Conditions: Male Infertility
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: no

Brief summary:
The study is a drug trial comparing the post-operative pain control provided by liposomal bupivacaine (a local anesthetic) against standard bupivacaine (a different formulation of the local anesthetic) for men undergoing testicular sperm extraction.

Detailed description:

Arms:
arm 1: Participants in this arm will have a single injection of liposomal bupivacaine admixed with standard bupivacaine (266mg liposomal bupivacaine mixed with 50mg bupivacaine hydrochloride) at the conclusion of their surgical sperm retrieval procedure. arm 2: Participants in this arm will have a single injection of standard bupivacaine (100mg bupivacaine hydrochloride) at the conclusion of their surgical sperm retrieval procedure.

Interventions: intervention 1: Liposomal Bupivacaine intervention 2: Standard Bupivacaine
Intervention descriptions: intervention 1: After surgical sperm retrieval, the wound will be injected with liposomal bupivacaine (266 mg) mixed with standard bupivacaine (bupivacaine hydrochloride 50mg) for post-operative pain relief. intervention 2: After surgical sperm retrieval, the wound will be injected only with standard bupivacaine (bupivacaine hydrochloride 100mg) for post-operative pain relief.

Protocol document:
Prot_SAP_000.pdf: 
 
 
  
 
 
TITLE:  Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine 
 
IRB Protocol #: 1802018993 
NCT #: NCT03802864 
IND/IDE # (if applicable): NA 
Version Date: 11/14/2018 
 
Principal Investigator: 
 
Name: Russell Hayden 
Address: 525 E 68th St, Box 269, NYC, NY 10065 
Telephone: 732-691-1883 
Fax: 212-746-0977 
E-mail address: rph9002@med.cornell.edu 
 
Co-Investigators: 
 
Name: Peter Schlegel 
Address: 525 E 68th St, Suite 900, NYC, NY 10065 
Telephone: 212-746-5491 
Fax: 212-746-8425 
E-mail address: pnschleg@med.cornell.edu 
 
 
Statistician: 
Study Coordinator: 
 
Name: Clara Oromendia 
Name: Russell Hayden (as above) 
 
Address: 402 East 67th Street, New York, NY 10065  
 
Telephone: 646-962-8023 
 
 
Fax: 646-962-0281 
 
 
E-mail address: mco2004@med.cornell.edu 
 
 
Responsible Research Nurse: 
Responsible Data Manager: 
 
Name: Kathleen Hart 
Name: Russell Hayden (as above) 
 
Address: 525 E 68th St, Suite 900, NYC, NY 10065 
 
 
Telephone: 212-746-5491 
 
 
Fax: 212-746-8425 
 
 
E-mail address: khart@med.cornell.edu 
 
 
Participating Sites:  Only Weill Cornell Urology.  


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Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others 
without written authorization from WCM. 


iii | P a g e  
 
 
 
 
List of Abbreviations 
 
All abbreviations used throughout the protocol must be defined.  
 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTSC 
Clinical Translational Science Center  
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
Humanitarian Use Device  
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
UAP 
Unanticipated Problem 
WCM 
Weill Cornell Medicine 


1| Page 
 
  
 
Protocol Summary 
Full Title:  
 
 
 
Post-operative Pain Control of Testicular Sperm Extraction Using 
Liposomal Bupivacaine  
Short Title: 
 
 
 
Liposomal Bupivacaine in sperm extraction 
Clinical Phase: 
 
 
IV 
Principal Investigator: 
 
Russell Hayden  
Sample Size: 
 
N= 85 
Accrual Ceiling: 
 
This study will enroll 85 subjects   
Study Population: 
 
Healthy men (>18yo) presenting for testicular sperm extraction 
for fertility 
Accrual Period: 
 
6 months  
Study Design: 
 
Double blinded randomized control trial comparing standard 
bupivacaine against standard bupivacaine plus liposomal 
bupivacaine. The local anesthetic will be injected into the surgical 
bed at the conclusion of the procedure prior to emergence from 
anesthesia.  Each arm will have 25 men.  
Study Duration: 
 
Three weeks.  Patients will keep a pain diary for 7 days post-op 
and will have a routine post-op clinic appointment at 3 weeks. 
Study projected end date: 7/2019.  
Study Agent/  
Intervention Description: 
Liposomal bupivacaine, 266mg/20mL.  One dose (20mL) will be 
infiltrated into the wound at the end of surgery. 
Primary Objective: 
 
Area under the curve of pain rankings on the 11-point numerical 
pain rating scales (NRS-11) scale assessed every 8 hours in the first 
48 hours post-surgery.  
Secondary Objectives: 
Area under the curve of pain rankings on the 11-point numerical 
pain rating scales (NRS-11) scale in the first 60 hours post-surgery. 
Area under the curve of pain rankings on the 11-point numerical 
pain rating scales (NRS-11) scale in the first 7 days post-surgery.  
 
