Conditions: Arthroplasty, Replacement, Knee
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 75
Healthy volunteers: no

Brief summary:
The primary aim of this pilot study will be to develop a clinically meaningful, patient-centric, and pragmatic protocol to evaluate the comparative effectiveness of different strategies for achievement of the ideal balance between analgesia and functional mobility following total knee arthroplasty (TKA).

Detailed description:
Pain management for total knee replacement (TKR) patients has evolved rapidly over the previous decade. The most recent advances in anesthesia include peripheral nerve blockade, which offers the promise of earlier postoperative mobilization in addition to effective pain relief. The rapidity with which these advancements have been adopted seems to have outpaced the science to support them. The result has been the institution of countless combinations of perioperative pain management strategies in centers nationwide with little standardization, consistency, or objective evidence. The extent to which these various strategies achieve safe and effective perioperative pain control or functional preservation remains poorly defined. This prospective randomized control trial will aim to identify meaningful patient-centric outcome measures, differentiate from among three perioperative TKR anesthetic and analgesic strategies, and provide a template for interdisciplinary collaboration among orthopedic surgeons, anesthesiologists, physical therapists, and patients. With the knowledge gained further study will continue to refine the most optimal early pain control protocol.

All primary TKR patients undergoing surgery at the Medical University of South Carolina who are able to receive spinal anesthesia will be randomized prior to surgery to one of three forms of lower limb nerve blockade: 1) Continuous femoral nerve catheter plus single injection sciatic nerve block, 2) Adductor canal catheter plus selective tibial nerve block, 3) Adductor canal catheter alone. All patients will receive additional standardized pain medications as well as early mobilization with physical therapy. The primary outcome measure will be postoperative visual analog pain scale (VAS), with secondary measures to include validated patient-reported outcome measures, objective functional measures (timed-up-and-go (TUG), patient satisfaction scores, length of stay, discharge disposition, and complications. The investigators plan to enroll approximately 90 patients. This will allow us to reach our randomization goal of at least 75 patients while taking into account withdrawals. The 75 patients will be randomized into the three treatment three treatment arms over a 6-month recruitment period, with a 3 month follow-up for patient reported outcome and satisfaction data. A focus group will facilitate patient engagement and provide information for generation of a preference survey to guide future study design.

Arms:
arm 1: Femoral nerve catheter and sciatic nerve block arm 2: Adductor canal catheter and selective tibial block arm 3: Adductor canal catheter only

Interventions: intervention 1: Femoral nerve catheter and sciatic nerve block intervention 2: Adductor canal catheter and selective tibial block intervention 3: Adductor canal catheter only
Intervention descriptions: intervention 1: This nerve block is believed to cause both muscle weakness and numbness. A catheter remains in place for up to 36 hours after surgery for the purpose of adding additional medication should the patient require it. This technique causes both the front and the back of the knee to be numb. intervention 2: This nerve block is believed to cause numbness only, without any muscle weakness. A catheter remains in place for up to 36 hours after surgery for the purpose of adding additional medication should the patient require it to control pain. This technique causes both the front and the back of the knee to be numb. intervention 3: This nerve block is believed to cause numbness only, without any muscle weakness. A catheter remains in place for up to 36 hours after surgery for the purpose of adding additional medication should the patient require it. This technique causes only the front of the knee to be numb

Protocol document:
Prot_000.pdf: 
Version 7/13/2016 
 
 
1 of  12 
 
 
 
 
 
PI Name:  Jacob M Drew MD  
 
Study Title:   Randomized Comparative Effectiveness Trial of 
Anesthesia/Analgesia Techniques for Primary Total Knee Arthroplasty (TKA) 
.  
 
TABLE OF CONTENTS –  
Specific Aims 
 
 
 
 
1 
Background and Significance 
 
 
2 
Preliminary Studies/Experience  
 
2 
Research Design and Methods 
 
 
3 
Protection of Human Subjects 
 
 
5 
References  
 
 
 
 
9 
 
 
A. SPECIFIC 
AIMS____________________________________________________________
_______________ 
The primary aim of this pilot study will be to develop a clinically meaningful, patient-
centric, and pragmatic protocol to evaluate the comparative effectiveness of different 
modalities for achievement of the ideal balance between analgesia and functional mobility 
following total knee arthroplasty (TKA).  
 
