Conditions: Cancer Debulking Enlarged Uterus Fibroid Uterus Adnexal Mass
Keywords: ERAS Multi-modal anesthesia Opioid consumption Intrathecal Epidural Ileus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 110
Healthy volunteers: no

Brief summary:
To determine if opioid consumption postoperatively among patients undergoing non-emergent laparotomy by the gynecologic oncology service who receive intrathecal morphine with intraoperative lidocaine (IML) infusion are lower than patients who have epidural anesthesia with PCA (EPCA).

Detailed description:

Arms:
arm 1: * Standard of care at Washington University School of Medicine/Barnes-Jewish Hospital
* Day of surgery: preoperative tylenol, gabapentin, celebrex, and epidural dosing per standard protocol.
* Intraoperative: dexamethasone and epidural bupivacaine
* Day of surgery postoperative: hydromorphone PCA, toradol, ibuprofen, tylenol, epidural bupivacaine
* Postoperative: hydromorphone PCA, ibuprofen, oxycodone arm 2: * Day of surgery: tylenol, gabapentin, celebrex, and preoperative intrathecal morphine one time injection (150mcg)
* Intraoperative: dexamethasone and lidocaine infusion 1 mg/kg ideal body weight
* Day of surgery postoperative: toradol, ibuprofen, tylenol
* Postoperative: ibuprofen, oxycodone, and hydromorphone prn

Interventions: intervention 1: Bupivacaine intervention 2: Morphine intervention 3: Lidocaine
Intervention descriptions: intervention 1: -Epidural bupivacaine 0.1% 2-6ml/hr based on MAP within 10% of patient's baseline MAP intervention 2: -Preservative-free intrathecal morphine (duramorph) 150mcg injection (0.15ml or a 0.5mg/0.5ml prepared solution) intervention 3: -Lidocaine infusion 1 mg/kg ideal body weight (IBW)

Protocol document:
Prot_SAP_000.pdf: 
Protocol ID#:  
 
202105007 
 
NCT#:  
 
 
NCT05017246 
 
Date:  
 
 
06/12/2024 
 
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 1 of 27 
 
RESEARCH PROTOCOL 
 
 
A randomized trial comparing intrathecal morphine and intraoperative lidocaine infusion to epidural 
anesthesia with postoperative PCA for patients undergoing exploratory laparotomy on the gynecologic 
oncology service. 
 
Protocol #202105007 
Version 11, Version Date:  - 12th June 2024 
 
Principal Investigator: 
Premal H. Thaker, MD, MS 
David and Lynn Mutch Distinguished Professor of Obstetrics and Gynecology 
Division of Gynecologic Oncology 
Department of Obstetrics and Gynecology, Washington University School of Medicine 
660 S. Euclid Ave 
Saint Louis, MO, 63110 
E-mail: thakerp@wustl.edu 
 
Co-investigators: 
 
Lindsay Kuroki, MD, MSCI 
Assistant Professor of Gynecology Oncology 
Division of Gynecologic Oncology 
Department of Obstetrics and Gynecology, Washington University School of Medicine  
E-mail: kurokil@wustl.edu 
 
 
Lara Crock, MD, PhD 
Department of Anesthesiology and Pain Management Center 
Washington University School of Medicine 
E-mail: crockl@wustl.edu 
 
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 2 of 27 
Protocol Revision History 
 
Initial Version [PRMC only] 
 
 
 
 
 
 
 
5/28/2021 
Initial IRB Approved Version 
 
 
 
 
 
 
 
7/28/2021 
 
Amendment #3 Version   
 
 
 
 
 
 
 
9/22/2021 
Amendment #4 Version   
 
 
 
 
 
 
 
11/17/2021 
Amendment #5 Version   
 
 
 
 
 
 
 
1/31/2022 
Amendment #6 Version   
 
 
 
 
 
 
 
4/17/2022 
Amendment #7 Version   
 
 
 
 
 
 
 
8/19/2022 
Amendment #8 Version   
 
 
 
 
 
 
 
4/16/2023 
Amendment #9 Version   
 
 
 
 
 
 
 
6/13/2023 
Amendment #10 Version  
 
 
 
 
 
 
 
5/15/2024 
Amendment #11 Version 
 
 
 
 
 
 
 
6/12/2024 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 3 of 27 
1.  SYNOPSIS 
Study Title 
A randomized trial comparing intrathecal morphine and intraoperative 
lidocaine IV infusion to epidural anesthesia with postoperative PCA for 
patients undergoing exploratory laparotomy on the gynecologic oncology 
service. 
 
Objective 
To determine if opioid consumption postoperatively among patients 
undergoing non-emergent laparotomy by the gynecologic oncology service 
who receive intrathecal morphine with intraoperative lidocaine (IML) IV 
infusion are lower than patients who have epidural anesthesia with PCA 
(EPCA).  
Hypothesis 
IML will result in a decreased rate of opioid consumption in the postoperative 
hospital course. 
Study Period 
Planned enrollment duration: Approximately 8 months 
Planned study duration: Approximately 12 months 
Number of Subjects 
174 patients undergoing exploratory laparotomy  
Study Design 
Prospective, randomized, controlled study. 
Inclusion and 
Exclusion Criteria 
Inclusion Criteria 
1. Female patients ≥18 years old 
2. Undergoing non-emergent exploratory laparotomy with the Gynecologic 
Oncology service 
3. No evidence of end organ failure (as stated in 2.3.2 inclusion criteria) 
 
Exclusion Criteria 
1. Patients not giving consent to participate in the study 
2. Unable to complete self-report pain questionnaire 
3. Moderate to severe kidney or liver failure per lab criteria as outlined  
4. Inability to hold anticoagulant medications for a safe amount of time per 
current ASRA guidelines 
5. Contraindication to lumbar puncture or epidural placement, such as known 
coagulopathy or history of clotting disorders, history of scoliosis or lumbar 
fusion, infection at site of entry, or current systemic infection 
6. Complete bowel obstruction 
7. Contraindication to intravenous (IV) lidocaine 
8. Current pregnancy or lactation 
9. Currently septic 
10. Patient currently taking more than 30 MME a day preoperatively 
11. BMI >50kg/m2 
12. Intolerance/ contraindication or allergy to receiving non-steroidal anti-
inflammatory drugs or acetaminophen or any other medications in the Pre-
operative order set 
 Measurements 
1. Morphine Milligram Equivalent (MME) in the postoperative hospital course  
2. The rate of postoperative ileus 
3. Hospital length of stay  
4. Postoperative hypotension.  
5. Patient satisfaction with pain control.  