 
Total number of narcotic tablets required between the 
intervention and control arms during post-operative day 1 
through 7. 
Time to first rescue narcotic utilization between the two arms. 
Overall satisfaction of pain control regimen (self reported on post-
operative day 7). 
The percentage of patients remaining opiate free by post-
operative day 7. 
Exploratory Objectives: 
NA 
Endpoints: 
 
Study ends once 50 patients have undergone surgery and finished 
the surveys and post-surgical follow-up. 


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SCHEMA 
 


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Table of Contents 
1. 
STUDY OBJECTIVES .................................................................................................................. 5 
1.1 
Primary Objectives ........................................................................................................... 5 
1.2 
Secondary Objectives ....................................................................................................... 5 
1.3 
Exploratory Objectives ..................................................................................................... 5 
2. 
BACKGROUND ......................................................................................................................... 5 
2.1 
Disease ............................................................................................................................. 5 
2.2 
Investigational Agent or Device ....................................................................................... 6 
2.3 
Rationale .......................................................................................................................... 7 
2.4 
Risk/Benefit Assessment .................................................................................................. 8 
3. 
SUBJECT SELECTION ................................................................................................................ 8 
3.1 
Study Population .............................................................................................................. 8 
3.2 
Inclusion Criteria .............................................................................................................. 8 
3.3      Exclusion Criteria .............................................................................................................. 8 
4. 
REGISTRATION PROCEDURES .................................................................................................. 8 
4.1 Patient Registration .............................................................................................................. 9 
5. 
STUDY PROCEDURES ............................................................................................................... 9 
5.1 Schedule of Evaluations ...................................................................................................... 10 
5.2 
Treatment Administration ............................................................................................. 10 
5.3 
General Concomitant Medication and Supportive Care Guidelines .............................. 11 
5.4 
Duration of Therapy and Criteria for Removal from Study ............................................ 11 
5.5 
Duration of Follow Up .................................................................................................... 11 
6. 
DOSING DELAYS/DOSE MODIFICATIONS .............................................................................. 11 
7. 
PHARMACEUTICAL INFORMATION ....................................................................................... 11 
7.1 
Investigational Agent ..................................................................................................... 11 
7.2 
Availability ...................................................................................................................... 12 
7.3 
Agent Ordering ............................................................................................................... 12 
7.4 
Agent Accountability ...................................................................................................... 12 
8. 
CORRELATIVE/SPECIAL STUDIES ........................................................................................... 12 
9. 
MEASUREMENT OF EFFECT .................................................................................................. 13 
9.1 Response Criteria ................................................................................................................ 13 
9.2 Duration of Response ......................................................................................................... 13 
9.3 Progression-Free Survival (if applicable) ............................................................................ 13 
9.4 Other Response Parameters ............................................................................................... 13 


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10.  DATA REPORTING / REGULATORY CONSIDERATIONS .......................................................... 13 
10.1 Data Collection .................................................................................................................. 13 
10.1.1 REDCap ....................................................................................................................... 13 
10.2 Regulatory Considerations ................................................................................................ 14 
11. STATISTICAL CONSIDERATIONS (STATISTICAL ANALYSIS PLAN) ........................................... 14 
11.1 Study Design/Endpoints .................................................................................................... 14 
11.2 Sample Size/Accrual Rate ................................................................................................. 15 
11.3 Stratification Factors ......................................................................................................... 16 
11.4 Analysis of Endpoints ........................................................................................................ 16 
11.4.1 Analysis of Primary Endpoints ....................................................................................... 16 
11.4.2 Analysis of Secondary Endpoints ................................................................................... 16 
11.5 Interim Analysis ................................................................................................................. 16 
11.6 Reporting and Exclusions .................................................................................................. 17 
11.6.1 Evaluation of toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with Liposomal bupivicaine. ................................................................ 17 
11.6.2 Evaluation of response. .......................................................................................... 17 
12. ADVERSE EVENT REPORTING REQUIREMENTS ....................................................................... 17 
12.1 
Adverse Event Definition ............................................................................................ 17 
12.1.1 Investigational Agent or Device Risks ..................................................................... 17 
12.1.2 Adverse Event Characteristics and Related Attributions ........................................ 18 
12.1.3    
Recording of Adverse Events............................................................................... 18 
12.1.4   
Reporting of AE to WCM IRB ............................................................................... 18 
12.2 
Definition of SAE ......................................................................................................... 18 
12.2.1 Reporting of SAE to IRB ........................................................................................... 19 
12.2.2 Reporting of SAE to FDA [For protocols where WCMC is the Sponsor-Investigator]
 
19 
12.2.3 Reporting of SAE to Insert Pharmaceutical Company Name .................................. 19 
12.4 AE/SAE Follow Up ............................................................................................................. 19 
13.  DATA AND SAFETY MONITORING PLAN (DSMP) .................................................................. 20 
REFERENCES .................................................................................................................................. 21 
 
 
 
 
 
 
 
 
 


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1. 
Study Objectives 
 
 
 
1.1 Primary Objectives 
 
 
Our primary endpoint is the area-under-the-curve in the first 48 hours post-
surgery for 11-point numerical pain rating scales (NRS-11) of patients who were 
injected with liposomal bupivacaine (mixed with standard bupivacaine) at the 
time of surgery against standard bupivacaine only. 
  
