Clinical trial NCT05188053
Conditions: Total Knee Arthroplasty
Sponsor: Mayo Clinic
Start date: 2022-03-11; Completion date: 2024-04-18
Enrollment: 209 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare an FDA-approved medication for post-operative pain control (HTX-011) to the standard of care institutional practice for periarticular analgesia after primary total knee arthroplasty (weight based dosing of Ropivacaine, epinephrine and ketorolac diluted with saline). We are doing this research study to find out if this new medication provides superior pain control within 72 hours following surgery.

Detailed description:

Arms: arm 1: Subjects undergoing a total knee arthroplasty will receive HTX-011 (Zynrelef) for perioperative analgesia arm 2: Subjects undergoing a total knee arthroplasty will receive standard of care arthroplasty block for perioperative analgesia
Interventions: intervention 1: HTX-011 intervention 2: ropivacaine , epinephrine , ketorolac diluted in sodium chloride
Intervention descriptions: intervention 1: Single dose administration periarticular 400mg bupivacaine and 12mg meloxicam extended release solution intervention 2: Single dose administration in 100cc of standard formulation, there is 225mg of ropivacaine 5mg/mL, 0.6mg epinephrine 1mg/mL, 30mg ketorolac 30mg/mL diluted in sodium chloride

Protocol documents:
Prot_SAP_000.pdf: 
Periarticular Bupivacaine + Meloxicam ER Solution Versus Standard Practice During Total 
Knee Arthroplasty: A single institution, single-blinded, randomized clinical trial
NCT05188053
Document updated 1/29/2024  
Document Submitted to PRS 3/4/2025


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Periarticular Bupivacaine + Meloxicam ER Solution Versus Standard Practice During 
Total Knee Arthroplasty: A single institution, single-blinded, randomized clinical trial 
Principal Investigator(s) 
[Co-Investigator(s)] 
Matthew P. Abdel, M.D. 
Harold I. Salmons, M.D. 
Dirk R. Larson, M.S. 
Robert T. Trousdale, M.D.
Mark W. Pagnano, M.D.
Cory G. Couch, M.D. 
Adam W. Amundson, M.D.
Christopher M. Duncan, M.D.
Hugh M. Smith, M.D., PhD.
Department of Orthopedic Surgery 
Funding Sponsor: 
Mayo Clinic 
200 First St. SW 
Rochester, MN 55905 
507-284- 2511
Study Product: 
bupivacaine +meloxicam ER solution, HTX-011 


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Protocol Number: (IRBe) 
 
 
 
Updated version: 
[1/29/2024] Version (2.0)  
Abstract: 
Total joint arthroplasty (TJA) remains one of the most prevalent and successful surgical 
procedures performed on patients seeking return to function from arthritic pain. Effective pain 
control is critical after surgery to permit earlier mobilization, maximize patient satisfaction, 
and facilitate outpatient surgery. Multimodal analgesia protocols are the back bone for post-
operative functional recovery after TJA, and efforts to optimize these protocols with new FDA 
approved medications remain of significant importance. The purpose of this study is to 
examine the efficacy of a recent FDA approved medication: bupivacaine +low dose meloxicam 
extended release (ER) solution (HTX-011), for post-operative pain control after total knee 
arthroplasty. This is a 1:1 randomized, single blinded, clinical trial studying this new 
medication against our institution’s standard of care arthroplasty block cocktail. Patients will 
be randomized by dynamic allocation into treatment and active control groups. The primary 
outcome of interest is pain control over 72 hours after surgery collected through pain diaries 
recording an 11-point numeric rating scale (NRS) of 0-10. These scores will be computed as 
area under the pain curve at 24, 48 and 72 hours, and standardized by daily morphine 
equivalents required to arrive at our end points. Additional endpoints include distance walked 
with PT at discharge, , length of stay in the hospital, and adverse events.  We hypothesize that 
this new medication will provide superior analgesia at 72 hours and reduced opioid 
consumption, in comparison to our current standard of care.  
 


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Table of Contents 
STUDY SUMMARY ................................................................................................................................6 
1 
INTRODUCTION ...........................................................................................................................8 
1.1 
BACKGROUND ...................................................................................................................................... 8 
1.2 
CLINICAL DATA TO DATE .................................................................................................................. 11 
1.3 
ANTICIPATED DURATION OF THE CLINICAL INVESTIGATION .............................................................. 14 
2 
STUDY OBJECTIVES ................................................................................................................. 14 
2.1 
STUDY RATIONALE AND RISK ANALYSIS (RISKS TO BENEFITS RATIO)ERROR! 
BOOKMARK 
NOT 
DEFINED. 
2.1.1 
Study Rationale ................................................................................................................. 16 
2.1.2 
Anticipated Risks .............................................................................................................. 17 
2.1.3 
Potential Benefits .............................................................................................................. 19 
3 
STUDY DESIGN .......................................................................................................................... 19 
3.1 
GENERAL DESIGN .............................................................................................................................. 19 
3.2 
PRIMARY STUDY ENDPOINTS ............................................................................................................. 20 
3.3 
SECONDARY STUDY ENDPOINTS ........................................................................................................ 21 
3.4 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 21 
4 
SUBJECT SELECTION, ENROLLMENT AND WITHDRAWAL .............................................. 21 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 22 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 22 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING .................................................................. 23 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................... 24 
4.4.1 
When and How to Withdraw Subjects ................................................................................. 24 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ....................................................... 25 
5 
STUDY DEVICE ......................................................................................................................... 25 
5.1 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................... 27 
5.2 
PREPARATION AND ADMINISTRATION/IMPLANTATION OF INVESTIGATIONAL DEVICE ....................... 28 
5.3 
SUBJECT COMPLIANCE MONITORING ................................................................................................. 29 
5.4 
PRIOR AND CONCOMITANT THERAPY ................................................................................................ 29 
5.5 
PACKAGING AND LABELING ............................................................................................................... 30 
5.6 
MASKING/BLINDING OF STUDY ......................................................................................................... 30 
5.7 
RECEIVING, STORAGE, DISTRIBUTION AND RETURN .......................................................................... 31 
5.7.1 
Receipt of Investigational Devices ...................................................................................... 31 
5.7.2 
Storage ............................................................................................................................ 32 
5.7.3 
Distribution of Study Device .............................................................................................. 32 
5.7.4 
Return or Destruction of Study Device ................................................................................ 32 
5.7.5 
Cleaning/Sterilization Procedures (optional) ....................................................................... 32 
6 
STUDY PROCEDURES............................................................................................................... 32 
6.1 
ENTIRE STUDY VISIT ........................................................................................................................... 32 
7 
STATISTICAL PLAN .................................................................................................................. 34 
7.1 
SAMPLE SIZE DETERMINATION .......................................................................................................... 34 
7.2 
STATISTICAL METHODS ..................................................................................................................... 35 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ........................................................................................... 39 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................ 39 