We propose a study by which focused patient-centered inquiry will quantify the 
relative value of various outcome measures believed to be most meaningful to this patient 
population.  Emphasis on patient experience and guided reflection combined with 
objective data will establish the optimal methodology for comparing different techniques 
of perioperative analgesia. We will identify those outcome measures that most accurately 
reflect the overall patient experience as well as the clinical result.  Patient input has been 
conspicuously absent from previously published work on this topic, and we propose a 
mechanism by which the patients in cooperation with the investigators will guide the 
research, and ultimately clinical care. 
In addition to applying a patient-centric perspective towards the identification of 
meaningful outcome measures, we intend to establish the feasibility and cost-
efficiency of our study design and protocol.  Ease of implementation, and seamless 
integration of clinical measures and data collection into routine workflow is necessary in 
order for the protocol to be attractive to other centers as part of a future multi-center 
trial. Previous orthopaedic surgery randomized controlled trials have set the precedence 
that such studies can be completed in an economical manner when such aspects of design 
are carefully considered(21).  Through promotion of collaborative relationships between 
and continued engagement of the orthopaedic, anesthetic, nursing, and postoperative 
rehabilitative teams, the final protocol will allow all participants – care givers and patients 
alike - to feel invested and unburdened by the process.  
 
Though the primary goals of the project pertain to establishment and application of 
proper scientific methodology to the clinical query addressing the most efficacious method 
Medical University of South Carolina 
Protocol 


Version 7/13/2016 
 
 
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of perioperative analgesia for TKA patients, we do expect to produce clinically meaningful, 
if not statistically significant findings.  We expect the study to be adequately powered to 
establish estimates of variance that will help refine subsequent power analyses for 
outcome measures that may not yet have precedence in the literature.  
 
At the conclusion of this pilot study, we hope to have compiled valuable experience 
and knowledge, established collegial relationships across a number of disciplines, and 
effected a mechanism of meaningful patient engagement in design of a study that will be 
well-positioned to compete for the expected Patient-Centered Outcomes Research 
Institute (PCORI) funding via the Large Pragmatic Studies to Evaluate Patient—Centered 
Outcomes opportunity in the Spring of 2016 
 
 
 
 
 
B. BACKGROUND AND 
SIGNIFICANCE____________________________________________________
_____ 
According to the CDC, over 700,000 TKA’s are performed in the United States 
annually. That number continues to rise exponentially, and is predicted to eclipse 3 million 
procedures by 2030(14).  Though 98% of patients report pain relief following TKA, 
unfortunately up to one-third fail to achieve significant functional improvements (7).  
Nearly 20% of primary TKA patients report they are dissatisfied with their outcome, and 
up to 33% experience some residual symptoms (4, 17).  Various associative factors have 
been suggested to influence outcome, ranging from socioeconomic factors, to depressed 
mood, age, gender, suCarolinargical technique, and comorbid conditions(3, 13). 
  
 
The early postoperative period following total knee arthroplasty is widely believed 
to be critically important for regaining range of motion and mobility in order to optimize 
the ultimate clinical outcome and minimize the risk of complications including venous 
thromboembolic events(15).  Perioperative analgesia for TKA patients has evolved 
considerably since the popularization of the procedure decades ago. Historically, 
perioperative interventions such as general anesthesia and patient-controlled analgesia 
pumps (PCAs) have aggressively treated postoperative pain, but have been associated 
with side effects including lethargy, somnolence, nausea, and mental status changes, all 
of which have a detrimental effect on early mobility. Furthermore, contemporary emphasis 
on value in healthcare has led to efforts to promote “rapid recovery” programs that 
facilitate early mobilization and discharge, thereby reducing total costs to the health care 
system.  Recent trends in perioperative analgesic strategies may be related to these 
evolving priorities(5, 11).   
 
Recently, with growing appreciation of the importance of early mobilization in 
addition to pure pain control, centers across the country have trended away from general 
anesthesia and PCA’s in favor of regional anesthetic techniques(5).  A wide range of 
strategies have emerged, most of which combine either spinal or epidural anesthesia with 
a spectrum of peripheral nerve blockade techniques and/or periarticular analgesic 
injection formulations(3).  Unfortunately, the rate of institution of these varied modalities 
has outpaced the scientific evidence to support any one strategy over another.  Multiple 
randomized trials have been published comparing one combination of interventions 
against another with little consistency, reproducibility, or generalizability in either 
methodology or results(1, 2, 8-10, 12, 16, 18-20, 22-24).  The primary outcome measure 


