Clinical trial NCT03090152
Conditions: Osteoarthritis, Hip
Keywords: Total Hip Replacement Total Hip Arthroplasty
Sponsor: Hospital for Special Surgery, New York
Start date: 2017-03-08; Completion date: 2019-09-27
Enrollment: 180 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Total hip arthroplasty can be associated with significant postoperative pain. Side effects of pain management may impair participation in physical therapy and slow readiness for discharge from the hospital. In a previous study done by the investigators' group, epidural patient controlled analgesia (EPCA) with a hydromorphone containing solution appeared to have a more favorable pain profile with ambulation, but greater side effects compared to injection of a peri-articular cocktail. The use of opioid was greater in the peri-articular injection group (PAI). There was no difference in length of stay. In view of the controversy over opioid use, the investigators would like to develop an optimal opioid sparing pain management approach by comparing 3 different protocols 1) Plain local anesthetic EPCA; 2) PAI; 3) EPCA + PAI; all in conjunction with a multimodal opioid sparing pain regimen. The goal would be to maximize pain control while minimizing opioid use and side-effects.

Detailed description:
Long acting narcotics or scheduled doses of narcotics are often used as part of a multimodal pain regimen. In this study, this is eliminated. Instead, it uses a cocktail of different drugs including intraoperative Ketamine use (NMDA receptor antagonist), intra-op Benadryl (to decrease excitation of nociceptors) and IV Tylenol. The narcotic free regimen starts preoperatively with the use of Aspirin,Clonidine patch, Cymbalta (Duloxetine), and is maintained both intraoperatively and post operatively. Baby ASA (81mg) is being used as an anti-inflammatory agent. A number of studies including the one by Morris et al. (2009), have shown via in vitro experiments that low dose aspirin decreases polymorphonuclear leukocyte and macrophage accumulation. It inhibits thromboxane making it an antithrombotic agent as well. The concern with aspirin has been major bleeding. Several studies in the orthopedic patient population using ≤81 mg of aspirin have shown that it does not increase bleeding (Cuellar, Mantz). At HSS, patients are routinely continued on baby aspirin when needed for its cardio protective effect. Devereaux in the POISE trial did show an increased risk of bleeding when ASA was given preoperatively at a dose of 200 mg. In our study, all patients will be given intravenous tranexamic acid which should mitigate against the risk of bleeding. Duloxetine is also being added. In a recent study done at HSS. Duloxetine was found to decrease the amount of opioid use and nausea. If found to be more effective with the use of EPCA vs. PAI or combination of the two, a new way of managing postop pain while minimizing Nnartcuoreti co fu Ssetu adsy per CDC recommendation will be helpful in managing patients post-operatively.

Arms: arm 1: * Aspirin and nerve pain medications including duloxetine and clonidine patch prior to surgery.
* Peri-articular injection in the operating room
* Combined Spinal Epidural with 1.5% Mepivacaine 4cc
* A pain regimen while in the hospital that includes EPCA (saline) Duloxetine (Cymbalta) - by mouth Ketorolac (Toradol) - IV Celecoxib (Celebrex) - by mouth Acetaminophen (Tylenol) - IV
* Acetaminophen and celecoxib for pain control once out of the hospital. Patients will also receive a prescription for an opioid medication in case they need it. arm 2: * Aspirin and nerve pain medications including duloxetine and clonidine patch prior to surgery.
* Combined Spinal Epidural with 1.5% Mepivacaine 4cc
* A pain regimen while in the hospital that consists of Epidural PCA (EPCA) with 0.06% bupivacaine. Duloxetine (Cymbalta) - by mouth Ketorolac (Toradol) - IV Celecoxib (Celebrex) - by mouth Acetaminophen (Tylenol) - IV The EPCA will be removed when pain is well-controlled. Other medications, including opioids, will be available.
* Acetaminophen and celecoxib for pain control once out of the hospital. Patients will also receive a prescription for an opioid medication in case they need it. arm 3: * Aspirin and nerve pain medications including duloxetine and clonidine
* Combined Spinal Epidural with 1.5% Mepivacaine 4cc
* Anesthetic, Antiemetic and peri-articular injection in the operating room
* A pain regimen while in the hospital that consists of EPCA (with 0.06% bupivacaine) Duloxetine (Cymbalta) - by mouth Ketorolac (Toradol) - IV Celecoxib (Celebrex) - by mouth Acetaminophen (Tylenol) - IV The EPCA will be removed when pain is well-controlled. Other medications, including opioids, will be available.
* Acetaminophen and celecoxib for pain control once out of the hospital. Patients will also receive a prescription for an opioid medication in case they need it.
Interventions: intervention 1: Periarticular injection (Deep injection) intervention 2: Periarticular injection (Superficial injection) intervention 3: Bupivacaine intervention 4: Placebo
Intervention descriptions: intervention 1: Deep injection of "cocktail" containing Bupivacaine with Epi, 30mL; Morphine, 8mg/mL, 1mL; Methyprednislone, 40mg/mL, 1mL; Cefazolin, 500mg in 10 mL; saline, 22mL into the anterior capsule, the periosteum, the gluteus maximus, and the abductor muscles and fascia lata. intervention 2: Superficial injection of 40mL 0.25% Bupivacaine into subcutaneous tissue prior to wound closure. intervention 3: EPCA: Bupivacaine 0.06%. intervention 4: EPCA: Saline.