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8.1 
DEFINITIONS ...................................................................................................................................... 39 
8.2 
RECORDING OF ADVERSE EVENTS ..................................................................................................... 43 
8.3 
SPONSOR-INVESTIGATOR REPORTING OF UNANTICIPATED ADVERSE DEVICE EFFECTS AND 
UNANTICIPATED PROBLEMS ............................................................................................................................. 44 
9 
DATA HANDLING AND RECORD KEEPING ........................................................................... 44 
9.1 
CONFIDENTIALITY.............................................................................................................................. 44 
9.2 
SOURCE DOCUMENTS......................................................................................................................... 45 
9.3 
CASE REPORT FORMS ........................................................................................................................ 45 
9.4 
RECORDS RETENTION ........................................................................................................................ 47 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ......................................................... 47 
10.1 
STUDY MONITORING PLAN ................................................................................................................ 47 
10.2 
AUDITING AND INSPECTING ............................................................................................................... 47 
11 
ETHICAL CONSIDERATIONS .................................................................................................. 48 
12 
STUDY FINANCES ..................................................................................................................... 49 
12.1 
FUNDING SOURCE .............................................................................................................................. 49 
13 
PUBLICATION PLAN ................................................................................................................ 49 
14 
REFERENCES ............................................................................................................................ 50 
15 
ATTACHMENTS ........................................................................................................................ 51 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
UADE 
Unanticipated Adverse Device Effect 
 
 
 
 
 


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Study Summary 
Title 
Periarticular bupivacaine + meloxicam ER solution (HTX-011, 
Zynrelef) Versus Standard Practice During Total Knee 
Arthroplasty for Perioperative Analgesia: A single institution, 
single-blinded, randomized clinical trial 
 
Running Title 
Periarticular bupivacaine + meloxicam ER solution vs standard 
practice during TKA: An RCT 
IRB Protocol 
Number 
21-010044 
Phase 
Comparative Study, RCT, single institution, single blind 
Methodology 
Single blind, randomized, clinical trial; active control (standard 
practice) 
Overall Study 
Duration 
1 year 
Subject 
Participation 
Duration 
72-hours of direct study involvement 


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Objectives 
This study will investigate if bupivacaine +meloxicam ER solution 
is going to improve patient care at Mayo Clinic through superior 
and prolonged analgesia following total knee arthroplasty compared 
to our standard of care.  
Number of Subjects 
Using preliminary calculations based on the literature, we anticipate 
enrolling a total of 250 subjects. However, a pilot study will be 
performed on a total of 10 patients using the exact study 
medications and methods presented for the formal RCT to more 
accurately calculate the required sample size. The final sample size 
for the formal RCT will be based on the results of the pilot study.  
Diagnosis and Main 
Inclusion Criteria 
Examination of a new FDA approved extended release bupivacaine 
+meloxicam solution for periarticular instillation during total knee 
arthroplasty (TKA) versus institutional standard practice.  
Inclusion Criteria: Older than 18 years, all genders, presenting for 
primary total knee replacement for degenerative joint disease and 
deemed healthy for TKA surgery, patient can provide their own 
informed consent.  
 
 
Study Drug 
Bupivacaine + meloxicam ER solution, HTX-011 (Zynrelef)- FDA 
approved for total knee arthroplasty 


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Duration of 
Exposure 
One time intraoperative dose prior to closure of total knee 
arthroplasty index procedure 
Reference therapy 
Mayo clinic standard arthroplasty block : In 100cc of standard 
formulation, there is 225mg of ropivacaine 5mg/mL, 0.6mg 
epinephrine 1mg/mL, 30mg ketorolac 30mg/mL diluted in sodium 
chloride 
Statistical 
Methodology 
Area under the curve at 24, 48 and 72 hours will be calculated 
based on serial numeric rating scale (NRS) pain scores on an 11 
point scale with two-sample t-tests for parametric and Wilcoxon 
rank sum tests for non-parametric data. Dynamic allocation will be 
used for randomization. Descriptive statistics will be used where 
appropriate.  
1 Introduction 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the procedures described in this protocol, applicable United States 
government regulations and Mayo Clinic policies and procedures.  
1.1 
Background 
Total joint arthroplasty remains one of the most prevalent and successful surgical 
procedures performed on patients seeking return to function from arthritic pain. Effective pain 
control is critical after surgery to permit earlier mobilization, maximize patient satisfaction, 
and facilitate outpatient surgery. 


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 As advancements in medicine and surgery continue to progress, more emphasis is being 
placed on earlier ambulation following surgery as it has been shown to improve outcomes and 
decrease hospital length of stay and decrease total cost of care.1-3. Optimizing perioperative 
pain control is crucial to achieving these goals.  
Current practice for perioperative pain management during TKA involves the use of 
multimodal analgesia (MMA). MMA includes multiple oral and IV medications tasked with 
blocking sensory input around the knee for a period around the indexed surgery4. Together, 
MMA protocols are designed to reduce the need for opioids, decrease postoperative pain 
intensity and encourage earlier discharges. These effects drive down costs of care. Included 
with these medications are periarticular injections, which have proven effective in achieving 
both pain intensity and functional improvement after surgery.5 While multiple agents have 
been tested in practice including bupivacaine hydrochloride and ropivacaine as components to 
MMA protocols, observed effects are often limited to approximately 8 to 12 hours post-
operative6. More recently, certain bupivacaine liposomal emulsions designed to have 
prolonged effect have been tested with conflicting evidence reported in their efficacy compared 
to “shorter acting” substances beyond 24 hours7. Thus, continuing to examine new medications 
and optimize MMA protocols is an important ongoing pursuit both from a quality 
improvement, patient outcome, and cost effectiveness point of view. 
Recently, the FDA approved a new periarticular extended release (ER) solution 
consisting of low dose meloxicam + bupivacaine for total knee arthroplasty pain control. Their 
decision is based on the results of a recent Phase 2b clinical trial investigating this drug against 
standard local periarticular analgesic options.4 In this Phase 2 clinical trial, 232 patients 
undergoing primary unilateral total knee arthroplasty under general anesthesia were studied, 


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and the authors’ results ultimately demonstrated that the unique, needle-free, instillation of 
400mg bupivacaine/12mg meloxicam ER solution intraarticularly prior to closure provided 
superior pain reduction out to 72 hours following TKA compared to placebo and active control 
groups. Bupivacaine + meloxicam ER solution (HTX-011, Zynrelef) is FDA-approved for 
three specific surgical indications: bunionectomy, herniorrhaphy, and total knee arthroplasty, 
with the FDA approval stemming from primarily industry involved studies4,8,9.  Notable 
benefits included prolonged duration of pain control out to 72 hours postoperative and a 
concomitant decrease in opioid requirements after surgery10.  
The primary goal of this study is to investigate whether this medication will improve 
patient care at our institution by conducting the first, non-industry supported, randomized, 
single-blinded clinical trial comparing bupivacaine + low dose meloxicam ER solution to our 
institutional standard practice arthroplasty block cocktail during total knee arthroplasty by 
providing superior analgesia through 72 hours. Our second goal is to evaluate the impact of 
this medication on patient opioid consumption after surgery and return to ambulation end 
points in comparison to our standard of care. We hypothesize that this medication will provide 
improved pain control at 72 hours post-operative resulting in less consumption of opioids and 
improved ambulation at 72 hours compared to our current standard of care. However, these 
effects may be associated with a significant increase in cost of care.  
 
