Conditions: Anesthetics, Local
Keywords: Anesthesia Mohs lidocaine ropivacaine bupivacaine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 75
Healthy volunteers: yes

Brief summary:
This is a research study to compare how long injectable pain medications (anesthetics) commonly used in dermatologic surgery are effective for. This study will compare a short-acting anesthetic, lidocaine with epinephrine, to one of two long-acting anesthetics (ropivacaine or bupivacaine). This study will also directly compare the duration of actions of ropivacaine and bupivacaine. The investigators hypothesize that the duration of anesthesia of short-acting anesthetics will not differ significantly from long-acting anesthetics at a single site and there will not be a significant difference between the two long-acting anesthetics at a single site.

Detailed description:
This study will compare the relative durations of local anesthetics within the same subject at a highly vascularized anatomic region of skin, the nasal ala. This study will test and compare the relative durations and efficacy of commonly used long acting (ropivacaine or bupivacaine) and short acting local anesthetics (lidocaine with epinephrine), delivered via local anesthesia. This study will use a modification of a previously published approach of non-invasive pinprick testing to assess the duration of local anesthetic.

Arms:
arm 1: Each site of the nasal ala will be tested for normal sensation using sterile 30-gauge needles. Other eligibility criteria will be confirmed. Participants in this arm will receive an injection of 0.5ml of . Xylocaine + epinephrine 1:100,000 (lidocaine + epinephrine 1:100,000), buffered 1/10 with sodium bicarb into one side of the nose (nasal ala) and 0.5ml of Naropin (ropivacaine) 0.5% into the opposite nasal ala. Laterality of each anesthetic administration will be randomly assigned for each patient. Subjects will be evaluated for duration of effect of anesthesia every 15 minutes on both sides of the face, until the patient reports return of a sharp sensation upon the pinprick test. arm 2: Each site of the nasal ala will be tested for normal sensation using sterile 30-gauge needles. Other eligibility criteria will be confirmed. Participants in this arm will receive an injection of 0.5ml of lidocaine + epinephrine into one side of the nose (nasal ala) and 0.5ml of Marcaine (bupivacaine) 0.5% into the opposite nasal ala. Laterality of each anesthetic administration will be randomly assigned for each patient. Subjects will be evaluated for duration of effect of anesthesia every 15 minutes on both sides of the face, until the patient reports return of a sharp sensation upon the pinprick test. arm 3: Each site of the nasal ala will be tested for normal sensation using sterile 30-gauge needles. Other eligibility criteria will be confirmed. Participants in this arm will receive an injection of 0.5ml of Naropin (ropivacaine) 0.5% into one side of the nose (nasal ala) and 0.5ml of Marcaine (bupivacaine) 0.5% into the opposite nasal ala. Laterality of each anesthetic administration will be randomly assigned for each patient. Subjects will be evaluated for duration of effect of anesthesia every 15 minutes on both sides of the face, until the patient reports return of a sharp sensation upon the pinprick test.

Interventions: intervention 1: lidocaine + epinephrine 1:100,000 intervention 2: Ropivacaine 0.5% Injectable Solution intervention 3: Bupivacaine 0.5% Injectable Solution
Intervention descriptions: intervention 1: 0.5 ml lidocaine + epinephrine 1:100,000, buffered 1/10 with sodium bicarb. intervention 2: 0.5 ml Ropivacaine 0.5% Injectable Solution intervention 3: 0.5ml bupivacaine 0.5%

Protocol document:
Prot_SAP_000.pdf: 
 
Page # i
TITLE:  Characterizing and Comparing the Duration of Local Anesthetic in Dermatologic Surgery
IRB Protocol #: 22-10025244
IND/IDE #: IND Exempt
Version Date: 04/07/2024
Funding Source(s): none
Principal Investigator:
Name: Kira Minkis, MD, PhD
Director of Mohs and Dermatologic Surgery 
Assistant Professor of Dermatology
Address: 1305 York Avenue, 9th Floor, New York, NY 10021
Telephone: 646-962-6647
Fax: 646-962-0033
E-mail address: kim9036@med.cornell.edu
Co-Investigators:
Name: Jeremy Orloff [Administrative Contact]
Address 1305 York Avenue, 9th Floor, New York, NY 10021
Telephone: 917-371-8676
Fax: 646-962-0033
E-mail address: jeo2018@med.cornell.edu
Name: Benedict Ho [Administrative Contact]
Address 1305 York Avenue, 9th Floor, New York, NY 10021
Telephone: 917-502-5230
Fax: 646-962-0033
E-mail address: beh2024@med.cornell.edu
Statistician:
Name: Debra D’Angelo
Address: 402 East 67th St, New York, NY 10021
Telephone: 646-962-8135
Fax: 646-962-0281
E-mail address: ded2011@med.cornell.edu
Participating Sites:  
Weill Cornell Medical College 
Department of Dermatology
1305 York Avenue, 9th Floor, New York, NY 10021
PI: Kira Minkis, MD, PhD
 
