Multimodal Pain Management After Robotic-Assisted Total Laparoscopic Hysterectomy
Phase: PHASE3
Conditions: Pain, Postoperative
Sponsor: State University of New York at Buffalo

 
Official Title: 
Multimodal Pain Management After Robotic-Assisted Total Laparoscopic Hysterectomy 
NCT number: 
04429022 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the Document: 5.10.2023

Multimodal Pain Management After Robotic-Assisted 
Total Laparoscopic Hysterectomy 
National Clinical Trial (NCT) Identified Number:  04429022 
UB Protocol Number: 00004549 
Principal Investigator: Sarah Andres, D.O. 
Sponsor: University at Buffalo 
Funded by: Not applicable 
Version Number:  v.1.0 
10 May 2023 
 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
 
 
 
 
 
 

  
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 2 
2 
INTRODUCTION ............................................................................................................................................ 4 
2.1 
Study Rationale .................................................................................................................................... 4 
2.2 
Background........................................................................................................................................... 4 
2.3 
Risk/Benefit Assessment .................................................................................................................... 5 
2.3.1 
Known Potential Risks ..................................................................................................... 5 
2.3.2 
Known Potential Benefits ................................................................................................ 5 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 5 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 6 
4 
STUDY DESIGN ............................................................................................................................................. 6 
4.1 
Overall Design ...................................................................................................................................... 6 
4.2 
Scientific Rationale for Study Design................................................................................................ 7 
4.3 
Justification for Dose ........................................................................................................................... 8 
4.4 
End of Study Definition ....................................................................................................................... 8 
5 
STUDY POPULATION .................................................................................................................................. 8 
5.1 
Inclusion Criteria .................................................................................................................................. 8 
5.2 
Exclusion Criteria ................................................................................................................................. 8 
5.3 
Lifestyle Considerations ...................................................................................................................... 8 
5.4 
Screen Failures .................................................................................................................................... 8 
5.5 
Strategies for Recruitment and Retention ........................................................................................ 8 
6 
STUDY INTERVENTION .............................................................................................................................. 9 
6.1 
Study Intervention(s) Administration ................................................................................................. 9 
6.1.1 
Study Intervention Description ....................................................................................... 9 
6.1.2 
Dosing and Administration ............................................................................................ 10 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 10 
6.2.1 
Acquisition and accountability ...................................................................................... 10 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 10 
6.2.3 
Product Storage and Stability ....................................................................................... 11 
6.2.4 
Preparation ...................................................................................................................... 11 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 11 
6.4 
Study Intervention Compliance ........................................................................................................ 11 
6.5 
Concomitant Therapy ........................................................................................................................ 11 
6.5.1 
Rescue Medicine ............................................................................................................ 11 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 11 
7.1 
Discontinuation of Study Intervention ............................................................................................. 11 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 12 
7.3 
Lost to Follow-Up ............................................................................................................................... 12 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 13 
8.1 
Efficacy Assessments ....................................................................................................................... 13 
8.2 
Safety and Other Assessments ....................................................................................................... 14 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 15 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 15 

  
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 15 
8.3.3 
Classification of an Adverse Event .............................................................................. 16 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 16 
8.3.5 
Adverse Event Reporting .............................................................................................. 17 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 17 
8.3.7 
Reporting Events to Participants ................................................................................. 17 
8.3.8 
Events of Special Interest ............................................................................................. 17 
8.3.9 
Reporting of Pregnancy ................................................................................................ 18 
8.4 
Unanticipated Problems .................................................................................................................... 18 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 18 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 18 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 18 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 19 
9.1 
Statistical Hypotheses ....................................................................................................................... 19 
9.2 
Sample Size Determination .............................................................................................................. 19 
9.3 
Populations for Analyses .................................................................................................................. 19 
9.4 
Statistical Analyses............................................................................................................................ 19 
9.4.1 
General Approach .......................................................................................................... 19 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 20 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 20 
9.4.4 
Safety Analyses .............................................................................................................. 20 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 20 
9.4.6 
Planned Interim Analyses ............................................................................................. 20 
9.4.7 
Sub-Group Analyses ..................................................................................................... 20 
9.4.8 
Tabulation of Individual participant Data .................................................................... 20 
9.4.9 
Exploratory Analyses ..................................................................................................... 20 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 20 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 20 
10.1.1 
Informed Consent Process ........................................................................................... 20 
10.1.2 
Study Discontinuation and Closure ............................................................................. 21 
10.1.3 
Confidentiality and Privacy ........................................................................................... 21 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 22 
10.1.5 
Key Roles and Study Governance .............................................................................. 22 
10.1.6 
Safety Oversight ............................................................................................................. 22 
10.1.7 
Clinical Monitoring .......................................................................................................... 22 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 23 
10.1.9 
Data Handling and Record Keeping ............................................................................ 23 
10.1.10 
Protocol Deviations ........................................................................................................ 23 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 24 
10.1.12 
Conflict of Interest Policy .............................................................................................. 24 
10.2 
Additional Considerations ................................................................................................................. 24 
10.3 
Abbreviations ...................................................................................................................................... 25 
10.4 
Protocol Amendment History ........................................................................................................... 27 
11 
REFERENCES ............................................................................................................................................. 28 
 

