Double Blind Randomized Clinical Trial Comparing Time To Return of Lower Extremity Motor Function Following Spinal Anesthetic With Mepivacaine Versus Low-Dose Bupivacaine For Primary Total Hip and Knee Arthroplasty
Phase: PHASE2
Conditions: Knee Osteoarthritis, Hip Osteoarthritis
Sponsor: Mayo Clinic

 
 
Double Blind Randomized Clinical Trial Comparing 
Time To Return of Lower Extremity Motor Function 
Following Spinal Anesthetic With Mepivacaine 
Versus Low-Dose Bupivacaine For Primary Total Hip 
and Knee Arthroplasty 
 
NCT03838874 
 
September 3, 2018 

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IRB Minimal Risk Protocol Template  
 
General Study Information 
 
Principal Investigator: Matthew P. Abdel, MD  
Co-Principal Investigators: Christopher M. Duncan, MD, Hugh M. Smith, MD, PhD 
Co-Investigators: Mark W. Pagnano MD, Rafael J. Sierra, MD, Kevin I. Perry, MD, Cody C. Wyles, MD, 
David J. Harris, MD, Adam W. Amundson MD, Adam D. Niesen, MD, David J. Harris, MD 
 
 
 
 
 
 
 
 
Study Title:  Double Blind Randomized Clinical Trial Comparing Time To Return of Lower Extremity Motor 
Function Following Spinal Anesthetic With Mepivacaine Versus Low-Dose Bupivacaine For Primary Total Hip 
and Knee Arthroplasty 
 
Protocol version number and date: Version 1 – 9/3/2018      
 
Research Question and Aims 
 
Hypothesis: Patients treated with mepivacaine spinal anesthetic will have faster return of lower extremity motor 
function than patients treated with low-dose bupivacaine following primary total hip arthroplasty (THA) and 
total knee arthroplasty (TKA). 
 
Aims, purpose, or objectives: 
 
#1 Evaluate time to return of lower extremity motor function between mepivacaine and low-dose bupivacaine 
spinal anesthetic among patients undergoing primary THA and TKA. This will be assessed by measuring time 
from spinal anesthetic administration to postoperative achievement of Bromage 0 function (return of 
spontaneous ankle, knee, and hip movement) in the non-operative extremity. 
Note: If this study establishes a human specimen repository (biobank) for research 
purposes, do not use this template. Use the Mayo Clinic Human Specimen Repository 
Protocol Template found on the IRB home page under Forms and Procedures at 
http://intranet.mayo.edu/charlie/irb/ 
 
First-time Use: Use this template to describe your study for a new IRB submission. 
1. Complete the questions that apply to your study. 
2. Save an electronic copy of this protocol for future revisions.    
3. When completing your IRBe application, you will be asked to upload this document to the protocol 
section. 
Modification:  To modify this document after your study has been approved: 
1. Open your study in IRBe. Click on the study ‘Documents’ tab and select the most recent version of the 
protocol. Save it to your files. 
2. Open the saved document and activate “Track Changes”.  
3. Revise the protocol template to reflect the modification points , save the template to your files 
4. Create an IRBe Modification for the study and upload the revised protocol template. 

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#2 Evaluate postoperative outcomes potentially related to anesthetic administration including pain scores, 
opioid consumption, urinary retention, transient neurologic symptoms, length of PACU stay, length of hospital 
stay, time to participation in physical therapy and walking distance with physical therapy. This will be 
determined by nurse and physical therapy charting and review of the medical record. 
 
Background (Include relevant experience, gaps in current knowledge, preliminary data, etc.):   
 
Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are two of the most common orthopedic 
procedures performed in the United States, with significant growth in procedure volume expected over the 
coming decades.  Coupled with the growing number of surgeries, is a growing cost to perform these procedures. 
In order to accommodate the increased demand for total joint arthroplasty (TJA) while also reducing 
complications and costs, optimized recovery pathways are needed to enhance resource utilization.  One way to 
significantly impact recovery and length of stay is for patients to participate in physical therapy earlier in their 
episode of care.  In addition to facilitating patient readiness for discharge from the hospital, early physical 
therapy and ambulation reduces post-operative complications such as venous thromboembolism and 
pneumonia. Multiple factors related to anesthesia can affect a patient’s ability to participate in physical therapy 
on the day of surgery; these include post-operative nausea and vomiting, orthostatic hypotension and residual 
muscle weakness.  The use of spinal anesthesia for TJA has been shown to reduce the risk of these 
complications.  Shortening the duration of motor blockade in spinal anesthesia can reduce the time to patient 
physical therapy readiness, facilitating early ambulation and discharge to home.   
Historically, short to intermediate duration local anesthetics such as lidocaine have been used for spinal 
anesthetics in short duration knee procedures such as knee arthroscopy.  However, the use of lidocaine in spinal 
anesthesia has been dramatically reduced due to a high incidence of transient neurologic symptoms (TNS).  
TNS was first defined in 1993, and is defined as a painful condition of the buttocks and thighs with possible 
radiation to the lower extremities, beginning as soon as a few hours after spinal anesthesia and lasting as long as 
ten days. All local anesthetics can cause TNS but it is most commonly associated with lidocaine and reported to 
occur in 4% to 40% of patients undergoing spinal anesthesia with lidocaine.  
Bupivacaine has been shown to have the lowest incidence of TNS and is currently the most widely used 
medication for spinal anesthesia.  While advantageous for avoiding TNS, bupivacaine has a slow onset time 
coupled a long duration of action, which can delay postoperative recovery. Low-dose bupivacaine (10 mg) 
regimens are increasingly used; however, issues remain with the unpredictable temporal profile. Mepivacaine 
(70 mg) is a shorter acting local anesthetic compared to bupivacaine with a more predictable duration of action, 
raising interest as an alternative for procedures such as TKA and THA with consistent performance times.   
In this randomized controlled trial, mepivacaine will be compared to low dose bupivacaine spinal anesthetics.  
The primary outcome will be time from spinal insertion to return of motor function.  Secondary outcomes will 
evaluate pain scores, opioid consumption, urinary retention, transient neurologic symptoms, length of PACU 

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stay, length of hospital stay, time to participation in physical therapy and walking distance with physical 
therapy. 
 
Study Design and Methods 
 
Methods:  Describe, in detail, the research activities that will be conducted under this protocol:   
 
Preoperative Visit and Anesthesiologist Assessment: Patients meeting eligibility criteria will be approached 
during their surgical preoperative visit by the study coordinator in the clinic of the orthopedic Co-Principal 
Investigators. Those choosing to participate will be screened for inclusion and exclusion criteria. Patients will 
be assessed for ability to undergo a spinal anesthetic, but will be counseled that the decision between a spinal 
and general anesthetic will ultimately be determined by the anesthesiologist on the day of surgery. Thus, 
patients may be withdrawn on the day of surgery if the staff anesthesiologist does not agree with their candidacy 
to undergo a spinal anesthetic. Furthermore, patients will be counseled they may be withdrawn from the study if 
placement of a spinal anesthetic in the operating room proves unsuccessful and a general anesthetic is required. 
 
Randomization and Blinding: Patients will be randomized in a 1:1 fashion. The first arm will be the 
“Mepivacaine” (70 mg) group and the second arm will be the “Low-Dose Bupivacaine” (10 mg) group. This 
trial will be conducted in a double-blinded manner. The patient and the postoperative outcomes assessors 
(PACU and Orthopedic Inpatient Nurses and Physical Therapists) will be the blinded parties. The anesthesia 
and surgical teams will not be blinded given they won’t be responsible for any assessments. After a patient has 
been consented and enrolled, the study coordinator will randomize the patient to either Mepivacaine or Low-
Dose Bupivacaine using a custom electronic randomization system which will be maintained by the study 
statistician. The surgical team and anesthesia team will be notified after the assignment is complete so the 
surgical listing can be completed with the appropriate medication.  
 