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for most of these studies has been early post-operative pain levels, measured either 
directly via a visual analog scale (VAS), or indirectly via quantification of analgesic 
medication requirements(1, 2, 8-10, 12, 16, 18-20, 22-24).  Most of these studies have 
failed to report outcomes beyond the typical 2 or 3 day hospital stay(1, 2, 8-10, 12, 16, 
18-20, 22-24).  Only one study that we are aware of has presented patient reported 
outcomes (PROs) using a validated measure, the Knee Society Score, and that was only 
recorded at discharge (22).  Increasingly studies have reported secondary outcomes to 
include objective functional measures such as the Timed-up-and-go (TUG) (7, 19).  
Functional and patient reported outcomes beyond the immediate postoperative period are 
lacking in the literature.  The proposed study will address these evidence gaps. 
C. PRELIMINARY 
STUDIES/EXPERIENCE______________________________________________
_________ 
During residency training at the University of Massachusetts Medical School, Dr. 
Drew elected to pursue a “research-track”, which consisted of an additional year of 
training exclusively dedicated to research. Specifically, during that year Dr. Drew worked 
extensively to help develop the infrastructure that would ultimately become the NIH-
funded FORCE-TJR.  Additionally, he coordinated a prospective randomized control trial 
using radiostereometric analysis to quantify polyethylene wear and femoral stem 
migration differences between conventional and highly-cross-linked polyethylene liners in 
total hip replacement patients.  Subsequently, productive research efforts have included 
an award-winning project resourcing the Nationwide Inpatient Sample database to 
characterize national trends in total joint replacement.   
Dr. Bolin’s interest in research began during his undergraduate years when he 
spent two years in a Drosophila lab. His primary project during that time involved isolation 
of a gene important in neural development in Drosophila. He presented this research at 
the North Carolina Academy of Science Meeting and received an award. During medical 
school Dr. Bolin worked on a project to culture human keratinocytes to produce skin grafts 
for burn patients. Currently Dr. Bolin has active projects that include development of a 
novel regional anesthetic technique and the evaluation of regional anesthetic techniques 
for post-operative pain management in mastectomy patients. 
Dr. Pellegrini has previously served as a successful mentor for more junior faculty, 
and has demonstrated both interest and ability to secure extramural research funding.  In 
support of this application as a mentor, Dr. Pellegrini has recommended quarterly 
mentorship meetings.  These meetings will address study progress via benchmarks 
including the pace of recruitment, enrollment, and follow-up.  Preliminary analyses will be 
prepared in advance of and reviewed at the mentorship meetings.  Barriers, challenges, 
and opportunities for improvement in the process will be discussed, not only for the 
current project, but also with an eye towards optimizing subsequent study design in 
advance of planned application for PCORI funding. Of particular relevance, Dr. Pellegrini is 
the PI for a comparative effectiveness trial that has passed initial review for PCORI 
funding and is in the final stage prior to acceptance. 
Dr. Drew & Bolin’s strong foundational experiences combined with Dr. Pellegrini’s 
exemplary track record of success suggests potential for a productive partnership and 
sound study leadership.  With the proposed timetable of extramural funding during the 
calendar year following the pilot study, the expectation is that the mentor-mentee 
relationship will remain necessary for initiation of a multi-center trial, but investigator 
independence will gradually be achieved during the course of that trial. 


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D. RESEARCH DESIGN AND METHODS (including data analysis) 
__________________________________ 
 
All primary TKA patients undergoing surgery at the Medical University of South 
Carolina (MUSC) will be offered the opportunity to participate in the study.  Those with 
valgus deformity greater than 10 degrees on plain radiographs will be excluded from the 
study.  Participants will be reflective of the population of TKA candidates at MUSC, and will 
include adults over the age of 18 of both genders and all races.  Consenting patients will 
all receive spinal anesthetic, and will be randomized to one of three arms: 1) Continuous 
femoral nerve catheter plus single injection sciatic nerve block, 2) Adductor canal catheter 
plus selective tibial nerve block, and 3) Adductor canal catheter alone.  Patients unable to 
receive spinal anesthetic will be excluded.  All patients will receive a standardized 
multimodal pain regimen and early mobilization.   
Preoperative data will include basic demographics, visual analog pain scale (VAS) 
score, range of motion, body mass index (BMI), primary insurer, coronal angular 
deformity, and baseline opioid use.  Surgical data will include tourniquet time and implant 
type.  Time spent in pre-operative holding area, the operating room, and the post-
anesthesia recovery unit will be recorded. SF-12, Patient Reported Outcomes 
Measurement Information System (PROMIS), and Knee Injury and Osteoarthritis Outcome 
Score (KOOS) will be collected as part of our participation in the Function and Outcomes 
Research for Comparative Effectiveness in Total Joint Replacement (FORCE-TJR). 
The primary outcome measure will be postoperative visual analog pain scale (VAS) 
score area under the curve (AUC) for 48 hours, recorded every six hours.  Pain will be 
measured indirectly via total in-hospital opioid consumption.  Functional outcome 
measures will be administered by members of the physical and occupational therapy 
team, who typically evaluate and treat patients once on the day of surgery and twice daily 
each day thereafter.  They will document the patient’s ability to perform independent 
terminal knee extension and grade knee buckling with ambulation on a scale of 0-2 during 
each encounter.  Additionally, in the morning of postoperative day #1, a Katz Index of 
Independence in Activities of Daily Living score will be calculated.  On the morning of 
postoperative day #2, the therapist will document distance walked by the patient, passive 
range of motion (flexion and extension), a timed up-and-go test (TUG), and calculate the 
AM-PAC (Activity Measure for Post-Acute Care) score.  Patient reported outcome 
measures, specifically SF-12, PROMIS, and KOOS will be collected at 6 weeks and 3 
months postoperatively.  These time points are not included in the FORCE-TJR registry, 
and therefore will be independently collected and stored. Postoperative complications will 
be recorded.  Finally, a brief survey will be administered at 3 months, presenting inquiries 
regarding satisfaction with the hospital stay, pain control, mobility, and the overall TKA 
experience.  These inquiries will pose each question with a 0-10 scale, and respondents 
will be asked to select the number that corresponds to their level of satisfaction with each 
domain of their experience.   
Via partnership with the FORCE-TJR, collection of patient-reported outcomes (PRO) 
data for arthroplasty patients at MUSC is both well-established and sophisticated.  These 
data will be available as baseline measures for this project.  Preoperative data are 
collected at a mandatory appointment 2-3 weeks in advance of elective arthroplasty.  At 
that appointment and again at follow-up, our research coordinator facilitates patient 
recruitment and participation with the FORCE-TJR using validated computerized survey 


