Clinical trial NCT04559347
Conditions: Thoracic Surgery
Keywords: Thoracic surgery
Sponsor: Poovendran Saththasivam
Start date: 2020-12-10; Completion date: 2024-08-07
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research is to compare a single shot long acting local anesthetic to catheter infusion of local anesthetic in patients undergoing video assisted thoracoscopic (VAT) surgery.

Detailed description:
The purpose of this research is to compare Single Shot Liposomal Bupivacaine (EXPAREL®)/Bupivacaine (a long acting local anesthetic) to Ropivacaine (0.5% bolus followed by 0.2% infusion of local anesthetic using a catheter) in patients undergoing video assisted thoracoscopic (VAT) surgery.

Arms: arm 1: Single Shot Liposomal Bupivacaine (EXPAREL®)/Bupivacaine for erector spinae block as local anesthetic arm 2: Ropivacaine (0.5% bolus followed by 0.2% infusion) using a continuous catheter for erector spinae plane block as local anesthetic
Interventions: intervention 1: Liposomal Bupivacaine (EXPAREL®)/Bupivacaine intervention 2: Ropivacaine (0.5% bolus followed by 0.2% infusion)
Intervention descriptions: intervention 1: Single shot for erector spinae block intervention 2: Continuous catheter infusion for erector spinae plane block

Protocol documents:
Prot_000.pdf: 
1 
CONFIDENTIAL 
Title : Single Shot Liposomal Bupivacaine (EXPAREL®)/bupivacaine versus Continuous 
Erector Spinae Plane Block Catheter in Patients Undergoing Video Assisted Thoracoscopic 
(VAT) Surgery; Single Center Non Inferiority Open Label Prospective Randomized 
Clinical Trial 
Protocol version date:  09 April 2025 
Principal Investigator : Poovendran Saththasivam MD1 
Sub -Investigators: 
Sudhakar Kinthala MD1 
      
Burdett Porter MD1  
      
Mary Hicks MS, BSN, RN-NPD2 
 
Emmanuel Uddoh, MD3 
      
Sanjib Adhikary MBBS, MD3 
1 Department of Anesthesiology and Perioperative Medicine, Robert Packer Hospital, Sayre PA 
2 Department of Nursing Education & Research, Robert Packer Hospital, Sayre, PA 
3 Department of Anesthesiology and Perioperative Medicine, Penn State Hershey Medical Center, 
Hershey, Pennsylvania 
 
 


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CONFIDENTIAL 
Contents 
Background and Rationale______________________________________________________ 3 
Objectives ___________________________________________________________________ 7 
Trial Design __________________________________________________________________ 7 
Study Setting ________________________________________________________________ 7 
Inclusion Criteria ______________________________________________________________ 8 
Exclusion Criteria _____________________________________________________________ 8 
Consent _____________________________________________________________________ 9 
Sample Size __________________________________________________________________ 9 
Study Endpoints ______________________________________________________________ 9 
Primary Endpoint __________________________________________________________________ 9 
Secondary Endpoints _______________________________________________________________ 9 
Interventions _______________________________________________________________ 10 
Randomization and Blinding ___________________________________________________ 11 
Procedures _________________________________________________________________ 12 
Erector Spinae Plane (ESP) Block Method ______________________________________________ 12 
Multimodal analgesia in ERAS protocol _______________________________________________ 13 
Anesthetic regimen _______________________________________________________________ 13 
Video Assisted Thoracic Surgery (VATS) Approach _______________________________________ 13 
Postoperative Care ________________________________________________________________ 14 
Investigational Product _______________________________________________________ 15 
Potential Risks ___________________________________________________________________ 16 
Central Nervous System Reactions ___________________________________________________________ 16 
Cardiovascular System Reactions ____________________________________________________________ 17 
Allergic Reactions _________________________________________________________________________ 17 
Chondrolysis _____________________________________________________________________________ 18 
Accidental Intravascular Injection ____________________________________________________________ 18 
Adverse Reactions ________________________________________________________________________ 19 
Risk Mitigation ___________________________________________________________________ 20 
Outcomes & Definitions _______________________________________________________ 20 
Primary Endpoint _________________________________________________________________ 20 


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CONFIDENTIAL 
Secondary Endpoints ______________________________________________________________ 20 
Data Collection and Management ______________________________________________ 22 
Data Safety Monitoring _______________________________________________________ 23 
Statistical Methods __________________________________________________________ 23 
Research Ethics Approval ______________________________________________________ 24 
Funding ____________________________________________________________________ 24 
Confidentiality ______________________________________________________________ 24 
Declaration of Interest ________________________________________________________ 24 
Environmental Assessment of Human Drug and Biologics Applications _________________ 24 
References _________________________________________________________________ 25 
 
Background and Rationale 
Roughly 51 million Americans undergo various inpatient surgeries with opioids being the 
mainstay of acute pain management.1 Excessive opioid prescriptions for postoperative pain control 
have been related to the opioids-related crisis.2,3 Preoperative opioid use, lower socioeconomic 
status, medical comorbidities and preexisting depression have been shown to cause chronic 
persistent opioid use after surgery.4 Over 60% of people with opioid abuse obtain the medication 
from friends or relatives with unused prescriptions.5 Thus, an effective acute pain management 
technique that mitigates opioid consumption for post-operative pain management warrants 
research. 
In the perioperative period, a multidisciplinary approach that emphasizes various opioid sparing 
techniques can mitigate the risk of persistent chronic opioid use after surgery6,7. Anesthesiologists 
are the forefront players in providing effective pain control strategies in the perioperative period. 
Nerve blocks have been shown to effectively provide pre-emptive analgesia and acute post-
operative pain relief, while preventing central sensitization and chronic neuropathic pain.8 


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CONFIDENTIAL 
Video assisted thoracoscopic (VAT) surgery has gained popularity among thoracic surgeons. This 
technique has been shown to be superior in improving post-operative lung function, decreasing 
hospital stays and has better patient satisfaction compared to traditional open thoracotomy.9,10. This 
minimally invasive technique has been widely used in various thoracic surgeries; lobectomy, 
wedge resection, decortication and pleurodesis. Some patients undergoing VAT surgery have been 
known to develop acute and chronic neuropathic pain.11,12 The intercostal injury has been proposed 
as mechanism of chronic pain and numbness following VAT surgery.13  
Although thoracic epidural was once considered a gold standard for acute pain management 
following thoracic surgery, this technique is becoming less popular in the VAT surgery.14 While 
shown to be effective in acute post-surgical pain control, paravertebral block and intercostal block 
require an experienced operator, multiple level injections and risk of pneumothorax.15 Recently, 
fascial plane block (erector spinae plane block, serratus anterior plane block, PEC, transverse 
thoracic plane block) have gained wide popularity in thoracic wall analgesia.  Of interest is 
ultrasound guided Erector Spinae Plane (ESP) block, a novel technique first described in 2016 by 
Forero et al. (2016)16. The uniqueness of this technique is the minimal risk as compared to 
neuraxial blockade because of the myofascial location of this block.  ESP block has been utilized 
for thoracic, cardiac, shoulder and abdominal surgeries with excellent pain control post 
operatively.17-20   ESP blockade at the level of T5 spinous process provides analgesia from T2 to 
T10 sensory level.21  The proposed mechanism of action of ESP block is due to diffusion into 
paravertebral space, effectively blocking the dorsal and ventral rami of the spinal nerves, as well 
as the rami communicantes that transmits sympathetic fibers as well as the intercostal nerves.22-24  


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CONFIDENTIAL 
 
Reproduced from Forero, M., Rajarathinam, M., Adhikary, S., & Chin, KJ. (2017). Continuous Erector Spinae Plane 
Block for Rescue Analgesia in Thoracotomy After Epidural Failure: A Case Report, A Prac, 8(10), 254-256. 
 
Figure 1.  Showing ultrasound anatomy depicting the skin, subcutaneous tissue, trapezius muscle, 
rhomboid muscle, erector spinae muscle and the tip of the transverse processes. The arrow shows 
the erector spinae plane location for successful deposition of the local anesthetic. 
 
The Food and Drug Administration (FDA) has approved liposomal bupivacaine for interscalene 
block, bunionectomy, hemorrhoidectomy, transversus abdominis plane block and wound 
infiltration. Liposomal bupivacaine, or EXPAREL® the brand name, is a long-acting extended 
release liposomal bupivacaine with microsomal liposomes (DepoFoam drug delivery system) 
containing multiple aqueous chambers of encapsulated bupivacaine. Bupivacaine is slowly 
released from the liposomes by diffusion as the unprotonated (uncharged) from of bupivacaine. 


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CONFIDENTIAL 
This preparation allows sustained release of bupivacaine at the site of injection without exposing 
patients to toxic plasma concentration. 25-26  
 
Reproduced from https://www.researchgate.net/figure/Cross-sectional-diagram-of-DepoFoam-containing-
bupivacaine-Image-supplied-courtesy-of_fig2_232226382 
Figure 2  Showing The DepoFoam system containing the bupivacaine.  
 