In Hospital Evaluation: A standardized study card will be used to track patients throughout their various phases 
of care. At the time of discharge, the cards will be returned to the study coordinator for data entry in a secure 
spreadsheet available only to study staff. The study will begin with the anesthesiologist recording the time the 
spinal anesthetic is administered. The anesthesiologist will also record the time of incision, time of surgical 
closure, and time leaving the OR. The PACU nursing staff will then record the time of PACU entry and exit as 
well as the status of lower extremity function in the non-operative lower extremity at 15 minute intervals. The 
choices will be Bromage 3 (no movement), Bromage 2 (ankle movement only), Bromage 1 (ankle and knee 
movement), Bromage 0 (ankle, knee, and hip movement). Once the patient transitions to the general inpatient 
floor, the nursing staff will be responsible for recording motor function in a similar fashion at 15 minute 
intervals until the patient achieves Bromage 0 status. The physical therapy team will be responsible for 
recording the time of the first physical therapy session and the distance the patient ambulates during this 
session. Additional data points to be recorded by nursing staff will be total opioid consumption in the first 24 
hours after surgery, pain scores, presence of nausea and/or vomiting, presence of orthostatic hypotension, and 
length of hospital stay.  TNS will be evaluated twice, once during hospitalization by either the orthopedic or 
anesthesia team rounding on the patient on post-operative day one and a follow-up phone call performed on 
POD 6-9 by a study member not blinded to patient assignment.   A standardized questionnaire will be used to 
determine the presence of symptoms of backache.  TNS will be defined as new onset of back pain that radiates 

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bilaterally to buttock or distally.  Back pain that does not meet these criteria will not be considered TNS. (ref. 
Anesth Analg 2005;101:661-5) 
 
 
Follow-up Evaluation: Assessment will only take place during the hospitalization for the intended surgery. 
There will be a single phone call during post-operative day 6-9 for assessment of TNS. 
 
Resources:  Describe the available resources to conduct the research (personnel, time, facilities, mentor 
commitment, etc.):  
 
The Co-Principal Investigator orthopedic surgeons maintain high volume practices specializing in TKA and 
THA. This group of surgeons works exclusively with the Co-Principal Investigator anesthesiologists who 
specialize in the care of TKA and THA patients. 
 
Cody Wyles is an orthopedic surgery resident who will assist with study execution and data analysis. A study 
coordinator in the department of orthopedic surgery will work with the residents and the midlevel providers for 
the orthopedic consultants to enroll patients at the preoperative visit. Standardized study cards will be created 
for patients enrolled in the study so that PACU and floor nursing staff as well as physical therapists can track 
relevant study endpoints. These cards will be returned to the study coordinator for data entry.  
 
Dirk Larson is a master level statistician in the Division of Biomedical Statistics and Informatics with 
significant experience in the department of orthopedics and executing randomized clinical trials. He will serve 
as the lead statistician.  
 
All funding for the study including statistical and coordinator FTE will be covered by the Department of 
Orthopedic Surgery and research royalty accounts of the Co-Principal Investigators. 
 
Subject Information 
 
Target accrual is the proposed total number of subjects to be included in this study at Mayo Clinic. A “Subject” 
may include medical records, images, or specimens generated at Mayo Clinic and/or received from external 
sources.    
 
Target accrual: 300 patients 
 
Subject population (children, adults, groups):  Adult males and females 
 
Inclusion Criteria:  
 
1. Unilateral primary TKA or THA  
2. 18+ years of age 
3. Able to provide informed consent 
 
Exclusion Criteria:   

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1. Body mass index (BMI) > 45 kg/m2 
2. Severe drug allergy* to medications used in this study, including non-steroidal anti-inflammatory drugs 
(i.e. celecoxib and ketorolac), and local anesthetics.   
• *defined as an immune reaction resulting in shortness of breath, hives, anaphylaxis, wheezing, 
and fever 
•  
3. Contraindication to spinal anesthesia technique (e.g., known spinal stenosis, coagulopathy, sepsis, 
infection at site of injection, uncooperative, refusal, anticoagulation medications not held within 
appropriate time frame*).  
• 
*Per ASRA guidelines, Clopidogrel (Plavix) held for at least 7 days, Dabigatran (Pradexa) held 
for at least 5 days, Rivaroxaban (Xarelto)held for at least 3 days, Warfarin (Coumadin)held for at 
least 5 days or recent INR of less than 1.4, Enoxaparin (Lovenox) with doses > 1 mg/kg held for 
close to 24 hours.  
4. Known to be currently pregnant or actively breastfeeding++ 
• 
++ Patients that have a previous history of menopause, hysterectomy, or tubal ligation will not be 
required to perform a pregnancy test.   Female patients that do not meet this criterion will be asked 
to submit a urine sample, and will require a negative urine sample in order to proceed with study 
protocol.  Urine sample be collected pre-procedurally.  
5.  Impaired cognition 
6. Lower extremity motor deficit 
 
 
Research Activity 
 
Check all that apply and complete the appropriate sections as instructed.  
  