Investigational Device 
Bupivacaine + low dose meloxicam ER solution (HTX-011) is a recent FDA approved 
medication used for periarticular instillation to reduce postoperative pain. Bupivacaine + low 
dose meloxicam ER solution has been approved for bunionectomy, open inguinal 


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herniorrhaphy, and total knee arthroplasty. Its efficacy has been described out to 72 hours 
due to a proprietary polymer based formulation with prolonged elusion pharmacokinetics. It 
is found to be safe, with existing clinical studies suggesting its most common side effects 
being headache, nausea and constipation4,8,9.  
 
1.2 Clinical Data to Date 
Recently, the FDA approved this new periarticular pain medication, low dose 
meloxicam + bupivacaine ER solution for total knee arthroplasty pain control, bunionectomy 
and open inguinal herniorraphy4,8,9. For total knee arthroplasty (TKA), this approval decision 
is based on the results of a recent clinical trial investigating this drug against local periarticular 
analgesic options (active control) and placebo groups.4 In that Phase 2 clinical trial, 232 
patients undergoing primary unilateral total knee arthroplasty under general anesthesia were 
studied, and the authors’ results ultimately demonstrated that the application of the study drug, 
400mg bupivacaine/12mg meloxicam ER solution, intraarticularly prior to closure of a 
standard TKA midline incision provides superior pain reduction through 72 hours following 
TKA compared to their placebo or active control groups. The recent FDA approval of this new 
analgesic medication stemmed from primarily industry involved studies, with notable benefits 
being prolonged duration of pain control out to 72 hours postoperative and a concomitant 
decrease in opioid requirements after surgery10. Importantly, we asked our pharmacist to 
critically review the safety of single shot adductor canal blocks, spinal anesthesia, and local 
skin anesthetic in patients receiving this study medication. Nathaniel Brinkman, Pharm D., 
RPh, provided a critical analysis of the dosing of this medication, plasma concentrations and 


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concluded that it is safe to use a single shot adductor canal block plus spinal for patients 
receiving bupivacaine + low dose meloxicam ER solution. His decision is based on available 
clinical information which is outlined as follows. Inter-patient variability aside, pertinent data 
points include a local anesthetic systemic toxicity (LAST) from bupivacaine is thought to occur 
around 2,000ng/mL. Concentration max for HTX-011 400mg in TKA was 695 ng/mL, which 
was reached at 21 hours per the package insert. A poster by Yamamoto et al. included a range 
of 368-1,550 ng/mL (mean 710 ng/mL) in mammoplasty, i.e. not an intra articular use, which 
reached max concentration at 3.58 hours (1.27-34.58). Median plasma concentration for 
combination spinal and single shot femoral blockade was 538 ng/mL (range, 176-1,384 
ng/mL)11. The theoretical max if all serum concentration maximums were reached at the same 
time would be 2,079 ng/mL, however the intra articular instillation and prolonged elution of 
this medication protects against simultaneous serum peak concentrations. This extends to the 
use of 75 mg bupivacaine as a local skin anesthetic during closure as is the preference of senior 
author MPA. Local use of bupivacaine in this manner will result in a peak between 200-300 
ng/mL at approximately 60 minutes, but the time to peak was identified as variable. Dr. 
Brinkman expects the combination of spinal anesthesia, adductor blockade and skin infiltration 
of bupivacaine will have a cumulative peak of 800-900 ng/mL within the 30-120-minute 
timeframe, well before the bupivacaine +low dose meloxicam ER solution instilled intra 
articularly peaks, and below the 2,000 ng/mL toxicity threshold.  


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<https://zynrelef.com/pdf/4-Clinical-Evidences/Yamamoto-Pharmacokinetics-Safety-
Different-Bupivacaine-Formulations-2019.pdf> 
 


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<https://zynrelef.com/pdf/4-Clinical-Evidences/Luke-HTX-011-Predictable-release-
rates-2021.pdf> 
1.3 
Anticipated Duration of the Clinical Investigation 
This study is anticipated to be completed within one year of initiation. Each subject will be 
enrolled for the duration of the study; however, will only require contact over the first 72 
hours when they are expected to mail in self-reported pain diaries. They may be contacted by 
a study coordinator if the diaries are not mailed back to the investigational team. 
 
2 Study Objectives 
 


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The overall objective of this study is to investigate whether or not this new FDA approved 
medication is a viable addition to the Mayo Clinic formulary to improve the quality of patient 
care following total knee arthroplasty. To this end, we will examine pain at 72 hours as our 
primary outcome. Secondarily, we will also investigate pain at 48 hours in the study versus 
control group. Pain at 24 hours will be compared between groups as a tertiary goal, while 
recognizing that the study medication is reported to differentiate itself through its extended 
duration of effects. We will collect opioid use information and monitor for standard safety 
parameters after total knee surgery post-operative. The anticipated duration for complete data 
collection to analysis is one year.  
 
2.1 Primary Objective 
 
This investigation constitutes a comparative study involving the first non-industry funded 
investigation of the use of a recently FDA approved periarticular pain medication for 
controlling postoperative pain following total knee arthroplasty.  
 
Primary Objective 
 
To assess the effectiveness of bupivacaine +meloxicam periarticular ER solution in 
controlling postoperative pain out to 72 hours in subjects receiving primary total knee 
arthroplasty compared to standard arthroplasty block controls. 
 
2.2 Secondary Objective 


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Secondary outcomes will be evaluating pain control at 24 and 48 hours, total post-operative 
opioid consumption (standardized into MMEs), hospital length of stay, adverse reactions or 
events, distance walked at time of discharge with PT.  
2.1.1 Study Rationale 
Based on available literature, periarticular bupivacaine + low dose meloxicam ER solution 
has been demonstrated as a new and safe means of providing prolonged patient analgesia 
after total knee arthroplasty. Its novelty is in both its formulation and needle-free instillation. 
As the available studies to date examining this medication are industry-funded, the primary 
rationale for examining this FDA approved medication at our institution is to provide an 
unbiased evaluation of this new medication in the setting of quality improvement initiatives 
to our institution’s patient care. Multimodal analgesia (MMA) is critical to achieving better 
outcomes after total joint arthroplasty, as it has been shown to decrease hospital length of 
stay through earlier ambulation and patient satisfaction. It also has the benefit of reducing 
narcotic consumption postoperatively. Continuing to evaluate optimal protocols and new 
medications for MMA consideration remains of significant value.  
 