Multimodal Pain Management After Robotic-Assisted Total Laparoscopic Hysterectomy 
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STATEMENT OF COMPLIANCE 
The trial was conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and applicable United States (US) Code of Federal Regulations (CFR). The Principal 
Investigator assured that no deviation from, or changes to the protocol will take place without prior 
agreement from the Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor, 
funding agency and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the 
conduct of this study have completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials were 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form were 
obtained before any participant was enrolled. During this study, no amendments were made to the 
protocol or consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Multimodal Pain Management After Robotic-Assisted Total Laparoscopic 
Hysterectomy 
Study Description: 
The standard of care for pain management after laparoscopic 
hysterectomy is non-specific, however in light of the ongoing opioid 
epidemic, a transition to non-opioid pain medication regimens is desired 
by both physicians and patients. This study aims to create a standardized 
non-opioid multimodal pain management regimen for women undergoing 
robotic hysterectomy with the goal of minimizing postoperative opioid 
usage. Using a prospective cohort with historical controls study design, a 
traditional opioid based pain medication was compared to a multimodal 
pain protocol which included an emphasis on non-opioid pain medications. 
Objectives: 
Primary Objective: To decrease opioid use (measured in morphine 
milligram equivalents or MME) following Robotic-Assisted Total 
Laparoscopic Hysterectomy (RA-TLH) 
 
Secondary Objectives: To decrease inpatient length of stay (LOS) and pain 
following RA-TLH 
Endpoints: 
Primary Endpoint: Total opioid pain medications required hour 0-3 post-
operatively in morphine milligram equivalents (MME), Total opioid pain 
medications required through hours 3-24 post-operatively in MME. 
Secondary Endpoints: Length of stay in hours, pain scores, return to the 
clinic or emergency department (ED) due to post-operative pain within 
two weeks of hospital discharge. 
Study Population: 
Adult women undergoing robotic-assisted total laparoscopic hysterectomy 
with a single surgeon in Western New York 
Description of 
Sites/Facilities Enrolling 
Participants: 
Single site study enrolling at an academic-affiliated community hospital  
Description of Study 
Intervention: 
A standardized non-opioid multimodal pain management regimen was 
designed for women undergoing robotic hysterectomy with the goal of 
minimizing postoperative opioid usage. Using a prospective cohort with 

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historical controls study design, a traditional opioid based pain medication 
was compared to a multimodal pain protocol which included an emphasis 
on non-opioid pain medications. Pain medications were given pre-
operatively, intra-operatively and post-operatively, via oral, intravenous 
and intramuscular or subcuticular routes. 
Describe the study intervention. If the study intervention is a drug or 
biologic, include dose and route of administration.   
Study Duration: 
11.27.2018- 5.24.2022 
Participant Duration: 
seven days 
 
 
1.2 
SCHEMA 
    
 
 
 
 
 
 
 
 
 
 

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INTRODUCTION 
2.1 
STUDY RATIONALE  
The standard of care for pain management after laparoscopic hysterectomy is non-specific, however in 
light of the ongoing opioid epidemic, a transition to non-opioid pain medication regimens is desired by 
both physicians and patients. 
 
2.2 
BACKGROUND  
Hysterectomy is the most common major gynecologic surgery performed in the US and is performed for 
a variety of indications including malignancy, pelvic mass, endometriosis, leiomyoma, and pelvic organ 
prolapse (5). The standard of care for pain management after laparoscopic hysterectomy is non-specific. 
This includes general anesthesia and a focus on non-opioid pain medications. Unfortunately, there is no 
standardized medication regimen as standard of care and pain management after hysterectomy varies 
widely from surgeon to surgeon. The traditional regimen for post-operative pain control is opioid-based, 
however there is limited research regarding the necessary amount of opioids required for adequate pain 
relief postoperatively. Some studies suggest that patients only take 28% of prescribed opioids (4). A 
recent case-control cohort study by Dr. Mark from Roswell Park regarding ultra-restrictive opioid 
prescribing after laparoscopic or robotic surgery showed no change in pain scores, complications or 
medication refill requests; suggesting that far fewer opioids can be prescribed after surgery (7). New 
persistent opioid use is a common and under-recognized surgical complication which occurs in 6.5% of 
patients undergoing major surgery (3). In light of the ongoing opioid epidemic, a transition to non-opioid 
pain medication regimens is desired by both physicians and patients alike.  
 
A recent quality improvement study by Adajar showed a reduction in post-operative opioid use with a 
pain medication regimen using gabapentin, celecoxib, acetaminophen and local ropivacaine at 
laparoscopic port sites (1). Multiple small randomized control trials have shown a reduction in post-
operative opioid use when a paracervical block is used in the setting of a vaginal hysterectomy (2). The 
goal of our study is to assess the effect of a multimodal non-opioid pain medication regimen- including 
gabapentin, celecoxib, acetaminophen, ketorolac, ropivacaine at port sites combined with a paracervical 
block- on postoperative opioid use after robotic assisted total laparoscopic hysterectomy. We chose this 
regimen after considering success in prior studies, cost minimization and resource availability. While 
NSAIDs such as celecoxib and ketorolac are associated with risks of renal insufficiency and gastric ulcers, 
these risks are dose dependent and these medications are well-tolerated in the majority of our patient 
population. NSAIDs have become a staple in pain medication regimens due to their capacity to 
effectively treat pain after hysterectomy while minimizing opioid use (5). Ropivacaine was chosen due to 
its longer half- life than lidocaine as well as its cost and resource availability as compared to liposomal 
bupivacaine. An emphasis was placed on pain medications taken by mouth or per os (PO) to facilitate 
post-operative milestones and decreased length of stay. The pain medications chosen in the above 
multimodal regimen are largely well-tolerated by patients, effectively treat pain and show promise in 
reducing opioid use-postoperatively.  
 
Our primary outcomes are total opioid pain medications required hours 0-3 and hours 3- 24 post-
operatively in morphine milligram equivalents (MME). Opioid pain medications will be reported in MME, 
as it is most often reported in literature, to increase generalizability and applicability.   
 