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 4 of 27 
6. Pain scores pre-op, each post-op day inpatient, 2 weeks follow-up and 6 
week follow-up.  
7. Intravenous bolus volume intraoperatively (mL) and postoperatively (mL) 
8. The 30 day readmission rate (#) 
9. Operative time (minutes) 
10. Rates of DVT and PTE (#) 
11. Rate of persistent pain at 6-week follow-up as determined by an NRS pain 
score greater than or equal to 5 
 
2. STUDY PROTOCOL 
 
2.1 Background and Significance 
Enhanced recovery after surgery (ERAS) was established in Europe to decrease variance in how patients 
were treated postoperatively. This movement has subsequently optimized the patients are cared for in 
the postoperative setting. Gynecologic oncology guidelines were established in 2016 and include a 
variety of recommendations within the umbrella of ERAS (Nelson et al, 2016). Four main tenants of ERAS 
include multi-modal pain control, euvolemia, early ambulation, and early feeding. Two acceptable 
options for regional anesthesia that fit into the multi-modal approach to pain control within ERAS 
include epidural anesthesia and intrathecal injections.  
 
Current standard of care at Washington University, Barnes Jewish Hospital (WU/BJH) consists of 
preoperative bupivacaine epidural placement with patients receiving a PCA (patient-controlled 
anesthesia) for pain control postoperatively. A recent paper from this institution compared epidural 
anesthesia to no regional anesthesia for patients undergoing laparotomy while implementing ERAS 
guidelines. The authors found a decrease in opioid use on day 0 in the epidural group, but equivalent 
usage on days 1-3 (Huepenbecker et al, 2019). In this study, hospital stay MME approached 200mg in 
the epidural group, which is significantly higher than other published work (Kjølhede et al, 2019, 
Colibaseanu et al, 2019). Other studies have found equivalent pain scores and increase opioid use in 
patients using epidural analgesia when compared with patients with no epidural analgesia (Chen L-M et 
al, 2009, Belavy et al, 2013).  
 
Historic institutional data has shown the ileus rate to be 11.5% vs 14% (p=0.39) (Huepenbecker et al, 
2019), but more recently, in our institution, the ileus rate on the gynecologic oncology service is 
substantially higher with epidural use. Retrospective data from other institutions have shown lower 
rates of ileus when using intrathecal injections as a part of ERAS in comparison to the pre-ERAS era 
which largely used epidurals (2.8% vs 15.7%, p<0.01) (Boitano et al, 2018). Similarly, two studies showed 
slower return of bowel function with epidural usage (Levy et al, 2011; Ackroyd et al., 2020).  
 
Other studies, including two randomized clinical trials have shown an increase length of stay when 
comparing epidural anesthesia to other forms of postoperative analgesia in both the gynecologic and 
colorectal surgery literature (Boitano et al, 2018; Kjølhede et al, 2019, Levy et al, 2011; Ackroyd et al., 
2020, Belavy et al, 2013). This is particularly important in the age of COVID-19 when length of stay 
decreases the exposure to patients, most of whom have a cancer diagnosis. Additionally, there is 
documented increase in intraoperative hypotension and increased fluid bolus with epidural usage 
(Huepenbecker et al, 2019). 
 
Recently, there has been a national emphasis on decreasing opioid consumption given the addictive and 
deadly potential for these medications. Opioid related deaths have increased by a factor of six over the 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 5 of 27 
last twenty years (Centers for Disease Control, Atlanta, GA 2020). Studies have shown that one third of 
chronic opioid users and over 50% of heroin users report being introduced to opioids from the medical 
profession. In addition, in opioid naïve patients undergoing surgery, approximately 6% become opioid 
dependent whether they are having major or minor surgery (Callinan et al 2017, Compton et al 2016, 
Lev et al 2015). This lead the Society of Gynecologic Oncology to release a practice statement in 
February of 2020 in order to address acute postoperative pain without placing patients at risk for opioid 
misuse (Kim et al., 2020). The authors advocate for multimodal therapy, however they do not make 
specific recommendations because “few [strategies] have been evaluated in rigorous trials with 
gynecologic oncology patients.” The purpose of our study is to compare postoperative MME 
consumption among patients undergoing laparotomy by the gynecologic oncology service who receive 
epidural anesthesia with PCA (current standard of care) versus intrathecal morphine with intraoperative 
lidocaine IV infusion. Our hypothesis is patients who receive preoperative intrathecal morphine with 
intraoperative lidocaine IV infusion will have a lower MME consumption than those who receive 
epidural anesthesia. Additionally, we believe intrathecal morphine will control patient’s pain, allow early 
feeding, early ambulation, and allow better euvolemia when compared to epidural anesthesia.  
2.2 Preliminary Data 
Unidentified preliminary data was collected. Briefly, the number of exploratory laparotomy surgeries 
and MME usage was collected from January through March of 2021. The mean MME consumption in 
those who received an epidural was 121.30mg. This was done for sample size and rate calculations.  
2.3 Objectives: 
The primary objective of this study is: 
 
To compare the MME consumption in the postoperative hospital course among patients undergoing 
laparotomy by the gynecologic oncology service who receive IML versus EPCA.  
The secondary objectives of this study are to compare the two treatment groups with respect to: 
 
• 
Postoperative ileus rate 
• 
Hospital length of stay 
• 
Postoperative hypotension 
• 
Patient satisfaction with pain control 
• 
Pain scores pre-op, post-op day 1, 2 weeks follow-up and 6 week follow-up 
• 
30 day readmission rate 
• 
Rates of DVT and PTE (collected from day of surgery to 6 weeks after surgery) 
• 
Rate of persistent pain at 6 week follow-up 
 
2.3.1 Subject Selection 
Patients undergoing an exploratory laparotomy meeting inclusion criteria will be recruited from the 
Gynecologic Oncology surgical service. 
 