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Table of Contents
CONFIDENTIALITY STATEMENT......................................................................................V
LIST OF ABBREVIATIONS................................................................................................VI
SUMMARY OF CHANGES (PROTOCOL VERSION DATE 1-15-2024):.......................VII
1. PROTOCOL SUMMARY..................................................................................................1
1.1
Schema......................................................................................................................3
1.2
Study Objectives and End Points .........................................................................4
1.2.1 
Primary Objectives........................................................................................4
To compare the relative duration of commonly used local anesthetics (lidocaine 
+ epinephrine, ropivacaine and bupivacaine) as well as different volumes of the 
same local anesthetic, lidocaine with epinephrine, delivered subcutaneously at 
the nasal ala. ......................................................................................................................4
1.2.2
Secondary Objectives...................................................................................4
1.2.3 
Exploratory Objectives.................................................................................4
1.2.4
Primary Endpoints ........................................................................................4
1.2.5
Secondary Endpoints ...................................................................................4
2. BACKGROUND................................................................................................................4
2.1
Disease......................................................................................................................4
2.2
Investigational Agent/Device, or Surgical Treatment/Method..........................4
2.3
Rationale ...................................................................................................................7
2.4
 Risk/Benefit Assessment ......................................................................................9
2.4.1
Known Potential Risks .................................................................................9
2.4.2
Known Potential Benefits...........................................................................11
2.4.3
Assessment of Potential Risks and Benefits..........................................11
2.5
Correlative Studies Background .........................................................................12
3. STUDY DESIGN .............................................................................................................12
3.1
Overall Design........................................................................................................12
3.2
Scientific Rationale for Study Design.................................................................14
3.3
Justification for Dose............................................................................................15
3.4
End of Study Definition.........................................................................................15
4. SUBJECT SELECTION .................................................................................................15
4.1
Study Population ...................................................................................................15
4.2
Inclusion Criteria....................................................................................................15
4.3
Exclusion Criteria ..................................................................................................15
4.4
Lifestyle Considerations.......................................................................................15
4.5
Screen Failures ......................................................................................................16
4.6
Strategies for Recruitment and Retention .........................................................16
 
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5. REGISTRATION PROCEDURES..................................................................................16
5.1
Subject Registration (WCM only)........................................................................16
5.2 Subject Registration (Sub-sites).............................................................................17
6. STUDY PROCEDURES .................................................................................................17
6.1
Schedule of Assessments....................................................................................17
7. STUDY INTERVENTION................................................................................................18
7.1
Study Intervention/Device Description ..............................................................18
7.2
Availability ..............................................................................................................18
7.3
Acquisition and Accountability ...........................................................................18
7.4
Formulation, Appearance, Packaging, and Labeling.......................................18
7.5
Product Storage and Stability..............................................................................18
7.6
Preparation .............................................................................................................18
7.7
Dosing and Administration ..................................................................................19
7.7.1
Dosing Delays/Dose Modifications...........................................................19
7.8
General Concomitant Medication and Supportive Care Guidelines..............19
7.9
Duration of Therapy and Criteria for Removal from Study .............................19
7.10  Duration of Follow Up............................................................................................19
7.11 Measures to Minimize Bias: Randomization and Blinding ...............................19
7.12 Study Intervention/Follow-up Compliance..........................................................20
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...............................................................................20
8.1
Discontinuation of Study Intervention ...............................................................20
8.2
Participant Discontinuation/Withdrawal from the Study.................................20
8.3
Lost to Follow Up...................................................................................................20
9. CORRELATIVE/SPECIAL STUDIES............................................................................20
10.  MEASUREMENT OF EFFECT ...................................................................................20
10.1 Response Criteria....................................................................................................20
10.2 Duration of Response.............................................................................................21
10.3 Progression-Free Survival .....................................................................................21
10.4 Other Response Parameters .................................................................................21
11. DATA REPORTING / REGULATORY CONSIDERATIONS .....................................21
11.1 Data Collection ........................................................................................................21
11.1.1 REDCap..............................................................................................................21
11.2 Regulatory Considerations....................................................................................21
11.2.1 Institutional Review Board/Ethics Committee Approval............................21
11.2.2 Ethical Conduct of the Study..........................................................................22
11.2.3 Informed Consent.............................................................................................22
11.2.4 Compliance with Trial Registration and Results Posting Requirements 23
 
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11.2.5 Record Retention..............................................................................................23
12. STATISTICAL CONSIDERATIONS............................................................................23
12.1 Study Design/Endpoints ........................................................................................23
12.2 Sample Size/Accrual Rate......................................................................................23
12.3 Stratification Factors ..............................................................................................23
12.4 Analysis of Endpoints ............................................................................................24
12.4.1
Analysis of Primary Endpoints .................................................................24
12.4.2
Analysis of Secondary Endpoints ............................................................24
12.5 Interim Analysis.......................................................................................................24
12.6 Reporting and Exclusions......................................................................................24
12.6.1
Evaluation of Toxicity .................................................................................25
12.6.2
Evaluation of Response .............................................................................25
13. ADVERSE EVENT REPORTING REQUIREMENTS .................................................25
13.1 Adverse Event Definition .......................................................................................25
13.1.1
Investigational Agent or Device Risks (Expected Adverse Events)....25
13.1.2
Adverse Event Characteristics and Related Attributions .....................25
13.1.3
Recording of Adverse Events....................................................................26
13.1.4
Reporting of AE to WCM IRB.....................................................................26
13.1.5
Reporting Events to Participants..............................................................26
13.1.6
Events of Special Interest ..........................................................................26
13.1.7
Reporting of Pregnancy .............................................................................26
13.2 Definition of SAE .....................................................................................................26
13.2.1
Reporting of SAE to IRB.............................................................................26
13.2.2
Reporting of SAE to FDA [For Protocols Where WCMC is the 
Sponsor-Investigator] .................................................................................................26
13.3 AE/SAE Follow Up...................................................................................................27
13.4 Time Period and Frequency for Event Assessment and Follow Up................27
14. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS27
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO).........................................................................................................................27
14.1.2
Unanticipated Problem Reporting ............................................................27
15. DATA AND SAFETY MONITORING PLAN (DSMP).................................................28
16. REFERENCES..............................................................................................................30
Statement of Compliance
 
