Clinical trial NCT05053087
Conditions: Osteoarthritis, Knee
Sponsor: Mayo Clinic
Start date: 2022-04-13; Completion date: 2023-02-27
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research is to study how well the adductor canal pain catheters works after a total knee arthroplasty or replacement of the knee joint. The catheter works by using either an intermittent bolus injection to provide a large dose of medication or continuous infusion of pain medicine, ropivacaine 0.2%, compared to a single-shot adductor canal block.

Detailed description:

Arms: arm 1: Subjects will have a catheter placed in the Post Anesthesia Care Unit following clinically indicated surgery with 0.2% ropivacaine dispersed in pulsed intermittent bolus. arm 2: Subjects will have a catheter placed in the Post Anesthesia Care Unit following clinically indicated surgery with 0.2% ropivacaine dispersed in a continuous infusion. arm 3: Subjects will have a catheter placed in the Post Anesthesia Care Unit following clinically indicated surgery with saline.
Interventions: intervention 1: Ropivacaine Continuous Infusion intervention 2: Ropivacaine Intermittent Bolus intervention 3: Placebo
Intervention descriptions: intervention 1: 0.2% continuous infusion 6mL/hr intervention 2: 0.2% intermittent bolus infusion 8mL every 2 hours intervention 3: Saline filled catheter

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A Three-Arm, Double-Blinded, Randomized Controlled Trial 
Comparing the Efficacy of Adductor Canal Pain Catheters 
Following Total Knee Arthroplasty 
 
NCT05053087 
 
December 13, 2022 


Adductor Catheter Efficacy Following Total Knee Arthroplasty  
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A Three-Arm, Double-Blinded, Randomized Controlled Trial 
Comparing the Efficacy of Adductor Canal Pain Catheters following 
Total Knee Arthroplasty  
 
 
Investigator(s): 
Principal Investigator: 
Benjamin Wilke MD   
Departments of Orthopedic Surgery  
Mayo Clinic Florida  
4500 San Pablo Road S 
Jacksonville, FL 32224 
 
Co-Principal Investigator 
 
Department of Anesthesia 
Mayo Clinic Florida 
4500 San Pablo Road S 
Jacksonville, FL 32224 
 
Co-Investigator 
 
Departments of Orthopedic Surgery  
Mayo Clinic Florida  
4500 San Pablo Road S 
Jacksonville, FL 32224 
 
Co-Investigator 
 
Department of Anesthesia 
Mayo Clinic Florida 
4500 San Pablo Road S 
Jacksonville, FL 32224 
 
 
 
Funding Sponsors: 
Pending 
 
 
 
Study Product: 
Adductor Canal Pain Catheter Dosing  
Protocol Number: (IRBe) 
 
 Pending 
 


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IND Number: 
N/A 
 
Initial version: 12/5/2020 Version (3.0)  
May 6, 2022 Version 3.1 
June 22, 2022 Version 3.2 
September 14, 2022 Version 3.3 
December 13, 2022 Version 3.4 
 
Table of Contents 
 
Study Summary 
6 
1 
Introduction 
7 
1.1 
Background 
7 
1.2 
Investigational Agent 
8 
1.3 
Clinical Data to Date 
8 
1.4 
Dose Rationale 
8 
1.5 
Risks and Benefits 
9 
2 
Study Objectives 
9 
3 
Study Design 
9 
3.1 
General Description 
10 
3.2 
Number of Subjects 
11 
3.3 
Duration of Participation 
11 
3.4 
Primary Study Endpoints 
12 
3.5 
Secondary Study Endpoints 
12 
3.6 
Primary Safety Endpoints 
13 
3.7 
Identification of Source Data 
13 
4 
Subject Selection Enrollment and Withdrawal 
14 
4.1 
Inclusion Criteria 
14 
4.2 
Exclusion Criteria 
14 
4.3 
Subject Recruitment, Enrollment and Screening 
14 
4.4 
Early Withdrawal of Subjects 
14 
4.4.1 
When and How to Withdraw Subjects 
14 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects 
15 
5 
Study Drug 
15 
5.1 
Description 
15 
5.2 
Treatment Regimen 
15 
5.3 
Method for Assigning Subjects to Treatment Groups 
15 
5.4 
Preparation and Administration of Study Drug 
15 
5.5 
Subject Compliance Monitoring 
15 
5.6 
Prior and Concomitant Therapy 
15 