Protocol documents:
Prot_SAP_000.pdf: 
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Minimal Opioid Use After Total Hip Replacement 
(THR): A Blinded, Randomized, Placebo-Controlled 
Study 
 
FUNDER: 
Anesthesiology Department,  
Hospital for Special Surgery 
PROTOCOL NO.: 
2017-0721 
DATE: 
0625/2020 
 
 
 
 
 
 
 
 
 
 
 
 
This document contains the confidential information of the Hospital for Special Surgery.  It is provided to you and your company’s personnel for 
review.  Your acceptance of this document constitutes an agreement that you will not disclose the information contained herein to others without 
the prior written consent of the Hospital for Special Surgery.  No other use or reproduction is authorized by Hospital for Special Surgery, nor does 
the Hospital for Special Surgery assume any responsibility for unauthorized use of this protocol. 
 
 


 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS................................................................................................................... 2 
PROTOCOL SYNOPSIS.................................................................................................................. 3 
1.0     INTRODUCTION .................................................................................................................... 4 
    2.0 
PRODUCT DESCRIPTION………………………..……………………………………………….4 
3.0      OBJECTIVE OF CLINICAL STUDY ...................................................................................... 4 
4.0      STUDY HYPOTHESIS ........................................................................................................... 4 
5.0      STUDY DESIGN .................................................................................................................... 4 
5.1 
Study Duration ................................................................................................................ 4 
5.2 
Endpoints ....................................................................................................................... 4 
5.2.1 
Primary Endpoint ...................................................................................................... 4 
5.2.2 
Secondary Endpoints ................................................................................................ 4 
5.2.3 
Safety Evaluations. ................................................................................................... 4 
5.3 
Study Site ....................................................................................................................... 4 
6.0        STUDY POPULATION ......................................................................................................... 4 
6.1 
Number of Subjects ........................................................................................................ 4 
6.2 
Inclusion Criteria............................................................................................................. 5 
6.3 
Exclusion Criteria: .......................................................................................................... 5 
    6.4        Randomization………………………………………………………………………………..5 
7.0         PROCEDURES .................................................................................................................... 5 
7.1 
Surgical Procedure ......................................................................................................... 5 
 
7.1.1. Investigational Product Administration………………………………………………. .…..5 
7.2 
Imaging Procedure ......................................................................................................... 5 
7.3 
Medical Record Requirements ....................................................................................... 5 
7.4 
Data Collection ............................................................................................................... 5 
    7.5        Schedule of Assessments……………………………………………………..…………….. 6 
7.6 
Radiological Evaluations ................................................................................................ 7 
7.7 
Clinical Evaluations ........................................................................................................ 7 
 