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The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
•
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
Confidentiality Statement
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCM, unless disclosure on ClinicalTrials.gov is federally required.
Weill Cornell Medicine
_________________________________________________________________
Institution Name
Kira Minkis, MD, PhD
_________________________
Principal Investigator’s Name      
 
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List of Abbreviations
AE
Adverse Event
CFR
Code of Federal Regulations
CRF
Case Report Form
CTSC
Clinical Translational Science Center 
DSMP
Data Safety Monitoring Plan
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICF
Informed Consent Form
IDE
Investigational Device Exemption 
IND
Investigational New Drug
IRB
Institutional Review Board
PHI
Protected Health Information
PI
Principal Investigator
REDCap
Research Electronic Data Capture
SAE
Serious Adverse Event
WCM
Weill Cornell Medicine
 
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Summary of Changes (Protocol Version Date 4-7-2024):
This amended protocol includes language to clarify that data from the fourth cohort (added in the 
previous amended protocol) will be analyzed separately from the data collected from the first three 
cohorts.
Language to this effect has been added to the protocol in relevant sections (all changes in red):
Page # 13: Study design, overall design. We have included the following text, “Data from this 
fourth cohort, which will compare two doses of the same anesthetic, will be analyzed separately 
from the data collected from cohorts 1-3.”
Page # 14: Table 2. In reviewing the protocol, we found a typo in Table 2 on page 14.  The 
comparison within for the fourth cohort is between two doses (0.5 ml and 1.0ml) of 
Lidocaine+epinephrine, not Ropivacaine as was erroneously included in the previous version. 
 
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Page # 1
1. Protocol Summary
Full Title:
Characterizing and Comparing the Duration of Local Anesthetic in 
Dermatologic Surgery   
Short Title:
Split Face Study of the Duration of Local Anesthetics 
Principal Investigator:
Kira Minkis MD, PhD
Study Description: 
This study will allow us to compare the relative durations of local 
anesthetics within the same subject at a highly vascularized 
anatomic region of skin, the nasal ala. We will test and compare 
the relative durations and efficacy of commonly used long acting 
(ropivacaine or bupivacaine) and short acting local anesthetics 
(lidocaine with epinephrine), delivered via local anesthesia. We 
will use a modification of a previously published approach of non-
invasive pinprick testing to assess the duration of local anesthetic. 
We hypothesize that the duration of anesthesia of short-acting 
anesthetics will not differ significantly from long-acting anesthetics 
at a single site and there will not be a significant difference 
between the two long-acting anesthetics at a single site.  
Additionally, we will investigate the role of anesthetic volume on 
the duration of action at highly vascular sites.
Sample Size:
N=100 patients total (N=25 in each of the following cohorts 
comparing local anesthetics: 1) lidocaine + epinephrine vs. 
ropivacaine, 2) lidocaine + epinephrine vs. bupivacaine, 3) 
ropivacaine vs. bupivacaine, 4) 0.5 ml lidocaine with epinephrine 
vs 1.0 ml lidocaine with epinephrine)
Enrollment:
This study will enroll up to 100 subjects and screen up to 125 
subjects.
Study Population:
Volunteers over the age of 18 will be included in the study. 
Volunteers under age of 18, those with previous adverse reactions 
to local anesthetics, those who are pregnant, those with altered 
mental status or those with a history of peripheral vascular 
disease or known diseases affecting nerve function will be 
excluded from the study.
Enrollment Period:
We anticipate it will take approximately 18 months to enroll the 
subjects.
Study Design:
Eligible participants will be randomized to receive two different 
local anesthetics (or two different volumes of the same local 
anesthetic) to be administered to both sides of the nose.  See 
Table 2 for the sequential cohorts to be enrolled. The 
dermatologic surgeon/PI (Dr. Kira Minkis, MD, PhD) will administer 
the local anesthetic. We will assay the duration of local anesthetic 
at 15-minute increments using a modification of the previously 
published non-invasive pinprick testing.  The co-investigator and 
participant will be blinded to the side (left or right) to which each 
anesthetic (or volume of the same local anesthetic) is injected. 
 
