Clinical trial NCT03250507
Conditions: Hysterectomy
Keywords: TAP block Liposomal bupivicaine
Sponsor: Henry Ford Health System
Start date: 2017-03-13; Completion date: 2019-01-30
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study is to evaluate the effectiveness of different formulations of bupivacaine infiltrated into the transversus abdominis plane (TAP) on post-operative pain management after open abdominal hysterectomy.

Detailed description:
All eligible patients who consent to the study will be randomized to one of three groups. Group 1 will receive a TAP block with 60 mL 0.25% bupivacaine. Group 2 will receive a TAP block with 20 mL liposomal bupivacaine and 40 mL saline. Group 3 will receive a TAP block with 20 mL liposomal bupivacaine and 40 mL 0.25% bupivacaine. Patients will be assessed in the post-anesthesia care unit (PACU) at once each on Post-operative day 1,2, and 3.

Arms: arm 1: Patients will receive a TAP block with 60 mL 0.25% bupivacaine. this group will not receive Liposomal bupivacaine arm 2: Patients will receive a TAP block with 20 mL liposomal bupivacaine and 40 mL saline.

this group will not receive bupivacaine. they receive only liposomal bupivacaine. arm 3: Patients will receive a TAP block with 20 mL liposomal bupivacaine and 40 mL 0.25% bupivacaine.

this group will receive the mixture of Liposomal bupivacaine and bupivacaine.
Interventions: intervention 1: Bupivacaine intervention 2: Liposomal bupivacaine intervention 3: Saline
Intervention descriptions: intervention 1: 0.25% bupivacaine for TAP block intervention 2: Exparel for TAP block intervention 3: Saline for TAP block that will be mixed with liposomal bupivacaine to bring the liposomal bupivacaine group to 60 mL total volume.

Protocol documents:
Prot_SAP_001.pdf: 
  
                       Page 10                                                   New Application: Revised 09-2015  
A randomized-controlled trial comparing liposomal bupivacaine, 
plain bupivacaine, and the mixture of liposomal bupivacaine 
and plain bupivacaine in transversus abdominus plane block 
for postoperative analgesia for open abdominal hysterectomies 
 
Clinical Trials registration number: NCT03250507 
 
Document date: 6/22/2016 
 
 


  
                       Page 11                                                   New Application: Revised 09-2015  
 
HENRY FORD HEALTH SYSTEM IRB PROTOCOL FORMAT  
Appendix 1  
(Incomplete applications will be returned, & inadequate responses may lead to a delay in review.)You may mark your responses in the 
shaded areas following each question.  Supporting documents (articles, drug toxicity information, etc.) must be submitted when applicable.  
A "See Attached" response will not be accepted for review.  Be concise & clear.  
  
Directions:  
Sponsored protocol: If you have a sponsored protocol (e.g., pharmaceutical), a grant application (e.g., National 
Institutes of Health), or another peer-reviewed protocol, you may submit that protocol/application along with the 
application elements.  It is the responsibility of the Principal Investigator to assure, however, that the 
protocol/application contains the information requested in this "IRB Protocol Format".  Additional sheets should be 
attached to the protocol/application as necessary to provide the information (e.g., a description of the process of 
consent) required for IRB review.  When available, the Investigator's Brochure must be submitted along with the 
research protocol, or a summary of the preclinical/animal data and any relevant clinical data.   
  
Physician Initiated protocol:  If you have not been provided a protocol from an outside source, you must develop one. 
The following is the "Henry Ford Health System “IRB Protocol Format".  
  
1. PURPOSE:  State in one or two sentences the purpose or objective of this project.  The goal of this study is to evaluate the 
effectiveness of different formulations of bupivacaine infiltrated into the transversus abdominis plane (TAP) on post-
operative pain management after open abdominal hysterectomy.  
  
2. SPECIFIC AIMS:  Number your aims so that the aims can be referred to in the Project Design and Data Analysis sections 
of this outline. 1) To determine if a TAP block with liposomal bupivacaine provides effective post-operative analgesia 
after open abdominal hysterectomy.  2) To determine if the mixing of liposomal bupivacaine with bupivacaine 
hydrochloride provides improved analgesia as compared to either drug alone when used for a TAP block.  
  