Various means of controlling post-operative pain are currently employed at Mayo Clinic. 
Standard arthroplasty block is a cocktail of multiple medications instilled with a needle prior 
to closure of total knee arthroplasties. In 100cc of our current formulation, there is 225mg of 
ropivacaine 5mg/mL, 0.6mg epinephrine 1mg/mL, 30mg ketorolac 30mg/mL diluted in 
sodium chloride. While effective at controlling patients’ pain intensity postoperatively, 
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the pain following total knee arthroplasty experienced by a patient can be quite limiting at 
first, continuing to evaluate MMA protocols using new, FDA approved medications remains 
of significant value.  
 
An essential component to a new drug reaching FDA approval is an analysis of not only the 
drug’s efficacy but also its safety profile. Bupivacaine + low dose meloxicam ER solution 
has been shown through multiple large clinical trials to be safe with its most common 
adverse effects reported as constipation, nausea and headache4,8,9.   
 
2.1.2 Anticipated Risks 
The existing evidence on this new FDA approved medication suggests that it is safe. The 
adverse effects with >/= 10% incidence that have been reported are constipation, vomiting 
and headache. This is a single one-time intra articular dose of this medication. As such, the 
standard risks of intravenous instillation of local analgesics such as bupivacaine 
(cardiotoxicity) and meloxicam (renal, GI, bleeding and cardiovascular toxicity) are likely 
mitigated by the local instillation and one-time dose. Further, following thorough discussion 
with on staff pharmacy expert, Nathaniel Brinkman, Pharm D, the elution kinetics of this 
medication outlined in the available literature does not show brisk accumulation in serum 
given the local instillation and prolonged elution kinetics of the medication as detailed above 
in section 1.2. Thus, the drug is considered safe with adjuvant neural blockade such as spinal 
anesthesia, single shot adductor canal block and local anesthetic instillation to skin during 


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closure. Given the ingredients of this medication, the list of possible risks and adverse effects 
includes:  
- 
Hypersensitivity/ allergic response 
- 
Hypertension 
- 
Renal toxicity 
- 
Cardiac toxicity 
- 
Hepatotoxicity/transaminitis 
- 
Methemoglobinemia 
- 
Heart failure and edema  
- 
Prolongation of postoperative bleeding 
- 
Drug-drug interactions with other NSAIDs, hemostasis interfering medications (e.g. 
warfarin, aspirin, SSRI/SNRIs) 
 
There are also risks associated with the index surgery which are explained to every patient 
during their informed consent for surgery. These risks include: 
• Death 
• Fever 
• Infection 
• Damage to surrounding neurovascular or ligamentous structures during surgery 
• Stroke 
• Wound complications 
• Deep venous thrombosis or Pulmonary embolism 


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• Fracture and subsequent surgeries 
2.1.3 Potential Benefits 
The anticipated benefit of this study will be identifying the effectiveness of a new FDA 
approved periarticular analgesic in a non-industry sponsored cohort of subjects receiving 
total knee arthroplasty at a single high-volume orthopedic hospital. This information will 
inform clinical practice through quality improvement initiatives as it may prove worthwhile 
to be incorporated into existing MMA protocols at our hospital. There is a proposed 
advantage of this medication having a 72 hour analgesic effect with an associated reduction 
in opioid requirements. 
3 Study Design 
3.1 
General Design 
• Randomized, single-blinded, standard of care group as a control, single institution, 
clinical trial 
• 72 hours direct patient study involvement may be contacted out to the point of 
publication for general follow-up.   
• Patients will be recruited for the study at their preoperative appointments. They will be 
randomized using a computer algorithm with dynamic allocation. They will not be 
informed as to their study group. They will receive their scheduled pTKA. They will 
follow up with their pain diaries over the subsequent 72-hours after which time they 
will return them to the investigational team with pre-paid postage.  


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• There is no long term follow up outside of their normal scheduled post-operative visits 
with their surgeon to monitor their progress with surgical recovery. Primary and 
secondary endpoints will be observed and collected over the first 72 hours after 
surgery.  
 
 
 
3.2 
Primary Study Endpoints 
Mean patient reported (0-10) numeric rating scale (NRS) pain scores area under the curve 
(AUC) at 72 hours adjusted for opioid consumption. 
 


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3.3 
Secondary Study Endpoints 
Secondary outcomes will be mean patient reported (0-10) NRS pain scores area under the curve 
(AUC) at 24 and 48 hours postoperative, total post-operative opioid consumption (standardized 
into MMEs), hospital length of stay, adverse reactions or events, and distance walked with PT 
prior to discharge. 
 
3.4 
Primary Safety Endpoints 
This is an FDA approved medication for the present indication. It is not investigational in this 
setting but is rather being evaluated for quality improvement of patient care at Mayo Clinic. 
As such, standard post-operative evaluation for patients who have received total joint 
arthroplasty will be utilized. This will include serial neurovascular examinations and notation 
of any complications including but not limited to unexpected ICU admissions, prolonged 
hospitalizations, venous thromboembolic disease, wound problems and drug hypersensitivity 
reactions.  
4 Subject Selection, Enrollment and Withdrawal 
Consecutive adults greater than the age of 18 years old who have consented for this study and 
are receiving primary total knee arthroplasty to treat degenerative joint disease are qualified 
for inclusion. These subjects must all be deemed healthy for surgery (American Society of 
Anesthesiologists (ASA) physical classification I to III) will be included in this randomized, 
controlled trial as this simulates our clinical practice population. We will exclude patients 
with contraindications to NSAIDs or bupivacaine including allergies (Type 1 


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hypersensitivity) and severe renal disease.  We aim to represent a standard patient population 
receiving total joint arthroplasty at our institution. 
4.1 
Inclusion Criteria 
 
• ASA classification I to III older than or equal to 18 years old 
• All genders 
• Presenting for primary total knee replacement for degenerative joint disease  
• Patient capable of providing their own informed consent 
 
4.2 
Exclusion Criteria 
 
• Vulnerable study populations including prisoners 
• Patients with a contralateral total knee arthroplasty <2 years prior to the index 
procedure 
• Compromised health barring the patient from proceeding with surgery  
• Patients unable to provide their own informed consent 
• Pregnancy 
• Patients with documented chronic pain syndromes 
• Patients with a history of prolonged daily opioids (more than 1 month) with an oral 
morphine equivalent of greater than 5mg/day 
• BMI >45 kg/m2 


