay will be measured in days, hours and minutes. 
Patients receiving an opioid prescription after short stay surgeries have a 44% increased risk of 
long term opioid use. The first 4-24 hours postoperatively is the time when these prescriptions 
are provided. With appropriate control of postoperative pain in the first 4-24 hours, patients 
may be able to be discharge without opiate prescription. 
 
 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 


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List the criteria:  
• 
Age >= 18 years 
• 
Access to cell phone with text messaging capabilities (for same day 
surgery discharge) 
• 
Patients undergoing pelvic organ prolapse repair with peritoneal access 
4.2 
Exclusion Criteria 
List the criteria:  
• 
Bupivacaine allergy 
• 
History of epilepsy or other seizure disorder 
• 
EKG demonstrating asymptomatic sinus bradycardia <40 bpm, 
symptomatic sinus bradycardia <60 bpm, first degree AV block, second 
degree AV block, third degree AV block, prolonged QT, atrial fibrillation, 
supraventricular tachycardia, or myocardial infarction 
• 
Chronic liver disease proved by any ALT or AST elevation greater than 2x 
upper limit of normal 
• Serum bilirubin elevation in excess of 5 mg/dL 
• 
G6PD deficiency 
• 
Weight less than 100 lbs 
• 
Chronic opiate use 
5.0 
Study Design 
This will be a double blinded randomized controlled trial. This is the ideal study design as it will 
serve the purpose of measuring the effectiveness of an understudied intervention 
(intraperitoneal Bupivacaine) in the management of postoperative pain. Randomization and 
blinding will help to reduce bias and better assess cause-effect relationships between the 
intervention and outcome. This study will be done in conjunction with Investigational Drug 
Services (IDS), who will manage randomization and blinding according to their division 
protocols. Covariate to be collected include age, BMI, menopausal status, type of surgical 
procedure, surgical time, and intraoperative complications (Y/N). 
 
 
 
 
 
 
 
 
 
Obtain informed consent. Screen participants by inclusion and exclusion criteria. 
Obtain history. Document. 
Randomize 
1:1 
Arm 1 
N= 45 
Arm 2 
N= 45  
Administer study intervention (Bupivacaine vs placebo) 
Refer to section 8 


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6.0 
Enrollment/Randomization 
The patients will present to the office for a preoperative visit. At that appointment, the patient 
will be screened based on the inclusion and exclusion criteria. Consents will be obtained at that 
visit by a fellow or faculty in the female pelvic medicine and reconstructive surgery (FPMRS) 
department. 
Alternatively, patients can be screened by scheduled operation date and informed of the study 
during a preoperative phone call. In these circumstances, patients will be consented on the day 
of surgery. Consents will be obtained by a fellow or faculty in the FPMRS department. 
This study will be done in conjunction with Investigational Drug Services (IDS), who will 
manage randomization and blinding according to their division protocols. This will be done by 
means of a randomization log that is provided to IDS by the statistician involved. 
 
Patients will be randomized 1:1 to the two pain strategies using stratified randomization with 
surgery technique being the strata.  Block randomization will be used with blocks of size 4.  
Randomization lists will be constructed by the study statistician using statistical software. 
7.0 
Study Procedures 
In the study, patients will be randomized to one of two groups. Arm 1 will be participants who 
receive intraperitoneal bupivacaine and arm 2 will be participants who receive placebo (saline).  
All patients involved in the study will be undergoing pelvic organ prolapse surgery with 
peritoneal access and will receive either 30 mL of 0.25% Bupivacaine or 30 mL of saline by 
means of intraperitoneal lavage. This will be performed at which point peritoneal access will no 
longer be available, and the solution will be left in the abdomen upon completion of the 
procedure.  
Preoperatively, patients will receive a standardized pain control regimen of Ibuprofen and 
Tylenol in accordance with hospital ERAS protocol. Postoperatively, patients will receive 
standardized pain control regimen of Ibuprofen and Tylenol in accordance with hospital ERAS 
protocol. Patients can be given as needed narcotics if pain is poorly controlled on the initial 
regimen. 
All patients will have pain scores measured at approximately 4 hours using a NRS following 
completion of the procedure. All patient will have pain scores measured at approximately 8, 12 
and 24 hours by means of text message NRS (in the event of same day surgery discharge) vs 
inpatient in person NRS (for planned admission), following completion of the procedure, which 
will be stored directly into REDCap. Time to first narcotic dose will be obtained through the 
hospital electronic medical record. Hospital length of stay will be obtained through the hospital 
electronic medical record. 
8.0 
Study Calendar 
Enrollment 
Surgery day 
4h 
8h 
12h 
24h 


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Consent 
Either 
intervention or 
placebo 
Pain assessed 
with NRS 
Pain assessed 
with NRS 
Pain assessed 
with NRS 
Pain assessed 
with NRS 
 