1.2 Secondary Objectives 
 
Secondary endpoints: 
Area-under-the-curve in the first 60 hours and 108 hours (7 days) post-surgery for 
11-point numerical pain rating scales (NRS-11). 
Average total number of narcotic tablets required between the intervention and 
control arms during post-operative day 1 through 7. 
Time to first rescue narcotic utilization between the two arms. 
Overall satisfaction of pain control regimen (ranked by the patients on post-
operative day 7). 
The percentage of patients remaining opiate free by post-operative day 7. 
 
1.3 Exploratory Objectives 
 
 
 
 
 
NA 
 
2. 
Background 
 
2.1 Disease 
 
Approximately 640,000 men in the United States are azoospermic, a condition 
characterized by the lack of sperm in the ejaculate. For these individuals, 
microdissection testicular sperm extraction (microTESE or MESA) represents the 
only means to procure sperm for in vitro fertilization. Our center initially described 
the technique, which now represents the standard of care for these individuals [1]. 
Given the sensitivity of scrotal/testicular surgery, post-operative pain remains a 
major concern for our patient population. 
 
1. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield 
with minimal tissue excision. Human reproduction (Oxford, England). 
1999;14(1):131-135. 
 


6 | P a g e  
 
 
 
2.2 Investigational Agent or Device 
 
Liposomal bupivacaine has garnered significant interest in the peri-operative arena. 
Multiple studies have now documented varying levels of success with intra-operative 
administration [1-3]. Relevant to our patient population, the liposomal delivery 
vehicle provides an extended release over 72 hours, which corresponds to the time-
period of maximum narcotic utilization in men undergoing testicular sperm 
extraction. For this latter reason, we believe liposomal bupivacaine to be a promising 
adjunct to manage our patient population. As standard practice, we currently use 
1/4% bupivacaine hydrochloride infiltrated into the peri-testicular tissue, the 
spermatic cord, and the scrotal wound. This agent only provides analgesia for ~6 
hours. 
 
The mechanism of action for both bupivacaine hydrochloride and liposomal 
bupivacaine is the same, intracellular binding of voltage gated sodium channels. This 
blockade prevents pain fibers from initiating and propagating an action potential. In 
the case of liposomal bupivacaine, the agent is packaged into liposomes in order to 
slow the release of the medication. This extends the theoretical period of action 
from 6 to ~72 hours. The Phase III trials that studied liposomal bupivacaine utilized a 
dose of 120mg [4] and 266mg [5].  These studies found liposomal bupivacaine 
effective against placebo for bunionectomy and hemorrhoidectomy [4-5]. 
Subsequently, a multitude of studies have used the 20mL vial (266mg), best 
described by a Cochrane Review/Meta-analysis [6]. These studies found a similar 
safety profile of liposomal bupivacaine compared to the standard preparation of 
bupivacaine. The pharmacokinetics were as follows: T1/2 23.8 – 34.1 hours, Cmax 166 
– 867 ng/mL, and Tmax 0.5 – 2 hours [4-5,7]. Liposomal bupivacaine carries the same 
risks of CNS toxicity and cardiovascular toxicity as standard bupivacaine. Major drug 
interactions occur with simultaneous administration with lidocaine, which may 
destabilize the liposomes and cause premature release of the agent. We do not plan 
on use lidocaine due to this reason. Both standard and liposomal bupivacaine are 
metabolized in the liver and excreted primarily by the kidneys. We plan to exclude 
men with either hepatic or renal impairment. 
 
1. Hamilton TW, Athanassoglou V, Mellon S, et al. Liposomal bupivacaine infiltration 
at the surgical site for the management of postoperative pain. The Cochrane 
database of systematic reviews. 2017;2:Cd011419. 
2. Hamilton TW, Athanassoglou V, Trivella M, et al. Liposomal bupivacaine peripheral 
nerve block for the management of postoperative pain. The Cochrane database of 
systematic reviews. 2016(8):Cd011476. 
3. Dasta J, Ramamoorthy S, Patou G, Sinatra R. Bupivacaine liposome injectable 
suspension compared with bupivacaine HCl for the reduction of opioid burden in the 
postsurgical setting. Current medical research and opinion. 2012;28(10):1609-1615. 


7 | P a g e  
 
 
 
4. Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of 
DepoFoam(R) bupivacaine (extended-release bupivacaine local analgesic) in 
bunionectomy. Advances in therapy. 2011;28(9):776-788. 
5. Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended-release 
liposome injection for prolonged postsurgical analgesia in patients undergoing 
hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled 
trial. Diseases of the colon and rectum. 2011;54(12):1552-1559. 
6. Hamilton TW, Athanassoglou V, Mellon S, et al. Liposomal bupivacaine infiltration 
at the surgical site for the management of postoperative pain. The Cochrane 
database of systematic reviews. 2017;2:Cd011419. 
7. U.S. Food and Drug Administration. Drug approval package: Exparel (bupivacaine 
liposome) injectable suspension:.  
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022496Orig1s000Lbl.p
df. Accessed 1-25, 2018. 
 