Our study design is a prospective cohort study with historical controls. While a randomized control trial 
would be ideal, the expected variation in outcomes precludes this possibility at this institution. Because 

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of the wide variation in opioid needs postoperatively, an adequately powered randomized control trial 
would require significantly higher case numbers than available at this institution. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS  
When taking any medication, there is a risk of allergic reaction. Standard of care medications after 
hysterectomy include Tylenol and NSAIDs such as ibuprofen. As with the above medications and any 
medication in general, the medications in this study inherently carry a potential risk of allergic reaction. 
There is a risk of allergic reaction gabapentin and celecoxib. Most allergic reactions are minimal and 
treated quickly with a resolution of allergic symptoms in less than 4 hours. There is a risk of toxicity from 
local anesthetic, ropivacaine. All medications are considered safe in study outlined dosages and 
regimen.  
 
The paracervical block carries small, preventable risks to the patient. The dosage of ropivacaine local 
anesthetic has been titrated to provide maximal pain relief and minimize chance of toxicity. Toxicity is 
always possible however all steps to minimize toxicity (e.g. ensuring injection into cervical stroma not 
blood vessel) will be undertaken. 
 
During any surgery, there is an inherent risk of needle stick. There is a risk to surgeons and staff of 
needle-stick during paracervical block. As a whole, the paracervical block does not significantly increase 
the risk profile of the procedure. 
 
Breach of confidentiality is always a risk however collected information in this study is generally benign. 
Assigning a number to each record in the spreadsheet and coding the record will minimize it risk for 
breach of confidentiality. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Subjects may decrease need for opioid medication for pain management. This may decrease their risk of 
opioid addiction. They may have lower pain scores and therefore decreased pain after surgery. They 
may have a decreased length of hospital stay. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Potential risks and benefits were discussed with all patients in an informed consent discussion with their 
surgeon. Overall, risk of harm during participation in this study was deemed minimal. Subjects were 
monitored in the hospital while taking prescribed study medications. No new medications were 
prescribed for the patient to take at home; all medications had been trialed by the patient in the 
hospital. 
 
 
 
 
 
 
 
 
 

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3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To decrease opioid use (measured in 
morphine milligram equivalents or 
MME) following RA-TLH 
1. Total opioid pain medications 
required hour 0-3 post-
operatively in MME 
2. Total opioid pain medications 
required through hours 3-24 
post-operatively in MME 
Objective measurement 
of opioid use in the 
immediate and longer 
term postoperative 
periods 
Secondary 
 
 
To decrease inpatient length of stay 
(LOS) and pain following RA-TLH. To 
minimize postoperative complications 
related to pain management. To 
establish safety and efficacy of the 
intervention.  
1. Length of stay in hours 
2. Pain scores 
3. Return to the clinic or 
emergency department (ED) due 
to post-operative pain within 
two weeks of hospital discharge 
Objective markers of 
post-operative 
complications 
 
 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
The purpose of this study was to create a non-opioid multimodal pain regimen for women undergoing 
gynecologic robotic surgery with the goal of minimizing postoperative opioid usage. We hoped to create 
a protocol that was feasible for implementation in a majority of gynecologic practices. 
 
We hypothesized that there is no difference in post-operative opioid use between a multimodal pain 
medication regimen and traditional opioid-based pain medication regimen. 
 
This study is a single site, prospective cohort study with historical controls. While a randomized control 
trial would be ideal, the expected variation in outcomes precludes this possibility at this institution. 
Because of the wide variation in opioid needs postoperatively, an adequately powered randomized 
control trial would require significantly higher case numbers than available at this institution. Our study 
took place from November of 2018 to December of 2022.  
 
To prevent bias in our interventional group, patients will be monitored in the same manner as historical 
controls. No changes will be made to the patient’s ability to obtain pain medications nor assessing their 
pain scores. 
 
The study interventions included a multimodal pain management protocol with an emphasis on non-
opioid pain medications. Standardized protocol is listed below.  
 
Pre-op:  Gabapentin 600mg PO once and Acetaminophen 1000mg per os (PO) once 
Intra-op: Paracervical block with 0.5% ropivacaine; 10mL bilaterally for total of 20mL 
Ropivacaine 0.5% injection at laparoscopic port sites; 10mL spread equally between all port sites 

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Operate at goal of intraabdominal pressure of 12mmHg; max 15mmHg 
 
Ketorolac 30mg IV once at end of procedure 
Post-op: Gabapentin 300mg PO twice daily (BID) for seven days 
 
Acetaminophen 975mg PO every six hours (q6h) for two days then 975mg q6h as needed (PRN) 
 
Celecoxib 200mg PO q12h for seven days 
 
Hydromorphone 1mg IV PRN q3h 
 
Oxycodone 5mg PO PRN q4h while inpatient 
Discharge home medications:  Gabapentin 300mg PO BID for seven days 
 
 
 
 
Acetaminophen 975mg PO q6h x 2d then 975mg q6h PRN 
 
 
 
 
Celecoxib 200mg PO q12h for seven days 
 
 
 
 
+/- oxycodone 5mg PO q4h x 12 tablets* 
*If patient uses opioid medication while hospitalized, will discharge home with oxycodone 5mg PO q4h x 
12 tablets   
 
Patients in the prospective cohort group were compared to historical controls who underwent surgery 
without a standardized pain management protocol.  
 
No interim analysis was planned and no sub-group analyses were performed. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
A recent quality improvement study by Adajar showed a reduction in post-operative opioid use with a 
pain medication regimen using gabapentin, celecoxib, acetaminophen and local ropivacaine at 
laparoscopic port sites (1). Multiple small randomized control trials have shown a reduction in post-
operative opioid use when a paracervical block is used in the setting of a vaginal hysterectomy (2). The 
goal of our study is to assess the effect of a multimodal non-opioid pain medication regimen- including 
gabapentin, celecoxib, acetaminophen, ketorolac, ropivacaine at port sites combined with a paracervical 
block- on postoperative opioid use after robotic assisted total laparoscopic hysterectomy. We chose this 
regimen after considering success in prior studies, cost minimization and resource availability.  
 