2.3.2: Inclusion Criteria 
1. Female patients ≥18 years old 
2. Undergoing non-emergent exploratory laparotomy with the Gynecologic Oncology service 
3. No clinical or laboratory evidence of end organ failure: 
If available: 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 6 of 27 
• 
Platelets > 100 K/cumm 
• 
Hemoglobin > 8.0 g/dl 
• 
Serum creatinine <1.5 mg/dl 
• 
Creatine clearance (CrCl) ≥30 based on the original Cockcroft-Gault formula adjusted for weight.  
• 
INR <1.3 reference range 
• 
All other lab values obtained as part of general preoperative work-up must be ≤1.5x normal 
laboratory value. 
 
2.3.3 Exclusion Criteria 
1. Patients not giving consent to participate in the study 
2. Unable to complete self-report pain questionnaire 
3. Moderate to severe kidney or liver failure per lab criteria as outlined  
4. Inability to hold anticoagulant medications for a safe amount of time per current ASRA guidelines 
5. Contraindication to lumbar puncture or epidural placement, per acute pain management service such 
as known coagulopathy or history of clotting disorders, history of scoliosis or lumbar fusion, infection at 
site of entry, or current systemic infection 
6. Complete bowel obstruction 
7. Contraindication to intravenous (IV) lidocaine 
8. No known pregnancy and not lactating. 
9. Currently septic 
10. Patient currently taking more than 30 MME a day preoperatively (for >30 days) 
11. BMI >50kg/m2 
12. Intolerance/ contraindication or allergy to receiving non-steroidal anti-inflammatory drugs or 
acetaminophen or any other medications in the Preoperative order set 
 
2.4 Design and Procedures 
 
2.4.1 Study Design: 
This is a randomized trial in patients undergoing laparotomy with the Gynecologic Oncology service. 
Eligible patients will be randomly assigned (1:1) to EPCA (current standard of care at WU/BJH) or 
intrathecal morphine one time injection (150mcg) with intraoperative lidocaine IV infusion (IML) as 
previously described (Boitano et al, 2018). Randomization will be stratified by BMI (<30 vs. >/= 30) and 
surgical complexity scoring (low = score < 3 vs. high = score >/= 3). ERAS protocol with be enforced for 
both arms.  
 
Number of patients and study sites: 
Approximately 174 patients will be recruited at WU/BJH. Allocation is 1:1 resulting in 87 patients 
allocated to each arm. This is based on detecting a 35mg MME difference with 80% power and alpha of 
0.05. 
 
Hypothesis: IML will result in a decreased rate of opioid consumption in comparison to EPCA in the 
postoperative hospital course 
 
Randomization and Blinding: The study is designed as a randomized clinical trial. It will NOT be blinded 
as both participants and study staff will know which treatment group each participant is in. 
Randomization stratification is noted above. 
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 7 of 27 
 
 
 
 
Schema: 
 
 
  
 
*Intrathecal: Intrathecal morphine injection 
 
 
2.4.2 Pre-Study Period: 
Participants will be identified from the Washington University Gynecologic Oncologic service at their 
preoperative visit for a non-emergent exploratory laparotomy. As is standard for all patients undergoing 
an exploratory laparotomy, the following screening information will be collected: age, height and 
weight, known allergies, complete medical history, name and dosing regimen of any over the counter 
and prescription medications or dietary supplements. We will prescreen all potential participants prior 
to their pre-operative visit. 
 
Potential subjects meeting all inclusion and exclusion criteria will be consented prior to the surgery. The 
following will take place at the screening/consent visit: 
 
• 
Verbal discussion of the study procedures, benefits, and potential risks; 
• 
Subjects reads, understands, and signs informed consent (subjects will also be provided with a 
fully executed copy); 
• 
Brief history and physical, including vital signs, height and weight measurements, pain history 
and intensity, surgical complexity score, and medications. A data form for pain history and pain 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 8 of 27 
medications is added as appendix 1.6. The remainder of the information is standard 
documentation in the history and physical of a preoperative patient.  
 
 
 
2.4.3 Study Period  
Patients will be enrolled in the study prior to surgery. They will be randomized preoperatively to either 
EPCA or IML and will be followed daily while inpatient at WU/BJH. They may have scheduled visits at 2 
weeks (+/- 1 week)  and 6 weeks (+/- 1 week) after surgery as per normal postoperative Gynecologic 
Oncology protocols. We will call participants who are unable to make their follow-up visits or whose 
pain information was not collected at the time of their visit.  
 
Surrogates for opioid consumption between discharge and patient postoperative visits will be collected 
through recording refill of opioid pain prescriptions and emergency room visits. Postoperative pain 
scores and satisfaction survey will be completed at the postoperative visits and will be completed by 
phone if a patient is unable to attend the appointment for any reason or does not present.  
 
2.4.4: Minimization of Bias 
There will be no specific ethnic, racial, or gender background for enrollment.  
 
2.4.5 Observations and Measurements 
 
IML (Experimental Arm): 
 
Day of Surgery: 
Preoperative 
- Tylenol 1000mg 
- Gabapentin 600mg 
- Celebrex 200mg 
- Preservative-free intrathecal morphine 150mcg injection (0.15ml or a 0.5mg/0.5ml prepared solution) 
- Pulse oximetry will be used on postoperative day 0 on these patients.  
 