2.3 Rationale 
 
In general, the management of post-operative pain remains a prominent goal of 
urologic practice. Given the rising incidence of opiate abuse, it is prudent to study 
non-opiate strategies to lessen the potential risk of long-term dependence [1-3]. 
Ambulatory surgery is an ideal candidate for optimization of pain management.  Our 
group has previously reported success with the use of COX-2 inhibitors to diminish 
narcotic requirements [4]. In that study men undergoing testicular sperm extraction 
were randomized to celecoxib versus placebo. We demonstrated a significant 
decrease in the use of narcotics by post-operative day 2. Although encouraging, we 
strive to further improve our post-op pathway. 
 
1. Sun EC, Darnall BD, Baker LC, Mackey S. Incidence of and Risk Factors for Chronic 
Opioid Use Among Opioid-Naive Patients in the Postoperative Period. JAMA internal 
medicine. 2016;176(9):1286-1293. 
2. Clarke H, Soneji N, Ko DT, Yun L, Wijeysundera DN. Rates and risk factors for 
prolonged opioid use after major surgery: population based cohort study. BMJ 
(Clinical research ed). 2014;348:g1251. 
3. Alam A, Gomes T, Zheng H, Mamdani MM, Juurlink DN, Bell CM. Long-term 
analgesic use after low-risk surgery: a retrospective cohort study. Archives of 
internal medicine. 2012;172(5):425-430. 
4. Mehta A, Hsiao W, King P, Schlegel PN. Perioperative celecoxib decreases opioid 
use in patients undergoing testicular surgery: a randomized, double-blind, placebo 
controlled trial. J Urol. 2013;190(5):1834-1838. 
 
  
 


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2.4 Risk/Benefit Assessment  
 
 
The risks to the patient include: reaction to the liposomal bupivacaine or 
standard bupivacaine (these are exceedingly rare, about 1 in 50,000 patients), 
inconvenience due to the pain diary, and the routine privacy concerns involving 
clinical studies. The benefits may include improved pain control with liposomal 
bupivacaine. Indirect benefits to society include an improved pain control 
regimen if the trial results are positive, or cost-savings should liposomal 
bupivacaine prove infective, therefore limiting potential overutilization of this 
expensive medication in the health care system. It is possible that the addition of 
liposomal bupivacaine will remove a significant amount of opiate requirement 
post-op, which may translate to reduced rates of eventual dependence/abuse. 
We believe the risk/benefit ratio is appropriate, as the reaction rates are similar 
between standard bupivacaine (already widely used) and liposomal bupivacaine, 
and there is reasonable expectation of equivalent or improved post-op pain 
control given that both arms receive current standard of care (i.e. at least 20mL 
of 0.25% standard bupivacaine).  Privacy concerns will be handled in typical 
fashion in line with WCMC policies (coded data, secure storage, de-identification, 
etc.). 
 
3. 
Subject Selection 
 
3.1 Study Population 
 
Healthy patients presenting with a diagnosis of infertility, in which surgical sperm 
extraction is planned, will be offered inclusion into the study. 
 
3.2 Inclusion Criteria 
 
1) Men scheduled for MicroTESE sperm retrieval for infertility 
2) Men 18 years and older who can provide informed consent 
3) No documented allergy to bupivacaine or celecoxib 
 
3.3 Exclusion Criteria  
 
 
 
1) Prior history of substance abuse (narcotics, alcoholism) 
2) Any narcotic use within the last 3 months 
3) Concomitant use of aspirin 
4) Any of the following comorbidities: renal failure, heart disease, peptic ulcer 


9 | P a g e  
 
 
 
disease, cerebrovascular disease, significant liver disease, untreated depression, 
chronic pain disorder, or bleeding diatheses 
5) Medical history or concurrent illness that the investigator considers 
sufficiently serious to interfere with the conduct, completion, or results of this 
trial, or constitutes an unacceptable risk to the subject 
 
4. 
Registration Procedures 
 
4.1 Patient Registration 
 
 Patients will be centrally registered with the Office of Billing Compliance. To register 
a patient, we will submit the following documents via the JIRA Registration Process:  
 
• 
Legible copy of the HRBAF 
• 
First and last page of signed informed consent form  
 
 Registration will be completed within 24 hours of the signing of informed consent.  
 
5. 
Study Procedures 
 
Visit one: Pre-op clinic appointment 
The patients will be seen within 1 month of their scheduled sperm extraction per 
our usual practice patterns.  At this time, they will be offered inclusion into the 
study if they meet criteria.  Informed consent will take place at this time. 
 