This open label non inferiority prospective randomized clinical trial is important to confirm the 
hypothesis Single Shot Liposomal Bupivacaine (Exparel)/Bupivacaine in erector spinae plane 
block is non inferior compare to continuous erector spina plane block catheter group. The 
comparison of single shot ESP blockade using long acting local anesthetic with a continuous 
catheter technique is important to identify single shot ESP block using liposomal 
bupivacaine/bupivacaine as an acceptable method of pain relief. Currently, to the best of our 
knowledge, there is no prospective randomized clinical trial comparing Single Shot Liposomal 


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CONFIDENTIAL 
Bupivacaine (Exparel)/Bupivacaine in erector spinae plane block in patients undergoing VAT 
surgery.  
Objectives 
The purpose of this study is to evaluate erector spinae plane block using Single Shot Liposomal 
Bupivacaine (EXPAREL®) plus bupivacaine for pain relief in comparison to continuous erector 
spinae plane block catheter using ropivacaine local anesthetic in patients undergoing video assisted 
thoracoscopic surgery (VATS). 
Trial Design 
Non-Inferiority Prospective Open Label Randomized Clinical Trial. Double arm study comparing 
effectiveness of Single Shot Liposomal Bupivacaine (EXPAREL®) plus Bupivacaine (SS) and 
continuous erector spinae plane block catheter using ropivacaine intermittent automatic bolus (CC) 
in patients undergoing VAT surgery. 
Study Setting 
This trial will be done at Robert Packer Hospital in Sayre, PA. The Department of Anesthesiology 
will be conducting this research. The research will be conducted in the operating room (OR) and 
post-operative cardiothoracic surgical unit at Guthrie Robert Packer Hospital. 
The erector spinae block will be done in the preoperative area, a fully monitored area with 
immediately available resuscitation and airway equipment. The VAT surgery will be done in the 
general operating room and, upon completion of the surgery, study subjects will be transferred to 
Prep and Recovery Unit (PRU) for immediate post-operative care. Data collection will occur in 
the operating room, PRU and the post-operative cardiothoracic surgical floor at Guthrie Robert 


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CONFIDENTIAL 
Packer Hospital. If the participant is discharged prior to 72 hours the surveys will be completed in 
their outpatient location.  
Inclusion Criteria 
Subjects who are age > 18, undergoing video thoracoscopic surgery, and following Guthrie 
Robert Packer Hospital’s Enhanced Recovery After Surgery (ERAS) protocol for Thoracic 
Surgery will be included in this study. 
Exclusion Criteria 
The exclusion criteria is weight < 50 kg, pregnant subjects,  left ventricular ejection fraction < 
30%, history of drug or narcotic abuse, history of allergic to amide local anesthetic, presence of 
contraindication for erector spinae plane block (local skin infection, sepsis, severe coagulopathy) 
unable to provide consent, unable to use pain rating scales as demonstrated by verbal feedback, 
preoperative chronic pain on narcotics, history of renal insufficiency ( Creatinine > 1.5 mg/dl), 
preoperative mild liver impairment ( i.e. AST/ALT above 1.5 times the upper normal limit) and 
lactating women. Urine pregnancy test will be done on all female patients of childbearing age to 
exclude pregnancy unless there is a history of hysterectomy. 
The following subjects will be withdrawn from study data analysis but will remain in the study for 
safety monitoring and study data collection as they have received the treatment: subjects that 
require conversion into open thoracotomy, and subjects who failed nerve block, defined by 
inability to determine the local anesthetic spread in the erector spinae plane on the ultrasound 
image. A screen failure is a participant who does not meet eligibility criteria after consenting or 
chooses to withdraw prior to surgery.  


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CONFIDENTIAL 
Consent 
Written consent will be required for all study participants prior to participation and will be obtained 
by the principal investigator (PI) or a sub-investigator during the preoperative period. 
Sample Size  
A power analysis was carried out using the PASS software 27 to determine the appropriate sample 
size given power set at 1 - β = 0.90.  One-tailed alpha was set at the Bonferroni-adjusted level 
0.008 given six time points at which the two treatment groups will be compared. The noninferiority 
limit was set as a between-group difference of two on the 11-point numeric pain scale, representing 
a clinically meaningful change. Assuming the standard deviation in each group is two, and that up 
to 20% of the sample may not complete the follow-up measures, the necessary sample size is 74 
(n = 37 in each treatment group).  
Study Endpoints 
Primary Endpoint  
Numerical Rated Pain Scale (NRP) while rest and with cough at 0-4 hours, 4-8 hours, 8-12 hours, 
12-24 hours, 24-48 hours and 48 to 72 hours post extubation. If the subject is discharged prior to 
72 hours post-surgery, a telephone interview will be done to assess the post-operative numerical 
pain score. 
Secondary Endpoints 
Post-operative opioid consumption at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-48 hours,  
and 48-72 hours post VAT surgery. All opioids will be calculated to morphine equivalents to 
determine total morphine requirements for each interval. Cumulative morphine equivalents used 
at time 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-48 hours, and 48-72 hours will be 


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CONFIDENTIAL 
documented. If the subject is discharged prior to 72 hours post-surgery, a telephone interview will 
be done to assess the post-operative opioid consumption. 
Total intraoperative opioid and adjunct pain medication (acetaminophen, gabapentin and 
ketorolac) consumed postoperatively at 0-4 hours, 4-8 hours 8-12 hours, 12-24 hours, 24-48 hour 
and 48-72 hours, post-operative incentive spirometry changes from preoperative baseline at 0-4 
hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-48 hours and 48-72 hours, length of hospital stay, 
number of days ESP catheter in place, postoperative quality of recovery score (QOR-15), 24-48 
hours (day 1) and 48-72 hours (day 2) post operatively and adverse events associated with erector 
spinae block and Single Shot Liposomal Bupivacaine (Exparel)/Bupivacaine.  
Interventions 
Participants will be screened for eligibility once decision has been made for thoracoscopic surgery. 
The cardio-thoracic surgery department will  screen for potential recruitment. The study will be 
introduced by the surgeon and a consent document offered for review. After fulfilling the inclusion 
and exclusion criteria, consent will be obtained by the anesthesiologist sub investigator at the pre-
admission appointment for the surgery. If the subjects need more time to review before deciding 
to participate, a consent form will be given for review before a decision is made at a later time.  
At the time of consenting, baseline incentive spirometry will be done, baseline quality of recovery 
questionnaire (QOR-15) which consist of 15 questions related to five domains of patient reported 
health status (pain, physical comfort, physical independence, psychological support and emotional 
state) will be administered and the patient will be educated on how to use the pain assessment tool 
during the study, the 11-point Numerical Rated Pain Scale (NRP).  


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CONFIDENTIAL 
On the day of the surgery, the participant’s history, physical, and laboratory results will be 
reviewed to confirm study eligibility by the study coordinator and the principal investigator/sub- 
investigators.  
Randomization and Blinding 
A computer-generated randomization table will be used for subject allocation to one of the 
two 
treatment 
arms; 
the 
Single 
Shot 
erector 
spinae 
using 
Liposomal 
Bupivacaine(EXPAREL®) plus Bupivacaine (SS)  or  erector spinae plane continuous 
catheter group (CC) using ropivacaine 0.2 % intermittent automatic bolus technique.  
In the SS group, the study drug will be 10 mL of EXPAREL (133mg) mixed with 20 mL 
Bupivacaine HCL 0.25 % (50mg).  A total volume of 30 cc will be injected into the erector spinae 
plane on the operative side at level of T5 transverse process. 
In the CC group, the study drug to be used is 20-30 cc of bolus Ropivacaine 0.5 % into the erector 
spinae plane via catheter placement. Subsequent analgesia will be maintained by using electronic 
infusion pump (Sapphire TM  Multitherapy Pump; San Clemente, CA, USA)  which will be 
programmed to deliver  20 cc intermittent Ropivacaine 0.2% automated bolus every 3 hours, with 
an additional patient demand bolus of 5 cc ropivacaine 0.2% with a lockout period of 30 min in 
the postoperative period at the PRU.  
Blinding is not possible in this study because the CC group has an indwelling nerve catheter 
whereas the SS group does not. 
The pharmacy department of the Robert Packer Hospital maintains the randomization table.  The 
day prior to the planned surgery the instructions to randomize the participant is sent to the 
pharmacy.  The anesthesiologist advances the treatment allocation orders for the study. The 


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CONFIDENTIAL 
pharmacist prepares the study medication on day of surgery. The randomization is sequential to 
the actual surgery date.  
Procedures 
Erector Spinae Plane (ESP) Block Method 
Ultrasound guided ESP block will be performed by single experienced anesthesiologist in both 
groups of study subjects. In the preoperative block room, 5 lead continuous electrocardiogram, 
noninvasive cuff blood pressure and continuous pulse oximetry will be applied to the study 
subjects. A 20-gauge IV access will be obtained by preoperative nursing staff. Supplementary 
oxygen will be administered, and patients will be positioned in sitting position. An Immediate 
airway rescue cart will be stationed where the block will be performed together with Intralipid, 
which is a rescue drug in the event of local anesthetic toxicity. 
After appropriate monitoring, a time out will be completed, identifying the correct patient and 
correct procedure.  Midazolam 1-2 mg in titrating dose will be given for anxiolysis. The skin will 
be cleaned with antiseptic chlorhexidine prep. A high frequency 6-13 MHz linear array transducer 
(HFL38x, Sonosite Inc Bothell, WA) will be placed in longitudinal orientation 3 cm lateral to T5 
spinous process. 
For the SS group, a 21 gauge 100mm echogenic needle (SonoPlex II Facet; Pajunk, Geisingen, 
Germany) will be used and an 18G catheter over the needle set for the CC group ( E Cath ; Pajunk, 
Geisingen, Germany). Using in plane technique, the echogenic needle will be directed from caudal 
to cranial direction. Under continuous visualization of the needle tip, contact will be made with T5 
transverse process. Then 1-2 mL of sterile normal saline, will be injected to confirm lifting of the 
erector spinae muscle. After negative aspiration, this will be followed by injection of the study 
drug, in 5 mL increment with continuous visualization of the linear spread of the local anesthetic 