7.7.1. Revision Surgery………………………………………………………………………. .……7 
8.0         STATISTICAL ANALYSIS .................................................................................................. 7 
9.0         ADVERSE EVENT ASSESSMENT ..................................................................................... 7 
9.1 
Adverse Event (AE) ........................................................................................................ 7 
9.2 
Serious Adverse Events (SAE) ...................................................................................... 7 
9.3 
Subsequent Surgical Interventions Definitions .............................................................. 7 
9.4 
Adverse Event Relationship ........................................................................................... 7 
9.5 
Adverse Event Recording .............................................................................................. 7 
9.6 
Adverse Event Reporting ............................................................................................... 7 
10.0         INVESTIGATOR RESPONSIBILITIES, RECORD AND REPORTS ................................ 7 
10.1 
Subject Consent and Information ................................................................................... 7 
10.2 
Subject Data Protection ................................................................................................. 7 
10.3 
Staff Information ............................................................................................................. 8 
10.4 
Protocol Reviews............................................................................................................ 8 
10.5 
Investigator Records ...................................................................................................... 8 
10.6 
Investigator Reports ....................................................................................................... 8 
 11.0  
REFERENCES……………………………………………………………….………………….8 
APPENDIX A: Case Report Forms .............................................................................................. 9 


 
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PROTOCOL SYNOPSIS 
Protocol Title: 
Minimal Opioid use after Total Hip Replacement (THR): a 
blinded randomized placebo-controlled study 
Protocol Number: 
2017-0721 
Protocol Date: 
6/25/2020 
Sponsor: 
Hospital for Special Surgery, Department of Anesthesiology 
Principal 
Investigator: 
Kethy Jules-Elysee, MD 
Objective: 
Total hip arthroplasty can be associated with significant 
postoperative pain. Side effects of pain management may impair 
participation in physical therapy and slow readiness for 
discharge from the hospital. In a previous study done by our 
group, epidural patient-controlled analgesia (EPCA) with a 
hydromorphone containing solution appeared to have a more 
favorable pain profile with ambulation, but greater side effects 
compared to injection of a peri-articular cocktail. The use of 
opioid was greater in the peri-articular injection group (PAI). 
There was no difference in length of stay. In view of the 
controversy over opioid use, we would like to develop an optimal 
opioid sparing pain management approach by comparing 3 
different protocols 1) Plain local anesthetic EPCA; 2) PAI; 3) 
EPCA + PAI; all in conjunction with a multimodal opioid sparing 
pain regimen.  The goal would be to maximize pain control while 
minimizing opioid use and side-effects. 
Study Design: 
Randomized Controlled Clinical Trial 
Enrollment: 
180 total (60 in each group) 
Subject Criteria: 
- 
Patients with osteoarthritis scheduled for primary total 
hip arthroplasty with participating surgeon 
- 
Age 45 to 80 years old 
- 
Planned use of regional anesthesia 
- 
Ability to follow study protocol 
- 
Planned posterolateral surgical approach 
Study Duration: 
Enrollment Period: Pre-op, intra-op, post-op (POD0-3, 7, 90); 
Duration of Follow ups: Approximately 15 mins each 
Data Collection: 
• 
Collected from medical records and patient. 
Outcome 
Parameters: 
• 
Opioid use (oral morphine equivalents, cumulative, within 
24 hours). 


 
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1.0 INTRODUCTION 
Total hip arthroplasty can be associated with significant postoperative pain. Side effects of 
pain management may impair participation in physical therapy and slow readiness for 
discharge from the hospital. In a previous study done by our group, epidural patient 
controlled analgesia (EPCA) with a hydromorphone containing solution appeared to have a 
more favorable pain profile with ambulation, but greater side effects compared to injection of 
a peri-articular cocktail. The use of opioid was greater in the peri-articular injection group 
(PAI). There was no difference in length of stay. In view of the controversy over opioid use, 
we would like to develop an optimal opioid sparing pain management approach by 
comparing 3 different protocols 1) Plain local anesthetic EPCA; 2) PAI; 3) EPCA + PAI; all in 
conjunction with a multimodal opioid sparing pain regimen. 
2.0 OBJECTIVE OF CLINICAL STUDY 
The objective of this study is to maximize pain control while minimizing opioid use and side 
effects. 
3.0 STUDY HYPOTHESES 
Hypothesis 1: Compared to EPCA or PAI alone, the EPCA + PAI protocol will result in: 
- 
lower opioid utilization 
- 
lower pain scores 
- 
lower opioid-related symptom distress scales 
- 
improved quality of recovery scores 
- 
higher patient satisfaction. 
Hypothesis 2: The use of EPCA + PAI protocol will lead to earlier “readiness for discharge” 
to home or to a rehab facility compared to plain EPCA alone or PAI alone. 
4.0 STUDY DESIGN 
4.1 
Endpoints 
4.1.1 
Primary Endpoint 
• 
Opioid use (oral morphine equivalents, cumulative, within 24 hours). 
4.1.2 
Secondary Endpoints 
• 
Pain at rest via NRS scale (POD 1,2,3, until D/C POD7 and 90) 
• 
Pain with physical therapy via NRS scale (POD 1,2,3,until D/C POD7 and 90) 
• 
Opioid side effects via ORSDS questionnaire (POD1,2) 
• 
Post-operative pain via Pain OUT questionnaire (POD 1) 