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5.7 
Packaging 
15 
5.8 
Masking/Blinding of Study 
16 
5.9 
Receiving, Storage, Dispensing and Return 
16 
5.9.1 
Receipt of Drug Supplies 
16 
5.9.2 
Storage 
16 
5.9.3 
Dispensing of Study Drug 
16 
5.9.4 
Return or Destruction of Study Drug 
16 
6 
Study Procedures 
16 
6.1 
Visit 1 
16 
6.2 
Visit 2 
17 
6.3 
Visit 3 
17 
6.4 
Visit 4 
17 
7 
Statistical Plan 
18 
7.1 
Sample Size Determination 
18 
7.2 
Statistical Methods 
18 
7.3 
Subject Population(s) for Analysis 
19 
8 
Safety and Adverse Events 
19 
8.1 
Definitions 
19 
8.2 
Recording of Adverse Events 
20 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
21 
8.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB 
21 
8.3.2 
Sponsor-Investigator reporting: Notifying the FDA 
21 
8.4 
Unmasking/Unblinding Procedures 
21 
8.5 
Stopping Rules 
21 
8.6 
Medical Monitoring 
21 
8.6.1 
Internal Data and Safety Monitoring Board 
22 
9 
Data Handling and Record Keeping 
23 
9.1 
Confidentiality 
23 
9.2 
Source Documents 
23 
9.3 
Case Report Forms 
23 
9.4 
Records Retention 
24 
10 
Study Monitoring, Auditing, and Inspecting 
24 
10.1 
Study Monitoring Plan 
24 
10.2 
Auditing and Inspecting 
25 
11 
Ethical Considerations 
25 
12 
Study Finances 
25 
12.1 
Funding Source 
25 
12.2 
Conflict of Interest 
25 
13 
Publication Plan 
25 


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14 
References 
25 
 
 


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List of Abbreviations 
 
 
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 
IB 
Investigator’s Brochure 
 
 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
TKA 
Total Knee Arthroplasty  
OME  
 
            Oral Morphine Equivalents 
 
 
 
 


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Study Summary 
Title 
A Three-Arm, Double-Blinded, Randomized Controlled Trial 
Comparing the Efficacy of Adductor Canal Pain Catheters following 
Total Knee Arthroplasty  
 
Running Title 
Adductor Catheter Efficacy Following Total Knee Arthroplasty  
Protocol Number 
Pending 
Phase 
Phase III 
Methodology 
Double-Blinded Randomized Controlled Trial 
Overall Study 
Duration 
12 months 
Subject Participation 
Duration 
60 days, or until discontinuation of narcotic medication (whichever is 
later) 
Single or Multi-Site  
Single Center 
Objectives 
● Aim 1 will be to compare postoperative pain levels between 
groups 
● Aim 2 will be to compare use of the patient-administered dosing 
between groups 
● Aim 3 will be to compare duration of narcotic use between 
groups 
 
Number of Subjects 
84 
Diagnosis and Main 
Inclusion Criteria 
Narcotic naïve patients who have a diagnosis of osteoarthritis and are 
undergoing a primary total knee arthroplasty are eligible for the study.  
Study Product, 
Dose, Route, 
Regimen 
This study will evaluate the efficacy of adductor canal pain catheters 
following total knee arthroplasty, using either an intermittent bolus or 
continuous infusion compared to a single-shot adductor canal block.    
Duration of 
Administration 
4 days 
Reference therapy 
Single-shot adductor canal block 
Statistical 
Methodology 
Statistical analysis will be performed on the basis of the intention to 
treat principle.  Comparisons between treatment groups will be made 
using Wilcoxon rank sum test or Fisher’s exact test.  
 
 
 


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1 Introduction 
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
1.1 
Background 
 
There has been a rapid rise in opioid consumption and deaths in the United States (US) due to 
opioid use and abuse. In 2017 the Center for Disease Control (CDC) estimated that 72,000 
deaths were related to drug overdose, with a large proportion of these stemming from 
prescription medications. This rate was an approximate two-fold increase over the previous 
decade and does not include an additional 2 million who are estimated to suffer from a substance 
abuse disorder related to opioid medications.1,2 The high rate of opioid over-prescription 
following surgery is thought to contribute to the current epidemic.3 In 2014 the National Survey 
on Drug Use and Health estimated that more than 10 million people in the United States used 
opioids outside of their prescribed intent, and that 55% of the medication was obtained from a 
friend or relative.4 Therefore, mitigating the amount of narcotics available for diversion is 
particularly important in order to help combat the opioid crisis. 
 