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instruments.  Additionally, for this study, she will assist with enrollment, consent, 
extraction of clinical data from the EPIC-EMR, and coordination of prescribed follow-up.  
Postoperative SF-12, PROMIS, and KOOS are collected at 6 months and 1 year via the 
FORCE-TJR, therefore the coordinator will additionally facilitate collection of these 
instruments at 6 and 12 weeks, as well as the satisfaction survey. If, in the surgeon’s 
opinion, the patient is doing well after surgery and does not have to return to clinic at the 
specified time points, the surveys will be mailed to the patient with instructions on how to 
complete them. The study coordinator will be available to field study-related patient 
questions in clinic and via telephone.  
 
At three months, a random subset of four patients from each randomization arm 
will be invited to participate in a focus group.  The purpose of the focus group will be to 
facilitate patient engagement with the hope of fulfilling our primary aim of this study, 
which is to identify the most meaningful outcome measures for perioperative analgesia 
among the TKA patients themselves.  Qualitative data obtained during the recorded 
session will prompt discussion related to the overall patient experience in addition to 
individual experiences related specifically to analgesia, postoperative mobility, 
transitioning to the out-patient setting, and involvement in a randomized trial.  The focus 
group will be held several months after surgery, on the MUSC campus in a private room.  
Audiotape of the focus group will be available to relevant study personnel only, and will be 
kept under lock and key within an office in the Department of Orthopaedics.  A preference 
survey will be developed and distributed for additional patient feedback.  
Though the main goal of conducting this pilot study is one of establishing the 
appropriate data points and testing the feasibility of such a design, we will conduct some 
preliminary hypothesis testing.  Tests on the effect of treatment upon outcomes will be 
performed using an intent-to-treat analysis.  Preliminary estimates suggest the study will 
be adequately powered to detect a significant VAS difference of 2 at 25 subjects per 
group. However, prior research suggests that the anticipated group differences may be 
much subtler, requiring a very large sample size to thoroughly address the issue of which 
treatment is superior to the others.  As a preliminary step towards a larger, more 
definitive comparative effectiveness trial, we plan to enroll approximately 90 patients. This 
will allow us to reach our randomization goal of at least 75 patients while taking into 
account withdrawals. The 75 patients will be randomized into the three treatment arms 
over a 6-month recruitment period, with a 3 month follow-up for patient reported 
outcome and satisfaction data. This sample will allow us to estimate means relatively 
precisely, with 95% confidence intervals extending just 0.4 standard deviation units in 
either direction.  We will also be able to make preliminary estimates of each treatment’s 
effectiveness on the various outcomes of interest. Such estimates can be made using 
generalized linear mixed models (GLMMs)(6). Effect sizes will then be estimated from the 
GLMMs in a pairwise manner, and this information will be extremely valuable for use in 
designing a larger, more definitive trial in the future. 
The study timeline calls for initiation in April of 2015, and completion of enrollment 
in October, 2015.  Three-month follow-up data will be collected by the end of January, 
2016, which will allow for data analysis and interpretation in advance of PCORI Letter of 
Intent, anticipated to be due in spring of 2016. 
We expect to demonstrate sound scientific methodology and a fully invested multi-
disciplinary team that will define clinically meaningful though perhaps not statistically 
significant differences in efficacy, safety, patient-reported and objective outcomes 
associated with various strategies of perioperative TKA pain management.  With continued 


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patient engagement, this pilot study will support development of a multi-center 
randomized comparative effectiveness trial that we expect will be strongly considered for 
extramural funding through the Patient Centered Outcomes Research Institute (PCORI) 
via the “Large Pragmatic Studies to Evaluate Patient-Centered Outcomes” Funding 
Announcement.   As a proposed randomized trial examining a poorly defined aspect of 
treatment that could affect nearly one million Americans per year, such a proposal meets 
the stated objectives outlined in the RFA.  This pilot study will allow us to present a well-
formulated, novel, scientific protocol supported by experience and data.  Furthermore, it 
will allow us to demonstrate commitment and capacity for patient engagement in the 
study design process. The ultimate goal after procurement of extramural funding is to 
expand and establish this methodology as the generalizable gold standard for comparative 
effectiveness studies assessing perioperative TKA analgesia, and foster the development 
of a healthcare learning environment capable of identifying the most optimal strategy for 
perioperative TKA analgesia. 
 