1. 
  Drug & Device:  Drugs for which an investigational new drug application is not required. Device for 
which (i) an investigational device exemption application is not required; or the medical device is 
cleared/approved for marketing and being used in accordance with its cleared/approved labeling. (Specify in 
the Methods section) 
 
2. 
  Blood:  Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture.  
 
3. 
  Biological specimens other than blood:  Prospective collection of human biological specimens by 
noninvasive means that may include: urine, sweat, saliva, buccal scraping, oral/anal/vaginal swab, sputum, 
hair and nail clippings, etc. 
 
4. 
  Tests & Procedures:  Collection of data through noninvasive tests and procedures routinely employed 
in clinical practice that may include: MRI, surface EEG, echo, ultrasound, moderate exercise, muscular 
strength & flexibility testing, biometrics, cognition testing, eye exam, etc.  (Specify in the Methods section) 
 

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5. 
  Data (medical record, images, or specimens):  Research involving use of existing and/or prospectively 
collected data. 
 
6. 
  Digital Record:  Collection of electronic data from voice, video, digital, or image recording. (Specify in 
the Methods section) 
 
7. 
  Survey, Interview, Focus Group:  Research on individual or group characteristics or behavior, survey, 
interview, oral history, focus group, program evaluation, etc.  (Specify in the Methods section) 
 
 
 NIH has issued a Certificate of Confidentiality (COC).  When checked, provide the institution and 
investigator named on the COC and explain why one was requested. ________________________ 

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HIPAA Identifiers and Protected Health Information (PHI) 
 
Protected health information is medical data that can be linked to the subject directly or through a combination 
of indirect identifiers.  
 
Recording identifiers (including a code) during the conduct of the study allows you to return to the medical 
record or data source to delete duplicate subjects, check a missing or questionable entry, add new data points, 
etc. De-identified data is medical information that has been stripped of all HIPAA identifiers so that it cannot be 
linked back to the subject. De-identified data is rarely used in the conduct of a research study involving a chart 
review.   
 
Review the list of subject identifiers below and, if applicable, check the box next to each HIPAA identifier 
being recorded at the time of data collection or abstraction.  Identifiers apply to any subject enrolled in the 
study including Mayo Clinic staff, patients and their relatives and household members.  
 
Internal refers to the subject’s identifier that will be recorded at Mayo Clinic by the study staff. 
External refers to the subject’s identifier that will be shared outside of Mayo Clinic. 
 
Check all that apply: 
INTERNAL 
EXTERNAL 
Name 
X 
 
Mayo Clinic medical record or patient registration number, lab accession, 
specimen or radiologic image number  
X 
 
Subject ID, subject code or any other person-specific unique identifying 
number, characteristic or code that can link the subject to their medical data   
 
 
Dates: All elements of dates [month, day, and year] directly related to an 
individual, their birth date, date of death, date of diagnosis, etc.   
Note: Recording a year only is not a unique identifier.  
X 
 
Social Security number 
 
 
Medical device identifiers and serial numbers 
 
 
Biometric identifiers, including finger and voice prints, full face photographic 
images and any comparable images 
 
 
Web Universal Resource Locators (URLs), Internet Protocol (IP) address 
numbers, email address 
X 
 
Street address, city, county, precinct, zip code, and their equivalent geocodes 
 
 
Phone or fax numbers 
 
 
Account, member, certificate or professional license numbers, health 
beneficiary numbers 
 
 
Vehicle identifiers and serial numbers, including license plate numbers 
 
 
Check ‘None’ when none of the identifiers listed above will be recorded, 
maintained, or shared during the conduct of this study.  (exempt category 4) 
 None 
 None 
 
 
 

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Data Analysis 
 
Power analyses and study endpoints are not required for minimal risk research, pilot or feasibility studies.  
 