Intraoperative 
Meds 
- Lidocaine IV infusion 1 mg/kg ideal body weight (IBW) 
The dose of lidocaine will be 1mg/kg ideal body weight (IBW), calculated by B. J. Devine Formula: 
IBW = 45.5 + 2.3 kg per inch over 5 feet       (woman)  
- Dexamethasone 0.1 mg/kg IBW (up to max of 8mg; 4mg max if diabetic) if no contraindication 
 
Postoperative (DOS) 
Meds: 
≥80kg and <65years 
- Toradol 30mg IV q6 hours x 24 hours 
- Ibuprofen 800mg q6 hours (6 hours after last Toradol dose) 
- Tylenol 1000mg q6 hours 
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 9 of 27 
<80kg or ≥65 years 
- Toradol 15mg IV q6 hours x 1 day 
- Ibuprofen 600mg q6 hours (6 hours after last Toradol dose) 
- Tylenol 1000mg q6 hours 
 
 
POD1: 
≥65 years 
- Ibuprofen 600 q6h 
- Oxycodone 2.5mg /5mg q4h 
- Hydromorphone 0.2mg q2 hours 
 
<65 years 
- Ibuprofen 800mg q6h 
- Oxycodone 5mg / 10mg q4h 
- Hydromorphone 0.4mg q2 hours 
 
EPCA (standard of care arm) protocol: 
 
Day of Surgery  
Preoperative 
- Tylenol 1000mg 
- Gabapentin 600mg 
- Celebrex 200mg 
- Epidural dosing per standard protocol. Opioids will be restricted from use in the epidural. 
 
Intraoperative 
Meds 
- Dexamethasone 0.1 mg/kg IBW (up to max of 8mg; 4mg max if diabetic) if no contraindication 
- Epidural bupivacaine 0.1% 2-6ml/hr based on MAP within 10% of patient’s baseline MAP 
 
Postoperative (DOS) 
- Physician's choice of Hydromorphone PCA (standard dosing 0.2mg every 10 minutes, 1.2 mg lockout) 
versus as needed (prn) intravenous hydromorphone in the amount of hydromorphone 0.2mg q2 hours if 
≥65 years and 0.4 q2 hours if <65 years 
 
≥80kg and <65years 
- Toradol 30mg IV q6 hours x 24 hours 
- Ibuprofen 800mg q6 hours (6 hours after last Toradol dose) 
- Tylenol 1000mg q6 hours 
- Epidural bupivacaine 0.1% 2-12ml/hr titrated per acute pain service  
 
<80kg or ≥65 years 
- Toradol 15mg IV q6 hours x 1 day 
- Ibuprofen 600mg q6 hours (6 hours after last Toradol dose) 
- Tylenol 1000mg q6 hours 
- Epidural bupivacaine 0.1% 2-12ml/hr titrated per acute pain service  
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 10 of 
27 
POD1: 
-If the physicians choice was  Hydromorphone PCA then this will be taken down if requirement allows 
and tolerating PO 
 
 
≥65 years 
- Ibuprofen 600 q6h 
- Oxycodone 2.5mg /5mg q4h 
- Hydromorphone 0.2mg q2 hours 
 
<65 years 
- Ibuprofen 800mg q6h 
- Oxycodone 5mg / 10mg q4h 
- Hydromorphone 0.4mg q2 hours 
 
ERAS to be followed for both arms: 
Prior to day of surgery 
- Counseling in clinic RE: ERAS 
- Carbohydrate rich drink (ie-Gatorade) 
 
Intraoperative period 
- Fluid intraop is 2-3cc/kg/hr for open laparotomy; avoidance of over hydration 
- Avoidance of oral, nasogastric, or intra-abdominal drains 
- Normothermia 
- Appropriate timing of antibiotics 
 
Postoperative period 
- IVF 40cc/hr and d/c’d once taking fluids 
- CLD immediately postop, advance as tolerated to regular diet within 24 hours 
- Encourage use of chewing gum 
- Oliguria is permitted, 500cc LR bolus if indicated (x 2 max then move to albumin). 
- SCDs plus VTE PPx 
- Early mobility (2h OOB on DOS, 8h POD1) 
 
CLD: Clear liquid diet 
OOB: Out of bed 
IVF: IV fluids 
 
Discharge medications: 
This will be completed by a Restrictive Opioid Prescribing Protocol (ROPA) 
- Standard discharge medications will be oxycodone 5mg X 15 
- Patients with excessive postoperative pain 
 
- Defined as needing breakthrough medications in the last 24 hours prior discharge 
 
- Will receive 3x the 24 hour total they received in 5mg or 10mg oxycodone tablets 
- Opioid users eligible for the study will be prescribed their normal regimen and similarly be prescribed 
3x their breakthrough dosage on discharge (Appendix 1.1). 
Refill of opioid pain prescriptions and emergency room visits for pain will be collected.  


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 11 of 
27 
Postoperative pain scores and satisfaction survey will be completed at the postoperative visits or by 
phone if a patient is unable to attend the appointment for any reason.  
 
 
 
 
2.4.5.1 Primary Outcome Measures 
Primary outcome: Amount of opioid usage in oral morphine milligram equivalents (MME) (conversions 
present in Appendix 1.2). This will be collected postoperatively while the patient is admitted to the 
hospital by chart review of the pain medicine tab.  
 