Visit two: Day of sperm extraction 
The patients will present to the ambulatory surgical center. On the day of the 
procedure, randomization will take place (1:1 ratio, standard bupivacaine versus 
standard bupivacaine plus liposomal bupivacaine). A computer-generated 
randomization scheme will be used. The attending surgeon will not know the 
randomization outcome until the conclusion of the surgery, the point at which 
local anesthetic is administered prior to final wound closure. He will be scrubbed 
out by an unblinded surgeon, who is not otherwise involved in subsequent 
patient contact, for administration of the local anesthetic. Note that this is 
necessary since liposomal bupivacaine has a different appearance than standard 
bupivacaine. The appropriate local anesthetic will be administered, the wound 
closed, and the patient awoken from anesthesia. The patient will remain blinded 
to which local anesthetic was used for the entire study. 
Post-operative recovery: week 1 
Study participants will complete online surveys generated from RedCap x 7 days. 
The survey will be administered every 8 hours in days 1-2, and every 12 hours in 
days 3-7. The surveys will ask the patients to rank their current pain (NRS-11), 
pain control satisfaction, and record the number of narcotic tablets required. 


10 | P a g e  
 
 
 
During the standard of care post-op call, the nurse will ask and record 
complications and also address patient questions. 
Post-op visit (2-3 weeks post-op): 
The post-op clinic visit allows for a routine wound check and a discussion of 
results. The subject will have an opportunity to ask questions regarding the 
surgery, should any debriefing be required. 
 
5.1 Schedule of Evaluations 
 
Table 1. Schedule of trial events 
   
Pre-op 
clinic visit 
Day of 
procedure 
First 
week 
post-op 
Post-op visit 
 
Agent Administration  
 
 
 
X 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
Physical exam 
 
X 
 
X 
 
 
 
X 
 
Vital signs 
 
X 
 
X 
 
 
 
X 
 
Adverse event evaluation 
 
 
 
X 
 
X 
 
X 
 
Outcome evaluation 
(online survey) 
 
 
 
X 
 
X 
 
X 
 
For a day-by-day description, please refer to the prior section. 
 
5.2 Treatment Administration 
 
The attending surgeon will not know the randomization outcome since he will be 
replaced by a second, unblinded surgeon for the portion of the case requiring 
administration of the local anesthetic. This is necessary since liposomal bupivacaine 
has a different appearance than standard bupivacaine. The control arm will receive 
40 mL of 0.25% standard bupivacaine. The intervention arm will be given 20 mL of 
0.25% standard bupivacaine mixed with 20mL/266mg of liposomal bupivacaine. The 
20 mL of 0.25% standard bupivacaine given to the intervention arm will insure an 
adequate block initially (liposomal bupivacaine has a delayed effect). Note that the 
mixing of 20mL/266mg of liposomal bupivacaine with 20mL of 0.25% standard 
bupivacaine has been evaluated in phase IV trials, and is now recommended 
practice as reflected in the FDA drug insert [1]. The appropriate local anesthetic 


11 | P a g e  
 
 
 
mixture is administered, the wound closed, and the patient awoken from 
anesthesia. No other local anesthetics will be available on the surgical field, as these 
are the most likely agents to adversely react with liposomal bupivacaine (i.e. 
lidocaine). 
 
1. Mont MA, et al. Local Infiltration Analgesia With Liposomal Bupivacaine Improves 
Pain Scores and Reduces Opioid Use After Total Knee Arthroplasty: Results of a 
Randomized Controlled Trial. The Journal of arthroplasty. 2018;33(1):90-96. 
 
5.3 General Concomitant Medication and Supportive Care Guidelines 
 
None 
 
 
5.4 Duration of Therapy and Criteria for Removal from Study 
 
o Not applicable – the study medication is administered once prior to wound 
closure during the surgery. Subjects may voluntarily withdrawal from the 
survey-portion of the study at anytime without consequences to their 
subsequent care. 
 
5.5 Duration of Follow Up 
 
Patient are routinely called on post-operative day one to ensure a smooth recovery 
and answer any practical questions (dressings, wound care, etc.). Any unexpected 
outcomes will be recorded by the study nurse.  Should a serious event occur, the 
patient will be forwarded to the emergency room for further evaluation. 
 
6. 
Dosing Delays/Dose Modifications 
 
Dose modification is not anticipated.  Should a patient be allergic to local anesthetics, or 
pre-operative medical conditions that may serve as a contraindication to bupivacaine, they 
will be identified and excluded during the pre-operative visit. 
 
 
7. 
Pharmaceutical Information 
 
7.1 Investigational Agent   
 
Liposomal bupivacaine is pre-packaged in sterile, 20mL/266mg vials that are single-
patient use. No reconstitution or special handling required.  The medication is stable at 


12 | P a g e  
 
 
 
room temperature and can be stored as such for more than a year (personal discussion 
with the manufacturer). 
The risks of liposomal bupivacaine are similar to standard bupivacaine, which include: 
 
Allergic reaction 
 
If administered at toxic dose (occurs 1 in 50,000 patients per the FDA): 
 
 
All local anesthetics have similar cardiovascular and nervous system effects: 
- 
Cardiovascular – depression, arrhythmia, and heart block 
- 
Nervous system – excitation or depression (varies), which can lead to 
respiratory depression 
Note that the phase III trials have established 20ml/266mg as the standard dose. 
The mixing of 20mL/266mg of liposomal bupivacaine with 20mL of 0.25% standard 
bupivacaine has been evaluated in phase IV trials, and is now recommended by the 
manufacturer and is reflected in the FDA drug insert [1]. Finally, unique to liposomal 
bupivacaine, concomitant administration with lidocaine can destabilize the 
liposomal vehicle. To remove this risk, lidocaine will not be allowed to be in the 
operating room during the case. 
 