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• Type I hypersensitivity to any component of the study medications 
• Patients with impaired cognitive function inhibiting ability to provide informed 
consent 
• Severe renal (estimated glomerular filtration rate less than 50ml/min)) 
4.3 
Subject Recruitment, Enrollment and Screening 
Subjects will be identified as those who meet the inclusion criteria and are receiving total 
knee arthroplasty for degenerative joint disease from the clinical practices of participating 
high-volume adult reconstruction surgeons at the Mayo Clinic that have agreed to participate 
in our study. We will recruit patients at their pre-operative visit, where they will be screened 
for exclusion/inclusion criteria and enrolled by a trained research coordinator at the time of 
consent for surgery. We anticipate 25 eligible patients seen in an average month, and assume 
that 70% of patients will agree to participate. While there should be no loss to follow-up in 
this study (due to the short nature of the follow-up), we assume that up to 10% of subjects 
will not complete or return their pain diaries.  Thus, we expect that there will be 15 patients 
enrolled with complete data per month. Preliminary sample size calculations (section 7.1) 
were based on previously published data. However, because of differences in the intervention 
and follow-up protocol in this proposed RCT, a pilot study of 10 patients following this same 
protocol using this on-formulary medication will be conducted in a single author (MPA’s) 
clinical practice. Five patients will receive HTX-011 and the other 5 patients will receive the 
standard practice pain block. The data from this pilot study will be used to refine the initial 
sample size estimate and will provide the final sample size determination for the RCT. 
However, the data from the pilot study will not be included in the full RCT analysis. The 


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other advantage of the pilot study is that it will provide study personnel an opportunity to 
become familiar with the procedures and flow of subject enrollment and data collection prior 
to the initiation of the actual RCT. The informed consent document will contain information 
about the study drug (benefits and safety information), the importance of the study, and the 
contact information of the investigative team for any questions. At that time, the pain diary 
will be shown to them with specific education provided by the coordinator as to how to use 
the diary (a second round of education will occur on the day of surgery when the patient is 
done with their surgery at which time the diary will be provided to them by the coordinator). 
The coordinator will screen patients for inclusion/exclusion criterion and confirm selection of 
any patient that they have questions. The coordinator will also remind patients of how to use 
the diary throughout their 3-day postoperative period through reminder  patient portal 
messages organized through Mayo Clinic. Patients will not be notified which treatment arm 
of the study they fall into as this is a single blind, randomized, controlled trial. Given the 
novel needle-free application of this medication compared to the active standard arthroplasty 
block control group (injection), the surgeons will not be blinded to treatment allocation, 
however the surgeons will not collect postoperative patient reported outcomes from the 
patient, who themselves will be blinded. Nurses who take care of the patients in the hospital 
and assist them in their initial pain diary recording will be blinded to the treatment allocation.  
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
 


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Study procedures include index TKA at which time the medication of interest will be 
administered. Subjects will then be asked to complete pain diaries using numerical rating 
scale (NRS) pain scores on an 11 point scale (0-10) for 72 hours while also tracking their 
opioid consumption. They will then return the diary to the investigators and their direct 
involvement will be complete. It is not anticipated to withdraw a qualified and consented 
subject for any reason except if they fail to complete and return the pain diary. If that 
happens, they will be replaced if insufficient data is provided for primary end point 
calculations. 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Not applicable. No long term follows up is being pursued for this study. 
  
5 Study Device 
Bupivacaine + low dose meloxicam ER solution is a recent FDA approved medication used 
for periarticular instillation to reduce postoperative pain. Bupivacaine + low dose meloxicam 
ER solution has been approved for bunionectomy, open inguinal herniorrhaphy, and total 
knee arthroplasty based on recent studies4,8,9. Its efficacy has been described out to 72 hours 
due to a proprietary polymer design with prolonged drug elusion pharmacokinetics. 
Bupivacaine exerts its analgesic effect by preventing cell membrane depolarization through 
blocking sodium ion influx into sensory neurons. Meloxicam is a non-steroidal anti-
inflammatory medication (NSAID) which exerts its effect through blockade of 


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cyclooxygenase enzymes and subsequent down regulation of pro inflammatory prostaglandin 
mediators. This combination medication is shown to be safe, with existing clinical studies 
suggesting its most common side effects are headache, nausea and constipation (incidence 
>/=10%)4,8-10. The device will be obtained through its manufacturer and will be received as a 
sterile unopened medication to be administered during surgery in standard sterile fashion.  
 
Description 
Bupivacaine + low dose meloxicam ER solution is a recent FDA approved medication used 
for periarticular instillation to reduce postoperative pain. Bupivacaine + low dose meloxicam 
ER solution has been approved for bunionectomy, open inguinal herniorrhaphy, and total 
knee arthroplasty. Its efficacy has been described out to 72 hours due to a proprietary 
polymer design with prolonged elusion pharmacokinetics of its two primary ingredient 
reagents. The drug has been designed and manufactured by Heron Therapeutics (Heron 
Therapeutics, San Diego, CA) for use as a multimodal analgesic local analgesic during 
surgery. This medication was recently approved for formulary status in TKA at Mayo Clinic. 
Traceability will be maintained through standard institutional practice for formulary drugs 
administered during a patient’s hospitalization. The specific purpose of the use of this 
medication in this study is to evaluate whether it provides superior analgesia for 72 hours in 
comparison to our standard of care. This quality improvement initiative seeks to augment the 
care of our patients while concomitantly evaluating a new FDA approved medication in a 
non-industry sponsored randomized controlled trial for this purpose. This device will be used 
in patients who have consented for this research and do not have contraindications to 
receiving this medication during their indexed primary total knee arthroplasty. The goal is to 


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reflect our standard practice and observe whether this medication improves patient care. The 
drug is administered through a novel needle-free instillation into the joint prior to closure, as 
described in the drug manual. No specific training outside of knowledge of the user manual 
for the medication is required.  
5.1 
Method for Assigning Subjects to Treatment Groups 
 
A study coordinator will handle subject screening, recruitment, and informed consent in a 
patient’s preoperative appointment for indexed primary total knee arthroplasty. Upon 
enrollment, study patients will be assigned to the available study number.   
Subjects will be randomized into one of two study groups using dynamic allocation.  To 
ensure the study groups are balanced on subject demographics, the subjects will be stratified 
on sex, age group (≥70 vs. <70), and BMI (≥32 vs. <32).  Within each stratum, subjects will 
be assigned to either of the two study groups using a computerized dynamic allocation 
program housed in an online application developed by personnel in the Division of Clinical 
Trials and Biostatistics. Using dynamic allocation will ensure that the subject allocation will 
remain balanced on the stratification factors and the study group assignment throughout the 
entire subject accrual phase.  This computer-based randomization system will be username 
and password protected and available only to the study personnel. The study group 
assignment will be concealed from the patient in this single-blind study, as the surgeon will 
instill the medication intraoperatively and cannot be blinded to it given its unique method of 
needle-free administration. 
 