 
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• 
Patient satisfaction (0-10 Likert scale) regarding pain control (POD 1, 2, 3; POD7 & 
POD90) 
• 
Neuropathic pain via S-LANSS SF-8 (Pre-Op, POD 7 & 90) 
• 
Quality of Recovery via QoR-40 (POD 1,2,3) 
• 
Readiness for discharge time (At D/C) 
4.2 
Study Sites 
This study will take place at the main campus of the Hospital for Special Surgery.  
5.0 STUDY POPULATION 
5.1 
Number of Subjects 
180 subjects (60 in each group).  
 
5.2 
Inclusion Criteria 
Subjects of either gender will be included if: 
- 
Patients with osteoarthritis scheduled for primary total hip arthroplasty with 
participating surgeon 
- 
Age 45 to 80 years old 
- 
Planned use of regional anesthesia 
- 
Ability to follow study protocol 
- 
Planned posterolateral surgical approach 
 
5.3 
Exclusion Criteria 
Subjects will be excluded from the study if: 
- 
Patients younger than 45 years old and older than 80 
- 
Patients intending to receive general anesthesia 
- 
Patients with an ASA of IV 
- 
Patients with insulin-dependent diabetes 
- 
Patients with hepatic (liver) failure (history of cirrhosis or elevated LFT’s) 
- 
Patients with chronic renal (kidney) failure (formal diagnosis of renal disease of 
elevated creatinine) 
- 
Chronic opioid use (taking opioids for longer than 3 months on a daily basis) 
- 
Patients with any prior major ipsilateral hip surgery 
 
5.4 
Randomization 
A block randomization scheme will be created by a statistician not involved with the study. 
Prior to study start, 1) the randomization scheme will be shared with pharmacy, and 2) 
sealed envelopes containing only the PAI portion of the randomization assignments will be 
prepared by an unaffiliated RA and attached to the study enrollment folders. When a patient 
is enrolled, pharmacy will be notified and they will prepare the EPCA solution according to 
the randomization scheme. The sealed envelope will be given to the physician who will open 


 
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it to reveal the PAI portion of the randomization. This way the anesthesiologist and surgeon 
can remain blinded as to the EPCA (active vs. placebo) portion of the randomization.  
6.0 PROCEDURES 
6.1 
Surgical Procedure 
 
EPCA GROUP 
 
Pre-Operative Anesthesia/Analgesia 
• 
Baby ASA 81 mg 
• 
Cymbalta 60mg 
• 
Clonidine Patch 0.1mg for 24hr 
 
Operating Room 
• 
Anesthetic: Combined Spinal-Epidural with 1.5% Mepivacaine (4 cc), (if need to 
induce hypotension, give Mepivacaine through epidural). IV sedation with 
Midazolam, Propofol (no opioids) *Ketamine 20 mg prior to incision 30 mg in 
Propofol infusion 
• 
IV TXA 10 mg/kg up to 1000mg 
• 
Antiemetic: 20mg famotidine (Pepcid) and 4mg ondansetron (Zofran) + *8 mg IV 
Decadron 
• 
*IV Tylenol prior to transfer to PACU 
• 
End of case: *Toradol (Ketorolac) (30 mg IV if age 64 or younger, 15 mg IV if age 
>=65 or weight <50 kg) 
 