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Description of Sites/ 
Facilities Enrolling
Participants:
This is a single-site study at the Department of Dermatology at 
Weill Cornell Medicine.
Study Duration:
The study should take approximately 18 months to complete. In 
summary, 6 months will be needed for patient recruitment and  
study completion, and 12 months for data analysis and manuscript 
preparation/peer review process.
Participant Duration:
It will take 1 visit for each patient to complete the study. Each visit 
will last approximately 3-4 hours.
Primary Objective:
To compare the duration of commonly used local anesthetics in 
dermatologic surgery, including lidocaine + epinephrine, 
ropivacaine and bupivacaine, as well as two different volumes of 
the same local anesthetic, lidocaine with epinephrine, delivered 
subcutaneously at the nasal ala.
Secondary Objectives:
To correlate patient demographics (including age, BMI, gender, 
hair color and co-morbidities) with the relative duration of different 
local anesthetics.
Exploratory Objectives:
N/A
Primary Endpoints:
The primary endpoint will be the time to return to baseline 
sensation (in minutes), as measured by a modification of the 
previously published non-invasive pin-prick testing method, and 
recorded by the questionnaire.
Secondary Endpoints:
None
 
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1.1 Schema
Figure 1: Flow Diagram
Prior to
Enrollment
 
Visit 1
Time Point 
 
Total 100:  Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria; obtain history, document.
*Refer to Section 6.1, Schedule of Assessments
•
Perform baseline assessments
•
Administer study intervention
Final Assessments
•
Perform outcome evaluation
•
Adverse event evaluation
•
Data analysis per Section 12, Statistical 
Considerations
Arm 1
Lidocaine + 
epinephrine 
vs 
Ropivacaine
25 
participants
Randomize
Arm 2
Lidocaine + 
epinephrine 
vs 
Bupivacaine
25 
participants
Arm 3
Ropivacaine 
vs 
Bupivacaine
25 
participants
Arm 4
0.5 ml Lidocaine with 
epinephrine
Vs. 
1.0 ml Lidocaine with 
epinephrine
 
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1.2 Study Objectives and End Points
The purpose of this study is to investigate how the duration of local anesthetics differ 
when administered to areas of skin with high vascularity during dermatologic surgery.
1.2.1 Primary Objectives
To compare the relative duration of commonly used local anesthetics (lidocaine + 
epinephrine, ropivacaine and bupivacaine) as well as different volumes of the same local 
anesthetic, lidocaine with epinephrine, delivered subcutaneously at the nasal ala.
1.2.2
Secondary Objectives
To correlate patient demographics (including age, BMI, gender, hair color and co-
morbidities) with the relative duration of different local anesthetics.
1.2.3 Exploratory Objectives
None
1.2.4
Primary Endpoints
The primary endpoint will be the time to return to baseline sensation, as measured by a 
modification of the previously published non-invasive pin-prick testing method, and 
recorded by the questionnaire.
1.2.5
Secondary Endpoints
None
2. Background
2.1 Disease
None
2.2 Investigational Agent/Device, or Surgical Treatment/Method
The interventional agents used in this study include 3 commonly used local anesthetics– 
lidocaine with epinephrine, ropivacaine, and bupivacaine (brand name Marcaine). These 
agents will be utilized in applications consistent with standard of care in dermatologic 
surgery and many procedures across various disciplines of medical care. All 3 anesthetics 
are FDA approved for use as local anesthetics, therefore, are being used on-label. These 
applications are well studied, allowing investigators to understand their efficacy and other 
drug properties to be outlined in this section. No changes are anticipated in the agents used 
in this study.
 
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Xylocaine with epinephrine (lidocaine with epinephrine)(1)
Mechanism of action:
Lidocaine HCL stabilizes the neuronal membrane by inhibiting the ionic fluxes required 
for the initiation and conduction of impulses thereby effecting local anesthetic function.
Major route of elimination:
Lidocaine crosses the blood-brain barrier and placental barriers, possibly through 
passive diffusion and is rapidly metabolized by the liver. Both metabolites and 
unchanged drug are metabolized by the liver.
Safety profile:
Lidocaine has a good safety profile. Toxicity is determined by both total dose (usually 6-7 
mg/kg) and rate of absorption, which depends on local tissue blood flow and the use of 
vasoconstrictors such as epinephrine.(2) See section 2.4.1 Known Potential Risks for an 
overview.
Potential for drug interactions:
There are clinically significant drug interactions. Administration of local anesthetics with 
epinephrine to patients receiving monoamine oxidase inhibitors or tricyclic 
antidepressants may produce severe prolonged hypertension. Phenothiazines and 
butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent 
administration of vasopressors and ergot-type oxytocic drugs may cause severe 
persistent hypertension or cerebrovascular accidents.
Lidocaine should be used with caution in patients receiving other local anesthetics or 
agents structurally related to amide-type local anesthetics, since the toxic effects of 
these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy 
ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was 
reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a 
selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, 
such as fluvoxamine, given concomitantly during administration of Naropin, can interact 
with Naropin leading to increased ropivacaine plasma levels. Caution should be 
exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs 
known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and 
imipramine may also occur. Coadministration of a selective and potent inhibitor of 
CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 
hour after ketoconazole) caused a 15% reduction in in vivo plasma clearance of 
ropivacaine. Patients who are administered local anesthetics are at increased risk of 
developing methemoglobinemia when concurrently exposed to the following drugs, 
which could include other local anesthetics: articaine, benzocaine, bupivacaine, 
lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine.
Rationale for the starting dose and regimen chosen:
We plan to use a minimal effective dose of 0.5mL of 1% lidocaine with epinephrine 
1:100,000 as well as 1.0 ml of 1% lidocaine with epinephrine, a common dose for local 
anesthesia, in addition to local anesthesia required for the Mohs surgery.
Marcaine (bupivacaine)(3)
Mechanism of action:
 