9.0 
Reportable Events 
Adverse Event (AE):  
Any medical occurrence in a human study participant, assessed by the principal investigator (PI) 
that is: 
• 
Unexpected (in terms of nature, severity, or frequency) given the research procedures 
that are described in the study-related documents, and the characteristics of the subject 
population being studied 
• 
Related or possibly related to study participation 
• 
Suggests that the research places subject(s) or others at greater risk of harm than was 
previously known. 
Serious Adverse Event (SAE):  
• 
Results in death  
• 
Is life threatening, or places the participant at immediate risk of death from the event as 
it occurred  
• 
Requires or prolongs hospitalization  
• 
Causes persistent or significant disability or incapacity  
AE’s and SAE’s will be reported as required in accordance with the IU HRPP Policy on 
Reportable Events..  
10.0 Data Safety Monitoring 
A data safety monitoring board (DSMB) composed of Douglass S. Hale (FPMRS faculty), Jennifer 
Hamner (FPMRS faculty), Elizabeth Fuller (FPMRS faculty) and Krystine Haglin (FPMRS fellow) 
will be scheduled to meet every 6 months and review the data for patient safety. This will be 
monitored as part of the Data Safety Monitoring Plan (DSMP): data quality, subject recruitment, 
accrual, retention, outcome and adverse event data, assessment of scientific reports or 
therapeutic development, results of related studies that may impact subject safety, and 
procedures designed to protect the privacy of subjects.  
The purpose of this committee will be to evaluate logistical problems and determine if the study 
should be stopped. Examples of logistical problems would include enrollment rates, follow up 
rates, or dropout rates. Reasons to stop the study would include if the objective is met 
prematurely, if the study gives sufficient data against the premise, if the study is proven to be 
futile, or if there is high index of suspicion that the intervention is harmful. The DSMB will also 
advise about study progress and performance, protocol changes, and if additional monitoring is 
necessary. 


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11.0 Study Withdrawal/Discontinuation 
Participants will be withdrawn from the study if they refuse to answer the NRS at the 
approximate 4 hour mark. Participants may elect to discontinue their involvement in the study 
at any time. In events of participant withdrawal, we will assess if they would like complete 
withdrawal of all data or up to that point of their involvement. 
12.0 Statistical Considerations 
Sample size/Power 
 
This is a double-blind randomized controlled study to compare two techniques of pain 
management strategies for woman undergoing advance-organ prolapse surgery with the 
primary outcome being the numeric rate scale (NRS) at 4 hours post-surgery.  Secondary 
outcomes will be the NRS collected at 8, 12, and 24 hours, and an indicator of whether woman 
required opioids (Y/N) within 4 hours of surgery.   
 
Assuming a SD = 2.142 in the NRS at 4 hours, to detect a meaningful change of 1.3 would be 
an ES = 0.60 (1.3/2.14).  To have 80% power to detect an effect size of this magnitude (i.e., a 
0.6 SD difference in the NRS between treatment arms) based on a two-sided two-sample 
independent t-test with type I error set at 0.05 requires a total sample size of N = 90 (45 per 
group).  As we expect no attrition or missing data on the primary outcome, N = 90 will be our 
planned sample size.   
 
Randomization 
 
Patients will be randomized 1:1 to the two pain strategies using stratified randomization with 
surgery technique being the strata.  Block randomization will be used with blocks of size 4.  
Randomization lists will be constructed by the study statistician using statistical software. 
 
Statistical Methods 
 
Descriptive statistics of N, mean, standard deviation, median, minimum, and maximum or 
frequency and percent will be provided for all baseline characteristics overall and by treatment 
arm. Baseline characteristics which will be reported include surgical procedure (uterosacral 
ligament suspension vs sacrocolpopexy), age, BMI, menopausal status, surgical time, and 
intraoperative complications.  Intraoperative complication will be a dichotomous variable of 
whether any complication occurred (Y/N).  Baseline characteristics will be compared between 
the two study arms to verify randomization achieved balanced groups.  Any characteristics that 
significantly differ will be considered in subsequent analyses. 
 
Assuming baseline characteristics are balanced between the two study arms, we will use a 
linear mixed model fit to all timepoints (4, 8, 12, and 24 hours) with effects of surgery 
technique, treatment group, time, and the time x treatment group interaction to estimate the 
mean difference in treatment groups at each time point.  All model assumptions will be checked 
for adequacy.  The mean difference and 95% confidence interval at each time point will be 
reported.  A p-value of 0.017 will be used to indicate statistical significance in the NRS collected 
at the three other time points (8, 12, and 24) to maintain familywise type I error at .05.  For 


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the dichotomous outcome of whether patients required opioids in the first 4 hours following 
surgery, a Fisher’s exact test will be used. 
 
Other outcomes can only be assessed among those that required opioids thus will have lower 
power.  Thus, caution will be used in interpretation of results.  These include the amount of 
MME in the first four hours and time to first dose.  Descriptive statistics by study group will be 
estimated.  For outcomes which may be normal, then a linear regression model will be fit with 
effect of surgery technique and treatment, to estimate the mean difference in the outcome by 
treatment and associated 95% confidence interval.  If any outcome is non-normal, then a 
generalized linear regression model will be used instead with an appropriate distribution and 
link function to detect the effect of treatment. 
 
1. 
Cohen J. Statistical power analysis for the behavioral sciences. L. Erlbaum Associates; 1988. 
2. 
Benlolo S, Hanlon JG, Shirreff L, Lefebvre G, Husslein H, Shore EM. Predictors of Persistent 
Postsurgical Pain After Hysterectomy-A Prospective Cohort Study. J Minim Invasive Gynecol. Dec 
2021;28(12):2036-2046.e1. doi:10.1016/j.jmig.2021.05.017 
 
13.0 Statistical Data Management 
Primary and secondary objective data will be collected and stored electronically in one REDCap. 
The storage location will be backed up automatically every day. Quality assurance steps will 
include testing of database by study team prior to moving to production mode. The following 
quality control methods will be used extraction and cleaning of data that will be used for 
analysis every 6 months. 
14.0 Privacy/Confidentiality Issues 
Every effort will be made to keep personal information confidential, but we cannot guarantee 
absolute confidentiality. No information which could identify participants will be shared in 
publications about this study. All data will be stored on an encrypted database (REDCap), and 
only team members who have appropriate training requirements will have access to private 
health information. 
15.0 Follow-up and Record Retention 
Data will be retained in accordance with the IU HRPP Policy on Research Data Management.  
16.0 References 
 
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