While NSAIDs such as celecoxib and ketorolac are associated with risks of renal insufficiency and gastric 
ulcers, these risks are dose dependent and these medications are well-tolerated in the majority of our 
patient population. NSAIDs have become a staple in pain medication regimens due to their capacity to 
effectively treat pain after hysterectomy while minimizing opioid use (5). Ropivacaine was chosen due to 
its longer half- life than lidocaine as well as its cost and resource availability as compared to liposomal 
bupivacaine. An emphasis was placed on pain medications taken by mouth or per os (PO) to facilitate 
post-operative milestones and decreased length of stay. The pain medications chosen in the above 
multimodal regimen are largely well-tolerated by patients, effectively treat pain and show promise in 
reducing opioid use-postoperatively.  
 
Our primary outcomes are total opioid pain medications required hours 0-3 and hours 3- 24 post-
operatively in morphine milligram equivalents (MME). Opioid pain medications will be reported in MME, 
as it is most often reported in literature, to increase generalizability and applicability.   
 
Our study design is a prospective cohort study with historical controls. While a randomized control trial 
would be ideal, the expected variation in outcomes precludes this possibility at this institution. Because 
of the wide variation in opioid needs postoperatively, an adequately powered randomized control trial 
would require significantly higher case numbers than available at this institution. 

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To prevent bias in our interventional group, patients will be monitored in the same manner as historical 
controls. No changes will be made to the patient’s ability to obtain pain medications nor assessing their 
pain scores. 
 
4.3 
JUSTIFICATION FOR DOSE 
Standard NSAID, acetaminophen and gabapentin dosing was chosen for their established safety. 
Ropivacaine dosing was standardized at a weight-safe dose. 
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study when seven days postoperative as this was 
deemed the standard immediate postoperative recovery period. Participants were monitored until 
postoperative day 14, to collect all data on return to clinic or the emergency department for pain. 
 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Female, of reproductive age or postmenopausal, undergoing hysterectomy 
4. In good general health as evidenced by medical history and without below exclusion criteria 
5. Uterine weight <325g on postoperative pathologic report 
6. Ability to take oral medication and be willing to adhere to the study intervention regimen 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Current use of opioid prescription or current opioid addiction 
2. Presence of contraindication to study medication; eg: gastric bypass, gastric ulcers, chronic 
kidney disease 
3. Known allergic reactions to study medications 
4. Non-English speaking patients, cognitively impaired adults 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable.  
 
5.4 
SCREEN FAILURES 
Not applicable, due to study design. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
The target study sample size was 200 women, with 100 subjects in the prospective intervention group 
and 100 subjects in the historical control group. We anticipated screening 200 subjects to reach the 
target sample for the prospective intervention group and screening 200 subjects to reach the target 
sample for the historical control group.  

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We expected 200 eligible prospective intervention subjects to be available within the anticipated 
recruitment period therefore only one in two potential subjects must agree. We expected to review 200 
charts within the anticipated collection period to obtain 100 historical control subjects. 
 
For the prospective intervention group, subjects undergoing hysterectomy were screened by the 
surgeon and the PI at their pre-operative visit. Patients were screened with a thorough history and 
physical to ensure they have no contraindication to the study intervention medications (ex: allergy, h/o 
gastric bypass, gastric ulcers, chronic kidney disease). Patients with current opioid prescription and 
current opioid addiction were excluded from both the historical controls and intervention arm. 
Cognitively impaired and non-English speaking patients were excluded. If eligible, patients were given 
verbal and written information regarding the study protocol. 
 
Historical controls were identified through EMR chart search for RA-TLH procedure performed by the 
surgeon. A review of the electronic chart via Surginet was used to screen for historical control eligibility. 
Reports were run to identify potential participants with the following criteria: date, physician and 
procedure. Further screening by the PI to exclude patients with exclusion criteria was then applied. 
Patients with contraindication to any study medications (ex: allergy, h/o gastric bypass, gastric ulcers, 
chronic kidney disease) were excluded. Patients with current opioid prescription and current opioid 
addiction were excluded from both the historical controls and intervention arm. Cognitively impaired 
and non-English speaking patients were excluded. 
 
As the study population included only adult women undergoing planned hysterectomy, pregnant 
women were excluded. Vulnerable participants including those who lack consent capacity, such as the 
mentally ill, prisoners, cognitively impaired participants and children were excluded.   
 
Participants were not compensated or provided any compensation. 
 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
As a preface, the standard of care for pain management after laparoscopic hysterectomy is non-specific. 
This includes general anesthesia and a focus on non-opioid pain medications with adequate treatment 
of pain. Unfortunately, there is no standardized medication regimen as standard of care after 
hysterectomy. As a result, pain management after hysterectomy varies widely from surgeon to surgeon 
and historically, there has been a heavy reliance on opioid pain medications.  
 
Intervention: 
Pre-op: Gabapentin 600mg PO PO x 1 prior to surgery (in pre-op), Acetaminophen 1000mg PO x1 prior 
to surgery (in pre-op) 
Intra-Op: Paracervical block with local anesthetic (0.5% ropivacaine); 10 mL bilaterally (2 injection sites) 
for total of 20mL. Local anesthetic (0.5% ropivacaine) injected at all laparoscopic port sites; 10mL spread 
equally between laparoscopic port incisions. Will operate at <15mmHg intra-abdominal pressure with a 
goal of <12mmHg. At end of procedure during closure of fascia, 30mg ketorolac IV will be given once. 
Post-Op: Gabapentin 300mg PO BID for 7 days, Acetaminophen 1000mg PO q6h x 2 days then 1000mg 
q6h PRN, Celecoxib 200mg PO q 12h x 7d. Hydromorphone 1mg IV PRN q3h and oxycodone 5mg PO PRN 
q4h while inpatient. Oxycodone 5mg PO x 12 tabs upon discharge (90MME) if patient needed opioid 
medications while hospitalized; if no opioid used while inpatient, patient will be discharged home with 

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only non-opioid pain medications. Patients will receive standard post-operative medications such as 
zofran, metoclopramide. Per standard of care, patients will be asked to rate their pain, on a scale from 1 
to 10, by nursing staff prior to administration of pain medications.  
After discharge, the patient’s opioid use while inpatient will be calculated in MME in addition to LOS in 
hours. MME will be calculated using the MDCalc MME calculator which uses the Centers for Disease 
Control and Prevention (CDC) conversion for various opioids to morphine equivalents. Pain scores are 
recorded in the medication administration record (MAR); pain scores from hour 0 – 3 and hour 3 to 24 
postoperatively will be averaged, respectively.  
 