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CONFIDENTIAL 
and separation of the erector spinae fascia plane from the transverse process. In the event the needle 
tip cannot be adequately visualized, the procedure will be aborted. Positive block characterized by 
sonographic evidence of the local anesthetic spread with evidence of lifting of the erector spinae 
muscle plane.  
Multimodal analgesia in ERAS protocol 
Thoracic surgery multimodal analgesia as per ERAS protocol will be utilized in all 
subjects. Preoperatively, acetaminophen 1000mg orally, gabapentin, 300mg orally and 
celecoxib 200mg orally will be given on the preoperative holding area.  
Postoperatively, acetaminophen 1000 mg Q8 hour prn, Gabapentin 100mg orally TID, 
Oxycodone 5 mg orally Q4H PRN for moderate pain, Oxycodone 10 mg orally Q6H PRN severe 
pain and morphine IV 2mg ( moderate pain) and 4mg ( severe ) pain will be given for 
breakthrough pain 4 hourly as needed. 
 Anesthetic regimen 
Intraoperative monitoring includes standard ASA monitor, Bispectral Index (BIS) and urine 
output. General anesthesia will be induced using propofol, fentanyl and rocuronium using balanced 
anesthetic technique. Maintenance of anesthesia will be achieved with inhalation agents, either 
sevoflurane, desflurane or isoflurane. For intraoperative analgesia, boluses of intravenous fentanyl 
only will be used for both groups.  
Video Assisted Thoracic Surgery (VATS) Approach 
The VATS procedure is done in a standard fashion. We utilize three ports, posterior 5mm 
camera, anterior inferior 5mm assistant, and 4cm working port in the 5th intercostal space. 
Dissection of the lung and lymph nodes proceeds from posterior to anterior with division of 
structures with bipolar electrocautery and endoscopic staplers.  Extraction of the lung tissue is 


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CONFIDENTIAL 
done through the working port with an endocatch bag and a chest tube is placed through the 
anterior port.  
Postoperative Care  
On arrival in PRU, subjects will be attended by nursing staff and placed on monitors. Intravenous 
fentanyl or hydromorphone as needed will be given based on the numerical rated pain ratings. 
Chest x ray will be taken and reviewed in the PRU. Signs and symptoms of local anesthetic toxicity 
( LAST) will be screened in the PRU.  
The ESP catheter in the CC study group will be connected to electronic infusion pumps in the 
PRU. (Sapphire TM  Multitherapy Pump; San Clemente, CA, USA) which will be programmed to 
deliver automatic intermittent bolus of 20 cc of ropivacaine 0.2% every 3 hours. Patient controlled 
bolus of 5 cc of ropivacaine 0.2%  will be allowed at a lockout period of every 30 minutes.   
All study subjects will be admitted and observed in the cardiothoracic surgery floor at least for 24 
hours post VATS with telemetry monitoring. In addition to standard resuscitation medication and 
equipment, Intralipid will be made available while the study subjects remain on the post-operative 
floor in the event local anesthetic systemic toxicity suspected. Signs and symptoms of LAST will 
be screened by nursing staff.  If the study subject experiences any signs and symptoms of LAST, 
12 leads EKG, vital signs, and plasma levels of bupivacaine or ropivacaine will be sent 
immediately. In addition to that, after the blood draw, prophylactic treatment of presumed LAST 
toxicity with Intralipid infusion 1.5cc/Kg will be done. Additional use of bupivacaine as local 
anesthetic will be avoided for 96 hours on subjects receiving single shot liposomal bupivacaine 
(SS) group; this will be accomplished through provider and patient education as well as a patient 
wrist band worn by patients who receive Exparel injection. If this occurs the patient will be 
monitored and assessed for any adverse events.  


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CONFIDENTIAL 
If the study subjects are deemed suitable for discharge home in less than 72 hours, the continuous 
catheter in the CC group will be removed. Subjects will be screened for LAST signs and symptoms 
for 8 hours after removal of the catheter and before being sent home. Subjects will be educated on 
signs and symptoms of LAST ( metallic taste, ringing in the ears, perioral tingling, agitation, 
seizure and cardiac arrythmias ) and if these signs are present, subjects will be instructed to go to 
the nearest emergency department for medical evaluation.  
Following home discharge, a telephone call will be made by the investigator team every 24 hours 
until 72 hours post-operative period to collect data on opioid consumption, QOR-15 questionnaire,  
numerical pain score, and screening questions for signs and symptoms of LAST.  
Investigational Product 
EXPAREL® (bupivacaine liposome injectable suspension), a marketed product indicated for 
single-dose infiltration in adults to produce postsurgical local analgesia and as an interscalene 
brachial plexus nerve block to produce postsurgical regional analgesia.   Safety and efficacy have 
not been established in other nerve blocks.  
EXPAREL® (bupivacaine liposome injectable suspension) is a white to off-white, milky aqueous 
suspension diluted with preservative-free normal (0.9%) saline for injection or lactated Ringer’s 
solution within 4 hours of preparation in a syringe. 
Chemically, Bupivacaine is 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide with a 
molecular weight of 288.4. Bupivacaine has the following structural formula: 


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CONFIDENTIAL 
 
EXPAREL® (bupivacaine liposome injectable suspension) is available as 266 mg/20 mL (13.3 
mg/mL) single-dose vial or 133 mg/10 mL (13.3 mg/mL) single-dose vial. 
The general objectives of this proposed investigation are to establish the incidence of adverse 
events in patients receiving a Single Shot Liposomal Bupivacaine (Exparel)/Bupivacaine, and to 
assess the efficacy of the erector spinae nerve block using Single Shot Liposomal Bupivacaine 
(Exparel)/Bupivacaine in order to determine if this is a safe regimen for routine use in patients 
undergoing video-assisted thoracic surgery (VATS). 
EXPAREL® (bupivacaine liposome injectable suspension) is an FDA-approved 
prescription drug that will be administered at a dose in accordance with the package insert 
but the site of the injection will be investigational. We plan to use a 10 mL vial (133 mg) 
of EXPAREL® mixed with 20 mL Bupivacaine HCL 0.25% (50 mg) for the SS group. A 
total volume of 30 cc will be injected. The ratio of the milligram dose of the bupivacaine 
and liposomal bupivacaine in the mixture is less than 1:2 as per package insert. 
Potential Risks 
The package insert for EXPAREL® (bupivacaine liposome injectable suspension) describes 
potential risks for patients: 
Central Nervous System Reactions  
The incidence of adverse neurologic reactions associated with the use of local anesthetics may be 
related to the total dose of local anesthetic administered and also dependent upon the particular 


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CONFIDENTIAL 
drug used, the route of administration, and the physical status of the patient. Many of these effects 
may be related to local anesthetic techniques, with or without a contribution from the drug. 
Neurologic effects following infiltration of soft tissue may include persistent anesthesia, 
paresthesia, weakness, and paralysis, all of which may have slow, incomplete, or no recovery. 
Central nervous system reactions are characterized by excitation and/or depression. Restlessness, 
anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to 
convulsions. However, excitement may be transient or absent, with depression being the first 
manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into 
unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, 
vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the 
use of local anesthetics varies with the procedure used and the total dose administered. 
Cardiovascular System Reactions  
Toxic blood concentrations depress cardiac conductivity and excitability, which may lead to 
atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. 
In addition, myocardial contractility is depressed, and peripheral vasodilation occurs, leading to 
decreased cardiac output and arterial blood pressure. 
Allergic Reactions  
Allergic-type reactions are rare and may occur as a result of hypersensitivity to the local anesthetic 
or to other formulation ingredients. These reactions are characterized by signs such as urticaria, 
pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, 
nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly 
anaphylactoid-like symptoms (including severe hypotension). Cross-sensitivity among members 


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CONFIDENTIAL 
of the amide-type local anesthetic group has been reported. The usefulness of screening for 
sensitivity has not been definitively established. 
Chondrolysis  
Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures 
is an unapproved use, and there have been post-marketing reports of chondrolysis in patients 
receiving such infusions. The majority of reported cases of chondrolysis have involved the 
shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric patients and 
adult patients following intra-articular infusions of local anesthetics with and without epinephrine 
for periods of 48 to 72 hours. There is insufficient information to determine whether shorter 
infusion periods are not associated with these findings. The time of onset of symptoms, such as 
joint pain, stiffness, and loss of motion can be variable, but may begin as early as the second month 
after surgery. Currently, there is no effective treatment for chondrolysis; patients who have 
experienced chondrolysis have required additional diagnostic and therapeutic procedures and some 
required arthroplasty or shoulder replacement. 
Accidental Intravascular Injection  
Caution should be taken to avoid accidental intravascular injection of EXPAREL. Convulsions 
and cardiac arrest have occurred following accidental intravascular injection of bupivacaine and 
other amide-containing products. 
 