2.4.5.2 Secondary Outcome Measures: 
 
1. The rate of postoperative ileus (defined in Appendix 1.3) 
2. Hospital length of stay.  
o Length of stay will be determined by the dates of admission as recorded on EPIC (days). 
3. Postoperative hypotension (defined in Appendix 1.4).  
4. Patient satisfaction with pain control.  
o Patients will be asked on day of discharge if they were satisfied with their pain control 
during their hospitalization. They will be able to choose from the following: 1=satisfied, 
2= somewhat satisfied, 3= neutral, 4=somewhat dissatisfied, 5=dissatisfied). 
5. Pain scores pre-op, each post-op day inpatient, 2 weeks (+/- 1 week) follow-up and 6 week (+/- 1 
week) follow-up. 
o Pain scores will be determined by the 0-10 numeric rating scale (NRS) 
6. The 30 day readmission rate (#) 
7. Rates of DVT and PTE (#) 
8. Rate of persistent pain at 6-week (+/- 1 week) follow-up as determined by an NRS pain score 
greater than or equal to 5 
 
2.4.5.3 Trial Arm Definitions: 
IML: Preoperative injection of intrathecal morphine (150mcg) with Lidocaine IV infusion 1 mg/kg ideal 
body weight (IBW). 
EPCA: Epidural bupivacaine 0.1% 2-12ml/hr titrated per acute pain service with hydromorphone patient-
controlled anesthesia (PCA). The standard PCA dose is 0.2mg per 10 minutes with a 1.2mg lockout. No 
bolus of hydromorphone will be ordered.  
 
Statistical Methods: 
All demographic, sensory, analytical and patient-reported data will be captured on case report forms, 
manually entered to a Research Electronic Data Capture (REDCap) database that has been created for the 
project. The amount of opioid usage in MME will serve as the primary outcome measure for the study. 
We do not expect missing outcomes data as all primary and most secondary outcomes will be collected 
with the participants physically present with the research team. Any missing data will be described, but 
no data imputation will be attempted. Intergroup comparisons for parametric data will be performed by 
paired t-test, and for non-parametric data by Wilcoxon signed-rank test for paired samples. McNemar’s 
test will be used to compare paired nominal data, and Fisher’s exact test to compare non-paired nominal 
data.  
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 12 of 
27 
Sample size calculation was based on primary outcome data. Preliminary data shows a mean and 
standard deviation of postoperative MME with EPCA is 121.3 74.7. Assuming a 5% dropout rate, 
sample size of 76 per group (152 total) achieve at least 80% power to detect a clinically meaningful MME 
difference of 35 between the two groups at a significance level of 5% using a two-sided two-sample 
equal-variance t-test. Powers were calculated using Power Analysis and Sample Size (PASS 15) software. 
This sample size calculation was increased to 174 total patients to accommodate unanticipated dropout 
during the COVID pandemic. Allocation is 1:1 resulting in 87 patients allocated to each arm. 
 
The primary analysis will be planned on an intention-to-treat basis regardless of the actual treatment 
received. Patients will be excluded from the analysis if they withdraw from the study before initiation of 
anesthesia, if they were no longer eligible for surgery, or if they do not undergo an exploratory 
laparotomy.  
 
Data Submission Schedule 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to surgery 
Surgical complexity scoring 
Prior to surgery 
On-Study Form 
Prior to surgery 
Questionnaire 
Following surgery and postoperative visit 
Pain scoring 
Preoperative appointment 
Postoperative (daily, duration of 
hospital stay) 
2 weeks (+/- 1 week) post-op 
6 weeks (+/- 1 week) post-op 
Acute Toxicity Form 
During postoperative course while inpatient 
(chart review and patient reported 
adverse events) 
Late Toxicity Form 
6 weeks 
 
  
 
All adverse events that occur beginning on the day of surgery (minus exceptions defined in the reporting 
section) must be captured in the Toxicity Form.   
 
 
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 13 of 
27 
Study Calendar 
 
 
Screening 
Preop 
visit 
TB 
Preop 
DOS 
Surgery 
POD 
Day of 
Discharge 
(+1 day) 
2  (+/- 1 
week) 
week 
postop 
6 (+/- 1 
week) week 
postop 
Eligible 
x 
 
 
 
 
 
 
 
 
Surgical consent 
 
x 
 
 
 
 
 
 
 
Informed 
consent 
 
 
x 
 
 
 
 
 
 
Physical exam 
 
x 
 
 
 
x 
 
x 
x 
Exploratory 
laparotomy  
 
 
 
 
x 
 
 
 
 
Intrathecal vs 
epidural 
placement 
 
 
 
x 
 
 
 
 
 
Randomization 
 
 
x 
 
 
 
 
 
 
Adverse events 
 
 
 
x 
 
x 
x 
x 
x 
Pain scoring 
 
x 
 
x 
x 
x 
x 
x 
x 
Satisfaction 
questionnaire 
 
 
 
 
 
 
xa 
xa 
xa 
Surgical 
complexity 
scoring 
 
x 
 
 
 
 
 
 
 
 
Preop: Preoperative 
Postop: Postoperative 
POD: Postopeartive days while inpatient 
TB: Time between preoperative visit and surgery – approximately 2 weeks  
a A 5 question Satisfaction questionnaire to be asked on the day of discharge (+ 1 day); A 2 question  pain survey (Q6 from the validated 
satisfaction questionnaire) to be asked at 2 (+/- 1 week) and 6 (+/- 1 week) post-op visit. 
 
Management of Intercurrent Events 
 
3.1 Adverse Events 
The investigators will closely monitor subjects for evidence of systemic adverse events. All adverse 
events related to participation will be reported and followed until satisfactory resolution. Subjects will 
notify the monitoring physician/RN coordinator of any adverse experience during the study period. If 
any patient should suffer any serious side effect, including but not limited to serious neurologic or 
cardiovascular dysfunction or a reaction concerning for anaphylactic or anaphylactoid reaction, patient 
recruitment and randomization will be halted until the etiology of such an adverse reaction can be 
determined. 
 
3.2 Premature discontinuation of protocol for a single patient: 
 
The study protocol may be discontinued prematurely for any patient(s) in the following scenarios: 
• 
Death 
• 
General or specific changes in the patient’s condition render the patient unable to receive 
further treatment in the judgment of the investigator 
• 
Suspected or confirmed pregnancy 
• 
Serious non-compliance with the study protocol 
• 
Lost to follow-up 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 14 of 
27 
• 
Patient withdraws consent 
• 
Investigator removes the patient from study 
• 
Investigator decides to close the study 
 
If a participant withdraws from the study, the participant will be replaced in order to provide the 
required number of evaluable subjects. Subjects will be withdrawn if the investigator decides that 
discontinuation is in the best interest of the subject, or the subject requests withdrawal from the study. 
 