Control: 
Patients may or may not have received Toradol during or after their procedure. The mainstay of pain 
medication regimen was opioid containing medications such as hydromorphone and oxycodone. 
Patients received standard post-operative medications such as zofran, metoclopramide. Per standard of 
care, patients were asked to rate their pain, on a scale from 1 to 10, by nursing staff prior to 
administration of pain medications. 
 
After discharge, the patient’s opioid use while inpatient will be calculated in MME in addition to LOS in 
hours. MME will be calculated using the MDCalc MME calculator which uses the Centers for Disease 
Control and Prevention (CDC) conversion for various opioids to morphine equivalents.  Pain scores are 
recorded in the medication administration record (MAR); pain scores from hour 0 – 3 and hour 3 to 24 
postoperatively will be averaged, respectively. 
6.1.2 DOSING AND ADMINISTRATION 
Pre-op: Gabapentin 600mg PO PO x 1 prior to surgery (in pre-op), Acetaminophen 1000mg PO x1 prior 
to surgery (in pre-op) 
 
Intra-Op: Paracervical block with local anesthetic (0.5% ropivacaine); 10 mL bilaterally (2 injection sites) 
for total of 20mL. Local anesthetic (0.5% ropivacaine) injected at all laparoscopic port sites; 10mL spread 
equally between laparoscopic port incisions. Will operate at <15mmHg intra-abdominal pressure with a 
goal of <12mmHg. At end of procedure during closure of fascia, 30mg ketorolac IV will be given once. 
 
Post-Op: Gabapentin 300mg PO BID for 7 days, Acetaminophen 1000mg PO q6h x 2 days then 1000mg 
q6h PRN, Celecoxib 200mg PO q 12h x 7d. Hydromorphone 1mg IV PRN q3h and oxycodone 5mg PO PRN 
q4h while inpatient. Oxycodone 5mg PO x 12 tabs upon discharge (90MME) if patient needed opioid 
medications while hospitalized; if no opioid used while inpatient, patient will be discharged home with 
only non-opioid pain medications. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Medications will originate from a Kaleida pharmacy at Millard Fillmore Suburban Hospital and be stored 
in the Pyxis medication dispensing station. The Pyxis machine is password and badge protected with 
medications assigned to specific study patients. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
The study intervention is a multimodal pain medication regimen including gabapentin, acetaminophen, 
celecoxib, ketorolac, oxycodone, paracervical block with 0.5% ropivacaine, and 0.5% ropivacaine at all 

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robotic port sites. No changes were made to the standard formulation, appearance, packaging or 
labeling to the above standard Kaleida administered medications. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
The study intervention is a multimodal pain medication regimen including gabapentin, acetaminophen, 
celecoxib, ketorolac, oxycodone, paracervical block with 0.5% ropivacaine, and 0.5% ropivacaine at all 
robotic port sites. No changes were made to the standard product storage of the above Kaleida 
administered medications in the Pyxis medication dispensing station. 
 
6.2.4 PREPARATION 
The study intervention is a multimodal pain medication regimen including gabapentin, acetaminophen, 
celecoxib, ketorolac, oxycodone, paracervical block with 0.5% ropivacaine, and 0.5% ropivacaine at all 
robotic port sites. No preparation for any of these medications was required; no thawing, diluting, 
mixing, or reconstitution was required. All medications administered during the intervention protocol 
were administered without additional preparation after being obtained from the Pyxis medication 
dispensing station. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable due to study design. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Consent documents were doubly reviewed by two providers. Adherence to the study protocol was 
verified by a double provider review of the patients’ EMR chart and medication administration 
summary. The surgeon was additionally present during all portions of the patients’ hysterectomy. 
 
6.5 
CONCOMITANT THERAPY 
All medications taken for chronic medical conditions were continued during the study period in both the 
intervention and control groups. No independent effects were expected from these medications and no 
effect on study outcomes was anticipated. 
 
6.5.1 RESCUE MEDICINE 
Not applicable as no rescue medications were used. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from the intervention arm does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol.  If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
medications administered 
• 
reason for study discontinuation 

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• 
time and date of discontinuation 
 
Data will be reviewed on a weekly basis by the PI to ensure no adverse events are occurring. All subjects 
will have their study data reviewed within a week of their surgery. The surgeon will report any adverse 
events throughout the study duration to the PI should a patient call or present to their office with an 
adverse event. All adverse events including medication reactions will be reviewed. Safety endpoints 
include allergic reaction to medications. Safety information will be collected in a case report form, on a 
weekly basis. The PI will review safety data. Cumulative safety data will be reviewed every 6 months. 
The safety data will be analyzed with rate of adverse events to determine if harm is occurring.  
 