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Bupivacaine is related chemically and pharmacologically to the aminoacyl local 
anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All 
three of these anesthetics contain an amide linkage between the aromatic nucleus and 
the amino, or piperidine group. They differ in this respect from the procaine-type local 
anesthetics, which have an ester linkage. Bupivacaine blocks the generation and the 
conduction of nerve impulses, presumably by increasing the threshold for electrical 
excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing 
the rate of rise of the action potential. In general, the progression of anesthesia is related 
to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, 
the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) 
proprioception, and (5) skeletal muscle tone.
Major route of elimination:
Amide-type local anesthetics such as bupivacaine are metabolized by the liver and 
excreted via the kidneys.
Safety profile:
The maximum single infiltration dose of bupivacaine is 2.5-3mg/kg.(2)
See section 2.4.1 Known Potential Risks for an overview.
Potential for drug interactions:
Bupivacaine should be used with caution in patients receiving other local anesthetics or 
agents structurally related to amide-type local anesthetics, since the toxic effects of 
these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy 
ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was 
reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a 
selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, 
such as fluvoxamine, given concomitantly during administration of Naropin, can interact 
with Naropin leading to increased ropivacaine plasma levels. Caution should be 
exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs 
known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and 
imipramine may also occur. Coadministration of a selective and potent inhibitor of 
CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 
hour after ketoconazole) caused a 15% reduction in in vivo plasma clearance of 
ropivacaine. Patients who are administered local anesthetics are at increased risk of 
developing methemoglobinemia when concurrently exposed to the following drugs, 
which could include other local anesthetics: articaine, benzocaine, bupivacaine, 
lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine.
Rationale for the starting dose and regimen chosen:
We plan to use a minimal effective dose of 0.5mL of 0.5% Marcaine (bupivacaine) in 
addition to local anesthesia required for the Mohs surgery.
Naropin (ropivacaine)(4)
Mechanism of action:
Ropivacaine is a member of the amino amide class of local anesthetics and is supplied 
as the pure S-(-)-enantiomer. Ropivacaine blocks the generation and the conduction of 
nerve impulses, presumably by increasing the threshold for electrical excitation in the 
nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise 
 
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of the action potential. In general, the progression of anesthesia is related to the 
diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the 
order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) 
proprioception, and (5) skeletal muscle tone.
Major route of elimination:
Metabolized by the liver and excreted via the kidneys.
Safety profile:
The maximum single infiltration dose of ropivacaine is 3-4 mg/kg.(2)
See section 2.4.1 Known Potential Risks for an overview.
Potential for drug interactions:
Ropivacaine should be used with caution in patients receiving other local anesthetics or 
agents structurally related to amide-type local anesthetics, since the toxic effects of 
these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy 
ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was 
reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a 
selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, 
such as fluvoxamine, given concomitantly during administration of Naropin, can interact 
with Naropin leading to increased ropivacaine plasma levels. Caution should be 
exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs 
known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and 
imipramine may also occur. Coadministration of a selective and potent inhibitor of 
CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 
hour after ketoconazole) caused a 15% reduction in in vivo plasma clearance of 
ropivacaine. Patients who are administered local anesthetics are at increased risk of 
developing methemoglobinemia when concurrently exposed to the following drugs, 
which could include other local anesthetics: articaine, benzocaine, bupivacaine, 
lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine.
Rationale for the starting dose and regimen chosen:
We plan to use a minimal effective dose of 0.5mL of 0.5% ropivacaine in addition to local 
anesthesia required for the Mohs surgery.
2.3 Rationale
Unlike other types of surgeries, patients undergoing dermatologic surgery are conscious and 
awake throughout the procedure. Perioperative anxiety, as can be caused by inadequate pain 
control, can lead to increased risk of surgical complications, including intraoperative and 
postoperative bleeding. Therefore, it is critical for physicians to minimize pain levels in order to 
maximize patient comfort throughout the surgery. While the time of onset and duration of local 
anesthetics is well defined, few studies to date have examined how different anatomical areas 
influence the duration of local anesthesia or how combination of different local anesthetics 
influences duration of anesthesia.  Earlier work completed by our research team (now in pre-
publication) has revealed clinically relevant differences in duration of both long and short acting 
local anesthetics between regions that differ in cutaneous vascularity.
 