1. Mont MA, et al. Local Infiltration Analgesia With Liposomal Bupivacaine Improves 
Pain Scores and Reduces Opioid Use After Total Knee Arthroplasty: Results of a 
Randomized Controlled Trial. The Journal of arthroplasty. 2018;33(1):90-96. 
 
7.2 Availability 
 
Liposomal bupivacaine is available from the manufacturer or a multitude of third party 
wholesalers. 
 
7.3 Agent Ordering 
 
 
 
The required amount of medication to complete the study (25 vials), will be ordered 
from a third party wholesaler.  
 
7.4 Agent Accountability 
 
Liposomal Bupivacaine Inventory Records – The investigator, or a responsible party 
designated by the investigator, will maintain a careful record of the inventory and 
disposition of all agents on a Drug Accountability Record Form (DARF).  
 
8. 
Correlative/Special Studies 
 
Not applicable – no correlative or special studies 
 


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9. 
Measurement of Effect 
 
9.1 Response Criteria 
The patients will be prompted to complete online surveys administered through 
REDCap. REDCap allows for HIPAA compliant data gathering through this format.  
Surveys will include the following: a numerical rating scale (0 through 11) to rank 
current pain, number of narcotic tablets consumed since the prior survey, and overall 
satisfaction of pain control (binary yes/no).  
 
9.2 Duration of Response (modify as necessary) 
 
Not applicable 
 
9.3 Progression-Free Survival (if applicable) 
 
Not applicable 
 
9.4 Other Response Parameters 
 
 
No further parameters. 
 
10.  
Data Reporting / Regulatory Considerations 
 
10.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, efficacy, and adverse event data for all enrolled patients. To ensure 
maximum compliance, subjects will be prompted with a text message to their 
mobile phone. To ensure HIPAA compliance, text messages will only read as “A new 
survey is due.” Participants will be informed of this prompting protocol beforehand. 
No PHI, or any details of medical therapy, will be revealed in the text message or in 
the surveys administered through REDCap (please see the survey attachment to 
review how each survey will appear). Texts will be sent from a study dedicated 
phone controlled by the study staff.  The study phone will be encrypted and 
managed by ITS per WCM regulation. Subjects will complete surveys at the following 
intervals: every 8 hours post-operative day 1 and 2, and every 12 hours post-
operative day 3 through 7. 
 
10.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software 
system that is fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool 


14 | P a g e  
 
 
 
for the creation of customized, secure data management systems that include Web-
based data-entry forms, reporting tools, and a full array of security features 
including user and group based privileges, authentication using institution LDAP 
system, with a full audit trail of data manipulation and export procedures.  REDCap is 
maintained on CTSC-owned servers that are backed up nightly and support 
encrypted (SSL-based) connections.  Nationally, the software is developed, 
enhanced and supported through a multi-institutional consortium led by the 
Vanderbilt University CTSA. 
 
 
10.2 Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the 
Principal Investigator. Pacira Pharmaceuticals, Inc. will have the opportunity to 
review and approve the changes prior to submission of these changes to the local 
IRB and distribution to participating sites. 
 
 
11. 
Statistical Considerations (Statistical Analysis Plan) 
 
All investigator-initiated trials must include a study statistician assigned by the Division 
of Biostatistics and Epidemiology.  
 
Clara Oromendia has been assigned as the statistician. 
 
 
 
 
11.1 Study Design/Endpoints 
 
The study will be a randomized double blind control trial. We will randomize into 
two arms: 25 patients in a control arm, and 25 patients in the intervention arm. 
 
During the 7 subsequent post-op days participants in both the intervention and 
control arms will be asked to maintain the NRS-11 pain diary (0=no pain, 11=worst 
possible pain).  Subjects will complete surveys at the following intervals: every 8 
hours post-operative day 1 and 2, and every 12 hours post-operative day 3 through 
7. The area under the curve will be computed using the linear trapezoidal rule to 
interpolate between survey responses, and assess overall pain burden over the time 
period.  
 
Our primary endpoint is to compare the area-under-the-curve of the NRS-11 in days 
1 and 2 (AUCdays1-2). Average AUCdays1-2 will be compared in treatment vs control 


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groups using a two-sample t-test allowing for unequal variances, with a two-sided 
alpha of 0.05. A 95% confidence interval for the difference in AUCdays1-2 between 
arms will be estimated along with estimate and confidence intervals of average 
AUCdays1-2 within each arm.  
 
A secondary analysis will be the comparison of AUC in the first 60 hours (AUC60_Hrs), 
followed by the full 7 days post-surgery (AUCdays1-7), and similarly analyzed as the 
primary endpoint. Additional  secondary analyses will include the percentage of 
patients who are opiate-free in days 1-7, the average number of narcotic tablets 
required at any time in days 1 through 7, and the time to first rescue narcotic 
utilization. Overall pain control satisfaction will be compared between the two arms 
(assessed on post-surgery day 7). 
  