A serious adverse event in response to a paracervical block will trigger an immediate suspension of 
research. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• Significant study intervention non-compliance  
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best interest of the 
participant 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• Participant unable to receive study intervention 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form but do not receive the study 
intervention may be replaced.  Subjects who sign the informed consent form and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study, will be 
replaced. 
 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for her post-operative visit 
and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• The site will attempt to contact the participant and reschedule the missed visit within 1 week 
and counsel the participant on the importance of maintaining the assigned visit schedule and ascertain if 
the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
EFFICACY ASSESSMENTS  
For the prospective intervention group, subjects undergoing hysterectomy were screened by the 
surgeon and the PI at their pre-operative visit. Patients were screened with a thorough history and 
physical to ensure they have no contraindication to the study intervention medications (ex: allergy, h/o 
gastric bypass, gastric ulcers, chronic kidney disease). Patients with current opioid prescription and 
current opioid addiction were excluded from both the historical controls and intervention arm. 
Cognitively impaired and non-English speaking patients were excluded. If eligible, patients were given 
verbal and written information regarding the study protocol. Subjects were given the consent form at 
their pre-operative visit, then asked to sign and return the consent form prior to their surgery. Timing 
between pre-operative visit and surgery ranged from 14 to 60 days.  
 
Historical controls were identified through EMR chart search for RA-TLH procedure performed by the 
surgeon. A review of the electronic chart via Surginet was used to screen for historical control eligibility. 
Reports were run to identify potential participants with the following criteria: date, physician and 
procedure. Further screening by the PI to exclude patients with exclusion criteria was then applied. 
Patients with contraindication to any study medications (ex: allergy, h/o gastric bypass, gastric ulcers, 
chronic kidney disease) were excluded. Patients with current opioid prescription and current opioid 
addiction were excluded from both the historical controls and intervention arm. Cognitively impaired 
and non-English speaking patients were excluded. 
 
For both the intervention and control groups, all hospital oral medications were administered by a 
registered nurse (RN). Once discharged, patients self-administered oral medications.  
 
For the intervention group, subjects were given oral acetaminophen and gabapentin in the pre-
operative holding area, prior to surgery. After general anesthesia was administered, the paracervical 
block with local anesthetic (0.5% ropivacaine) was administered by a physician; 10 mL of 0.5% 
ropivacaine was injected bilaterally (2 injection sites) for total of 20mL. Local anesthetic (0.5% 
ropivacaine) injected at all laparoscopic port sites by a physician; 10mL spread equally between 
laparoscopic port incisions. The surgeon operated at <15mmHg intra-abdominal pressure with a goal of 
<12mmHg. At end of procedure during closure of fascia, 30mg ketorolac IV was given once, by the 
anesthesia provider (physician or certified nurse anesthetist).  
 
Postoperatively for the intervention group, the following medications were given in a scheduled fashion: 
gabapentin 300mg PO BID for 7 days, acetaminophen 1000mg PO q6h x 2 days, and celecoxib 200mg PO 
q 12h x 7d. As needed medications for break through pain included: hydromorphone 1mg IV PRN q3h 
and oxycodone 5mg PO PRN q4h while inpatient.  
 
For the intervention group, oxycodone 5mg PO x 12 tabs was prescribed upon discharge (90MME), if 
patient needed opioid medications while hospitalized. If no opioid was used while inpatient, the patient 
was discharged home with only non-opioid pain medications. After 2 days of scheduled acetaminophen, 
patients were instructed to take acetaminophen 1000mg q6h PRN.  
 
For the control group, patients received a non-standardized pain medication regimen including opioids, 
acetaminophen and nonsteroidal anti-inflammatory medications (NSAIDs). They did not receive a 
paracervical block, nor did they receive local anesthetic at port site incisions.   
 

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In both the intervention and control groups, patients received standard post-operative medications such 
as zofran, metoclopramide. Per standard of care, patients will be asked to rate their pain, on a scale 
from 1 to 10, by nursing staff prior to administration of pain medications. 
 
Our primary outcomes are total opioid pain medications required hours 0-3 and hours 3- 24 post-
operatively in morphine milligram equivalents (MME). Opioid pain medications will be reported in MME, 
as it is most often reported in literature, to increase generalizability and applicability. Secondary 
outcomes include pain scores (1-10), length of stay in hours and return to the clinic or emergency 
department due to post-operative pain within a two-week period. 
 
Patient demographics collected included: age, BMI, smoking status (yes/no/prior), prior pelvic surgeries, 
preinvasive or benign vs malignant indication for surgery, history of diabetes, history of substance use 
disorder, pre-operative glucose level and pre-operative albumin.  
 
Financial identification number (FIN) was collected for subject identification during data collection as it 
is unique to the patient and the encounter. 
 
Operative variables collected included: operative time in minutes, docked robot time, quantitative blood 
loss as calculated by the change in pre- and post- hemoglobin in g/dL, estimated blood loss, 
intraoperative complications, and whether staging performed. 
 
Study outcome data collected included: total opioid pain medications required hour 0-3 post-operatively 
in morphine milligram equivalents (MME), total opioid pain medications required through hour 3-24 
post-operatively in MME, pain scores (1-10), length of stay in hours and return to the clinic or 
emergency department due to post-operative pain within a two-week period. 
 
All medications administered were logged in the patient’s MAR. Total opioid medication administration 
was calculated from the MAR. Pain scores were collected prior to and after receiving any pain 
medication- per hospital policy.  
 
All patients had a one to two week postoperative visit with the surgeon to assess compliance and 
tolerance of regimen. All patients had pre-operative blood work, including a complete blood count and 
basic metabolic panel, collected one to two weeks prior to their surgery. All patients who stayed 
overnight in the hospital had postoperative day one blood work, including a complete blood count and 
basic metabolic panel, completed. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
An initial safety meeting was held with the research team to educate research staff on the study 
protocol. Additionally, monthly meetings occurred with research mentor the surgeon, to ensure proper 
progress. Obstetric and gynecology resident physicians who were involved in care for hysterectomy 
patients received education and instructional materials on the study protocol. 
 