Post-Operative Procedures 
• 
Foley catheter until POD 1 at 10:00 AM. Oral diet and physical therapy upon block 
resolution. 
• 
Cymbalta 60 mg qd POD1-2 
• 
PCEA (Bupivacaine 0.06%) (4/4/10/20, initially). 
• 
Reduce PCA (0/4/10/20 POD1, 6:59). D/C PCA (POD1, 10:00) 
• 
Ondansetron (IV 4 mg q 8 hr PRN) 
• 
Nalbuphine (IV 5 mg q 6 hr PRN) 
• 
Continue IV Acetaminophen (1000 mg q 6 hr for 3 doses followed by oral dosing q 
6hr) 
• 
Toradol (30 mg IV q 6 hr until POD 1, total 4 doses including OR dose) 
• 
Oxycodone (5 mg q 3 hr PRN for mild pain / 10 mg for moderate to severe pain) 
• 
Celebrex 200 mg bid on POD 1 
• 
IV Pepcid 20 mg q 12 hr 
• 
Dilaudid (1 mg SQ q 4 hr PRN, after PCA D/C) 
• 
Remove Clonidine Patch 24 hours after application 
• 
Miralax 17g daily 
• 
ASA 325mg bid 
 
PAI GROUP 
 


 
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Pre-Operative Anesthesia/Analgesia 
• 
Baby ASA 81 mg 
• 
Cymbalta 60mg 
• 
Clonidine Patch 0.1mg for 24hr 
 
Operating Room  
• 
A. Anesthetic: At end of surgery, the surgeon performs a peri-articular injection. 
Protocolized method for injection. *Deep Injection: (0.5% Bupivacaine with Epi, 30ml; 
morphine, 8 mg/ml, 1ml; methylprednisolone, 40 mg/ml, 1ml; cefazolin, 500 mg in 10 
ml; normal saline, 22ml). Superficial injection: (40 ml 0.25% Bupivacaine). 
• 
B. Anesthetic: Combined Spinal-Epidural with 1.5% Mepivacaine (4 cc) (if needed, 
can add lidocaine to epidural), (if need to induce hypotension, give Mepivacaine 
through epidural). IV sedation with Midazolam, Propofol (no opioids) *Ketamine 20 
mg prior to incision 30 mg in Propofol infusion 
• 
IV TXA 10 mg/kg up to 1000mg 
• 
Antiemetic: 20mg famotidine (Pepcid) and 4mg ondansetron (Zofran).*No Decadron 
because of steroids in injection. 
• 
*IV Tylenol 1000 mg prior to transfer to PACU 
• 
End of case: *Toradol (Ketorolac) (30 mg IV if age 64 or younger, 15 mg IV if age 
>=65 or weight <50 kg) 
 
Post-Operative Procedures 
• 
Foley catheter until POD 1 at 10:00 AM. Oral diet and physical therapy upon block 
resolution. 
• 
Cymbalta 60 mg qd POD1-2 
• 
Placebo epidural pain pump containing normal saline, programmed as such: 
4/4/10/20, initially. Reduce PCA (0/4/10/20 POD 1, 6:59). D/C PCA (POD 1 10:00)  
• 
Ondansetron (IV 4 mg q 8 hr PRN) 
• 
Nalbuphine (IV 5 mg q 6 hr PRN). 
• 
Continue IV Acetaminophen (1000 mg q 6 hr for 3 more doses following oral dosing 
q 6 hr) 
• 
Toradol (30 mg q 6 hr until POD 1, total 4 doses including OR dose) 
• 
Oxycodone q 3 hr PRN (5 mg for mild pain / 10 mg for moderate to severe pain) 
• 
Celebrex 200 mg bid on POD 1 
• 
IV Pepcid 20 mg q 12hr 
• 
Dilaudid (1 mg SQ q 4 hr PRN, after PCA discontinuation) 
• 
Remove Clonidine Patch 24 hours after application 
• 
Miralax 17g daily 
• 
ASA 325 mg bid 
 
EPCA + PAI GROUP 
 
Pre-Operative Anesthesia/Analgesia 
• 
Baby ASA 81 mg 
• 
Cymbalta 60mg 
• 
Clonidine Patch 0.1mg for 24hr 
 