3.3 Potential Risks 
Lumbar Puncture (LP) for the injection of morphine is widely used technique for post-operative pain 
control. LP of opioids with local anesthetic is a major clinical tool used in obstetric anesthesia as a fast 
and safe method to induce surgical conditions for a cesarean section. Intrathecal administration of 
morphine is a widely accepted procedure for postoperative pain management that is used at multiple 
academic centers for post-operative pain control (Boitano et al, 2018). An important complication of LP 
is post-lumbar puncture headache (PLPH) developing within a week after LP. In a multisite international 
trial, 9% of 3868 enrolled patients reported PLPH [Duits 2016], with 0.3% patients requiring and epidural 
blood patch (procedure of introducing autologous blood into epidural space). Other adverse events 
were non-specific headache (10.2%), back pain (17%), nausea and/or vomiting (2.5%), dizziness 45 
(1.3%). Other possible complications may include bleeding as well as temporary or permanent 
neurological damage, although these are extremely rare. Management of these potential adverse 
events are described below in section 3.4.  
 
Epidural placement 
The placement of a thoracic epidural (TE) for acute postoperative pain is currently our standard of care 
for major abdominal surgeries in which there are no contraindications. And important complication of 
TE is an inadvertent lumbar puncture and the development of a post-dural puncture headache, back 
pain, hypotension. Other rare adverse events, include bleeding as well as temporary or permanent 
neurological damage. Management of these potential adverse events are described below in section 3.4 
 
3.3.1 Procedures to Minimize Potential Risks 
Inclusion and exclusion criteria, monitoring, and the clinical protocol are designed to ensure that risks 
are absolutely minimal. Both arms of the study are routinely performed at multiple institutions. 
Currently, epidural placement for post-operative pain is our standard of care for these patients. We will 
be comparing our standard of care to a standard of care at multiple institutions (Boitano et al, 2018). 
The major differences between our study and standard of care is the recording of various outcomes.  
Participants are informed that participation is voluntary and they may refuse to participate and may 
withdraw from the study at any time without penalty. A pregnancy test will be performed (as is standard 
on all operative patients) on women of childbearing potential and subjects excluded if pregnant. 
Subjects will be told that in the event of a physical injury as the direct result of study procedures, they 
will be cared for by a member of the investigating team at no cost, within the limits of the Washington 
University compensation plan. 
Subjects will be instructed at the beginning of the visit that they can alert the investigator any time they 
experience bothersome side effects. Medical personnel will be immediately available throughout the 
visit. The subject can voluntarily withdraw from the study at any time. 
 
With regard to confidentiality; 1) all subjects will be assigned a study ID number, 2) Samples will be kept 
confidentially. They will be coded, with a key to the code linking code numbers to names kept at a 
separate location, under lock and key.  3) The link to identifiers will be destroyed at the end of the study. 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 15 of 
27 
4) Data will be stored under lock and key (office, file cabinet) and only the investigators and research 
team will have access. If data are published, there will be no link to identifiers.  
 
3.3.2 Preparation and Administration of Intrathecal Morphine 
The morphine preparation is a preservative free compounded solution regularly prepared by the BJH 
pharmacy in a 0.5mg/0.5ml in a 3mL syringe. We will use the 0.5mg/0.5ml pharmacy prepared product 
with the plan to administer 0.15mg (150mcg) per patient. 0.15ml will be drawn up using a sterile insulin 
syringe with attending physician present and then mixed with 2mL of preservative free normal saline in 
a 5mL syringe prior to injection. Dilution of the morphine will minimize the amount of medication lost in 
the dead space of the needle. This strategy is similar to standard practice for intrathecal morphine 
administration by the obstetric anesthesia service and will be applied to this study.  
 
3.3.3 Prevention, diagnosis and management of post-lumbar puncture headache (PLPH) 
Lumbar puncture and intrathecal morphine injection will conducted in a way to minimize the effect of 
risk factors contributing PLPH development. Particularly, an atraumatic needle of 24 G diameter will be 
used for LP procedure. 
 
Subjects will be asked to notify clinical personnel immediately if they develop a positional headache 
while in the hospital. Additionally, the periodic nursing assessment performed routinely but the nurses 
include questions about pain such as headache. If a participant endorses new-onset positional 
headache, the anesthesiologist on the Acute Pain Service will be notified. The anesthesiologist will 
perform a brief history and physical exam to determine whether or not the symptoms suggest PLPH. If 
PLPH is likely and symptoms are mild, conservative treatment will be initiated. The participant will be 
encouraged to lie in a comfortable position and drink fluids. The subject will also be offered analgesics 
including acetaminophen/butalbital/caffeine (e.g. Fioricet®), ibuprofen, or acetaminophen alone. IV 
fluids or medication will be reserved for subjects who cannot tolerate oral administration due to 
nausea/vomiting. If symptoms are severe (e.g. uncontrollable nausea/vomiting, severe subject distress), 
the subject will be removed from the study and epidural blood patch will be offered (procedure 
described below).  
 
Discharge paperwork will include clear descriptions of PLPH and instructions about whom to contact in 
the case of headache. If a subject reports likely PLPH by contacting study personnel or during a follow-
up phone call, symptom severity will be assessed. Conservative treatment (as described above) will be 
offered for the first 24-48 hrs. Although rare, any unresolved post-dural puncture headache in either 
group would be treated per standard of care by the inpatient pain service.  
 
Epidural blood patches are commonly performed by our Acute Pain Service. Using sterile technique 
(including chlorhexidine swabs, caps, masks, and sterile gloves). First, the provider locates the epidural 
space using a standard Tuohy needle and loss-of-resistance technique. Second, the provider obtains 
approximately 20ml of the subject’s blood, which is then injected through the Tuohy needle. Injection is 
stopped if the subject complains of pressure or paresthesia that could indicate compression of the 
cauda equina.  
 