Orthopedic surgeons are the third highest opioid prescribers (Combatting Opioid Misuse. 2017. 
https://www.aaos.org/AAOSNow/2017/Jun/YourAAOS/youraaos10/?ssopc=1). Previous work 
demonstrated that surgeons prescribe three times the narcotics required by the patient and that 
most patients do not properly dispose of leftover medication.5-8 Additionally, in a separate study, 
13% of narcotic naïve patients became prolonged opioid users following elective orthopedic 
procedures.9 There is a critical need to find alternative approaches to postoperative pain 
management that rely less on narcotic medication.  
 
We previously reported on risk factors for patients requiring additional opioid prescriptions 
following surgery and have demonstrated that a collaborative approach between the anesthesia 
and orthopedic teams, utilizing both local and regional nerve blocks, reduced pain scores with a 
simultaneous 43% decrease in oral morphine equivalents consumed during the 
hospitalization.10,11 Additional studies have focused on multimodal pain regimens, but have not 
evaluated the efficacy of these regimens with adductor pain catheters.12-17 We recently performed 
a randomized, prospective, double-blinded, placebo-controlled trial using a multimodal regimen 
with and without schedule II opioids following total knee arthroplasty. In that study we utilized 
an adductor canal pain catheter with a continuous infusion for four days postoperatively. We 
demonstrated equivalent postoperative pain scores in the oxycodone and placebo group with use 
of the adductor catheter. However, despite these similar pain scores, 20% of the oxycodone 
cohort required continued narcotic medication at 60 days postoperatively (submitted for 
publication).  
 
It is currently unknown if a continuous infusion is the most efficacious form of medication 
delivery through the catheter. Recent studies have begun to evaluate intermittent bolus infusions, 
with the belief that catheter placement is less critical when compared to a continuous infusion. 


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Our study is intended to directly compare these delivery modes in a double-blinded, randomized 
controlled trial.  
1.2 
Investigational Agent 
 
This study is not evaluating a specific drug, but rather the safety and efficacy of delivery modes 
for an adductor canal pain catheter following total knee arthroplasty.  
1.3 
Clinical Data to Date 
 
Research has focused on prescribing practices, demonstrating the risks of long-term opioid use 
with large initial prescriptions.5,8,20  This has led hospitals to develop institutional guidelines to 
reduce excessive prescriptions of narcotics following routine surgical procedures. For example, 
Wyles et al. demonstrated a reduction in the average oral morphine equivalents (OMEs) prescribed 
at discharge from 750 to 388 following total joint arthroplasty, after departmental adoption of 
standard prescribing guidelines. Interestingly, the authors reported no increase in refill rates, 
suggesting that the change largely reduced the amount of unused medication.21   
  
At our own center we reported that the number of OMEs prescribed at discharge was not predictive 
of patients requesting a refill of their medication. We instead found that patients with lower pain 
scores on postoperative day #1, but not postoperative day #2, had a lower risk of requiring a refill 
of their pain medication.11 We hypothesized that patients who developed an early reliance on 
narcotics would be harder to wean from the medication and be at a greater risk of long-term opioid 
use. Due to this we began to utilize an adductor canal pain catheter for total knee arthroplasty 
patients to provide improved pain control early in the postoperative period. Following adoption of 
the adductor canal catheter we reported a subsequent 43% decrease with in-hospital narcotic use.10 
Building upon this we then completed a prospective, randomized, double-blinded, placebo-
controlled trial comparing our multimodal regimen with and without schedule II narcotics 
(oxycodone). In that study we demonstrated equivalent pain scores between the narcotic and 
placebo group when using a continuous infusion adductor canal pain catheter. The narcotic group, 
however, had a higher proportion of patients that required pain medication at 60 days 
postoperatively (submitted for publication). 
 
Our goal is to expand upon our previous work and evaluate the safety and efficacy of differing 
modes of medication delivery with the adductor catheter in order to further optimize postoperative 
pain control (Aim 1). It is hypothesized that intermittent bolus infusions of the medication will 
provide improved pain control when compared to a continuous infusion due to the ability to more 
completely saturate the surrounding anatomy in cases where the catheter is not placed in the 
optimal location adjacent to the nerve. We additionally intend to compare the use of patient-
administered dosing (Aim 2) and overall duration of narcotic use between cohorts (Aim 3).   
 