 
 
 
 
 
 
 
 
 
E. PROTECTION OF HUMAN 
SUBJECTS________________________________________________________ 
 
1.  RISKS TO THE SUBJECTS  
Targeted/Planned Enrollment Table 
 
Total Planned Enrollment 90 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
   4 
3 
7 
Not Hispanic or Latino 
   53 
30 
83 
Ethnic Category: Total of All 
Subjects* 
9 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0      
0 
0 
Native Hawaiian or Other Pacific Islander 
0      
0 
0 
Black or African American 
24      13 
37 
White 
34      19 
53 
Racial Categories: Total of All 
Subjects* 
58      32 
90 
 
 
 
 
 
 


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We anticipate that patients recruited for this study will be reflective of the South Carolina 
population of candidates for total knee replacement in terms of ethnicity, race, and 
gender.  All participants will be over the age of 18.  No prisoners will be included. 
 
b.  Sources of Materials  
 
Clinical data will be obtained from living human subjects for use in this project.  
This data will include basic demographic data in addition to the variables described above, 
including visual analog pain scale (VAS) score, range of motion, body mass index (BMI), 
primary insurer, coronal angular deformity, and baseline opioid use.  Surgical data will 
include tourniquet time and implant type.  Time spent in pre-operative holding area, the 
operating room, and the post-anesthesia recovery unit will be recorded. SF-12, Patient 
Reported Outcomes Measurement Information System (PROMIS), and Knee Injury and 
Osteoarthritis Outcome Score (KOOS) will be collected as part of our participation in the 
Function and Outcomes Research for Comparative Effectiveness in Total Joint 
Replacement (FORCE-TJR). 
The primary outcome measure will be postoperative visual analog pain scale (VAS) 
score area under the curve (AUC) for 48 hours, recorded every six hours.  Pain will be 
measured indirectly via total in-hospital opioid consumption.  Functional outcome 
measures will be administered by members of the physical and occupational therapy 
team, who typically evaluate and treat patients once on the day of surgery and twice daily 
each day thereafter.  They will document the patient’s ability to perform independent 
terminal knee extension and grade knee buckling with ambulation on a scale of 0-2 during 
each encounter.  Additionally, in the morning of postoperative day #1, a Katz Index of 
Independence in Activities of Daily Living score will be calculated.  On the morning of 
postoperative day #2, the therapist will document distance walked by the patient, passive 
range of motion (flexion and extension), a timed up-and-go test (TUG), and calculate the 
AM-PAC (Activity Measure for Post-Acute Care) score.  Patient reported outcome 
measures, specifically SF-12, PROMIS, and KOOS will be collected at 6 weeks and 3 
months postoperatively.  These time points are not included in the FORCE-TJR registry, 
and therefore will be independently collected and stored. Postoperative complications will 
be recorded.  Finally, a brief survey will be administered at 3 months, presenting inquiries 
regarding satisfaction with the hospital stay, pain control, mobility, and the overall TKA 
experience.  These inquiries will pose each question with a 0-10 scale, and respondents 
will be asked to select the number that corresponds to their level of satisfaction with each 
domain of their experience.   
 
Data will be collected primarily by our study coordinator, but also by the PI.  
RedCap will be used to compile and store data.  Collected data will be stored in a 
password-protected, MUSC network drive.  Individual patient data will be linked to 
medical record number, but no other personal identifiers.  These data and patient 
identifiers will only be accessible by study investigators.  Most of the data collected are 
already part of the standard clinical care for total knee replacement patients, and are 
therefore already routinely available within the electronic medical record. 
 
c.  Potential Risks  
Risks and side effects of nerve blocks may include elevated blood sugars, rash, 
itching, soreness at the site of injection, and localized bleeding.  More serious 
complications, such as delayed recovery of nerve function, persistent numbness and/or 
tingling, or persistent weakness are extremely rare. 