 
 


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CONFIDENTIAL 
Adverse Reactions 
Table 1. Adverse reactions reported with use of Exparel 
Incidence 
Adverse reactions 
Most common 
(≥ 10%) 
Nausea, constipation, vomiting 
Common 
(≥2 or ≤ 10%) 
Pyrexia, dizziness, peripheral edema, anemia, hypotension, 
pruritus, tachycardia, headache, insomnia, postoperative 
anemia, muscle spasm, hemorrhagic anemia, back pain, 
somnolence, procedural pain 
Less 
common/rare 
(<2%) 
Chills, erythema, bradycardia, palpitations, 
supraventricular/ventricular extrasystoles, ventricular 
tachycardia, anxiety, urinary retention, pain, edema, tremor, 
postural dizziness, paresthesia, syncope, incision site edema, 
procedural hypertension/hypotension, procedural nausea, 
muscular weakness, neck pain, pruritus generalized, rash 
pruritic, sinus bradycardia, hypertension, pallor, laryngospasm, 
respiratory depression, respiratory failure, body temperature 
increased, BP increased, BP decreased, oxygen saturation 
decreased  cold sweat, urticaria, confusional state, depression, 
agitation, hyperhidrosis, restlessness, blurred vision, tinnitus, 
hypoxia, apnea, urinary incontinence, drug hypersensitivity, 
hypersensitivity 
Reproduced from Exparel Prescribing Information. 23 Jan 2012. Pacira Pharms, Inc. San Diego, CA 
 
 


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CONFIDENTIAL 
Risk Mitigation 
To minimize risks, all study participants will receive the injection being studied at the Robert 
Packer Hospital, which has full resuscitation facilities available. There will be a presence of one 
anesthesiologist or certified registered nurse anesthetist (CRNA) directly monitoring the study 
subject from the time of injection to the arrival of the patient in the PRU.  
Any interventions necessary to treat adverse events will be given at the discretion of the attending 
physician and consent to do so will be provided by the patient. EKG will be monitored 
continuously from the time of injection to the discharge of the patient. Upon transfer from PRU, 
patients will be on the telemetry floor. The availability of emulsified lipid or Intralipid will be 
made available immediately in the operating room and PRU. Signs and symptoms of LAST will 
be screened continuously by the nursing team, investigator team and surgical team. 
Outcomes & Definitions 
Primary Endpoint  
“NRP (Numerical Rated Pain Score) at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-48 hours 
(day 2), 48-72 hours (day 3) post VAT surgery” is defined as numerical pain score with 0 being 
no pain and 10 being the most severe pain. The value obtained within the specified time interval 
will be used for analysis. The highest NRP value will be taken if multiple values are obtained 
within specified time interval.  
Secondary Endpoints  
“Post-operative opioid consumption at 0-4 hours, 4-8 hours, 8-16 hours, 16-24 hours, 24-48 hours 
(day 2), 48-72 hours (day 3) post VAT surgery” is defined as time that starts from the arrival to 
PRU and opioid that was administered to achieve adequate pain control at the specified time 
interval. 


21 
CONFIDENTIAL 
All opioids will be converted to morphine equivalents in order to calculate total morphine 
requirements for each interval. Cumulative morphine equivalents used at time interval at 0-4 hours, 
4-8 hours, 8-16 hours, 16-24 hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery 
will be done. 
“Total intraoperative narcotic” is defined as total opioids administered in the operating room. 
“Adjunct pain medication consumption at 0-4 hours, 4-8 hours 8-12 hours, 12-24 hours, 24-48 
hour and 48-72 hours postoperatively” is defined as all non-narcotic pain medications such as 
acetaminophen, gabapentin, ketorolac, etc. 
“Incentive spirometry changes at rest and with cough post extubation at 0-4 hours, 4-8 hours, 8-
16 hours, 16-24 hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery”  is defined as 
the percentage change from preop incentive spirometry value at 0-4 hours, 4-8 hours, 8-16 hours, 
16-24 hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery . The value obtained 
within the specified time limit will be used for analysis, and average spirometry value will be used 
if multiple values are obtained within each specified time interval. 
“Length of hospital stay” is defined in days. 
“QOR-15” is a survey on patient reported outcome which consists of 15 questions related to quality 
of recovery. It will be administered at the time of consenting (baseline), and repeated on days 1, 2 
and 3 post VATS surgery. 
Adverse events associated with liposomal bupivacaine and erector spinae block will be recorded 
as listed in table 2.  Common Terminology Criteria for Adverse Events (CTCAE) version 5, 
published November 27, 2017, will be used for standard classification of adverse events for this 
project. Additionally, will record any of the following: 


22 
CONFIDENTIAL 
• Cardiac: anginal, myocardial infarction, arrythmia suspect related to local anesthetic 
• Neurologic: Transient Ischemic attack (TIA), stroke, seizure, nerve injury from ESP block 
• Gastrointestinal: Nausea, vomiting, constipation, ileus, bowel obstruction 
• Pulmonary: pneumonia, pneumothorax 
•  Infection at the site of the block               
• Local anesthetic systemic toxicity (LAST) necessitating use of Intralipid     
Benefits 
There may be no benefit to participants in this project.  The hope is to attain longer acting pain 
control, which may result in quicker recovery, shorter hospital stays, better breathing 
techniques due to pain relief, and less use of narcotics which may decrease risks of nausea, 
vomiting and constipation. This information may lead to knowledge that could be useful in 
decision-making for local pain relief in future patients.  
Data Collection and Management 
Upon completion of the overall intervention, data will be downloaded from the EPIC electronic 
health record with the help of EPIC consultants from the database by an analyst not involved in 
the research. Telephone conversations will be done to assess pain score and opioid consumption if 
the subject is discharged home during the data collection time period (72 hours post intervention). 
Data will be stored for five years after the conclusion of the trial in a secure location and access 
will be allowed to investigators. In compliance with the ICH/GCP guidelines, the investigator will 
maintain all source documents that support the data collected from each subject, as well as all 
study documents. 


23 
CONFIDENTIAL 
Data Safety Monitoring 
A Data Safety Monitor (DSM) will be appointed to monitor and identify alarming trends in adverse 
events involving the study subjects. The DSM will not be involved in data collection or patient 
interaction. The DSM will be unblinded to assist in detecting trends of serious events that may 
warrant modification or stopping the study. The DSM will conduct periodic review on every 5 
patients enrolled in the study. If enrollment is slow, then the DSM will review at least annually. 
A Clinical Monitor will be appointed to review all adverse events in each study subject. This will 
also ensure that the adverse events occur with reasonable expectation within the study. The Clinical 
Monitor will contact the DSM within 24 hours of recognizing the occurrence of adverse events or 
serious adverse events. The DSM will review the events in unblinded fashion and if there is an 
alarming trend significant enough to modify or suspending the trial, then the DSM will notify the 
PI.  
The study will be stopped if one death where a clear alternate cause is not readily apparent, two 
non-fatal serious adverse events where a clear alternate cause is not readily apparent and two 
moderate to severe symptoms related to local anesthetic systemic toxicity.  
Statistical Methods 
Demographic and clinical characteristics of the study groups will be reported by obtaining number 
of observations (percentages) and mean (standard deviation) or median (range) as required for the 
primary and secondary outcomes. Comparison of treatment groups will be performed by using 
ANOVA with planned contrasts between the groups at each time point. A Bonferroni adjustment 
will be made for multiple comparisons in the post hoc testing. Test statistics, P-values and 95% CI 
(Confidence Interval) will be obtained to report any statistically significant differences. 


24 
CONFIDENTIAL 
Research Ethics Approval 
This research protocol will be submitted for approval to the Institutional Review Board of the 
Guthrie Clinic prior to its implementation. 
Funding 
Grant from Donald Guthrie Foundation for Education and Research is supporting this 
project. 
Confidentiality 
The minimal amount of Protected Health Information (PHI) necessary to identify patients (medical 
record number and date of birth) will be collected and stored in a secure, password-protected file 
on a Guthrie workstation. This information will be kept for the duration of the trial to allow for 
collection of information from the subject’s electronic medical record as described under “Data 
Collection and Management.” All information will be de-identified at the conclusion of the trial. 
Declaration of Interest 
Poovendran Saththasivam MD, Sudhakar Kinthala MD,  Burdett Porter MD, and Mary Hicks, RN-
NPD have no conflicts of interest to report. 
Environmental Assessment of Human Drug and Biologics Applications 
An Environmental Assessment is not required because the action requested qualifies for a 
categorical exclusion per 21 CFR 25.31(e). To the applicant’s knowledge, no extraordinary 
circumstances exist per 21 CFR 25.15(d) 
 