 
 
1.4 
Dose Rationale  
 


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The dosing of the medications are all currently used following joint replacement procedures.  
 
1.5 
Risks and Benefits 
 
The benefits of the study will be to evaluate the efficacy of the differing modes of medication 
delivery through the adductor canal pain catheter. If optimized, we believe this will allow us to 
continue to reduce the amount of narcotic medications prescribed following orthopedic surgery.  
 
All components of the multimodal pain regimen are currently safely used in orthopedic patients.  
There is a theoretical risk of renal damage or GI upset with the use of anti-inflammatory 
medications, but we have not seen this with our total knee study. There is also the possibility that 
patients will have uncontrolled pain following surgery. These patients will have IV narcotic 
medication as a safety net during their hospitalization and will be able to utilize our standard 
opioid regimen upon discharge.  
 
2 Study Objectives 
Primary Objective 
 
The primary objective will be to compare postoperative pain levels between the treatment groups, 
using the Numerical Rating Scale (NRS).  
 
 
Secondary Objective 
 
The secondary objectives will be to compare the amount of patient-administered medication use 
between groups as well as duration of narcotic use between groups.  
 
3 Study Design 
 
This project will be conducted as a three-arm double-blinded, randomized controlled trial 
comparing differing modes of medication dispersion using the adductor canal pain catheters. The 
three arms will be a single shot adductor canal block (with saline filled catheter) compared to 
ropivacaine 0.2% continuous infusion, and ropivacaine 0.2% intermittent bolus infusions. 
Treatment groups will be assigned to patients using computer-based randomization via the 
dynamic allocation method of Pocock and Simon. Subjects will be screened in the outpatient clinic 
setting and those interested and eligible will be consented and enrolled in the trial.  
 
A total of 84 patients will be enrolled in this study. Twenty eight patients will be in each 
comparison group. After enrollment patients will undergo randomization by the research 
pharmacy in order to maintain blinding of the surgical team, nursing staff, and patient. The patient 
will then undergo their surgical procedure and receive a multi-modal pain regimen as described 
below. All treatment groups will receive the same regimen with the exception of the adductor canal 
catheter. All of the patients will have the catheter placed in the Post Anesthesia Care Unit following 


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surgery and bolused with 10 mL of 0.5% ropivacaine. The pumps will be loaded with saline (single 
shot adductor canal group), or ropivacaine 0.2%, dispersed in either a continuous infusion (6 
mL/hr) or pulsed intermittent bolus (8 mL every 2 hours). All groups will have a patient demand 
dose of 6 mL/hr for anterior knee pain. The medication for the adductor catheter will be dispersed 
to the anesthesia team by the research pharmacy. The anesthesia team will place the catheter under 
ultrasound guidance in the recovery room. They will adjust the delivery mode based on patient 
randomization. The anesthesia team will record the serial number of the pump at the time of 
placement. 
 
Questionnaires will be sent electronically to the patient. Results will be collected daily for 14 
days postoperatively, followed by weekly questionnaires until they discontinue narcotic 
medications. Additional questionnaires will be collected at 30 and 60 days postoperatively in 
order to record pain and KOOS Jr. scores. The questionnaires will be sent in the morning; if a 
patient fails to fill out the questionnaire by the afternoon, a member of the research team will 
contact the patient to obtain the data. The questionnaires will document numerical rating scale 
(NRS) pain scores, information on symptoms of nausea, vomiting, and constipation, and will 
inquire if the patient is still consuming narcotic medication.  
 
Following discontinuation of the catheter the patient will remove and return the device to the 
supplier. The supplier will then provide the rate of on-demand usage to the research team by way 
of device serial number. This information will be stored in Redcap.  
 
Subjects will be withdrawn prior to completion if they ask to be removed from the study. They 
may also be withdrawn from the study if they have a serious adverse reaction to one of the 
prescribed medications. Finally, subjects may be withdrawn at the discretion of the treating 
physician. If subjects are withdrawn early their last recorded pain score will be carried forward 
until study conclusion in order to perform intention to treat analysis. The study will continue to 
ascertain duration of narcotic use with weekly questionnaires, until the patient has stopped the 
medication. 
3.1 
General Description 
 
Patients will receive the following multi-modal pain regimen in addition to the adductor canal 
pain catheter.  
 