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As a result of the randomization process, an individual patient may receive a 
treatment that ultimately proves less effective or otherwise inferior to the other study 
treatments or other available treatments. 
The experimental treatments may have unknown side effects. 
Other risks of anesthesia and total knee replacement are not expected to be 
affected by the experimental treatments in this study.  These risks apply to all total knee 
replacement patients and are not specific nor exclusive to this particular study. 
Risks of data breach and breach of confidentiality exist for participants in this study.  
In order to minimize such risks, data will be stored in a password-protected, MUSC 
network drive, and unlinked to personal identifiers other than medical record number.  
Only study investigators will have access to these data. 
Current practice for perioperative analgesia for total knee replacement patients at 
MUSC, routinely includes arbitrary selection of one of the three treatments available in 
this study.  Non-study participants will in all but very few cases receive one of the three 
experimental treatments in a non-random fashion, at the discretion of their surgeon.  
Patients may refuse to receive a nerve block of any type and still undergo total knee 
replacement.  In our experience, a nerve block makes post-surgical pain much easier to 
manage, and therefore we recommend nerve blocks to all patients. 
Spinal anesthesia is our default and preferred method of anesthesia for total knee 
replacement patients.  For patients who are unable to receive spinal anesthesia, general 
anesthesia remains an option.  Such patients will be excluded from this study. Spinal 
anesthesia is preferred over general for benefits in early recovery and a lower incidence of 
side effects such as nausea and postoperative confusion. 
 
2.  ADEQUACY OF PROTECTION AGAINST RISKS  
 
a.  Recruitment and Informed Consent 
 
In the outpatient clinic, at the time that the decision to proceed with primary total 
knee replacement is agreed upon, the surgeon will introduce the study to every primary 
TKR patient.  If a patient decides to participate, the full informed consent process will be 
completed during a separate preoperative clinic visit (a mandatory visit for all elective TJR 
patients), which occurs 2-3 weeks in advance of surgery.  A research coordinator will be 
responsible for the informed consent process.  
 
Specifically, informed consent will include an explanation of the three possible treatment 
arms, all of which are currently available and common practice, though selection for an 
individual patient is per surgeon discretion.  This discussion will be supported by a study 
description document.  Potential risks and benefits of the randomized treatments will be 
addressed.  Potential participants will also be educated on the additional surveys and 
functional tests that they will be asked to complete as a part of their study participation.  
They will be informed that deidentified data will be recorded and stored in a password-
protected, MUSC network drive.  It will also be explained that randomly selected 
individuals may be contacted and asked to participate in a focus group, though consent to 
participate in the study does not require participation in the focus group.  Consenting 


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individuals will be required to sign a formal consent form, which will be kept in a secured 
file folder within a locked office in the Department of Orthopaedics. Patients who agree to 
participate in the focus group will be verbally consented prior to conducting any focus 
group procedures. 
Any patient requiring re-consenting can be consented via telephone. The coordinator will 
mail the patient a consent form. Once the patient receives the form, the full informed 
consent process will be completed. The patient and the coordinator will each sign and date 
a consent form. The patient will mail the form back to the coordinator. Once the 
coordinator receives the form, the two signed forms will be combined as one fully 
executed informed consent form. The coordinator will then mail the patient a copy of the 
form.  
 
No children or individuals under the age of 18 will be included in the study. 
 
b.  Protection against Risk 
Risks of data breach and breach of confidentiality exist for participants in this study.  
In order to minimize such risks, data will be stored in a password-protected, MUSC 
network drive, and unlinked to personal identifiers other than medical record number.  
Only study investigators will have access to these data. 
 
In the event of adverse effects to the subjects, necessary medical intervention will 
be provided in the routine manner.  There will be no deviation from the routine 
postoperative protocol for a total knee replacement other than collection of additional data 
points mentioned earlier in this proposal.   
 
Adverse events and complications will be recorded and monitored as a part of the 
study protocol.  Any trend suggesting an association between treatment and adverse 
events will be noted, and study investigators will have the ability to stop randomization 
into any treatment arm seemingly associated with increased rates of adverse events at 
their discretion.  Any such occurrence will be reported to the IRB. 
 
3.  POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND OTHERS  
 
As it is unclear which of the three research arms may be superior, direct benefit to 
participating patients cannot be guaranteed.  The results of this study are expected to 
inform design of a subsequent larger randomized comparative effectiveness trail that will 
be adequately powered to prove clinically meaningful differences between treatments.  
Ultimately, knowledge gained from this project will provide clinicians the ability to choose 
the most optimal treatment option for TKR patients, and therefore benefit future patients. 
Current literature suggests equivalent risks among the three proposed treatment 
arms.  The remaining risks inherent with major surgery, and TKR specifically, are not 
expected to be affected by randomization.  All proposed treatments are currently available 
and in use for TKR patients at MUSC. 
 