Operating Room 


 
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• 
Anesthetic: Combined Spinal-Epidural with 1.5% Mepivacaine (4 cc), (if need to 
induce hypotension, give Mepivacaine through epidural). IV sedation with 
Midazolam, Propofol (no opioids) *Ketamine 20 mg prior to incision 30 mg in 
Propofol infusion 
• 
IV TXA 10 mg/kg up to 1000mg 
• 
Antiemetic: 20mg famotidine (Pepcid) and 4mg ondansetron (Zofran) 
• 
*IV Tylenol prior to transfer to PACU 
• 
End of case: *Toradol (Ketorolac) (30 mg IV if age 64 or younger, 15 mg IV if age 
>=65 or weight <50 kg) 
• 
*No Decadron given 
• 
C. At end of surgery, the surgeon performs a peri-articular injection. Protocolized 
method for injection. *Deep Injection: (0.5% Bupivacaine with Epi, 30ml; morphine, 8 
mg/ml, 1ml; methylprednisolone, 40 mg/ml, 1ml; cefazolin, 500 mg in 10 ml; normal 
saline, 22ml). Superficial injection: (40 ml 0.25% Bupivacaine). 
 
Post-Operative Procedures 
• 
Foley catheter until POD 1 at 10:00 AM. 3. Oral diet and physical therapy upon block 
resolution. 
• 
Cymbalta 60 mg qd POD1-2 
• 
PCEA (Bupivacaine 0.06%) (4/4/10/20, initially). 
• 
Reduce PCA (0/4/10/20 POD1, 6:59). D/C PCA (POD1, 10:00) 
• 
Ondansetron (IV 4 mg q 8 hr PRN) 
• 
Nalbuphine (IV 5 mg q 6 hr PRN) 
• 
Continue IV Acetaminophen (1000 mg q 6 hr for 3 doses followed by oral dosing q 
6hr) 
• 
Toradol (If age <=64, 30 mg IV q 6 hr until POD 1, total 4 doses including OR dose) 
If age >=65 or weight <50kg, 15mg 
• 
Oxycodone (5 mg q 3 hr PRN for mild pain / 10 mg for moderate to severe pain) 
• 
Celebrex 200 mg bid on POD 1 
• 
IV Pepcid 20 mg q 12 hr 
• 
Dilaudid (1 mg SQ q 4 hr PRN, after PCA D/C) 
• 
Remove Clonidine Patch 24 hours after application 
• 
Miralax 17g daily 
• 
ASA 325mg bid 
 
6.2 
Data Collection 
Data will be collected by an investigator or research assistant. Sources of data include 
medical records and patient physical assessments/interviews conducted by study personnel. 
Data will be recorded and managed using REDCap electronic data capture tools hosted at 
the Clinical and Translational Science Center (CTSC) at Weill Cornell Medical College. 
REDCap (Research Electronic Data Capture) is a secure, web-based application designed 
to support data capture for research studies, providing: 1) an intuitive interface for validated 
data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated 
export procedures for seamless data downloads to common statistical packages; and 4) 
procedures for importing data from external sources. Connection to REDCap occurs via the 


 
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hospital’s encrypted cable and wireless networks, and data will be entered through a 
password protected computer terminal or iPad. 
The following data will be collected: 
 
Pre-operative/Baseline 
• 
basic demographic data 
• 
patient weight & height, BMI 
• 
Comorbidities 
• 
NRS Pain score at rest and with activity 
• 
SF-8 Acute 
• 
S-LANSS 
 
POD 1 
• 
date of surgery 
• 
type of surgery 
• 
NRS pain score at rest and with activity  
• 
ORSDS 
• 
QoR-40 
• 
Pain outcomes questionnaire  
• 
Opioid dose 
• 
Patient Satisfaction 
 
POD 2 
• 
NRS pain score at rest and with activity 
• 
ORSDS 
• 
QoR-40 
• 
Opioid dose 
• 
Patient satisfaction  
 
POD 3 
• 
NRS pain score at rest and with activity 
• 
QoR-40 
• 
Opioid dose 
• 
Patient satisfaction  
 
 
At Discharge 
• 
Blinding assessment  
 
 
POD 7 (Phone F/U) 
• 
NRS pain score at rest and with activity 
• 
SF-8 Acute 
• 
S-LANSS 
• 
Blinding Assessment  
• 
Opioid dose 
• 
Patient satisfaction  


 
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90 Days (Phone F/U) 
• 
NRS pain score at rest and with activity 
• 
SF-8 Acute 
• 
S-LANSS 
• 
Opioid dose 
• 
Patient satisfaction  