25 
CONFIDENTIAL 
References 
1. Wunsch, H., Wijeysundera, D.N., Passarella, M.A., & Neuman, M.D. (2016). Opioids 
Prescribed After Low-Risk Surgical Procedures in the United States, 2004-2012. JAMA, 315(15), 
1654-1657. 
2. Makary, M.A., Overton, H.N., & Wang, P. (2017). Overprescribing is major contributor to 
opioid crisis. BMJ, 59, 4792. 
3. Soffin, E.M., Lee, B.H., Kumar, K.K., & Wu, C.L. (2019). The prescription opioid crisis: Role 
of the anaesthesiologist in reducing opioid use and misuse. Br J Anaesth, 22(6), 198-208. 
4. Hah, J.M., Bateman, B.T., Ratliff, J., Curtin, C., & Sun, E. (2017). Chronic Opioid Use After 
Surgery: Implications for Perioperative Management in the Face of the Opioid 
Epidemic. Anesth Analg, 25(5), 733-740. 
5. Tuminello, S., Alpert, N., Flores, R., & Taioli, E. (2019). Physician prescribing practices and 
opioid misuse in the USA. Lancet Psychiatry, 6(3), 7. 
6. Moutzouros V, Jildeh TR, Khalil LS, Schwartz K, Hasan L, Matar RN, Okoroha KR.( 2020) 
A Multimodal Protocol to Diminish Pain Following Common Orthopedic Sports 
Procedures: Can We Eliminate Postoperative Opioids? Arthroscopy. Apr 27. 
7. Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, 
Carter T, Cassidy CL, Chittenden EH, Degenhardt E, Griffith S, Manworren R, 
McCarberg B, Montgomery R, Murphy J, Perkal MF, Suresh S, Sluka K, Strassels S, Thirlby R, 
Viscusi E, Walco GA, Warner L, Weisman SJ, Wu CL. Management of 
Postoperative Pain: A Clinical Practice Guideline from the American Pain Society, the American 
Society of Regional Anesthesia and Pain Medicine, and the American Society of 
Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and 


26 
CONFIDENTIAL 
Administrative Council. J Pain. 2016 Feb;17(2):131-57. doi: 10.1016/j.jpain.2015.12.008. 
Erratum in: J Pain. 2016 Apr;17(4):508-  
8. Kehlet, H., Jensen, T.S., & Woolf, C.J. (2006). Persistent postsurgical pain: risk factors and 
prevention. Lancet, 367(9522), 1618-1625. 
9. Nagahiro I, Andou A, Aoe M, Sano Y, Date H, Shimizu N. (2001). Pulmonary function, 
postoperative pain, and serum cytokine level after lobectomy: A comparison of VATS and 
conventional procedure. Ann Thorac Surg, 72:362-5.   
10. Flores RM, Alam N. (2008) Video-assisted thoracic surgery lobectomy (VATS), open 
thoracotomy, and the robot for lung cancer. Ann Thorac Surg; 85: S710–5. 
11. Takenaka S, Saeki A, Sukenaga N, Ueki R, Kariya N, Tatara T, Hirose M. (2020) Acute and 
chronic neuropathic pain profiles after video-assisted thoracic surgery: A prospective study. 
Medicine (Baltimore) (13):e19629.  
12. Schnabel A. (2018) Acute neuropathic pain and the transition to chronic postsurgical pain. 
Pain Manag Sep 1;8(5):317-9 
13.  Haroutiunian S, Nikolajsen L, Finnerup NB, et al. (2013) The neuropathic component in 
persistent postsurgical pain: a systematic literature review. Pain, 154:95–102. 
14. Rawal N. Epidural technique for postoperative pain: gold standard no more? (2012) Reg 
Anesth Pain Med. 37(3):310-7 
15. Naja Z, Lönnqvist PA.(2001) Somatic paravertebral nerve blockade. Incidence of failed 
block and complications. Anaesthesia, 56(12):1184-8. 
16. Forero M, Adhikary SD, Lopez H, Tsui C, Chin KJ. (2016) The Erector Spinae Plane 
Block: A Novel Analgesic Technique in Thoracic Neuropathic Pain. Reg Anesth Pain  
Med. Sep-Oct;41(5):621-7 


27 
CONFIDENTIAL 
17. Chin, K.J., Malhas, L., & Perlas, A. (2017). The Erector Spinae Plane Block Provides Visceral 
Abdominal Analgesia in Bariatric Surgery: A Report of 3 Cases. Reg Anesth Pain Med, 42(3),372-
6. 
18. Krishna, S.N., Chauhan, S., Bhoi, D., Kaushal, B., Hasija, S., Sangdup, T., & Bisoi, A.K. 
(2019). Bilateral Erector Spinae Plane Block for Acute Post-Surgical Pain in Adult Cardiac 
Surgical Patients: A Randomized Controlled Trial. J Cardiothorac Vasc Anesth, 33(2), 368-375. 
19. Nagaraja, P.S., Ragavendran, S., Singh, N.G., Asai, O., Bhavya, G., Manjunath. N., & Rajesh, 
K. (2018). Comparison of continuous thoracic epidural analgesia with bilateral erector spinae 
plane block for perioperative pain management in cardiac surgery. Ann Card Anaesth, 21(3), 323-
-7. 
20. Kimachi, P.P., Martins, E.G., Peng, P., & Forero, M. (2018). The Erector Spinae Plane Block 
Provides Complete Surgical Anesthesia in Breast Surgery: A Case Report. A Pract, 11(7), 186-
188. 
21. Forero M, Rajarathinam M, Adhikary S, Chin KJ.(2017) Continuous Erector Spinae Plane 
Block for Rescue Analgesia in Thoracotomy After Epidural Failure: A Case Report.  
A Case Rep. 15;8(10):254-6 
22. Vidal E, Giménez H, Forero M, Fajardo M.(2018)  Erector spinae plane block: A cadaver 
study to determine its mechanism of action. Rev Esp Anestesiol Reanim. 65(9):514-519 
23. Adhikary SD, Bernard S, Lopez H, Chin KJ. (2018) Erector Spinae Plane Block Versus 
Retrolaminar Block: A Magnetic Resonance Imaging and Anatomical Study. Reg Anesth Pain 
Med, 43(7):756-762 


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CONFIDENTIAL 
24. Onishi E, Toda N, Kameyama Y, Yamauchi M. (2019) Comparison of Clinical Efficacy and 
Anatomical Investigation between Retrolaminar Block and Erector Spinae Plane Block. Biomed 
Res Int,  Mar 28;2019:2578396 
25. Mantripragada, S. (2002). A lipid-based depot (DepoFoam technology) for sustained release 
drug delivery. Prog Lipid Res, 41(5), 392-406. 
26. Davidson, E.M., Barenholz, Y., Cohen, R., Haroutiunian, S., Kagan, L., & Ginosar, Y. (2010). 
High-dose bupivacaine remotely loaded into multivesicular liposomes demonstrates slow drug 
release without systemic toxic plasma concentrations after subcutaneous administration in 
humans. Anesth Analg. 110(4),1018-1023. 
27: PASS 2020 Power Analysis and Sample Size Software (2020). NCSS, LLC. Kaysville, Utah, 
USA, ncss.com/software/pass. 

SAP_001.pdf: 
 
1 
 
 
 
 
 
 
 
 
Date: February 3, 2025 
 
Statistical Analysis Plan 
Single Shot Liposomal Bupivacaine (EXPAREL®)/bupivacaine versus 
Continuous Erector Spinae Plane Block Catheter in Patients Undergoing Video 
Assisted Thoracoscopic (VAT) Surgery; Single Center Noninferiority Open 
Label Prospective Randomized Clinical Trial 


 
2 
Table of Contents 
1. 
Introduction .................................................................................................... 3 
a. 
Background and Rationale ....................................................................................... 3 
b. 
Study Objectives ..................................................................................................... 4 
2. 
Study Design................................................................................................... 5 
a. 
Study Overview ....................................................................................................... 5 
Research location ............................................................................................................................. 5 
Brief description of clinical intervention ............................................................................................. 5 
Design and Hypotheses .................................................................................................................... 5 
Summary of Endpoints ...................................................................................................................... 6 
Data Collection ................................................................................................................................ 7 
Data Safety Monitoring ...................................................................................................................... 8 
b. 
Study Groups .......................................................................................................... 8 
Recruitment and Consent ................................................................................................................. 9 
Randomization and Allocation Concealment: ..................................................................................... 9 
Blinding ............................................................................................................................................ 9 
Inclusion Criteria ............................................................................................................................ 10 
Exclusion Criteria............................................................................................................................ 10 
c. 
Intervention ........................................................................................................... 10 
d. 
Sample Size ........................................................................................................... 12 
3. 
Outcomes .................................................................................................... 12 
a. 
Primary Outcomes ................................................................................................. 12 
b. 
Secondary Outcomes ............................................................................................. 12 
4. 
Statistical Analysis ....................................................................................... 13 
a. 
General Considerations .......................................................................................... 13 
b. 
Baseline data ......................................................................................................... 14 
c. 
Primary Outcomes ................................................................................................. 15 
d. 
Secondary Outcomes ............................................................................................. 16 
e. 
Adverse Events ...................................................................................................... 17 
f. 
Software ................................................................................................................ 17 
5. 
References ................................................................................................... 17 
6. 
Appendices ............................................................ Error! Bookmark not defined. 
 