4.  IMPORTANCE OF THE KNOWLEDGE TO BE GAINED  
 
We expect to demonstrate sound scientific methodology and a fully invested multi-
disciplinary team that will define clinically meaningful though perhaps not statistically 
significant differences in efficacy, safety, patient-reported and objective outcomes 


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10 of  
12 
associated with various strategies of perioperative TKA pain management.  With continued 
patient engagement, this pilot study will support development of a multi-center 
randomized comparative effectiveness trial that we expect will be strongly considered for 
extramural funding through the Patient Centered Outcomes Research Institute (PCORI) 
via the “Large Pragmatic Studies to Evaluate Patient-Centered Outcomes” Funding 
Announcement.   As a proposed randomized trial examining a poorly defined aspect of 
treatment that could affect nearly one million Americans per year, such a proposal meets 
the stated objectives outlined in the RFA.  This pilot study will allow us to present a well-
formulated, novel, scientific protocol supported by experience and data.  Furthermore, it 
will allow us to demonstrate commitment and capacity for patient engagement in the 
study design process. The ultimate goal after procurement of extramural funding is to 
expand and establish this methodology as the generalizable gold standard for comparative 
effectiveness studies assessing perioperative TKA analgesia, and foster the development 
of a healthcare learning environment capable of identifying the most optimal strategy for 
perioperative TKA analgesia.  Identification and establishment of a new “gold standard” in 
perioperative analgesia for TKA patients has the potential to positively impact the 
perioperative experience and clinical outcomes for nearly 1 million Americans annually. 
Each of the proposed treatments are currently commonly used in centers 
nationwide.  There are no reports in the literature that we are aware of suggesting that 
any of the proposed treatments are associated with increased risk, and all are well-
accepted as safe options for perioperative analgesia following total knee surgery.  The 
safety and efficacy of each relative to the others is unknown. 
 
5.  SUBJECT SAFETY AND MINIMIZING RISKS (Data and Safety Monitoring Plan) 
 
 
Complications thought to be directly related to the treatment will be assessed and 
documented at each patient encounter during and beyond the study period, beginning 
with the inpatient hospital stay, and continuing with the 3 week, 6 week, 3 month, 6 
month and annual follow up visits.  Such complications will include paresthesias, 
dysesthesias, motor weakness, neuroma, persistent pain, patient falls, and hematoma.  
Other serious adverse events that may be observed following total knee arthroplasty, but 
thought to be unrelated to the peripheral nerve block will also be noted.  Such events 
might include wound infections, venous thromboembolic events, and cardiac events, 
among others.  Individual surgeons will be responsible for such monitoring, and all 
adverse events and complications will be reported to the PI. 
 
 
F. REFERENCES/LITERATURE 
CITATIONS______________________________________________________ 
 
1. 
Al-Zahrani T, Doais KS, Aljassir F, Alshaygy I, Albishi W, and Terkawi AS. 
Randomized clinical trial of continuous femoral nerve block combined with sciatic nerve 
block versus epidural analgesia for unilateral total knee arthroplasty. The Journal of 
arthroplasty 30: 149-154, 2015. 
2. 
Bagsby DT, Ireland PH, and Meneghini RM. Liposomal bupivacaine versus 
traditional periarticular injection for pain control after total knee arthroplasty. The Journal 
of arthroplasty 29: 1687-1690, 2014. 