1. Mont MA, Beaver WB, et al. Local Infiltration Analgesia With Liposomal 
Bupivacaine Improves Pain Scores and Reduces Opioid Use After Total Knee 
Arthroplasty: Results of a Randomized Controlled Trial. The Journal of arthroplasty. 
2018;33(1):90-96. 
 
 
11.2 Sample Size/Accrual Rate 
 
The minimal clinically important difference of pain ranking in the post-operative 
period has been found to be approximately 2.4 point reduction for individuals with 
moderate severity pain[1,2]. Based upon the variance of pain reporting in prior 
studies, a standard deviation of 2.75 was assumed for the AUC over two days of 
NRS-11 scale surveys [1-4]. Incorporating a 1:1 randomization scheme, we will have 
85% power to detect a 2.4 point difference with 25 patients per arm, for a total of 50 
patients. However, not all patients who will be consented will ultimately undergo 
surgery (approximately 60% progress to surgery). We will therefore consent 85 
patients for a goal of operating on 50 patients, and randomize only those who go 
into surgery. The study will stop once 50 patients undergo surgery. 
Approximately 150 to 250 microTESE procedures are conducted at our site annually. 
As a result, we plan to accrue and complete the study in 6 months (i.e. ~9 patients 
per month). 
 
1. Cepeda MS, et al. What decline in pain intensity is meaningful to patients with 
acute pain? Pain. 2003;105(1-2):151-157. 
2. Yeung J, et al. Liposomal Bupivacaine During Robotic Colpopexy and Posterior 
Repair: A Randomized Controlled Trial. Obstetrics and gynecology. 2018;131(1):39-
46. 
3. Karcioglu O, et al. A systematic review of the pain scales in adults: Which to use? 
The American journal of emergency medicine. 2018. 


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4. Mehta A, et al. Perioperative celecoxib decreases opioid use in patients 
undergoing testicular surgery: a randomized, double-blind, placebo controlled trial. J 
Urol. 2013;190(5):1834-1838.   
 
 
11.3 Stratification Factors 
 
Not applicable 
 
11.4 Analysis of Endpoints 
 
11.4.1 Analysis of Primary Endpoints 
 
Area-under-the-curve of the NRS-11 in days 1 and 2 (AUCdays1-2) will be 
compared in treatment vs control groups using a two-sample t-test allowing for 
unequal variances, with a two-sided alpha of 0.05. A 95% confidence interval for 
the difference in AUCdays1-2 between arms will be estimated along with estimate 
and confidence intervals of average AUCdays1-2 within each arm. If significant 
deviations from normality are observed in AUCdays1-2, a non-parametric Mann-
Whitney test will be used instead.  
 
11.4.2 Analysis of Secondary Endpoints 
 
AUC60_hrs will be similarly analyzed as the primary endpoint.  
AUCdays1-7 will be similarly analyzed as the primary endpoint.  
Total number of narcotics tablets required will be analyzed with a Poisson 
regression, with a relative rate estimated with appropriate 95% confidence 
intervals.  
Time to rescue narcotic requirements will be assessed with Kaplan-Meier and 
cumulative incidence curves. A log rank test will be used to compare treatment 
and control arms. If no censoring occurs, mean time to rescue narcotics will be 
assessed with a t test and 95% confidence intervals obtained. 
The percentage of patients who remain opiate free and the percentage of 
patients who are overall satisfied with pain control on day 7 will be analyzed 
with a chi-squared test, and a 95% confidence interval for the difference in 
proportions estimated. 
 
11.5 Interim Analysis  
 
Given the size of the trial and since the study agent is a local anesthetic that is given 
only once, and has been used in similar situations before, we will not conduct an 
interim analysis. We will not have any stopping rules based upon our study 
endpoint. This is reasonable given that both control and intervention arm subjects 


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will be given the standard of care (i.e. all will receive at least 20mL of 0.25% 
bupivacaine).  
However, at 50% accrual rate we will review procedure and resolve study-specific 
problems that may arise (e.g. problems with REDCap, issues with the survey 
instrument, etc.). Any changes that are deemed necessary at this point will be 
resubmitted to the IRB as an addendum. 
 
11.6 Reporting and Exclusions 
 
11.6.1 Evaluation of toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with liposomal bupivacaine.  
 
11.6.2 Evaluation of response. All patients included in the study will be assessed for 
response to treatment if they have received at least 1 treatments.   
 
12. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings 
that suggest significant hazards, contraindications, side effects, or precautions pertinent to 
the safe use of the drug or device under investigation.  Safety will be monitored by 
evaluation of adverse events reported by patients or observed by investigators or research 
staff, as well as by other investigations such as clinical laboratory tests, x-rays, 
electrocardiographs, etc. 
 
12.1 
Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment 
about causality. An adverse event can arise with any use of the drug (e.g., off-label 
use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose.  
 