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6.3 
Schedule of Assessments 
 
Procedures 
Role 
Day 
Before 
Surgery 
Pre-Op 
POD1 
POD2 
POD3 
At 
Discharge 
POD 7 
90 Day 
Phone 
F/U 
Eligibility Review 
RA 
X 
 
 
 
 
 
 
 
Obtain Consent 
Anes MD 
or RA 
 
X 
 
 
 
 
 
 
Demographics 
RA 
 
X 
 
 
 
 
 
 
Comorbidities 
RA 
 
X 
 
 
 
 
 
 
NRS Pain at rest/with activity 
RA 
 
X 
X 
X 
X 
 
X 
X 
SF-8 Acute 
RA 
 
X 
 
 
 
 
X 
X 
S-LANSS 
RA 
 
X 
 
 
 
 
X 
X 
ORSDS 
RA 
 
 
X 
X 
 
 
 
 
QoR-40 
RA 
 
 
X 
X 
X 
 
 
 
Pain Outcomes 
Questionnaire 
RA 
 
 
X 
 
 
 
 
 
Blinding Assessment  
RA 
 
 
 
 
 
X 
X 
 
Opioid Dose 
RA 
 
 
X 
X 
X 
 
X 
X 
Patient Satisfaction 
RA 
 
 
X 
X 
X 
 
X 
X 


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7.0 STATISTICAL ANALYSIS 
• 
Proposed analysis (e.g., student’s t-test, ANOVA, chisquare, regression, etc.): 
Independent two sample t-tests 
• 
Alpha level: 0.05/2 = 0.025. The primary goal of the study is to compare the 
combined intervention (EPCA+PAI) with EPCA alone and PAI alone. We ran a 
conservative power analysis for these two comparisons by applying Bonferroni 
corrections. We assume that EPCA alone and PAI alone will have similar effects. 
The comparison between these two groups is not the primary interest of the study. 
• 
Beta or power level: 80% 
• 
Primary outcome variable estimate (mean +/s.d. for continuous outcome): Mean ± 
SD opioid use (in 24hr)= 26 ± 22 mg OME 
• 
Number of groups being compared (use 1 for paired analysis within the same 
subjects): 2 (assuming that there is no difference between EPCA alone and PAI 
alone). 
• 
Effect size or change expected between groups: Opioid use (in 24hr): 50% reduction 
in OME 
• 
Sample size: We would need 60 patients per group to achieve 80% power for 
detecting the above effect size for opioid use. The sample size accounts for 10% 
missing observations due to withdraws, losses to follow up, etc. 
 
Continuous variables and discrete variables will be presented as mean+/-sd and proportion, 
respectively. Univariate analysis including t-test/Mann-Whitney Wilcoxon Rank test and Chi-
square/Fisher’s exact test will be conducted to compare continuous and discrete outcomes 
(both primary and secondary) between any two groups, respectively. Standard linear 
regression analysis can be used to compare opioid use between the intervention groups 
 
8.0 ADVERSE EVENT ASSESSMENT 
All Adverse Events (AEs) will be reported in the final study report. Definitions for Adverse 
Event (AE) used in this study are listed below and are based on FDA and international 
guidelines: 
 
8.1 
Adverse Event Reporting 
We will have data safety board to check if patients in the study experience increased pain, 
decreased quality of recovery and decreased satisfaction with the proposed regimens. The 
following physicians will be part of the safety board: Dr. Kirksey, Dr. DelPizzo, Dr. 
Memtsoudis.  
Individual Stopping Criteria: 
The DSMB will review data related to the following individual stopping criteria: 
- 
Gastrointestinal bleeding 
- 
Hematoma 


 
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- 
Blood in stool and/or vomit 
Incidences of these potential issues will be reported to the IRB using the SAE 
reporting form (attachment 3). The DSMB may recommend modification to individual 
stopping rules if necessary and may recommend stopping the study for the following 
reasons: 
- 
The data show a significantly increased risk of serious adverse effects from 
the established incidence in the literature. 
- 
If any mortality is seen in study participants 
- 
All serious adverse events (SAE) will be reported within 5 days of the 
occurrence to the DSMB 
 
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