 
3 
1. Introduction 
a. Background and Rationale 
Roughly 51 million Americans undergo various inpatient surgeries with opioids being the mainstay 
of acute pain management.1 Excessive opioid prescriptions for postoperative pain control have 
been connected to the opioids crisis.2,3 Preoperative opioid use, lower socioeconomic status, 
medical comorbidities and preexisting depression have been shown to cause chronic persistent 
opioid use after surgery.4 Over 60% of people with opioid abuse obtain the medication from friends 
or relatives with unused prescriptions.5 Thus, an effective acute pain management technique that 
mitigates opioid consumption for post-operative pain management warrants research. 
In the perioperative period, a multidisciplinary approach that emphasizes various opioid sparing 
techniques can mitigate the risk of persistent chronic opioid use after surgery6,7. Anesthesiologists 
are at the forefront in providing effective pain control strategies in the perioperative period. Nerve 
blocks have been shown to effectively provide pre-emptive analgesia and acute post-operative pain 
relief, while preventing central sensitization and chronic neuropathic pain.8 
Video assisted thoracoscopic (VAT) surgery has gained popularity among thoracic surgeons. This 
technique has been shown to be superior in improving post-operative lung function, decreasing 
hospital stays and has better patient satisfaction compared to traditional open thoracotomy.9,10. This 
minimally invasive technique has been widely used in various thoracic surgeries; lobectomy, wedge 
resection, decortication and pleurodesis. Some patients undergoing VAT surgery have been known 
to develop acute and chronic neuropathic pain.11,12 The intercostal injury has been proposed as 
mechanism of chronic pain and numbness following VAT surgery.13  
Although thoracic epidural was once considered a gold standard for acute pain management 
following thoracic surgery, this technique is becoming less popular in the VAT surgery.14  While 
shown to be effective in acute post-surgical pain control, paravertebral block and intercostal block 
require an experienced operator, multiple level injections and risk of pneumothorax.15 Recently, 
fascial plane block (erector spinae plane block, serratus anterior plane block, PEC, transverse 
thoracic plane block) have gained wide popularity in thoracic wall analgesia.  Of interest is 
ultrasound guided Erector Spinae Plane (ESP) block, a novel technique first described by Forero et 


 
4 
al. (2016)16. The uniqueness of this technique is the minimal risk compared to neuraxial blockade 
because of the myofascial location of this block. ESP block has been utilized for thoracic, cardiac, 
shoulder and abdominal surgeries with excellent pain control post operatively.17-20   ESP blockade at 
the level of T5 spinous process provides analgesia from T2 to T10 sensory level.21  The proposed 
mechanism of action of ESP block is due to diffusion into paravertebral space, effectively blocking 
the dorsal and ventral rami of the spinal nerves, as well as the rami communicantes that transmits 
sympathetic fibers as well as the intercostal nerves.22-24  
The Food and Drug Administration (FDA) has approved liposomal bupivacaine for interscalene block, 
bunionectomy, hemorrhoidectomy, transversus abdominis plane block and wound infiltration. 
Liposomal bupivacaine, or EXPAREL® the brand name, is a long-acting extended-release liposomal 
bupivacaine with microsomal liposomes (DepoFoam drug delivery system) containing multiple 
aqueous chambers of encapsulated bupivacaine. Bupivacaine is slowly released from the 
liposomes by diffusion as the unprotonated (uncharged) form of bupivacaine. This preparation 
allows sustained release of bupivacaine at the site of injection without exposing patients to toxic 
plasma concentrations. 25-26  
This open label noninferiority prospective randomized clinical trial is important to test the hypothesis 
that Single Shot Liposomal Bupivacaine (EXPAREL®)/Bupivacaine in erector spinae plane block is 
noninferior compared to continuous erector spina plane block catheter group. The comparison of 
single shot ESP blockade using long-acting local anesthetic with a continuous catheter is important 
to identify single shot ESP block using liposomal bupivacaine/bupivacaine as an acceptable method 
of pain relief. Currently, to the best of our knowledge, there is no prospective randomized clinical 
trial comparing Single Shot Liposomal Bupivacaine (EXPAREL®)/Bupivacaine in erector spinae plane 
block in patients undergoing VAT surgery.  
b. Study Objectives 
The objectives of this study are to assess the efficacy of the erector spinae nerve block using Single 
Shot Liposomal Bupivacaine (EXPAREL®)/Bupivacaine and establish the incidence of adverse events 
in order to determine if this is a safe regimen for routine use in patients undergoing video-assisted 
thoracic surgery (VATS). 


 
5 
2. Study Design 
a. Study Overview 
Research location 
This trial will be done at Robert Packer Hospital in Sayre, PA. The Department of Anesthesiology will 
be conducting the research in the operating room (OR) and post-operative cardiothoracic surgical 
unit at Robert Packer Hospital. The erector spinae block will be done in the preoperative area, a 
fully monitored area with immediately available resuscitation and airway equipment. The VAT 
surgery will be done in the general operating room and, upon completion of the surgery, study 
subjects will be transferred to Prep and Recovery Unit for immediate post-operative care.  
Brief description of clinical intervention 
In the Single Shot Liposomal Bupivacaine (EXPAREL®) plus Bupivacaine (SS group), the study drug 
will be 10 mL of EXPAREL® (133mg) mixed with 20 mL Bupivacaine HCL 0.25% (50mg). A total 
volume of 30 cc will be injected into the erector spinae plane on the operative side at level of T5 
transverse process.  
• EXPAREL® (bupivacaine liposome injectable suspension) is an FDA-approved prescription 
drug that will be administered at a dose in accordance with the package insert, but the site of 
the injection will be investigational. 
In the continuous erector spinae plane block catheter using ropivacaine intermittent automatic 
bolus (CC group), the study drug to be used is 20-30 cc of bolus Ropivacaine 0.5 % into the erector 
spinae plane via catheter placement. Subsequent analgesia will be maintained by using electronic 
infusion pump (Sapphire TM Multitherapy Pump; San Clemente, CA, USA) which will be programmed 
to deliver 20 cc intermittent Ropivacaine 0.2% automated bolus every 3 hours, with an additional 
patient demand bolus of 5 cc ropivacaine 0.2% with a lockout period of 30 min in the postoperative 
period at the Prep and Recovery Unit.  
Design and Hypotheses 
The study is a noninferiority, prospective, open label, randomized, double arm clinical trial 
comparing the effectiveness of Single Shot Liposomal Bupivacaine (EXPAREL®) plus Bupivacaine 


 
6 
(SS) and continuous erector spinae plane block catheter using ropivacaine intermittent automatic 
bolus (CC) in patients undergoing VAT surgery. The noninferiority limit was set as a between-group 
difference of two on the 11-point Numerical Rated Pain scale, representing a clinically meaningful 
change. 
Null Hypothesis (H₀):  The experimental treatment [Single Shot Liposomal Bupivacaine 
(EXPAREL®)/Bupivacaine in erector spinae plane block (SS)] is inferior to the control treatment 
[continuous erector spina plane block catheter group (CC)] by two or more points on the 11-point 
Numerical Rated Pain Scale 
Alternative Hypothesis (H₁): The experimental treatment [Single Shot Liposomal Bupivacaine 
(EXPAREL®)/Bupivacaine in erector spinae plane block (SS)] is not inferior to the control treatment 
[continuous erector spina plane block catheter group (CC)] by two or more points on the 11-point 
Numerical Rated Pain Scale. 
H₀ = 𝜇𝜇 experimental (SS) - 𝜇𝜇 control (CC) ≤ -2 
H₁ = 𝜇𝜇 experimental (SS) - 𝜇𝜇 control (CC) > -2 
𝜇𝜇 experimental is the mean pain score for the experimental treatment (SS) group 
𝜇𝜇 control is the mean pain score for the control treatment (CC) group 
If the difference of the mean Numerical Rated Pain Score between the groups is less than the 
noninferiority margin of two on the 11-point numeric pain scale, then the null hypothesis will be 
rejected. 
Summary of Endpoints 
The primary endpoints are: 
• 
Numerical Rated Pain Score (0-10) while at rest at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 
hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery. 
 
• 
Numerical Rated Pain Score (0-10) with cough at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 
hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery. 
The secondary endpoints are: 


 
7 
• 
Post-operative cumulative opioid consumption at 0-4 hours, 4-8 hours, 8-16 hours, 16-24 
hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery. 
• 
Total intraoperative opioid, defined as total opioids administered in the operating room. 
• 
Adjunct pain medication consumption (acetaminophen, gabapentin and ketorolac) at 0-4 
hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-48 hour and 48-72 hours postoperatively 
• 
Postoperative incentive spirometry changes from preoperative baseline at 0-4 hours, 4-8 
hours, 8-12 hours, 12-24 hours, 24-48 hours and 48-72 hours. 
• 
Number of days ESP catheter in place 
• 
Postoperative quality of recovery score (QOR-15) measured at 12-24 hours, 24-48 hours 
(day 1) and 48-72 hours (day 2) post operatively (scored as the mean of 15 items). 
• 
Adverse events associated with erector spinae block and Single Shot Liposomal 
Bupivacaine (Exparel)/Bupivacaine. 
Data Collection 
At the time of consenting, baseline incentive spirometry will be done, baseline quality of recovery 
questionnaire (QOR-15) will be administered, and the patient will be educated on how to use the 
pain assessment tool during the study.  
On the day of the surgery, the participant’s history, physical, and laboratory results will be reviewed 
to confirm study eligibility by the study coordinator and the principal investigator/sub- 
investigators.  
Data collection will occur in the operating room, Prep and Recovery Unit and the post-operative 
cardiothoracic surgical floor at Robert Packer Hospital. If the participant is discharged prior to 72 
hours the surveys will be completed in their outpatient location.  
Following home discharge, a telephone call will be made by the investigator team every 24 hours 
until 72 hours during the post-operative period to collect data on opioid consumption, QOR-15 
questionnaire, numerical pain score, and adverse events. 
All data will be documented in Epic® electronic medical records. An IT/ Epic® data analyst will 
develop flowsheets in Epic® for data collection. After the first patient is enrolled, an independent 
statistician will validate that the flowsheet includes each data point to be collected. Upon 
completion of the overall intervention, data will be downloaded from the Epic® electronic health 