Preoperative (All patients receive the following in the pre-op holding): 
Acetaminophen 1000 mg oral 
Celebrex 400 mg oral 
Dexamethasone 10 mg IV 
 
Intraoperative (All patients receive the following): 
Periarticular block   
● Ketorolac 30 mg with weight-based ropivacaine and epinephrine, diluted in normal saline 
to a total volume of 120 mL (50-74.9 kg – ropivacaine 200 mg, epinephrine 0.1 mg), (75 
– 99.9 kg – ropivacaine 300 mg, epinephrine 0.2 mg), (100 kg and greater – ropivacaine 
400 mg , epinephrine 0.3 mg).  


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Postoperative: 
Adductor canal pain catheter (saline or ropivacaine)  
Acetaminophen 1000 mg oral every 6 hours scheduled  
Tramadol 50 mg oral every 6 hours as needed 
Dexamethasone 10 mg IV scheduled daily while hospitalized (max 3 days) 
Toradol 10 mg oral every 6 hours scheduled daily while hospitalized (max 3 days)  
Oxycodone 5 mg every 3 hours as needed for pain  
Dilaudid 0.5 mg IV push every 3 hours as needed for pain > 8 on VAS score 
 
Discharge: 
Acetaminophen 1000 mg oral every 6 hours scheduled (x2 weeks) 
Tramadol 50 mg oral every 6 hours as needed for pain  
Celebrex 400 mg oral scheduled daily (x2 weeks) 
Oxycodone 5 mg every 3 hours as needed for pain  
 
At the time of discharge, medications will be filled for two weeks. Patients will report their 
pain scores during this time via electronic and phone surveys. If additional pain medications 
are required these will be filled per the treating physician’s discretion.  
 
3.2 
Number of Subjects 
 
Twenty eight patients will be recruited into each arm, for a total of 84 patients. This will serve as 
a pilot study to determine feasibility. 
 
3.3 
Duration of Participation 
 
Results will be collected daily for 14 days postoperatively, followed by weekly questionnaires 
until patients discontinue narcotic medication. Additional questionnaires will be collected at 30 
and 60 days postoperatively in order to record pain and KOOS Jr. scores. 
 


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3.4 
Primary Study Endpoints 
 
The primary endpoint will be pain scores, calculated by the Numerical Rating Scale. This score 
will be collected daily during the hospital examination and by online or phone surveys after 
discharge. We will calculate the mean difference in recorded pain scores between cohorts. We 
hypothesize that the intermittent bolus infusion cohort will report improved pain scores compared 
to continuous infusion catheters.  
3.5 
Secondary Study Endpoints 
 
The secondary endpoints will be the amount of medication administered via the patient-controlled 
function on the adductor catheter as well as duration of narcotic use required in each cohort. We 
hypothesize that the intermittent bolus cohort will require fewer doses of patient-administered 
medication and will use narcotic medication for a shorter duration when compared to the 
continuous infusion and placebo groups.   
 
We will additionally calculate the overall morphine equivalents used in each cohort during their 
hospitalization, and dividing this by the total number of post-surgical hospitalization hours in order 
to normalize the data.  
 
Nausea and vomiting will be recorded daily using the postoperative nausea and vomiting scale and 
compared between groups. Presence of constipation will be a subjective rating by the patient that 
is also recorded daily. We will compare the post-surgery length of hospitalization between groups. 
Finally, we will compare patient-reported outcomes using the KOOS Jr. questionnaire.  
 


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We hypothesize that the intermittent bolus cohort will use less narcotic mediation and will 
therefore have lower rates of constipation, nausea and vomiting. Furthermore, we believe this 
cohort will demonstrate equivalent lengths of stay and patient-reported outcomes as compared to 
the comparison groups.  
 
3.6 
Primary Safety Endpoints 
 
If patients report serious adverse side effects from a medication in the multi-modal regimen, or if 
they report uncontrolled pain, they will be withdrawn from the study and provided alternative 
medication per the treating surgeon’s discretion.  
 