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5.2 
Preparation and Administration/Implantation of Investigational Device 
 
Bupivacaine +meloxicam ER formulation is intended for single dose administration only. 
The drug is applied without a needle into the surgical site following final irrigation and 
suction and prior to suturing. The recommended dose that we will incorporate is 14cc to 
deliver 400mg bupivacaine/12mg meloxicam. Following standard sterile practice, the 
prepackaged, sterile medication kit will be brought to the surgical field for instillation prior 
to closure. The medication is a viscous solution supplied as a kit consisting of single dose 
glass vial and the following sterile components: Luer Lock syringe, a vented vial spike, Luer 
Lock cone-shaped applicator(s) and syringe tip cap(s). Per the manufacturer’s complete 
prescribing information materials, the contents of the drug vial are sterile. The vial exterior is 
not sterile. We will follow standard institutional practice to sterilely prepare and administer 
this medication for surgery.   
 
For the control/standard of care group receiving our standard arthroplasty block cocktail, the 
surgeon will instill the medication as an injectate into the posterior capsule, and soft tissues, 
during closure.  
 
Per the manufacturer guidelines, the complete steps to prepare the medication are the 
following: https://www.zynrelef.com/prescribing-information.pdf 
 


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5.3 
Subject Compliance Monitoring 
 
Subjects are only required to complete and return pain diaries after surgery. Subjects who do 
not return a pain diary within 1 week after surgery will be contacted by the study coordinator. 
If a pain diary is never recovered that subject will require exclusion so as to avoid recall bias 
of delayed diary completion.  
5.4 
Prior and Concomitant Therapy 
 


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Subjects will receive perioperative analgesia, regardless of treatment group, with our 
standardized institutional Multimodal Analgesia Total Joint Pathway consisting of immediate 
or controlled-release oxycodone, celecoxib and acetaminophen, unless contraindicated. 
Intraoperative management will include the primary anesthesia type (which will be 
standardized to spinal anesthesia with a single adductor canal block consisting of 0.25% 
bupivacaine +/- epinephrine 10cc total, as deemed safe by the treating anesthesiologist), 
antiemetics, and supplemental analgesia as deemed necessary. No patients will receive 
Precedex, which is otherwise considered at the physician’s discretion as a component to 
MMA pathways at Mayo Clinic. All patients will receive a posterior stabilized (PS) total 
knee arthroplasty through a medial parapatellar approach, and all procedures will be 
performed by high-volume, lower-extremity arthroplasty surgeons at the Mayo Clinic 
Hospital, Methodist Campus in Rochester, Minnesota. 
 
5.5 
Packaging and Labeling 
 
This is an FDA approved pharmaceutical being evaluated as a quality improvement initiative 
against our institution’s current standard of care. Its label will be that which is provided 
through standard purchasing by the formulary team at Mayo Clinic Methodist Hospital from 
the manufacturer, Heron Therapeutics (San Diego, CA). 
5.6 
Masking/Blinding of Study 
 


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A study coordinator will handle subject recruitment and informed consent in a patient’s 
preoperative appointment for indexed primary total knee arthroplasty. Upon enrollment, 
study patients will be assigned to an available study number. Subjects will be randomized 
into one of two study groups using dynamic allocation.  To ensure the study groups are 
balanced on subject demographics, the subjects will be stratified on sex, age group (≥70 vs. 
<70), and BMI (≥32 vs. <32).  Within each stratum, subjects will be assigned to either of the 
two study groups using a computerized dynamic allocation program housed in an online 
application developed by personnel in the Division of Clinical Trials and Biostatistics. Using 
dynamic allocation will ensure that the subject allocation will remain balanced on the 
stratification factors and the study group assignment throughout the entire subject accrual 
phase.  This computer-based randomization system will be username and password protected 
and available only to the study personnel. The randomization assignment will be concealed 
from the patient in this single blind study, as the surgeon will instill the medication 
intraoperatively and cannot be blinded to it given its unique method of needle-free 
administration. 
5.7 
Receiving, Storage, Distribution and Return 
5.7.1 Receipt of Investigational Devices 
 
This is not an investigational device. It is on formulary at Mayo Clinic and will be available 
through the pharmacy for total knee replacement surgery. 


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5.7.2 Storage 
This medication should be stored at room temperature (20 deg C to 25 deg C. Once vials are 
removed from the kit, they must be stored at controlled room temperature protected from 
light.  
5.7.3 Distribution of Study Device 
The device will be instilled intraoperatively as a onetime dose in patients randomized to the 
treatment group.  
5.7.4 Return or Destruction of Study Device 
 
Not applicable.  
 
5.7.5 Cleaning/Sterilization Procedures (optional) 
Not applicable. 
 
6 Study Procedures 
6.1 
Entire study visit 
 
Schedule of Events 
Study Activity 
Pre operative 
Appointment 
 
Index 
Surgery 
 
Post 
Operative 


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(>72 
hours) 
Identification and Screening 
X 
 
 
Consent 
X 
 
 
History 
X 
 
 
Physical Exam/ review of radiographs 
X 
X 
 
Case Report Forms 
X 
X 
 
+/- Preoperative health visit (POE, PAME, 
etc) 
X 
 
 
Collection of pain diary by pre paid mail in 
postage (Study Coordinator to Assist) 
 
 
X 
 
The endpoint of pain out to 72 hours will be assessed by asking patients to record pain scores 
on a 11-point (0-10) scale every four hours after surgery beginning POD 1 at 8AM in a pain 
diary. The pain diary set up is designed to replicate standard nursing pain score measurement 
intervals following surgery, to ensure continuity of pain scores and ease of collection. The 
NRS selected for this study is designed to mimic the standard orthopedic nursing pain scales 
used while a patient is in the hospital. POD 0 pain scores will be collected for each patient 
from the medical record following standard nursing practice at our institution including early 
post-operative assessment within one hour on arrival to the PACU, and then gradually 
increased intervals until q4hour standard checks are reached for outpatients in a bed and 
inpatients. Additional outcome measures include opioid consumption during and after 
hospitalization converted to daily oral morphine equivalents documented by either anesthesia 
or the orthopedic nursing staff while patients are inpatient, and then through the patient’s 


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pain diary (#pills and dose per pill) once they leave the hospital. Hospital length of stay will 
also be noted. After 72 hours post-operative, patients will be instructed to return their pain 
diaries to the investigating team using pre-paid, pre stamped postage from which data will be 
recorded by the study coordinator.  
 