3. RATIONALE FOR THE PROJECT:  
a. 
State the rationale for the project and support it with background information about the project. Critically evaluate 
existing knowledge, and specifically identify the gaps in knowledge the project will fill.  Liposomal  
bupivacaine is a novel formulation of the local anesthetic bupivacaine in which the drug is encapsulated and slowly 
released over time up until 72 hours post-injection Since liposomal bupivacaine is slow-released, liposomal 
bupivacaine may provide delayed post-operative analgesia.  Bupivacaine hydrochloride typically provides 24-48 
hours of analgesia.  We hypothesize that the combination of liposomal bupivacaine to bupivacaine hydrochloride will 
provide superior analgesia both immediately and up to 72 hours post-operatively.  Liposomal bupivacaine was 
initially FDA approved for surgical site infiltration and has been recently FDA approved for infiltration in the 
transversus abdominus plane.  TAP blocks are routinely used as a part of multimodal analgesia to decrease pain scores 
and decrease opioid consumption after abdominal surgery.  Liposomal bupivacaine infiltrated into the TAP plane has 
been shown to be effective for post-operative analgesia after robotic prostatectomy, laparoscopic colorectal surgery, 
and abdominal hernia repair; however, those studies did not compare the effectiveness of liposomal bupivacaine to 
bupivacaine hydrochloride or to the mixture of Liposomal Bupivicaine and Bupivicaine HCL.  Our experience at 
Henry Ford Hospital suggests that TAP blocks with liposomal bupivacaine provides similar analgesia as those with 
bupivacaine hydrochloride. This year, a randomized controlled single blinded study comparing liposomal bupivacaine 
to bupivacaine hydrochloride for TAP blocks for patients undergoing laparoscopic assisted donor nephrectomy 
showed no difference in pain scores or opioid consumption within the first 48 hours post-operatively.  Opioid 
consumption was slightly decreased 48-72 hours post-operatively in the liposomal bupivacaine group.    
b. State the applicant's prior research and experience in this research area. As a quality improvement initiative, we have 
retrospectively reviewed the effectiveness of TAP blocks with liposomal bupivacaine and bupivacaine hydrochloride 
for post-operative analgesia after laparoscopic asissted colectomy and open abdominal hysterectomy.  As members of 
the regional anesthesia division, we have extensive experience performing TAP blocks for a wide range of abdominal 
surgical procedures.  
  
4. SIGNIFICANCE:  State concisely the importance of this project by relating the purpose to broader, long-  
      range objectives.  Providing optimal post-operative analgesia to our patients is important to improve  


  
                       Page 12                                                   New Application: Revised 09-2015  
patient satisfaction, decrease opioid related side effects, and promote early recovery and discharge from the hospital.  This 
study will help determine if using liposomal bupivacaine alone or in combination with bupivacaine hydrochloride provides 
enhanced post-operative analgesia.         
  
5. SUBJECTS IN THE PROJECT:    
a. 
State the inclusion and exclusion criteria for enrollment of subjects.   Inclusion criteria: elective open abdominal 
hysterectomy with a midline incision, age>18, ASA 1-3.  Exclusion criteria: patient with a chronic pain condition,  
major unexpected surgical complication, unexpected prolonged intubation, patient refusal, local anesthetic allergy, 
any contraindication to regional anesthesia, and greater than two attempts for TAP block by residents and greater than 
one attempt by staff anesthesiologist.      
b. Describe the control population (if utilized) and justify its selection.Our current standard practice is to use 0.25% 
bupivacaine for TAP blocks, therefore, the control population is the group receiving 0.25% Bupivacaine.  
c. 
Support the likelihood of recruiting the number of subjects required to complete the project.  Relate this to other 
projects recruiting similar subjects.We estimate that 100-150 patients undergo open abdominal hysterectomy with a 
midline incision at Henry Ford Hospital each year.  We anticipate an 80% or higher recruitment rate.  Therefore, we 
anticipate recruiting 90 patients within a year.  No other studies are recruiting similar patients.  
  
6. PROJECT DESIGN AND PROTOCOL:  
  
a. 
Describe the experimental design/methodology.Prospective randomized observer-blinded controlled study.   
b. Outline the protocol, corresponding it to the specific aims; identify the data or endpoints to be analyzed to reach the 
specific aims. All eligible patients will be seen in the pre-operative holding area to discuss the study.  Informed 
consent will be obtained at that time.  The patient will be randomized to one of three groups by random envelope 
selection. Group 1 will receive a TAP block with a total of 60 mL 0.25% bupivacaine hydrochloride.  Group 2 will 
receive a TAP block with a total of 20 mL of liposomal bupivacaine and 40 mL normal saline.  Group 3 will receive a 
TAP block with a total of 20 mL of liposomal bupivacaine and 40 mL 0.25% bupivacaine hydrochloride.  Our 
standard sedation protocol for all patients receiving any nerve block is to provide a maximum of 2 mg midazolam and  
100 mcg fentanyl during procedure. The patient will be monitored per our routine practice standards.  The patients 
will undergo the surgical procedure with general anesthesia as directed by the attending anesthesiologist.  All patients 
will receive 30 mg ketoralac IV.  If ketoralac is contraindication, the patient will receive 1000 mg acetaminophen IV.  
The patient will be recovered and receive routine post-operative care.  Patients will be assessed immediately post-
operatively in the post-anesthesia care unit (PACU), and one time during each of the following time periods: 0-24 hrs 
post-operatively, 25-48 hours post-operatively, and 49-72 hours post-operatively.  Primary outcomes are total opioid 
consumption, time to the first opioid administration, and pain score during the above mentioned time periods.  
Secondary outcomes are patient satisfaction, length of stay in hospital, timing of ambulation, presence of nausea and 
vomiting, evidence of local anesthetic toxicity and any postoperative hemodynamic instability.    
c. 
Discuss potential limitations and difficulties in the protocol.We don't anticipate any difficulties with this protocol 
since patients typically receive a TAP block for post-operative analgesia for open abdominal hysterectomy at Henry 
Ford Hospital.  One limitation of our protocol is that it is not double-blinded.  Liposomal bupivacaine is white and 
distinctive from bupivacaine hydrochloride.  Therefore, the anesthesiologist performing the block cannot be blinded to 
group selection.  All other care team members including anesthesia team, surgical team, and floor nurses, will be 
blinded to the group selection.   
d. Provide a tentative schedule for conducting and completing this project and, if applicable, the multicenter study.We 
anticipate one year to recruit patients and collect data.  Data analysis will take a few months after study completion.  
e. 
Data collection: Submit a copy of the data collection tool or list the data fields to be collected (review IRB policy, 
Access to Medical Records for Research).Age, ASA classification, height, weight, BMI, indication for hysterectomy, 
surgeon, duration of surgery, time of TAP block, time to first break-through analgesic, cumulative analgesic doses  
and pain scores at rest and with movement in PACU and in the following time periods: 0-24 horus, 25-48 hours, 49-72 
hours.  in 6 hr increments for the first 24hrs,then every 12 hrs for the next 24 hours.  Satisfaction (ie not satisfied, 
satisfied, very satisfied), length of stay in the hospital, presence of ambulation, presence of nausea and vomiting, 
evidence of local anesthetic toxicity, presence of hypotension.  
  