Subject screening for eligibility was completed and verified by the PI, the research mentor and a 
research team member. As the study population included only adult women undergoing planned 
hysterectomy, pregnant women were excluded. Vulnerable participants including those who lack 
consent capacity, such as the mentally ill, prisoners, cognitively impaired participants and children were 
excluded.   

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For the intervention arm, recruitment and follow up occurred in the surgeon’s office. In a private room, 
with the surgeon, information regarding the trial will be given to potential subjects. All potential 
subjects will be reminded that participation is voluntary and regardless of enrollment, their 
postoperative pain will be treated. Data will be de-identified and no identifiable data will be published. 
Recruitment and follow up will occur in private exam rooms where subjects’ confidentiality will be 
ensured. The interventions will occur in an operating room equipped with Da Vinci robotic system at 
Millard Fillmore Suburban Hospital, a fully accredited tertiary care institution within New York State, 
equipped with badge access security system. 
 
For the control arm, retrospective data pulls will occur in a private, non-public setting. All data will be 
collected from Cerner electronic medical record (Powerchart and Surginet). All electronic medical 
resources are password protected with two-factor authentication sign in. Study consent forms will be 
scanned into the two-factor password security authentication protected UB domain. The electronic copy 
of consent forms will be retained however the paper copy will be destroyed following the creation of 
the scanned electronic form. 
 
An in-hospital Obstetrics & Gynecology physician was present at all times during this study. Data analysis 
for the project as a whole will occur in a private, non-public setting. 
 
Data will be reviewed on a weekly basis by the PI to ensure no adverse events are occurring. All subjects 
will have their study data reviewed within a week of their surgery. The surgeon will report any adverse 
events throughout the study duration to the PI should a patient call or present to their office with an 
adverse event. 
 
Collected study data will be stored in a password-encrypted datasheet, on a UB domain that is also 
password security protected with two-factor authentication sign-in. Only the research team will have 
access to the password protected spreadsheet. Once all data collection has been completed, all data 
identifiers will be deleted from the data collection sheet to create a de-identified data set. Individual 
results will not be shared with subjects. The results of this study will be presented and potentially 
published in aggregated format. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 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. 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 participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 

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8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of 
note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
• Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship between the 
study intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention and 
event onset, or an alternate etiology has been established. 
 
8.3.3.3 EXPECTEDNESS  
Both the PI and the surgeon will be responsible for determining whether an adverse event (AE) is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  

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Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The PI record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
Data will be reviewed on a weekly basis by the PI to ensure no adverse events are occurring. All subjects 
will have their study data reviewed within a week of their surgery. The surgeon will report any adverse 
events throughout the study duration to the PI should a patient call or present to their office with an 
adverse event. Adverse events including medication reactions will be reviewed. Safety endpoints include 
allergic reaction to medication. The safety information will be collected on a weekly basis in a case 
report form. The safety data will be analyzed with rate of adverse events to determine if harm is 
occurring. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the Data Coordinating Center (DCC)/study sponsor and should be 
provided as soon as possible. 
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
Individual results will not be shared with subjects however AEs and SAEs related to the study will be 
shared with participants. The results of this study will be presented and potentially published in 
aggregated format. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
Not applicable for this study. 
 

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8.3.9 REPORTING OF PREGNANCY  
Not applicable. 
 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved 
research protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• A description of any changes to the protocol or other corrective actions that have been taken 
or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
• UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 7 days of the investigator becoming aware of the event.  
• Any other UP will be reported to the IRB and to the DCC/study sponsor within 30 days of the 
investigator becoming aware of the problem.  
• All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for Human 
Research Protections (OHRP) within 30 days of the IRB’s receipt of the report of the problem from the 
investigator. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Individual results will not be shared with subjects however AEs and SAEs related to the study will be 
shared with participants. 
 
 
 

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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
Primary Efficacy Endpoint: There is no difference in post-operative opioid use between a multimodal 
pain medication regimen and traditional opioid-based pain medication regimen. 
 
Secondary Efficacy Endpoints: 
• 
A multimodal pain medication regimen does not change length of stay.  
• 
A multimodal pain medication regimen does not change pain scores. 
• 
A multimodal pain medication regimen does not change rate of return to the clinic or 
emergency department (ED) due to post-operative pain within two weeks of hospital discharge 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
We planned a study of opioid (measured in morphine milligram equivalents) use postoperatively from 
independent control and experimental subjects with 4 controls per experimental subject.  Previous 
studies suggest the response within each subject group was normally distributed with standard 
deviation 3.  If the true difference in the experimental and control means is 3, we will need to study 10 
experimental subjects and 40 control subjects to be able to reject the null hypothesis that the 
population means of the experimental and control groups are equal with probability (power) 0.8.   The 
Type I error probability associated with this test of this null hypothesis is 0.05. 
 
We expected to screen 50 subjects to reach my target sample for the prospective intervention group. 
We expected to screen 100 subjects to reach my target sample for the historical control group. 
 
Due to the COVID-19 pandemic, surgical volume drastically dropped, and during our study and 
recruitment period, only 60 subjects were available for screening in the prospective arm. Of the 60 
subjects, only 28 were eligible for the intervention arm. Of the 28 subjects who were assigned to the 
intervention, ten underwent the protocol as intended. 
 
This study was not powered for secondary endpoints.  
 
9.3 
POPULATIONS FOR ANALYSES 
Participants included and analyzed were those who satisfied the Per-Protocol Analysis Dataset. These 
patients complied with the protocol sufficiently to ensure that these data would be likely to represent 
the effects of study intervention according to the underlying scientific model.  
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
In general, continuous variables will be summarized with standard descriptive statistics including means, 
standard deviations, medians, and ranges. Categorical variables will be summarized with frequencies 
and percentages. Analysis of outcome measures will primarily be based on general linear models such as 
t-tests and multiple regression. For markedly non-normally distributed data, nonparametric methods 
will be used.  An overall alpha-level of 0.05 will be used as a cut-point for statistical significance and all 
statistical tests will be two-sided. All data will be analyzed using SPSS. 
 