Standard monitoring for adverse events after total knee arthroplasty will be utilized. This 
includes monitoring for patient falls while hospitalized, nerve injury through routine 
neurovascular exams, surgical site infection through physical examination or unanticipated 
intensive care unit admissions and drug hypersensitivity reactions.   
7 Statistical Plan 
7.1 
Sample Size Determination 
It has been shown that a reduction of 30% in NRS pain scores is associated with a 
meaningful benefit12. Therefore, sample size calculations were performed to estimate the 
number of subjects needed to detect a difference of this magnitude or greater between the 
two study groups.  In a similar study4, patients undergoing total knee arthroplasty (TKA) that 
received  HTX-011 + ropivacaine had a mean area under the curve (AUC) pain score from 0 
to 72 hours of 452.5 with a standard deviation of 194.1.  A difference of 136 represents a 
30% change relative to 452.5. Enrollment of 250 subjects is anticipated to allow for subject 
non-compliance with completing or returning the diaries. However, assuming similar 
variability is observed in the above proposed study, only 44 subjects  with completed diaries 
per group (88 total) will be required to have 90% power to detect a difference of at least 136 
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To more accurately estimate the required study sample size, a small pilot study will be 
conducted to refine the above estimates. The study PI (MPA) will randomize 10 patients 
from his practice scheduled for primary TKA to either the study medication (n=5) or the 
standard medication (n=5). The medications used, procedures followed, and data collected 
will be identical to those outlined for the full RCT. The data from this pilot study will be 
used to refine the initial sample size estimate and will provide the final sample size 
determination for the RCT. However, the data from the pilot study will not be included in the 
full RCT analysis.  
7.2 
Statistical Methods 
All statistics for this randomized controlled trial will be performed by senior statistician, Dirk 
Larson, M.S. who has developed and approved the following statistical plan. The data will be 
reported descriptively using appropriate summary statistics, including means and standard 
deviations for continuous variables and counts and percentages for categorical variables. 
Where appropriate, outcomes will be reported with 95% confidence intervals. Because this is 
a prospective, randomized trial, no formal between-group comparisons of baseline covariates 
will be performed. The primary study outcome will be patient reported pain over 72 hours 
following total knee arthroplasty. Patients will record their pain on an 11-point scale (0-10 
numerical rating scale, NRS) at specified intervals over the 72-hour period.  For each patient, 
these pain scores will be used calculate the area under the curve (AUC) representing a single 
measure of pain experienced over the 72-hour period4,13.    The AUC will be calculated using 
the trapezoid rule14. Secondary outcomes will include the AUC for pain over the first 24 and 
48 hours, maximum pain reported, total post-operative opioid consumption (standardized into 


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MMEs), hospital length of stay, adverse reactions or events, distance walked with physical 
therapist prior to discharge. Outcomes measured on a continuous scale will be compared 
between the 2 study groups using two-sample t-tests if the data are sufficiently normally 
distributed; otherwise non-parametric Wilcoxon rank sum tests will be used. Ordinal variables 
will be analyzed using non- parametric Wilcoxon rank sum tests.  Binary and nominal 
categorical outcomes will be compared between the study groups using chi-square tests or 
Fisher’s exact tests, if low expected cell counts are observed. Analysis of the primary outcome 
(AUC0-72) will be analyzed both with and without accounting for the need for opioid rescue 
medication.  The former will be performed by substituting NRS pain scores during opioid 
rescue medication usage with the most recent NRS pain value prior to the time of opioid rescue 
medication use4. Since this is a prospective, randomized trial, subjects in the two groups are 
expected to be similar with respect to their baseline characteristics; therefore, no formal 
comparisons of baseline data will be performed. However, if it is determined that an adjusted 
analysis is warranted, this will be done using a general linear models framework. The primary 
analysis will be conducted using an intent-to-treat approach in which subjects will be analyzed 
in the groups they were randomized to, even if they actually received the intervention for the 
other study group.  All statistical tests will be two-sided, and the threshold of statistical 
significance will be set at α = 0.05. 
 
Handling of Missing Data 
If a subject’s pain diary is missing a recording of their pain level or opioid consumption at a 
particular four hour time point after POD 1, we will assess the quality of the rest of the data 
provided. If sufficient data is deemed available for inclusion, missing NRS pain scores will 


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be imputed using the last observation carried forward approach. Missing opioid consumption 
data will not be imputed.  If insufficient data is presented the subject will be excluded from 
the analysis. A sensitivity analysis will be conducted by performing the analysis of the 
primary outcome after excluding any subjects for whom any NRS pain scores were imputed.  
 
Multiplicity 
Given the study design and outcome definitions, multiplicity will not be an issue.  The serial 
NRS pain scores will be converted into a single measure of pain as the area under the curve 
(AUC) over the 72-hour period. All other outcomes will also be recorded as a single value 
for each subject. The analysis will entail comparison of the outcomes between the two study 
groups.  Therefore, there will be no analyses involving multiple comparisons.  
 
Primary Hypothesis:  
The primary research hypothesis is that subjects randomized to bupivacaine + meloxicam ER 
solution instilled periarticular at the time of total knee arthroplasty will have superior 
analgesia over the first 72 hours post-surgery compared to subjects randomized to standard 
arthroplasty block.  
 
This hypothesis will be tested by comparing the area under the curve (AUC) for numerical 
rating scale (NRS) of pain over the first 72 hours following surgery between the two study 
groups using two-sample t-tests if the data are sufficiently normally distributed, or non-
parametric Wilcoxon rank sum tests if a high degree of non-normality is observed.  The 
primary analysis will be conducted using an intent-to-treat approach in which subjects will be 


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analyzed in the groups they were randomized to, even if they actually received the 
intervention for the other study group. A secondary per-protocol analysis may also be 
performed. 
 
Secondary Hypothesis:  
The secondary research hypotheses include the following. 
• Subjects randomized to HTX-011 will have lower mean NRS pain score area under 
the curve from 0 to 48 hours post-surgery compared to subjects randomized to the 
standard arthroplasty block.  
• Subjects randomized to HTX-011 will have lower opioid consumption in the 72 hours 
post-surgery  compared to subjects randomized to the standard arthroplasty block.  
• Subjects randomized to HTX-011 will be able to walk farther - prior to discharge than 
subjects randomized to the standard arthroplasty block.  
The secondary hypotheses will be compared between the two study groups using two-sample 
t-tests; however, if the data are not sufficiently normally distributed for any of these 
outcomes, the comparisons will be performed using non-parametric Wilcoxon rank sum tests.   
 
Interim Analysis 
Inasmuch as patient accrual is expected to be rapid and the study follow-up period is only 3 
days post-surgery, an interim analysis is not likely to be beneficial. Therefore, no interim 
analysis will be performed.  


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7.3 
Subject Population(s) for Analysis 
All subjects randomized into this study, in either the treatment or standard of care group will 
enter this analysis.  Thus, the primary analysis will be performed using an intent-to-treat 
approach.  It is not anticipated that many patients will receive a different intervention than 
the one they are randomized to, but if this is the case, a secondary analysis may be performed 
using a per-protocol approach.  
 
8 Safety and Adverse Events 
 
All adverse events occurring during the study, including those not meeting the criteria of an 
Unanticipated Adverse Device Effect (UADE) will be recorded.  Records of these events will 
be maintained and reports submitted to the IRB according to the regulatory requirements.  
Expected clinical adverse events and nonsignificant (not serious) clinical adverse events will 
not be reported. Expected clinical adverse events and anticipated adverse device effects are 
those listed in Section 1.5.2. 
8.1 
Definitions 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device if that effect, problem or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or 


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IDE application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
 
Adverse Effect (Event) 
Any untoward medical occurrence in a subject involved in clinical study of an investigational 
device; regardless of the causal relationship of the problem with the device or, if applicable, 
other study related treatment(s). 
 