3.7 
Identification of Source Data 
 
The following source data will be directly recorded on the Case Report Form (CRF) at the pre-op 
visit and inputted into REDcap, a password protected database. 
● Name 
● Medical Record Number 
● Email address 
● Date of Birth, Age 
● Gender 
● Race 
● Weight (lbs), Height (In), BMI 
● Previous surgeries? (yes, no) 
● Are you taking Nsaids? (yes, no) 
● Previous injections (yes, no) 
● Baseline NRS score  
● Laterality of surgery 
● KOOS Jr. Questionnaire 
● Device serial number  
 
 
The following source data will be recorded daily for two weeks using an online questionnaire 
recorded into REDcap, and continued weekly until discontinuation of narcotic medication. This 
data will again be collected at 30 and 60 days following the date of surgery.  
 
● Name 
● Medical Record Number 
● Date of Birth 
● How long has it been since your operation? (Less than 1 month, 1-2 months, Greater than 
2 months) 
● Are you using narcotic medication? (yes/no) 
o What was the date you last consumed narcotic medication? (if no to previous 
answer) 
● How would you rate the pain you have been experiencing? (0-10) 


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● Have you been experiencing constipation over the past 24 hours? (yes, no) 
● Have you been vomiting or had dry-retching over the past 24 hours? (once, twice, three 
or more times, no) 
● Have you been experiencing a feeling of nausea (an unsettled feeling in the stomach and 
slight urge to vomit) over the past 24 hours? (yes, no) 
● KOOS Jr. Questionnaire (only recorded during 1 month and 2 month questionnaires) 
● Rate of on-demand catheter use (recorded at final survey only) 
 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
 
1. Age > 18 and < 90 years. 
2. Willing to participate in the study and competent to provide informed consent.  
3. Willing to comply with protocol procedures. 
4. Has an underlying diagnosis of osteoarthritis indicated for a total knee arthroplasty. 
4.2 
Exclusion Criteria 
 
1. The patient must not have taken a schedule II narcotic daily, for 7 consecutive days, during 
the 3 months leading up to the surgery  
2. The patient must not be allergic or intolerant to a medication used in the multimodal pain 
pathway 
3. Revision knee arthroplasty 
4. Uncontrolled diabetes with A1C > 8.0 %  
5. Pregnant patients 
4.3 
Subject Recruitment, Enrollment and Screening 
 
Subjects will be identified and enrolled from the principal investigator and co-investigator’s 
clinical practices. If the patients are eligible for the study and wish to participate then they will 
be enrolled.  
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
 
Subjects will be withdrawn from the study prior to completion if they ask to be removed from 
the study. They will also be withdrawn if they do not complete the protocol requirements or have 
a serious adverse reaction to one of the medications in the multi-modal regimen. Finally, subjects 
may be withdrawn from the study at the discretion of the treating physician.  
 


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4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
If subjects are withdrawn from the study prior to completion we will collect the data prior to 
withdrawal. At the conclusion of the study we will note the number of subjects that were 
withdrawn from the study as well as the reasons for withdrawal.  
5 Study Drug  
5.1 
Description 
 
See section 3.1 for the multi-modal pain regimen that will be used. 
 
5.2 
Treatment Regimen 
 
See section 3.1 for the multi-modal pain regimen that will be used. 
  
5.3 
Method for Assigning Subjects to Treatment Groups 
 
Patients will undergo computer randomization by the research pharmacy prior to dispensing the 
medication in order to ensure that the treating physician (surgeon) remains blinded to the study.  
5.4 
Preparation and Administration of Study Drug 
 
The medication that will be loaded in the adductor catheter will be dispensed by the research 
pharmacy to the anesthesia team to ensure blinding of the surgical team.  
 
5.5 
Subject Compliance Monitoring 
 
Patient compliance during the hospitalization will be tracked by the surgical team. Following 
discharge patients will be contacted daily for 2 weeks, followed by weekly questionnaires until 
they have discontinued all narcotic medication.  
 
5.6 
Prior and Concomitant Therapy 
 
If a patient has taken a narcotic medication (schedule II) in the 3 months leading up to surgery 
they will be excluded from the study. Patients may request and be provided refills for narcotic 
medication at the discretion of the treating surgeon. 
 
5.7 
Packaging 
 


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The medication will be provided by the research pharmacy and dispensed to the anesthesia team 
for loading into the adductor canal pain catheter. This will be secured until the medication is 
fully dispensed.  
 