 
 
 
12.1.1 Investigational Agent or Device Risks  
 Liposomal bupivacaine carries the same risks of CNS toxicity (either 
excitation or depression) and cardiovascular toxicity (nodal blockade, 
arrhythmia) as standard bupivacaine. These toxicity events occur in 
approximately 1 out of every 50,000 patients (please refer to the 
attached FDA Report, page 79). There is also a risk of allergic reaction.  
The likelihood of these events are exceedingly small, but warrant 
monitoring nevertheless.  More pertinently, major drug interactions 


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occur with simultaneous administration with lidocaine, which may 
destabilize the liposomes and cause premature release of the agent. We 
do not plan on using any lidocaine due to this reason. Both standard and 
liposomal bupivacaine are metabolized in the liver and excreted primarily 
by the kidneys. We plan to exclude men with either hepatic or renal 
impairment.  
 
 
12.1.2 Adverse Event Characteristics and Related Attributions 
 
 CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
• 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
 
12.1.3    
Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific AE log in REDCap. 
The AE log will be maintained by the research staff on REDCap and 
appropriate documentation will also be kept in the patient’s chart.    
 
 
 
12.1.4   Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to 
the IRB policy, which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Im
mediate_Reporting_Policy.pdf.  
 
12.2 
Definition of SAE 
 
SAE’s include death, life threatening adverse experiences, hospitalization or 
prolongation of hospitalization, disability or incapacitation, overdose, 
congenital anomalies and any other serious events that may jeopardize the 
subject or require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  


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12.2.1 Reporting of SAE to IRB 
All SAEs occurring on this study will be reported to the IRB according to 
the IRB policy, which can be accessed via the following link:   
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Im
mediate_Reporting_Policy.pdf.  
 
 
 
12.2.2 Reporting of SAE to FDA  
 
If an SAE occurs on this study, the event will be filed on a MedWatch 
form with the FDA. The investigator must notify the FDA of any SAE’s as 
soon as possible but no later than 7 calendar days after the initial receipt 
of the information 
 
CDER INDs:  
Food and Drug Administration 
Center for Drug Evaluation and Research 
5901-B Ammendale Road  
Beltsville, MD 20705-1266  
 
 
12.2.3 Reporting of SAE to Pacira Pharmaceuticals, Inc. 
 
The institution will send Pacira Pharmaceuticals, Inc. copies of any and all 
serious adverse event reports filed with the FDA or other applicable 
regulatory authorities, as well as copies of any correspondence with the 
FDA or other applicable regulatory authorities, regarding any and all 
serious adverse events, irrespective of association with the Study Drug(s) 
in the course of the Clinical Trial, within five (5) business days of such 
report or correspondence being sent to the FDA or other applicable 
regulatory authorities.  Copies will be faxed directly to Pacira 
Pharmaceuticals, Inc. Safety Department.   
 
12.4 AE/SAE Follow Up 
 
Please specify any follow up procedures for any AEs/SAEs that occur on study. Sample 
language is provided below in italics.  
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. 
This requirement indicates that follow-up may be required for some events after the 
patient discontinues participation from the study.  


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13.  
Data and Safety Monitoring Plan (DSMP) 
 
In this section, please include a written plan of the measures that will be taken to ensure 
the safety of clinical research subjects and protect the validity and integrity of research 
data. The following questions should be addressed as a part of the DSMP and must be 
incorporated into your WCM eIRB application: 
 
• Adverse events will be recorded by the study nurse and clinical fellow during 
follow-up phone calls and clinic visits with each post-operative patient.  Minor 
adverse events will be examined and reviewed for intervals of every 10 patients 
during accrual.  Any significant adverse events (allergic reaction, central nervous 
system or cardiotoxicity) will trigger a temporary cessation of the trial and full 
review by the principal investigator.  
o Study stopping rules/protocol: the only stopping rule is if an SAE occurs, 
the study will be stopped fully. A full review by the PI will then take place 
and the IRB, FDA, and Pacira Pharmaceuticals, Inc. will be queried as to 
when and if the study should continue. 
• Data 
o Adverse event data 
 Major: Allergic reaction, central nervous system and cardiotoxicity 
 Minor: poor pain control, extended hospital stay, wound infection, 
scrotal hematoma, wound dehiscence, urinary retention, nausea, 
vomiting, diarrhea 
o Study-related data 
 Pain scores (NRS-11), Narcotic tablet tally, overall pain control 
satisfaction (Yes/No question) 
o Demographics 
o Patient age, male infertility diagnoses (i.e. presence of varicocele), prior 
surgical history, current medications, historical lab evaluation (FSH, LH, 
total testosterone, semen analyses, sperm DNA integrity tests such as 
tunel or SCSA assay, karyotype data, y-microdeletion status), pathology 
results of testis biopsy 
• Data safety 
o Data will be kept in REDCap, which is licensed by WCMC and is HIPAA 
compliant. Only study personnel will have access to the database. Hard or 
software copies of the database will not be allowed.  The database will 
only be accessed within the WCMC network utilizing WCMC tagged 
devices. Patient identifiers will be replaced by study identifiers as soon as 
data collection is complete.  
 
 


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References 
 
Citations provided within each corresponding section.  See above.