Associated with the investigational device: There is a reasonable possibility that the 
adverse effect may have been caused by the investigational device. 
 
Life-threatening adverse effect: Any adverse effect that places the subject, in the view of 
either the investigator or the sponsor, at immediate risk of death from the effect as it 
occurred.  It does not include a reaction that, had it occurred in a more severe form, might 
have caused death. 
 
Serious adverse effect: An adverse effect is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes:  
• death  
• a life-threatening AE 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacity 


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• a congenital anomaly/birth defect. 
 
Unanticipated adverse effect: Any adverse effect, the nature, specificity, severity, or 
frequency of which is not consistent with the risk information in the clinical study protocol or 
elsewhere in the current IDE application. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event will also be recorded and documented as an adverse 
event. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be 
documented and reported as an unanticipated adverse device effect unless specifically 
instructed otherwise in this protocol.  Any condition responsible for surgery should be 
documented as an adverse event if the condition meets the criteria for an adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as 
an adverse event in the following circumstances:  
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.   


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• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
 
Post-study Adverse Event 
Patients will follow up with their surgeon at standard intervals specific to their surgeons’ 
preference and the patient’s medical condition. If adverse events are identified, patients will 
be followed by their primary health care team.  
 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
will be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets all of the following three criteria: 
• 
Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: 
(1) death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, 
or prolonged; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, events, or new 


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information (i.e. publications, DSMB reports, interim findings, product labeling 
change) that in the opinion of the local investigator may adversely affect the rights, 
safety, or welfare of the subjects or others, or substantially compromise the research 
data, AND 
• 
Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• 
Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 
Adverse Event Reporting Period 
Adverse events associated with the study drug will be assessed as those events that have 
transpired during the 72 hour window following surgery.  
 
8.2 
Recording of Adverse Events 
 
No additional measures to collect adverse event information outside of 72 hours from surgery 
will be collected for this FDA approved medication. Patients will follow up with their 
treatment team as needed or as part of their consulting surgeons’ respective follow up 


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protocols. This medication is not investigational. It is FDA approved for TKA with expected 
analgesic effects out to 72 hours post-operative. 
  
 
 
8.3 
Sponsor-Investigator Reporting of Unanticipated Adverse Device Effects and 
Unanticipated Problems 
 
Not applicable to this FDA approved, on formulary medication. This is a quality 
improvement study assessing if this drug is superior to our current institutional practices. 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (long term 
survival status that the subject is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
 
Source data comprise all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, and 
data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification 
as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. When applicable, information 
recorded on the CRF shall match the Source Data recorded on the Source Documents. 
9.3 
Case Report Forms 
A Case Report Form (CRF) will be completed for each subject enrolled into the clinical 
study.  The investigator-sponsor will review, approve and sign/date each completed CRF; the 
investigator-sponsor’s signature serving as attestation of the investigator-sponsor’s 


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responsibility for ensuring that all clinical and laboratory data entered on the CRF are 
complete, accurate and authentic. 
 
 
 
 
Data Management 
Data will be compiled into a secure and password protected datasheet file for electronic 
storage. Study numbers will be assigned to each subject.  
 
Data Processing 
Data will flow from the coordinator who collects the pain diaries to the study investigators to 
Dirk Larson for analysis.  
 
Data Security and Confidentiality 
 
Patient study numbers will be assigned and they will be deidentified thereafter. A secure 
datasheet file will be used to store their information and endpoints will be updated after 
receipt of their pain diaries which may be associated with their patient ID number that is 
unique to them within the study.  
 
Data Clarification Process 
Not applicable  


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9.4 
Records Retention 
The sponsor-investigator will maintain records and essential documents related to the 
conduct of the study.  These will include subject case histories and regulatory documents. 
 
The sponsor-investigator will retain the specified records and reports during the study and for 
the longer of the following; 
1. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The Investigator will allocate adequate time for such monitoring activities.  The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all the study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The sponsor-investigator will permit study-related monitoring, audits, and inspections by the 
IRB, the monitor, and government regulatory agencies, of all study related documents (e.g., 
source documents, regulatory documents, data collection instruments, study data etc.).  The 


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sponsor-investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
 
Participation as a sponsor-investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study.  The decision of the IRB concerning the conduct of the study will be 
made in writing to the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for review 
and approval by the IRB for the study.  The formal consent of a subject, using the Approved 
IRB consent form, must be obtained before that subject undergoes any study procedure.  The 
consent form must be signed and dated by the subject or the subject’s legally authorized 
representative, and the individual obtaining the informed consent. 
 


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12 Study Finances 
12.1 Funding Source 
This study will be financed through a patient’s individual insurance to cover their surgery 
and course of care. Additional study fees will be incurred by funds that are supervised by Dr. 
Matthew P. Abdel. 
 
Conflict of Interest 
 
No member of the investigative team has a conflict of interest to disclose pertaining to this 
study drug of interest. 
 
13 Publication Plan 
 
Dr. Salmons and Dr. Abdel will oversee all phases of this study leading to its publication. 
They will be responsible for ensuring the results are published. This study will be registered 
on Mayo Clinic’s clinical trial’s website prior to subject recruitment and enrollment. Results 
will be posted within 12 months of final data collection for the primary outcome.  
 
 


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14 References 
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Yakkanti RR, Miller AJ, Smith LS, Feher AW, Mont MA, Malkani AL. Impact of early mobilization 
on length of stay after primary total knee arthroplasty. Ann Transl Med. 2019;7(4):69. 
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Molloy IB, Martin BI, Moschetti WE, Jevsevar DS. Effects of the Length of Stay on the Cost of 
Total Knee and Total Hip Arthroplasty from 2002 to 2013. J Bone Joint Surg Am. 
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Viscusi E, Gimbel JS, Pollack RA, Hu J, Lee GC. HTX-011 reduced pain intensity and opioid 
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Viscusi E, Minkowitz H, Winkle P, Ramamoorthy S, Hu J, Singla N. HTX-011 reduced pain 
intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the 
phase 3 EPOCH 2 study. Hernia. 2019;23(6):1071-1080. 
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Singla N, Winkle P, Bertoch T, Hu J, Beaton A, Redan J. Opioid-free recovery after 
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Lapmahapaisan S, Chinachoti T, Kongpatanakul S, et al. Plasma concentrations of bupivacaine 
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Assoc Thai. 2013;96(3):312-317. 
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Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment 
outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9(2):105-
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Mont MA, Beaver WB, Dysart SH, Barrington JW, Del Gaizo DJ. Local Infiltration Analgesia With 
Liposomal Bupivacaine Improves Pain Scores and Reduces Opioid Use After Total Knee 
Arthroplasty: Results of a Randomized Controlled Trial. J Arthroplasty. 2018;33(1):90-96. 
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Matthews JN, Altman DG, Campbell MJ, Royston P. Analysis of serial measurements in medical 
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