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3. 
Barrack RL, Ruh EL, Chen J, Lombardi AV, Jr., Berend KR, Parvizi J, Della 
Valle CJ, Hamilton WG, and Nunley RM. Impact of socioeconomic factors on outcome 
of total knee arthroplasty. Clinical orthopaedics and related research 472: 86-97, 2014. 
4. 
Bourne RB, Chesworth BM, Davis AM, Mahomed NN, and Charron KDJ. 
Patient satisfaction after total knee arthroplasty: who is satisfied and who is not? Clinical 
Orthopaedics & Related Research 468: 57-63, 2010. 
5. 
Danninger T, Opperer M, and Memtsoudis SG. Perioperative pain control after 
total knee arthroplasty: An evidence based review of the role of peripheral nerve blocks. 
World journal of orthopedics 5: 225-232, 2014. 
6. 
Fitzmaurice GM LN, Ware JH. Applied Longitudinal Analysis. New York: John 
Wiley & Sons, Inc., 2004. 
7. 
Franklin PD, Li W, and Ayers DC. The Chitranjan Ranawat Award: functional 
outcome after total knee replacement varies with patient attributes. Clinical orthopaedics 
and related research 466: 2597-2604, 2008. 
8. 
Fu H, Wang J, Zhang W, Cheng T, and Zhang X. Potential superiority of 
periarticular injection in analgesic effect and early mobilization ability over femoral nerve 
block following total knee arthroplasty. Knee surgery, sports traumatology, arthroscopy : 
official journal of the ESSKA 2015. 
9. 
Gi E, Yamauchi M, Yamakage M, Kikuchi C, Shimizu H, Okada Y, Kawamura 
S, and Suzuki T. Effects of local infiltration analgesia for posterior knee pain after total 
knee arthroplasty: comparison with sciatic nerve block. Journal of anesthesia 28: 696-
701, 2014. 
10. 
Grevstad U, Mathiesen O, Lind T, and Dahl JB. Effect of adductor canal block on 
pain in patients with severe pain after total knee arthroplasty: a randomized study with 
individual patient analysis. Br J Anaesth 112: 912-919, 2014. 
11. 
Guerra ML, Singh PJ, and Taylor NF. Early mobilization of patients who have had 
a hip or knee joint replacement reduces length of stay in hospital: A systematic review. 
Clinical rehabilitation 2014. 
12. 
Hanson NA, Allen CJ, Hostetter LS, Nagy R, Derby RE, Slee AE, Arslan A, 
and Auyong DB. Continuous ultrasound-guided adductor canal block for total knee 
arthroplasty: a randomized, double-blind trial. Anesth Analg 118: 1370-1377, 2014. 
13. 
Judge A, Arden NK, Cooper C, Kassim Javaid M, Carr AJ, Field RE, and 
Dieppe PA. Predictors of outcomes of total knee replacement surgery. Rheumatology 
(Oxford, England) 51: 1804-1813, 2012. 
14. 
Kurtz S, Ong K, Lau E, Mowat F, and Halpern M. Projections of primary and 
revision hip and knee arthroplasty in the United States from 2005 to 2030. The Journal of 
bone and joint surgery American volume 89: 780-785, 2007. 
15. 
Manrique J, Gomez MM, and Parvizi J. Stiffness after Total Knee Arthroplasty. 
The journal of knee surgery 2014. 
16. 
Mudumbai SC, Kim TE, Howard SK, Workman JJ, Giori N, Woolson S, 
Ganaway T, King R, and Mariano ER. Continuous adductor canal blocks are superior to 
continuous femoral nerve blocks in promoting early ambulation after TKA. Clinical 
orthopaedics and related research 472: 1377-1383, 2014. 
17. 
Parvizi J, Nunley RM, Berend KR, Lombardi AV, Jr., Ruh EL, Clohisy JC, 
Hamilton WG, Della Valle CJ, and Barrack RL. High level of residual symptoms in 
young patients after total knee arthroplasty. Clinical orthopaedics and related research 
472: 133-137, 2014. 
18. 
Patterson ME, Bland KS, Thomas LC, Elliott CE, Soberon JR, Jr., Nossaman 
BD, and Osteen K. The adductor canal block provides effective analgesia similar to a 


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12 
femoral nerve block in patients undergoing total knee arthroplasty-a retrospective study. 
Journal of clinical anesthesia 2014. 
19. 
Sato K, Adachi T, Shirai N, and Naoi N. Continuous versus single-injection 
sciatic nerve block added to continuous femoral nerve block for analgesia after total knee 
arthroplasty: a prospective, randomized, double-blind study. Reg Anesth Pain Med 39: 
225-229, 2014. 
20. 
Shah NA, and Jain NP. Is Continuous Adductor Canal Block Better Than 
Continuous Femoral Nerve Block After Total Knee Arthroplasty? Effect on Ambulation 
Ability, Early Functional Recovery and Pain Control: A Randomized Controlled Trial. The 
Journal of arthroplasty 2014. 
21. 
Shore BJ, Nasreddine AY, and Kocher MS. Overcoming the funding challenge: 
the cost of randomized controlled trials in the next decade. The Journal of bone and joint 
surgery American volume 94 Suppl 1: 101-106, 2012. 
22. 
Spangehl MJ, Clarke HD, Hentz JG, Misra L, Blocher JL, and Seamans DP. 
The Chitranjan Ranawat Award: Periarticular Injections and Femoral & Sciatic Blocks 
Provide Similar Pain Relief After TKA: A Randomized Clinical Trial. Clinical orthopaedics 
and related research 2014. 
23. 
Surdam JW, Licini DJ, Baynes NT, and Arce BR. The Use of Exparel (Liposomal 
Bupivacaine) to Manage Postoperative Pain in Unilateral Total Knee Arthroplasty Patients. 
The Journal of arthroplasty 2014. 
24. 
Tanikawa H, Sato T, Nagafuchi M, Takeda K, Oshida J, and Okuma K. 
Comparison of local infiltration of analgesia and sciatic nerve block in addition to femoral 
nerve block for total knee arthroplasty. The Journal of arthroplasty 29: 2462-2467, 2014. 
 
 
G. 
CONSULTANTS____________________________________________________________
______________ 
n/a.     
 
H. FACILITES 
AVAILABLE_______________________________________________________________
_____ 
 
The setting for this study will be the campus of the Medical University of South Carolina, 
Medical University Hospital, and outpatient clinic settings within the MUSC system.