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We conducted two prospective observational studies of patients undergoing Mohs surgery at a 
single academic institution. Patients with a history of adverse reactions to local anesthesia, 
peripheral vascular disease, neuropathy, or other impairment in nerve function were excluded. 
Patients less than 18 years old of age and those that were pregnant or breastfeeding were also 
excluded. Demographic and clinical information was collected. Baseline anxiety was recorded 
using the visual analog scale for anxiety (VAS-A). The nose and the shin were chosen to 
represent highly and poorly vascularized anatomic sites, respectively. Participants were 
anesthetized at each site with a subcutaneous injection of either 0.5 mL of buffered lidocaine 
1% + epinephrine 1:100,000 for our first study or 0.5 mL of 0.2% ropivacaine for our second 
study. Sensation was determined by pinprick prior to injection, at baseline, and every 15 
minutes until sensation returned or surgery concluded. The primary endpoint was time to return 
of pinprick sensation.
Our initial study utilizing lidocaine enrolled 25 patients. The mean age of the study cohort was 
68 years (range 23-95) with 15 men and 10 women. The duration of anesthesia was 
significantly shorter on the nose compared to the shin (p<0.0001). On the nose, there was an 
association between gender and duration of anesthesia. There was no correlation between 
baseline anxiety score, age, BMI, and duration of local anesthesia.
Our second study utilizing ropivacaine recruited 29 patients. The median age was 71.5 years 
(range 46-89) with 17 women and 12 men. The median duration of ropivacaine was 60.0 
minutes (45.0, 60.0) on the nose and 210.0 minutes (165.0, NA) on the shin. 22 of 29 (75.9%) 
participants did not regain sensation on the shin by study end, therefore the median duration 
was underestimated, and the upper quartile was unable to be determined. As shown in Figure 1, 
the Kaplan-Meier survival curve indicated that the duration of ropivacaine was higher at the shin 
than the nose (log-rank test, χ2=56.96; P<.0001). The percentage of subjects that regained 
sensation within 1-hour was 75.9% on the nose vs. 3.5% on the shin (χ2=21.00, p<0.0001). 
Participants with history of hypertension were more likely to regain sensation on the nose by 60 
minutes, though this did not achieve statistical significance (OR 6.16; 95% CI, 0.81 to 46.76; 
p=.079). Comorbidities including underlying anxiety/depression, diabetes, and kidney disease 
did not significantly impact duration of ropivacaine action on the nose.
Our results suggest that the duration of subcutaneous lidocaine + epinephrine and ropivacaine 
vary by anatomic region. We hypothesize that differences in vascularity of the nose and the shin 
contributes to these results. The duration of anesthesia was shorter in highly vascularized 
regions such as the nose, compared to less vascularized regions such as the shin. This study 
emphasizes a potential gap in effective pain control during dermatologic surgery, but also an 
opportunity to intervene to improve our patients’ surgical experience.
Given these findings, it is crucial that we now specifically compare reportedly long-acting and 
short acting anesthetics in highly vascularized tissue of anatomic regions commonly operated 
on by dermatologic surgeons. Furthermore, we will compare two different volumes of a single 
long-acting anesthetic (lidocaine with epinephrine) to determine the role that the quantity of 
anesthetic injected may play in duration of action in this area of particularly high vascularity. In 
such highly vascularized tissue, adjuvant use of reported long-acting anesthetics (or increased 
volume of anesthetic) may not confer additional benefit over a widely available and more cost 
effective short-acting lidocaine solution.
Adjuvant use of a long-acting anesthetic such as bupivacaine to prolong anesthesia is common 
with the intention to provide relief from multiple injections of shorter-acting lidocaine.(5) 
Additionally, pain is frequently reported on postoperative days 0 to 3, leading some to 
recommend the use of long-acting local anesthetics to prevent over-prescription or a gap in pain 
coverage.(6, 7) Adequate pain management both during and after surgery may improve 
recovery, hasten patient mobilization, and reduce postoperative complications. However, long-
acting anesthetics such as the commonly used bupivacaine are costly, with 50 milliliters of 0.5% 
 
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injectable solution costing $66.19. By comparison, 500 milliliters of 1:100000-1% 
epinephrine/lidocaine injectable solution costs $64.57.(8) Further, patients may actually 
experience shorter than expected anesthesia. In a double-blinded randomized block design of 
25 subjects, Collins et al reported no difference in the duration of anesthesia on the forearm 
between lidocaine + epinephrine, bupivacaine + epinephrine, and 2 mixtures of bupivacaine and 
lidocaine + epinephrine.(9)
The split-face design of this proposed study serves the role of advancing our understanding of a 
common clinical practice in dermatologic surgery.  Split-face design has been used widely in 
dermatological surgery research to answer a diverse set of topics from injectable associated 
pain to the efficacy of jawline augmentation techniques.(10, 11) Similarly, split-scar studies have 
been utilized to evaluate different closure techniques of a single defect.(12) With this approach, 
two different anesthetics will be administered to different sides of the body in the same subject. 
For example, short acting lidocaine may be injected subcutaneously to the right side of the 
nose, while long-acting bupivacaine is injected to the left side of the nose. This approach allows 
us to compare these local anesthetics. 
Despite advances in our understanding of mechanisms of action of local anesthetics and their 
application to outpatient surgeries, to date, there have been no studies evaluating how the 
duration of different anesthetics compare to one another when administered to skin with high 
vascularity. Based on the aforementioned studies and our own experience, we hypothesize that 
given the highly vascularized nature of the face and hand, the duration of long-acting 
anesthetics (ropivacaine or bupivacaine) will not differ significantly from the duration of short-
acting anesthetics (lidocaine ± epinephrine). Further, we hypothesize that the duration of 
ropivacaine will not differ significantly from bupivacaine, two different long-acting anesthetics 
with different reported durations of action. Defining the duration of local anesthetic based on 
anatomical regions will help guide better practice management, safe use of anesthesia and 
adequate pain control for patients undergoing dermatologic procedures.
2.4  Risk/Benefit Assessment 
2.4.1
Known Potential Risks
Xylocaine with epinephrine (lidocaine with epinephrine)(1)
•
WARNINGS: XYLOCAINE INJECTIONS FOR INFILTRATION AND 
NERVE BLOCK SHOULD BE EMPLOYED ONLY BY CLINICIANS WHO 
ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-
RELATED TOXICITY AND OTHER ACUTE EMERGENCIES THAT 
MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED AND THEN 
ONLY AFTER ENSURING THE IMMEDIATE AVAILABILITY OF 
OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY 
EQUIPMENT AND THE PERSONNEL NEEDED FOR PROPER 
MANAGEMENT OF TOXIC REACTIONS AND RELATED 
EMERGENCIES. (See  also ADVERSE REACTIONS and 
PRECAUTIONS.) DELAY IN PROPER  MANAGEMENT OF DOSE-
RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE 
AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT 
OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH. 
 