 
8 
record with the help of Epic® consultants from the database by an analyst not involved in the 
research.  
Data will be stored for five years after the conclusion of the trial in a secure location and access will 
be allowed to investigators. In compliance with the ICH/GCP guidelines, the investigator will 
maintain all source documents that support the data collected from each subject, as well as all 
study documents. 
Data Safety Monitoring 
A Data Safety Monitor (DSM) will be appointed to monitor and identify alarming trends in adverse 
events involving the study subjects. The DSM will not be involved in data collection or patient 
interaction. The DSM will be unblinded to assist in detecting trends of serious events that may 
warrant modification or stopping the study. The DSM will conduct periodic reviews on every 5 
patients enrolled in the study. If enrollment is slow, then the DSM will review at least annually. 
The Clinical Monitor will review all adverse events in each study subject. This will also ensure that 
the adverse events occur with reasonable expectation within the study. The Clinical Monitor will 
contact the DSM within 24 hours of recognizing the occurrence of adverse events or serious 
adverse events. The DSM will review the unblinded events and if there is an alarming trend 
significant enough to modify or suspend the trial, then the DSM will notify the Principal Investigator.  
The study will be stopped if one death where a clear alternate cause is not readily apparent, two 
non-fatal serious adverse events where a clear alternate cause is not readily apparent and two 
moderate to severe symptoms related to local anesthetic systemic toxicity.  
b. Study Groups 
In patients undergoing video assisted thoracoscopic (VAT) surgery, the study evaluates pain relief 
for two groups: 
1) Single Shot Liposomal Bupivacaine (EXPAREL®) plus bupivacaine (SS)  
2) Continuous erector spinae plane block catheter using ropivacaine 0.2% intermittent 
automatic bolus technique (CC). 


 
9 
Recruitment and Consent 
Patients at Robert Packer Hospital who are undergoing video assisted thoracoscopic (VAT) surgery 
who meet inclusion/exclusion criteria will be invited to take part. Participants will be screened for 
eligibility once a decision has been made for thoracoscopic surgery. The cardio-thoracic surgery 
department will screen for potential recruitment. The study will be introduced by the surgeon and a 
consent document offered for review.  
Written consent will be required for all study participants prior to participation and will be obtained 
by the principal investigator (PI) or a sub-investigator during the preoperative period. After fulfilling 
the inclusion and exclusion criteria, consent will be obtained by the anesthesiologist sub 
investigator at the pre-admission appointment for the surgery. If the subjects need more time to 
review before deciding to participate, a consent form will be given for review before a decision is 
made at a later time. 
Randomization and Allocation Concealment: 
Subjects are randomized by block randomization with random blocks. Block size (4, 6 or 8) 
remained concealed from the researchers until the end of enrollment. Randomization was done by 
a random number generated computer program using Sealed Envelope Ltd. by someone not 
involved in the research. The randomization schedule was placed in sealed envelopes to be 
concealed from the researcher until time of consent.   
Sealed Envelope Ltd. 2020. Simple randomisation service. [Online] Available from: 
https://www.sealedenvelope.com/simple-randomiser/v1/ [Accessed 2 Sep 2020]. 
The pharmacy department of the Robert Packer Hospital maintains the randomization table.  The 
day prior to the planned surgery the instructions to randomize the participant is sent to the 
pharmacy.  The anesthesiologist advances the treatment allocation orders for the study. The 
pharmacist prepares the study medication on day of surgery. The randomization is sequential to 
the actual surgery date.  
Blinding 
Blinding is not possible in this study because the CC group has an indwelling nerve catheter 
whereas the SS group does not. 


 
10
Inclusion Criteria 
Subjects who are age > 18, undergoing video assisted thoracoscopic (VAT) surgery, and 
following Robert Packer Hospital’s Enhanced Recovery After Surgery (ERAS) protocol for 
Thoracic Surgery will be included in this study. 
Exclusion Criteria 
The exclusion criteria is weight < 50 kg, pregnant subjects,  left ventricular ejection fraction < 30%, 
history of drug or narcotic abuse, history of allergic to amide local anesthetic, presence of 
contraindication for erector spinae plane block (local skin infection, sepsis, severe coagulopathy) 
unable to provide consent, unable to use pain rating scales as demonstrated by verbal feedback, 
preoperative chronic pain on narcotics, history of renal insufficiency (Creatinine > 1.5 mg/dl), 
preoperative mild liver impairment (i.e. AST/ALT above 1.5 times the upper normal limit) and 
lactating women. A urine pregnancy test will be done on all female patients of childbearing age to 
exclude pregnancy unless there is a history of hysterectomy. 
The following subjects will be withdrawn from study data analysis but will remain in the study for 
safety monitoring and study data collection as they have received the treatment: subjects that 
require conversion into open thoracotomy, and subjects who failed nerve block, defined by inability 
to determine the local anesthetic spread in the erector spinae plane on the ultrasound image. A 
screen failure is a participant who does not meet eligibility criteria after consenting or chooses to 
withdraw prior to surgery.  
c. Intervention 
The erector spinae block will be done in the preoperative area, a fully monitored area with 
immediately available resuscitation and airway equipment. The VAT surgery will be done in the 
general operating room and, upon completion of the surgery, study subjects will be transferred to 
Prep and Recovery Unit for immediate post-operative care.  
In the SS group, the study drug will be 10 mL of EXPAREL (133mg) mixed with 20 mL Bupivacaine 
HCL 0.25 % (50mg). A total volume of 30 cc will be injected into the erector spinae plane on the 
operative side at level of T5 transverse process. 


 
11
In the CC group, the study drug to be used is 20-30 cc of bolus Ropivacaine 0.5 % into the erector 
spinae plane via catheter placement. Subsequent analgesia will be maintained by using electronic 
infusion pump (Sapphire TM Multitherapy Pump; San Clemente, CA, USA) which will be programmed 
to deliver 20 cc intermittent Ropivacaine 0.2% automated bolus every 3 hours, with an additional 
patient demand bolus of 5 cc ropivacaine 0.2% with a lockout period of 30 min in the postoperative 
period at the Prep and Recovery Unit.  
The Video Assisted Thoracic (VAT) Surgery is done in a standard fashion. Thoracic surgery 
multimodal analgesia as per the ERAS protocol will be utilized in all subjects. Preoperatively, 
acetaminophen 1000mg orally, gabapentin 300mg orally and celecoxib 200mg orally will be given 
on the preoperative holding area. Postoperatively, acetaminophen 1000 mg Q8 hour prn, 
Gabapentin 100mg orally TID, Oxycodone 5 mg orally Q4H PRN for moderate pain, Oxycodone 10 
mg orally Q6H PRN severe pain and morphine IV 2mg (moderate pain) and 4mg (severe) pain will be 
given for breakthrough pain as needed. 
On arrival in the Prep and Recovery Unit, subjects will be attended by nursing staff and placed on 
monitors. Intravenous fentanyl or hydromorphone as needed will be given based on the numerical 
rated pain ratings. Chest x rays will be taken and reviewed in the Prep and Recover Unit, and signs 
of local anesthetic toxicity (LAST) will be screened.  The ESP catheter in the CC study group will be 
connected to electronic infusion pumps in the Prep and Recovery Unit. (Sapphire TM Multitherapy 
Pump; San Clemente, CA, USA) which will be programmed to deliver automatic intermittent bolus 
of 20 cc of ropivacaine 0.2% every 3 hours. Patient controlled bolus of 5 cc of ropivacaine 0.2% will 
be allowed at a lockout period of every 30 minutes.   
All study subjects will be admitted and observed in the cardiothoracic surgery floor at least for 24 
hours post VATS with telemetry monitoring. If the study subjects are deemed suitable for discharge 
home in less than 72 hours, the continuous catheter in the CC group will be removed. Subjects will 
be screened for LAST signs and symptoms for 8 hours after removal of the catheter and before 
being sent home. Subjects will be educated on signs and symptoms of LAST (metallic taste, ringing 
in the ears, perioral tingling, agitation, seizure and cardiac arrythmias) and if these signs are 
present, subjects will be instructed to go to the nearest emergency department for medical 
evaluation.  