3.4 Prevention, diagnosis and management of other intrathecal catheter-related complications  
The potential complication of epidural hematoma is exceedingly rare in patients with normal 
coagulation (Duits 2016). To minimize the risk of epidural hematoma, subjects will be asked about a 
history of clotting disorders, easy bleeding/bruising, liver disease, or use of anticoagulants. If indicated, a 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 16 of 
27 
complete blood count will be drawn during the screening visit to rule out thrombocytopenia. Any 
potential subject with abnormalities on history or lab work will be excluded from the study.  
 
To minimize the risk of infection or nerve damage from lumbar puncture or epidural placement, the 
procedure will be done by experienced anesthesia personnel (board-certified or board-eligible 
anesthesiologists) under sterile conditions. Specifically, the subject’s lumbar region will be sterilized with 
a chlorhexidine or duraprep swab, a sterile drape will be placed, the anesthesiologist will wear sterile 
gloves, all personnel in the room will wear a cap and mask, and a sterile occlusive dressing will be 
applied after LP or epidural catheter. Subjects will be instructed to notify the anesthesiologist of the 
occurrence and resolution of any paresthesia during LP or epidural procedure. If symptoms are severe 
(e.g., severe pain, motor deficits) the subject will be sent to the BJH ED for further evaluation including 
neurology consultation, imaging, or hospital admission, as needed. Subjects with temporary, minor 
paresthesia during placement may continue with the study.  
 
Regulatory and Reporting Requirements 
The entities providing oversight of safety and compliance with the protocol require reporting as outlined 
below.  Please refer to Appendix 1.7 for definitions and Appendix 1.8 for a grid of reporting timelines. 
 
Adverse events will be tracked from the day of surgery (pre-op) through 6 weeks following day of 
surgery.  All adverse events must be recorded on the toxicity tracking case report form (CRF).  
 
Refer to the data submission schedule for instructions on the collection of AEs in the EDC. 
 
Reporting to the Human Research Protection Office (HRPO) at Washington University 
 
Reporting will be conducted in accordance with Washington University IRB Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the change. 
 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at Washington 
University 
 
The PI (or designee) is required to notify the QASMC of any unanticipated problems involving risks to 
participants or others occurring at WU or any BJH or SLCH institution that has been reported to and 
acknowledged by HRPO.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
qasmc@wustl.edu.  Submission to QASMC must include the myIRB form and any supporting 
documentation sent with the form. 
 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described above include: 
• 
Planned hospitalizations 
• 
Hospitalizations < 24 hours 
• 
Respite care 
• 
Events related to disease progression 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 17 of 
27 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
3.5   Data and Safety Monitoring Plan 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, and 
commensurate with the risks of the proposed study, we will use an Independent Medical Monitor for 
data safety and monitoring for this study. The potential risks are attributable to intrathecal morphine 
administration or thoracic epidural placement. The Independent Medical Monitor will be an 
anesthesiologist who is not involved in the study, and who is knowledgeable in the risks associated with 
intrathecal morphine administration and thoracic epidural placement. This individual will review the 
annual summary of adverse events, prior to data and safety monitoring report submission to the 
Washington University IRB. In addition, this individual will review all reports of a Serious Adverse Event, 
or an Unexpected Adverse Event. 
 
The study principal investigator and Research Patient Coordinator will monitor for serious toxicities that 
are unexpected, related, and place the subject at greater risk. Once the principal investigator or 
Research Patient Coordinator becomes aware of an adverse event, the AE will be reported to the HRPO 
according to institutional guidelines. 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually beginning six 
months after accrual has opened (if at least one patient has been enrolled) or one year after accrual has 
opened (if no patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least monthly (or before each treatment 
escalation if occurring sooner than monthly) and provide a semi-annual report to the QASMC. This 
report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, regulatory 
coordinator name, and statistician. 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date of HRPO 
expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual suspensions 
including start/stop dates and reason; and summary of protocol exceptions, error, or breach of 
confidentiality including start/stop dates and reason. 
•    Study-wide target accrual and study-wide actual accrual 
•    Protocol activation date 
•    Average rate of accrual observed in year 1, year 2, and subsequent years 
•    Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who have met each 
objective 
•    Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have met the early 
stopping rules. 
• Summary of toxicities separated by cohorts with the number of dose-limiting toxicities indicated 
•    Abstract submissions/publications 
•    Summary of any recent literature that may affect the safety or ethics of the study 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 18 of 
27 
  
The study principal investigator and Research Patient Coordinator will monitor for serious toxicities on 
an ongoing basis. Once the principal investigator or Research Patient Coordinator becomes aware of an 
adverse event, the AE will be reported to the HRPO and QASMC according to institutional guidelines. 
 
 
4.  HUMAN SUBJECTS RESEARCH 
 
4.1 Protection of Human Subjects 
The study will be conducted under appropriate Washington University Institutional Review Board 
protocols and consent forms approvals.  The study will be conducted under the supervision of the co-PIs 
who is a gynecologic oncology surgeon with several years of experience in the conduct of human 
studies; a board-certified anesthesiologist and board-certified pain management specialist as co-PI,  with 
extensive clinical and human research experience; and a sixth year surgical fellow physician. 
 
4.2 Sources of Materials 
Subjects will be recruited from the greater Saint Louis area via their Washington University Gynecologic 
Oncologic physicians. Data on comorbidities and concomitant medication use are provided by subjects. 
No specimens will be collected that are not used directly in their perioperative care.  
 
4.3 Recruitment and Informed Consent 
Participants will be recruited through their Washington University Gynecologic Oncologic physicians. We 
may also screen the clinic schedule of the Washington University Gynecologic Oncologic physicians, to 
identify potentially eligible subjects. We will then approach or contact them to ask for their interest in 
the study. Subjects will be given verbal (initially) and then written descriptions of the study aims, 
procedures, risks, and benefits, and will be required to give written informed consent. A member of the 
study team provides all study descriptions, informed consent, and answers all questions. Subjects are 
informed verbally and in writing that participation is voluntary and they may refuse to participate and 
may withdraw from the study at any time without penalty. 
 