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•
Xylocaine with epinephrine solutions contain sodium metabisulfite, a 
sulfite that may cause allergic-type reactions including anaphylactic 
symptoms and life-threatening or less severe asthmatic episodes in 
certain susceptible people. The overall prevalence of sulfite sensitivity in 
the general population is unknown and probably low. Sulfite sensitivity is 
seen more frequently in asthmatic than in non-asthmatic people. For 
more information on Precautions, please see cited package insert.
Marcaine (bupivacaine)(3)
•
MARCAINE is contraindicated in patients with a known hypersensitivity to 
it or to any local anesthetic agent of the amide-type or to other 
components of MARCAINE solutions. 
•
LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY 
CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND 
MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE 
EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE 
EMPLOYED, AND THEN ONLY AFTER INSURING THE IMMEDIATE 
AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, 
CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE 
PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT 
OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See also 
ADVERSE REACTIONS, PRECAUTIONS, and OVERDOSAGE.) DELAY 
IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, 
UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED 
SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, 
CARDIAC ARREST AND, POSSIBLY, DEATH. 
•
Mixing or the prior or intercurrent use of any other local anesthetic with 
MARCAINE cannot be recommended because of insufficient data on the 
clinical use of such mixtures. 
•
MARCAINE with epinephrine 1:200,000 contains sodium metabisulfite, a 
sulfite that may cause allergictype reactions including anaphylactic 
symptoms and life-threatening or less severe asthmatic episodes in 
certain susceptible people. The overall prevalence of sulfite sensitivity in 
the general population is unknown and probably low. Sulfite sensitivity is 
seen more frequently in asthmatic than in nonasthmatic people. Single-
dose ampuls and single-dose vials of MARCAINE without epinephrine do 
not contain sodium metabisulfite. For more information on Precautions, 
please see cited package insert.
Naropin (ropivacaine)(4)
•
CONTRAINDICATIONS: Naropin is contraindicated in patients with a 
known hypersensitivity to ropivacaine or to any local anesthetic agent of 
the amide type. 
•
Local anesthetics should only be administered by clinicians who are well 
versed in the diagnosis and management of doserelated toxicity and 
other acute emergencies which might arise from the block to be 
employed, and then only after insuring the immediate (without delay) 
availability of oxygen, other resuscitative drugs, cardiopulmonary 
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management of toxic reactions and related emergencies (see also 
ADVERSE REACTIONS, PRECAUTIONS and MANAGEMENT OF 
LOCAL ANESTHETIC EMERGENCIES). Delay in proper Reference ID: 
4344175 9 management of dose-related toxicity, underventilation from 
any cause, and/or altered sensitivity may lead to the development of 
acidosis, cardiac arrest and, possibly, death. 
•
Naropin should be used with caution in patients receiving other local 
anesthetics or agents structurally related to amide-type local anesthetics, 
since the toxic effects of these drugs are additive. 
•
Patients treated with class III antiarrhythmic drugs (e.g., amiodarone) 
should be under close surveillance and ECG monitoring considered, 
since cardiac effects may be additive. 
•
Methemoglobinemia Cases of methemoglobinemia have been reported in 
association with local anesthetic use. Although all patients are at risk for 
methemoglobinemia, patients with glucose-6- phosphate dehydrogenase 
deficiency, congenital or idiopathic methemoglobinemia, cardiac or 
pulmonary compromise, infants under 6 months of age, and concurrent 
exposure to oxidizing agents or their metabolites are more susceptible to 
developing Reference ID: 4344175 10 clinical manifestations of the 
condition. If local anesthetics must be used in these patients, close 
monitoring for symptoms and signs of methemoglobinemia is 
recommended. Signs of methemoglobinemia may occur immediately or 
may be delayed some hours after exposure, and are characterized by a 
cyanotic skin discoloration and/or abnormal coloration of the blood. 
Methemoglobin levels may continue to rise; therefore, immediate 
treatment is required to avert more serious central nervous system and 
cardiovascular adverse effects, including seizures, coma, arrhythmias, 
and death. Discontinue Naropin and any other oxidizing agents. 
Depending on the severity of the signs and symptoms, patients may 
respond to supportive care, i.e., oxygen therapy, hydration. A more 
severe clinical presentation may require treatment with methylene blue, 
exchange transfusion, or hyperbaric oxygen. For more information on 
Precautions, please see cited package insert.
2.4.2
Known Potential Benefits
There is no benefit to the individual participant.  The results of this study will help 
inform choice of local anesthetics in dermatologic surgery.
2.4.3
Assessment of Potential Risks and Benefits
The maximum safe doses of commonly used anesthetics are known. Allergies to local 
anesthetic are also exceedingly rare, with allergic reactions to lidocaine representing only 1% of 
all adverse reactions.(13) The suggested maximum single infiltration dose of Lidocaine + 
epinephrine is 6-7 mg/kg, bupivacaine is 2.5-3 mg/kg, and ropivacaine is 3-4 mg/kg.(2) For 
example, a 58kg (~130 lb) individual may not exceed a single dose of 40.6 mL of lidocaine, or 
34.8 mL of bupivacaine, or 116 mL of ropivacaine at a time. We plan to use a minimal effective 
 