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9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Our primary outcome includes total opioid pain medications required 0-3 hours (h) and 3-24h post-
operatively in morphine milligram equivalents (MME).  MME is measured on a continuous scale. 
Comparisons will be made using either t-test or the non-parametric Mann-Whitney U test depending 
upon the skewness of the data.  Skewness will be determined by visual inspection of the histograms.  
Results will be presented as means and standard deviations or medians and ranges.   
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Our secondary outcomes include pain scores (1-10), length of stay in hours and return to the clinic or 
emergency department due to post-operative pain within a 2-week period. Pain scores were averaged 
from 0-3 hours and 3-24 hours post-operatively, for two separate data points.  Comparisons for pain 
scores and length of stay will be made using either t-test or the non-parametric Mann-Whitney U test 
depending upon the skewness of the data.  Skewness will be determined by visual inspection of the 
histograms.  Results will be presented as means and standard deviations or medians and ranges.  Return 
to clinic or emergency department will be compared using the chi-squared test. 
 
9.4.4 SAFETY ANALYSES 
No adverse events or serious adverse events occurred during this study. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Demographic information collected included age, BMI, smoking status (yes/no/prior), prior pelvic 
surgeries, preinvasive or benign vs malignant indication for surgery, history of diabetes, history of 
substance use disorder, pre-operative glucose level and pre-operative albumin. Comparisons will be 
made using t-tests, Mann-Whitney U-tests, and/or chi-squared tests as appropriate. 
 
9.4.6 PLANNED INTERIM ANALYSES  
No interim analysis was planned or performed. 
 
9.4.7 SUB-GROUP ANALYSES 
No subgroup analyses were performed. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will not be listed. Instead, all individual participant data was aggregated in a 
de-identified manner. 
 
9.4.9 EXPLORATORY ANALYSES 
No exploratory analyses were conducted. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 

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intervention/administering study intervention.  The following consent materials are submitted with this 
protocol:  
- 
UB IRB HRP 502 Consent Document Toolkit 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms were Institutional 
Review Board (IRB)-approved and the participant was asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants and regulatory authorities.  If the 
study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  

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All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be stored on an Excel electronic datasheet, saved on secure Kaleida domain, password encrypted, to be 
maintained for 3 years after the study closes. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites and by 
research staff will be secured and password protected. At the end of the study, all study databases will 
be de-identified and archived on a password encrypted, secure Kaleida domain. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored in an Excel electronic datasheet, on a password 
encrypted, secure Kaleida domain. After the study is completed, the de-identified, archived data will be 
stored for three years however will not be used by other researchers.  
No de-identified biological samples will be stored.  
When the study is completed, access to study data and/or samples will be provided to authorized 
parties through the PI. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Medical Monitor 
Sarah Andres, D.O., Resident 
physician  
George Danakas, M.D., Research 
mentor & attending physician 
University at Buffalo  
General Physicians, Adjunct 
faculty at the University at 
Buffalo 
1001 Main St, Buffalo, NY 
1001 Main St, Buffalo, NY 
(716) 323-0631 
(716) 323-0631 
seandres@buffalo.edu 
gdanaka@buffalo.edu 
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of the University at Buffalo IRB. Members of the IRB should 
be independent from the study conduct and free of conflict of interest, or measures should be in place 
to minimize perceived conflict of interest.  The IRB was updated annually with safety and efficacy data 
on each arm of the study. 
 
10.1.7 CLINICAL MONITORING 

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Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
• The PI conducted weekly monitoring of patient data. 
• Due to the small nature of this study, independent audits were not conducted. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.   
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the PI for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data is documented (recorded) and reported in compliance with the protocol, 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by local and regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
Data recorded in the password encrypted Excel sheet derived from the EMR should be consistent with 
the data recorded in the EMR.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be reported to the University at Buffalo IRB. 
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of three years after the formal discontinuation of 
study intervention. These documents should be retained for a longer period, however, if required by 
local regulations. 
 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 

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These practices are consistent with ICH GCP:  
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 5.1 Quality Assurance and Quality Control, section 5.1.1  
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the PI to use continuous vigilance to identify and report deviations within seven 
working days of identification of the protocol deviation. Protocol deviations must be sent to the 
reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations:  
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
journals.   
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the IRB has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable.  
 
 
 

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10.3 ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
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 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
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 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 

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US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2. Blanton, E., Lamvu, G., Patanwala, I., Barron, K., Witzeman, K., Tu, F., & As-Sanie, S. (2017). Non-
opioid pain management in benign minimally invasive hysterectomy: A systematic review.(Report). 
American Journal of Obstetrics and Gynecology, 216(6), 557–567. 
https://doi.org/10.1016/j.ajog.2016.12.175 
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surgical procedures in US adults.  JAMA Surg. 2017;152(6):e170504. doi:10.1001/jamasurg.2017.0504 
4. Chopra, V., Kown, D., & Sangha, R. (2018). Decreasing Postoperative Narcotic Use for Patients 
Undergoing Hysterectomy. Journal of Minimally Invasive Gynecology, 25(7), S194–S194. 
https://doi.org/10.1016/j.jmig.2018.09.526 
5. Cohen, S. (2020, May). Laparoscopic Hysterectomy. Retrieved from UpToDate: 
https://www.uptodate.com/contents/laparoscopic-hysterectomy 
6. Hill  MV, McMahon  ML, Stucke  RS, Barth  RJ  Jr.  Wide variation and excessive dosage of opioid 
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7. Mark, J., Argentieri, D., Gutierrez, C., Morrell, K., Eng, K., Hutson, A., … Zsiros, E. (2018). 
Ultrarestrictive Opioid Prescription Protocol for Pain Management After Gynecologic and Abdominal 
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