7. DATA ANALYSIS:  Describe the analysis of the data and relate this to the specific aims in detail. Case reports and 
medical record reviews also require a description of the planned data analysis (ie. descriptive, observational). The 
Committee recommends free consultation with the Division of Biostatistics and Research Epidemiology before IRB 
submission. Many clinical measurements will be recorded post operation. Some are one-time measurements such as total 
opioid consumption, and some are repeated measurements such as pain scores. Total 8-9 measuring times for those 


  
                       Page 13                                                   New Application: Revised 09-2015  
repeated outcomes. Ideally these time points are at baseline, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 60 
hours and 72 hours. Continuous variables will be summarized with n, mean, standard deviation and range. Frequency 
counts and percentage will be provided for categorical data. Estimates for averages and proportions will also include 95 % 
confidence intervals. One-way Analysis of Variance( ANOVA ) will be used to assess the efficacy of three anesthetic 
bupivacaine formulas ( G1: bupivacaine HCL; G2: liposomal bupivacaine ; G3: liposomal bupivacaine + bupivacaine 
HCL ) on total opioid consumption, patient satisfaction,  length of stay in hospital as well as timing of ambulation. 
Generalized Estimating Equations ( GEE ) will be utilized to evaluate the effects of these three anesthetic formulas on 
repeated measures of pain scores, presence of nausea and vomiting, evidence of local anesthetic toxicity and any 
postoperative hemodynamic instability. Cox proportion hazard models will be applied to assess the effect of these 
anesthetic formulas on the time to first opioid administration. The statistical analysis will be obtained by using SAS 9.4 
and the tests are claimed to be significant if the p- values are less than 0.05.   
  
8. JUSTIFICATION FOR NUMBER OF SUBJECTS OR DATA:    
  
a. 
State the number of subjects or data points to be analyzed in the project at this institution and the total number for 
multicenter studies. The Committee recommends consultation with the Division of Biostatistics and Research 
Epidemiology (313) 874-6360. Total 90 subjects are expected given at least 80% recruitment rate of total 100-150 
patients undergo open abdominal hysterectomy at Henry Ford Hospital each year.  
b. Describe the statistical justification for this number of subjects or data points.Total 90 patients ( 30 for each of these 3 
groups ) will have 80% power to detect the effect size of 0.33 by using One- Way ANOVA for assessing the effects of 
three formulas on total opioid consumption; and an effect size of 0.24 can be detected with 80% power assuming 0.5 
correlation among repeated measures by using repeated One - Way ANOVA for assessing the effects of three 
formulas on pain scores.   
  
FORM A  
HENRY FORD HEALTH SYSTEM (IRB) DRUG/SUBSTANCE INFORMATION   
(This form must be completed for each individual drug or substance -investigational or  marketed- that is 
being administered as part of this research study)  
  
1.  Generic/Chemical Name: Liposomal Bupivacaine   
2. Trade Name: Exparel  
3.  Manufacturer: Pacira Pharmaceuticals  
4. Mode of Administration:   other: infiltrated into the 
transversus abdominus plane  
5.  How Supplied (dose form & strength): 20 ML vials 
containing 266 mg liposomal bupivacaine.  
6. Who will be administer the drug/substance? Staff 
anesthesiologist and resident anesthetist  
7.  Dosage and Schedule Proposed:Groups 2 and 3 will receive 20 mL liposomal bupivacaine as a one time injection for a 
TAP block.  
8.  Will you be utilizing research pharmacy for storage or dispensing of any medication? (if this is an inpatient study, you 
are required to use research pharmacy).   
 Yes   
  No  
9. Describe the primary actions of the drug/substance:Sodium channel blocker that acts to block neuronal impulses.