4.4 Potential Benefits of the Proposed Research to the Subjects and Others 
Study subjects could potentially experience improvement in ileus rates or earlier discharge. Society 
could benefit from development of clear evidence on the best perioperative regiment for exploratory 
laparotomy for gynecologic surgery. 
 
4.5 Inclusion of Women 
Only women will be included in this study as men do not undergo gynecological surgery.  
 
4.6 Inclusion of Minorities 
All of our studies actively encourage the participation of minorities in the research. Our minority 
recruiting typically matches the demographic composition of the Washington University community 
from which subjects will be recruited (78% white, 21% Black, <1 % Hispanic).  
 
4.7 Inclusion of Children 
Children <18 years of age will not be studied in this investigation. Exploratory laparotomies are 
uncommon in this age group. 
 
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 19 of 
27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1.1: Validated tier system for restrictive opioid prescribing protocol (ROPA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 20 of 
27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1.2: Oral morphine milligram equivalents (MME) with the following conversions:  
 
The conversion from intrathecal (IT) morphine to IV morphine is 1:100 
- 
Conversion of IV morphine to PO morphine is 1:3 
- 
150mcg IT morphine is 15 mg IV morphine 
- 
Conversion of IV hydromorphone to PO morphine is 1:20 (1 mg IV hydromorphone is  20 mg PO 
morphine) 
- 
Conversion from oral opioids such as oxycodone to oral morphine will be done using the 
conversion factors published by CDC.gov (see below).  
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 21 of 
27 
 
 
 
 
 
 
Appendix 1.3: Definition of ileus 
Defined by bilious emesis requiring a change in diet to nothing-per-mouth (NPO) status or nasogastric 
tube placement (NGT) in the absence of other indications. Patients who had NGT placed prophylactically 
at the time of surgery were not considered to have an ileus unless an NGT was reinserted or they met 
the above criteria. Participants will be assigned a value of yes ileus or no ileus. The rate of post op ileus 
is defined as the observed number of yes ileus in each study arm divided by the total number of subjects 
in the study arm. Fisher’s exact test will be used to compare non-paired nominal data.  
 
Appendix 1.4: Definition of postoperative hypotension 
Definition: Postoperative hypotension will be defined as <90/50 (as previously defined by 
Huepenbecker, et al.) or a 20% decrease from the preoperative office visit.  


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 22 of 
27 
 
Management: If a patient has a blood pressure <90/50 and it is determined that their preoperative 
blood pressure was over 20% higher than either their systolic or diastolic blood pressures, the house 
staff physician managing the floor will bolus 500cc of lactated ringers or normal saline (0.9%). If the 
hypotension does not resolve the house staff physician should turn down the epidural by 2 ml/hr and 
monitor with an option to deliver an additional 500cc of lactated ringers or normal saline (0.9%). The 
remainder of resuscitation should occur with 250cc of 5% albumin. If patient remains <90/50 the house 
staff physician should turn down the epidural by an additional 2ml/hr. Once the blood pressure 
increases to >90/50 the physician should observe. Blood products will also be recorded separately as 
postoperative resuscitation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1.5: Surgical Complexity scoring (via Alletti et al., 2007) 
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 23 of 
27 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1.6: Data Form 
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 24 of 
27 
Questions to be asked a preoperative visit 
1. Are you currently in pain? If so, what is the severity of your pain 0-10? 
2. Have you ever seen a pain medicine specialist? 
3. Have you ever taken narcotic pain medication for over 30 days consecutively? 
4. When was the last time you consistently took narcotic pain medicine for over 30 days 
consecutively? 
5. Are you taken narcotic pain medicine currently? If so, what amount? 
 
Questions to be asked a the 2 week and 6 week post-operative visits 
1. After you were discharged from the hospital, did the medications help to relieve your pain? 
Please rate the level of pain control on a scale of 1 (not good) to 5 (very good). If you did not 
require pain medication at home, select NA. 
2. Are you currently in pain? If so, what is the severity of your pain 0-10? 
 
 
 
Appendix 1.7: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms listed that 
should be used are those provided by the Department of Health and Human Services’ Office for 
Human Research Protections (OHRP).  A copy of this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event.  “Reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  “Suspected adverse reaction” implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
 
 
 
 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 25 of 
27 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-threatening” if, 
in the view of the investigator, its occurrence places the patient at immediate risk of death. It does 
not include an adverse event or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the view of 
the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective IRB 
approval.  The term “research” encompasses all IRB-approved materials and documents including 
the detailed protocol, IRB application, consent form, recruitment materials, questionnaires/data 
collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact the 
rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 
 
 
 
 
 
 
Appendix 1.8: Reporting Timelines 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 26 of 
27 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Unanticipated problem 
involving risk to participants 
or others 
Report within 10 working days.  If the event 
results in the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working day. 
Report via email 
after IRB 
acknowledgment 
Major deviation 
Report within 10 working days.  If the event 
results in the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working day. 
 
A series of minor deviations 
that are being reported as a 
continuing noncompliance 
Report within 10 working days.   
 
Protocol exception 
Approval must be obtained prior to implementing 
the change 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 working 
day.  Otherwise, report at the time of continuing 
review. 
 
Breach of confidentiality 
Within 10 working days. 
 
Incarceration 
If withdrawing the participant poses a safety issue, 
report within 10 working days.   
 
If withdrawing the participant does not represent 
a safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or others 
OR noncompliance, report within 10 working 
days.  If the event results in the death of a 
participant enrolled at WU/BJH/SLCH, report 
within 1 working day.  Otherwise, report at the 
time of continuing review. 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 


Protocol Version: V11 – 12Jun2024 (AMD 11)                                                                                    Page 27 of 
27 
 
If withdrawing the participant does not represent 
a safety issue and the patient will be withdrawn, 
report at continuing review.