5.8 
Masking/Blinding of Study  
 
This will be a double-blinded study. Computer randomization will be used for patient grouping 
and the research pharmacy will dispense the medication to the anesthesia team, who will set the 
adductor catheter dosing based upon randomization. The surgical team and patient will remain 
blinded to the medication and dosing regimen.   
5.9 
Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
 
Not applicable 
5.9.2 Storage 
 
Once dispensed to the anesthesia team, the medication will be loaded into the adductor canal 
catheter, which will be secured until the medication is fully dispensed. 
 
5.9.3 Dispensing of Study Drug 
 
The adductor catheter settings (continuous versus intermittent bolus infusions) will be selected 
by the anesthesia team, based upon patient randomization. This information will be provided to 
the anesthesia team by the research pharmacy in order to maintain blinding of the surgical team. 
 
5.9.4 Return or Destruction of Study Drug 
 
After the medication has been fully dispensed (postoperative day #4), patients will remove the 
adductor catheter and send the pump to Avanos for processing.  
 
6 Study Procedures 
 
6.1 
Visit 1 
 
At visit #1 patients will be screened for eligibility for inclusion in the study. If agreeable, an 
informed consent will be signed.  


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6.2 
Visit 2 
Patients will undergo standard preoperative clearance testing. 
6.3 
Visit 3 
Patients will then proceed with the total knee replacement procedure. During the hospitalization 
we will record daily pain, nausea, vomiting, and constipation levels. Following the hospitalization 
these values will continue to be recorded daily utilizing an online questionnaire. If patients fail to 
complete the questionnaire then we will contact the patient via phone to record the daily value.  
6.4 
Visit 4 
At 2 weeks the patients will return for a standard postoperative visit.  The patient will then 
receive an online questionnaire weekly until they discontinue narcotic medication. They will 
receive additional surveys at 30 and 60 days following surgery.    
 
 
 
 
 
 
 
 
 
 


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7 Statistical Plan 
7.1 
Sample Size Determination 
 
Twenty eight patients will be recruited into each arm, for a total of 84 patients. This number has 
been chosen for feasibility rather than based on a formal power analysis. We will use this study 
to provide data for a formal power analysis in order to power a larger study.  
 
7.2 
Statistical Methods 
 
Descriptive and Inferential Statistics 
 
Continuous variables will be summarized with the sample mean, median, standard deviation, 
minimum, 25th percentile, 75th percentile, and maximum. Categorical variables will be summarized 
with number and percentage of patients. All analysis will be performed on the basis of the 
intention-to-treat principle. Comparisons of endpoints between the three treatment arms will be 
made using a Wilcoxon rank sum test (continuous or ordinal endpoints) or Fisher’s exact test 
(categorical endpoints).  Missing data will be imputed using either the last observation carried 
forward method, a regression-based approach, or another method, depending on the extent of 
missing data. In order to adjust for the three pair-wise comparisons between treatment groups that 
will be made for each endpoint, we will utilize a Bonferroni correction for multiple testing, after 
which p-values of < 0.0167 will be considered as statistically significant. All statistical tests will 
be two-sided.  
 
Primary Hypothesis:   
 
We hypothesize that the intermittent bolus infusion cohort will report improved pain scores 
compared to continuous infusion catheters and placebo cohorts.  
 
Secondary Hypothesis:   
 
We hypothesize that the intermittent bolus cohort will require fewer doses of patient-administered 
medication and will use narcotic medication for a shorter duration when compared to the 
continuous infusion and placebo groups.   
 
Interim Analysis 
 
We will evaluate the first twenty patients. If 50% of the patients are withdrawn from the study 
for poor pain control or serious adverse reactions to the study medication, then we will close the 
study early.  
 


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7.3 
Subject Population(s) for Analysis 
All patients who completed the study will be included in the final analysis. Additionally, we will 
note patient withdrawal rates as well as the reasons for patient withdrawal.  
8 Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets 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 information (i.e. 
publications, 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 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
● death 
● life threatening adverse experience 
● hospitalization 
● inpatient, new, or prolonged; disability/incapacity 
● persistent or significant disability or incapacity 
● birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 
 
 


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All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
 
For this study the follow-up period is defined as 2 weeks following the surgical procedure.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
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 must also be recorded and documented as an adverse 
event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the sponsor-investigator should instruct each subject to report, to the sponsor-
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if the post-treatment 
liver or renal function labs demonstrate a significant elevation from the recorded baseline value.  
 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event 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: Elective surgical procedures. 
8.2 
Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event section of the case report form (CRF). All clearly related signs, symptoms, and abnormal 
diagnostic, laboratory or procedure results should recorded in the source document. 
 