  No statistical information. If checked, please explain: 
 
Statistical Considerations 
Randomization 
Subjects will be randomized into one of two study groups: mepivacaine or low-dose bupivacaine.  In order to 
ensure balance on the subject demographics between the two study groups, the subjects will be stratified on 
procedure (TKA vs THA), gender, age group (≥70 vs. <70) and BMI (≥32 vs. <32).  Within each stratum, 
subjects will be assigned to either of the two study groups using a computerized dynamic allocation program 
housed in an online application developed by personnel in the Division of Biomedical Statistics and 
Informatics. Using dynamic allocation will ensure that the subject allocation will remain balanced on the 
stratification factors and the study group assignment throughout the entire subject accrual phase.   
Sample Size 
An a priori power analysis was conducted using internal data from Mayo patients undergoing primary TJA with 
mepivacaine (N=6) and low-dose bupivacaine (N=5). In these two cohorts, standard deviations of the time to 
return of full lower extremity motor function were 37 minutes and 89 minutes, respectively, yielding a pooled 
estimate of the common standard deviation equal to 65.6 minutes. Assuming that similar variability will be 
observed in the proposed study, a sample of 150 subjects per group (300 total) will be required to have 80% 
power to detect a difference of at least 30 minutes in mean time to return to full lower extremity motor function 
between the 2 study groups. With the typical volume of the participating surgical group, we anticipate 
enrollment will be complete within 3 months. 
Endpoints 
 
Primary: Evaluate time to return of lower extremity motor function between mepivacaine and low-dose 
bupivacaine spinal anesthetic among patients undergoing primary THA and TKA. This will be assessed by 
measuring time from spinal anesthetic administration to postoperative achievement of Bromage 0 function 
(return of spontaneous ankle, knee, and hip movement) in the non-operative extremity. 
 
Secondary: Evaluate postoperative outcomes potentially related to anesthetic administration including pain 
scores, opioid consumption, urinary retention, transient neurologic symptoms, length of PACU stay, length of 
hospital stay, time to participation in physical therapy and walking distance with physical therapy. This will be 
determined by nurse and physical therapy charting and review of the medical record. 
 
Analysis 

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Dirk Larson will lead the data analysis effort. All pre- and post-operative data will be entered by the study 
coordinator into standardized Excel Spreadsheets and RedCap forms as appropriate. The data will primarily be 
collected by the lead Study Coordinator and checked for accuracy and completeness by Cody Wyles. All 
outcomes will be reported descriptively using appropriate summary statistics, including 95% confidence 
intervals, where appropriate. Because this is a prospective, randomized trial, no formal between-group 
comparisons of baseline covariates will be performed. The primary study outcome will be time to return of full 
lower extremity motor function. Secondarily, we will assess a variety of both continuous and categorical 
outcomes between groups including pain scores, opioid consumption, urinary retention, transient neurologic 
symptoms, length of PACU stay, length of hospital stay, time to participation in physical therapy and walking 
distance with physical therapy. Outcomes measured on a continuous scale, including time to full lower 
extremity motor function, length of PACU stay and hospital stay, time to participation in physical therapy, and 
walking distance will be compared between the 2 study groups using two-sample t-tests if the data are 
sufficiently normally distributed; otherwise non-parametric Wilcoxon rank sum tests will be used. Ordinal 
variables such as pain scores will be analyzed using non- parametric Wilcoxon rank sum tests.  Binary and 
nominal categorical outcomes will be compared between the study groups using chi-square tests or Fisher’s 
exact tests, if low expected cell counts are observed. All statistical tests will be two-sided and the threshold of 
statistical significance will be set at α = 0.05.   
While it is expected that the study enrollment will be complete in approximately 4 to 6 months, one interim 
analysis will be performed at 2 months, or once half the subjects have been enrolled, whichever comes first.  
The Lan-DeMets alpha spending function with O’Brien-Fleming type boundaries will be utilized to maintain 
the overall type 1 error rate at alpha=0.05, regardless of the timing of the analysis.