 
12
Following home discharge, a telephone call will be made by the investigator team every 24 hours 
until 72 hours post-operative period to collect data on opioid consumption, QOR-15 questionnaire, 
numerical pain score, and screening questions for signs and symptoms of LAST.  
d. Sample Size 
A power analysis was carried out using PASS 202227 to determine the appropriate sample size given 
power set at 1 - β = 0.90.  One-tailed alpha was set at the Bonferroni-adjusted level 0.008 given six 
time points at which the two treatment groups will be compared. The noninferiority limit was set as 
a between-group difference of two on the 11-point numeric pain scale, representing a clinically 
meaningful change.28 Assuming the standard deviation in each group is two, and that up to 20% of 
the sample may not complete the follow-up measures, the necessary sample size is 74 (n = 37 in 
each treatment group). 
3. Outcomes 
a. Primary Outcomes 
The Primary Outcomes is the Numerical Rated Pain Score (at rest and with cough), which patients 
report on a scale that ranges from zero to ten. It will be collected at 0-4 hours, 4-8 hours, 8-12 
hours, 12-24 hours, 24-48 hours (day 2), and 48-72 hours (day 3) post VAT surgery by an 
independent provider (registered nurse) not directly involved in the research. Following home 
discharge, a telephone call will be made by the investigator team every 24 hours until 72 hours 
post-operation to collect pain scores. The value obtained within the speciﬁed time interval will be 
used for analysis. The highest score will be taken if multiple values are obtained within the 
speciﬁed time interval.  
b. Secondary Outcomes 
• 
“Post-operative cumulative opioid consumption at 0-4 hours, 4-8 hours, 8-16 hours, 16-24 
hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery” is defined as the total opioid 
that was administered to achieve adequate pain control up to the specified time interval 
starting from the arrival in the Prep and Recovery Unit. All opioids will be converted to 
morphine equivalents to determine total morphine requirements for each interval.  


 
13
• 
“Total intraoperative narcotic” is defined as total opioids administered in the operating room. 
• 
“Adjunct pain medication consumption at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-
48 hours and 48-72 hours postoperatively” is defined as all non-narcotic pain medications 
such as acetaminophen, gabapentin, and ketorolac measured in mg units. 
• 
“Incentive spirometry changes post-extubation at 0-4 hours, 4-8 hours, 8-16 hours, 16-24 
hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery” is defined as the change 
from preop incentive spirometry readings post VAT surgery. The value obtained within the 
specified time limit minus the value recorded preop will be used for analysis.  
• 
QOR-15 consists of 15 questions related to five domains of patient reported health status 
(pain, physical comfort, physical independence, psychological support and emotional 
state). It will be administered at the time of consenting (baseline), and repeated on days 1, 2 
and 3 post VATS surgery. The overall score, taken as the mean across the 15 questions, will 
be the measure used in the analysis. 
• 
Common Terminology Criteria for Adverse Events (CTCAE) version 5, published November 
27, 2017, will be used for standard classification of adverse events for this project. 
Additionally, any of the following will be recorded: 
o Cardiac: anginal, myocardial infarction, arrythmia suspected to be related to local 
anesthetic 
o Neurologic: Transient Ischemic attack (TIA), stroke, seizure, nerve injury from ESP 
block 
o Gastrointestinal: Nausea, vomiting, constipation, ileus, bowel obstruction 
o Pulmonary: pneumonia, pneumothorax 
o  Infection at the site of the block  
o Local anesthetic systemic toxicity (LAST) necessitating use of Intralipid  
4. Statistical Analysis 
a. General Considerations 
Both the intention-to-treat (ITT) and per protocol samples will be analyzed and reported if the full 
sample size identified in the power analysis section can be recruited. If full recruitment is not 
possible, and if incomplete post-operative data collection is common, the available data will be 


 
14
insufficient for the per protocol analysis to yield reliable results. In such a case, only the ITT sample 
will be analyzed. 
The primary outcomes will be summarized with means, standard deviations, and mean differences 
with 95% confidence intervals. For the two pain variables (at rest and with cough), the analysis will 
utilize independent samples t-tests with a noninferiority margin of two on the 11-point scale. With 
six time points, results will be considered statistically significant when p-values testing the null 
hypothesis of inferiority are less than a Bonferroni-adjusted 0.008. Cumulative morphine 
equivalents will be assessed in terms of superiority using independent samples t-tests, a null 
hypothesis of no difference, and p-values interpreted with the Bonferroni-adjusted cut-off of 0.008. 
Effect sizes (Cohen’s d) will also be reported. 
The secondary outcomes of adjunct medication doses (in mg units), QOR-15, and change in 
incentive spirometry results from baseline will be reported as means, standard deviations, 
medians, interquartile ranges, and mean differences with 95% confidence intervals. Results of 
independent samples t-tests with a null hypothesis of no difference will be reported. Due to the 
likely nonnormal distributions of these variables, p-values from Mann-Whitney are also reported. 
  
b. Baseline data  
Demographic and clinical characteristics of the study groups will be reported as the number of 
observations (percentages) and mean (standard deviation) or median (range). Differences in 
baseline characteristics between treatments will be assessed using independent samples t-tests, 
Mann-Whitney tests, or chi-square tests, depending on the variable type and definitions. 
 
Descriptive statistics for baseline demographics will include:  
• 
Age in years- mean (standard deviation) 
• 
Gender (male or female) – frequency, number of participants 
• 
Tobacco History – frequency, number of participants 
o Quit more than 12 months ago 
o Never  
o Current 


 
15
• 
Chronic Liver Disease (CLD) History - frequency, number of participants 
• 
Chronic Obstructive Pulmonary Disease (COPD) History - frequency, number of 
participants 
• 
Diabetes History - frequency, number of participants  
• 
Primary Procedure - frequency, number of participants 
o Video Assisted Thoracic Surgery (VATS) 
o VATS with lobectomy 
o VATS with wedge biopsy 
• 
American Society of Anesthesiology (ASA) Physical Status – frequency, number of 
participants.  
ASA Physical Status is a classification system to assess a patient’s pre-anesthesia medical 
co-morbidities and helps predict perioperative risk when used with other risk factors such 
as frailty, level of deconditioning and type of surgery. 
o ASA 1 – a normal healthy patient 
o ASA 2 – a patient with mild systemic disease 
o ASA 3 – a patient with severe systemic disease 
o ASA 4 - a patient with severe systemic disease that is a constant threat to life 
o  ASA 5 - a moribund patient who is not expected to survive without the operation. 
• 
Length of Stay – Reported in hours. Due to its likely skew, length of stay will be summarized 
with medains and interquartile ranges. 
 
For continuous variables, the two groups will be compared using independent samples two-
sample t-tests (age) or Mann-Whitney (length of stay). For categorical variables, the two groups at 
baseline will be compared using chi-square tests. 
 
c. Primary Outcomes 
Primary outcomes are: 
• 
Numeric pain score reported at rest – zero to ten scale collected at 0-4 hours, 4-8 hours, 8-
16 hours, 16-24 hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery 


 
16
• 
Numeric pain score reported with cough– zero to ten scale collected at 0-4 hours, 4-8 
hours, 8-16 hours, 16-24 hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery 
For both primary endpoints (reported separately), the means and standard deviations for each 
group will be reported along with the mean difference and its 95% confidence interval for each 
group. A one-sided independent samples t-test will be performed at each time point. The null 
hypothesis will be that the treated group report pain values of two or more points on average lower 
than the control group. 95% confidence intervals for mean differences that are bounded above -
2.0, along with Bonferroni-adjusted p-values less than 0.008, will be considered as evidence to 
reject the null hypothesis of inferiority. 
d. Secondary Outcomes 
Secondary outcomes: 
• 
Post-operative cumulative opioid consumption – reported in morphine equivalents at 0-4 
hours, 4-8 hours, 8-16 hours, 16-24 hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT 
surgery  
• 
Total intraoperative narcotics - total opioid equivalent units administered in the operating 
room 
• 
Adjunct pain medication consumption collected at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 
hours, 24-48 hours and 48-72 hours postoperatively. 
o Acetaminophen (mg) 
o Gabapentin (mg)  
o Ketorolac (mg) 
• 
Incentive spirometry changes post-extubation - The value obtained within the specified time 
limit minus the value recorded preop will be calculated at 0-4 hours, 4-8 hours, 8-16 hours, 
16-24 hours, 24-48 hours (day 2), 48-72 hours (day 3) post VAT surgery. The average 
spirometry value will be used if multiple values are obtained within each specified time 
interval. 
• 
QOR-15 – Calculated as the mean across the fifteen items that ask questions about pain, 
physical comfort, physical independence, psychological support and emotional state. It will 
be administered at the time of consenting (baseline), and repeated on days 1, 2 and 3 post 
VATS surgery.  


 
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These secondary outcomes will be summarized using means, standard deviations, medians, 
interquartile ranges, and mean differences [95% confidence interval]. Tests of the null hypothesis 
of no difference will be assessed using both independent samples t-tests and (because of likely 
nonnormality) Mann-Whitney tests. The same Bonferroni adjustment for multiplicity of tests will be 
applied when interpreting p-values.  
e. Adverse Events 
A table of all recorded adverse outcomes will be reported showing the type of event, its level of 
severity, and the arm into which the participant was randomized. All patients, including those 
removed from the study for the reasons listed above under Exclusion Criteria, will have any adverse 
events reported. Differences between study arms in terms of the occurrence of an adverse event 
and, among those who experienced an adverse event, the event severity will be tested using 
Fisher’s exact test and a Mann-Whitney test, respectively. 
f. Software 
Analysis will be performed using the most up-to-date version of R. 
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