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All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up, to determine the 
final outcome.  Any serious adverse event that occurs during the Adverse Event Reporting 
Period and is considered to be at least possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event Worksheet 
and log.  The sponsor-investigator will evaluate the event and determine the necessary follow-up 
and reporting required. 
 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 
 
 
8.3.2 Sponsor-Investigator reporting: Notifying the FDA 
 
Not applicable.  
 
8.4 
Unmasking/Unblinding Procedures 
 
If patients are withdrawn early from the study they will be unblinded at that time.  
 
8.5 
Stopping Rules  
 
Subjects will be withdrawn from the study if they have a serious adverse reaction to any of the 
study drugs. Additionally, if patients are unable to complete the follow-up questionnaires they 
will be withdrawn. If patient’s pain increases during the study period that is not tolerable without 
additional narcotic medication they will be withdrawn. Finally, we will withdraw patients from 
the study that no longer wish to participate.  
 
8.6 
Medical Monitoring 
 


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It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
8.6.1 Internal Data and Safety Monitoring Board 
 
Subject Safety 
Specific subject safety parameters include the following information: For the first twenty patients 
in the study, patients will return to the clinic at the two-week postoperative appointment. 
Documentation will include levels of pain at the site and any other concerns expressed by the 
patient. The patients will be assessed for any adverse reaction. This data will be submitted to the  
sponsor for review and the study will continue enrolling additional patients. Adverse events which 
would result in possible termination of the study include death, life-threatening adverse 
experience, patient hospitalization due to drug effects, disability and/or incapacity. 
 
For patients #21 through #84, the subject will be instructed to call the orthopedic department to 
report any concerns. If the patient has any concerns about a potential adverse reaction, the patient 
will be promptly seen in the orthopedic clinic.  
 
Data Integrity 
Data elements to be reviewed include subject inclusion criteria being met and that the transcription 
of data is accurate and complete.  Data elements will be reviewed at a minimum of every 20 
patients being collected by the research coordinator and principal investigator. 
 
Subject Privacy  
  
Consenting will take place in the orthopedic department. They will be informed of the study and 
given the opportunity to be consented to participate.  Consent to participate in the study will only 
be attempted once. 
 
Data Confidentiality  
 
Hard copy data such as consent forms will be stored in locked file cabinets; electronic data will be 
stored in our secure web-based database (REDCap) that will be designed with the help of the 
statistician.  
 
Product Accountability  
All portions of the multimodal regimen are commercially available.   
 
 
Study Documentation 
Study file management system as directed by the Study File Management Checklists for FDA-
Regulated Studies will be utilized where applicable. 


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Study Coordination  
Debriefing will be performed after the first 20 patients to determine if expectations are clear and 
if educational needs exist. Scheduled meetings will be sent out via departmental email, and 
meeting outcomes are noted and available to staff. 
 
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.  
 
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 is 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. 
9.3 
Case Report Forms 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  Do not erase or use “white-out” for errors.  For clarification 
of illegible or uncertain entries, print the clarification above the item, then initial and date it.  If 


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the reason for the correction is not clear or needs additional explanation, neatly include the 
details to justify the correction. 
 
 
Data Management 
 
Data will be verified by the investigator after each subject visit, then entered into REDcap 
database. 
 
Data Processing 
 
REDcap data will be exported into statistical software and analyzed. 
 
 
Data Security and Confidentiality 
 
All data will be stored on password and access protected shared drives. These drives contain 
archives with audit trails indicating the date, time, and person ID when the data is accessed. The 
patient information will be de-identified through the use of study IDs.  
 
Data Quality Assurance 
 
Data quality is checked during the archiving and organization process. Paper data is reviewed 
prior to scanning and e-filing. 
 
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 as outlined in the Mayo 
Clinic Research Policy Manual –“Retention of and Access to Research Data Policy” 
   
 
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. 
 


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10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an 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 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. 
 
12 Study Finances 
12.1 Funding Source 
 
Pending 
 
12.2 Conflict of Interest 
 
None of the investigators claim any relevant conflicts of interest in this study.  
13 Publication Plan 
 
We have no publication policy requirements for this study.  
14 References 
 


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