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dose of 0.5mL of each anesthetic per site, in addition to local anesthesia required for the Mohs 
surgery. We do not anticipate any side effects or anesthetic toxicity. As such, the study poses 
minimal risk to the patients. 
No agents in this study will be mixed, though their use will be concurrent at separate sites.  The 
simultaneous use of short and long-acting local anesthetics is considered safe and is common 
in Mohs surgery, having been studied extensively.(5) 
Risk of the additive effects of Ropivacaine with Class III anti-arrhythmics is mitigated given the 
small doses used in this study as  systemic absorption of these local anesthetics will be 
minimal.   Though there is a small risk of induced methemoglobinemia with local anesthetics, 
this risk will be mitigated as patients will be monitored for the duration of the study (3-4 hours) 
and instructed to seek immediate medical attention if they become symptomatic. 
There may be a small risk of ecchymosis at the injection site, however we will use a small 
quantity of injection and a 30-gauge needle to minimize this risk.  The risk of infection will be 
minimal due to appropriate skin preparation with antiseptic. We do not anticipate any adverse 
reactions in this study. The knowledge gained from this study which aims to improve patient 
comfort, anxiety and thus risk of bleeding and other associated risks, and reduce the overall 
amount of local anesthetic given by potentially revealing the futility in additional injections. This 
far outweighs the minimal risk associated with additional doses of commonly used local 
anesthetics utilized as standard of care. To this end, we’ve completed a similar study utilizing 
the same amount of a single anesthetic in >50 participants without a single adverse event, 
including minimal risks such as ecchymosis at the site of injection.
2.5 Correlative Studies Background
Not applicable.
3. Study Design
3.1 Overall Design
For this proposed observational study, we will compare the duration of local anesthetics 
(Lidocaine + epinephrine, ropivacaine and bupivacaine)at a highly vascularized region of 
the skin, the nasal ala. 
Subject recruitment: Volunteers will be recruited from the general population as well as 
current patients undergoing MMS. Given that MMS often takes multiple hours, interested 
patients will be eligible to participate in the study during their MMS day as long as 
relevant injection sites are not involved in their surgery.   
Intervention: After receiving written informed consent from each subject, each site of the 
nasal ala will be tested for normal sensation using sterile 30-gauge needles.  Other 
eligibility criteria will be confirmed.  Once determined to be eligible, participants will be 
randomized to one of the following 3 groups comparing local anesthetics: 1) lidocaine + 
epinephrine vs. ropivacaine, 2) lidocaine + epinephrine vs. bupivacaine, 3) ropivacaine 
vs. bupivacaine.  Participants in the trial who are recruited after these three initial groups 
 
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have been fully enrolled will join a fourth cohort.  Participants in this fourth cohort will 
receive two different volumes of the same local anesthetic (0.5 ml and 1.0 ml lidocaine 
with epinephrine).
Data from this fourth cohort, which will compare two doses of the same anesthetic, will 
be analyzed separately from the data collected from cohorts 1-3.  
Laterality of each anesthetic (or volume of anesthetic) administration will also be 
randomly assigned for each patient.  Previous studies have utilized alcohol-sterilized 
safety pins to test for sensation, however, using sterile needles will be more clinically 
relevant to dermatologic surgery[14]. Furthermore, using a sterile needle will remove any 
risk of infection compared to using a safety pin. The injection sites will be cleansed with 
an isopropyl alcohol swab, and allowed to dry. 0.5mL of local anesthetic will be injected 
into the skin of each participant by the one dermatologic surgeon (PI of the study, Dr. 
Kira Minkis, KM). Dr. Minkis will be unblinded to the laterality of the anesthetics and will 
not be involved in further assessments.
Sites: In order to compare the duration of different anesthetics, we will utilize a split-face 
design (figure 2). 
Figure 2: Schematic of the proposed split-face study design comparing long-acting to 
short-acting anesthetic at the face.
Randomization, blinding and anesthetic choice: For this study, there will be two different 
investigators taking part in the intervention and assessment. KM will inject the local 
anesthetic in each patient, while the co-investigator will assess for sensation and 
administer surveys. The anesthetics of interest include lidocaine + epinephrine, 
ropivacaine, and bupivacaine. For each of the first three cohorts, 2 of 3 anesthetics will 
be utilized and the duration compared to one another at a single site. For the fourth 
cohort, two volumes of a single local anesthetic will be used (0.5 ml and 1.0 ml lidocaine 
with epinephrine). As each anesthetic is injected to the mirror opposite side at each site, 
the side at which a single anesthetic will be injected will be randomized as follows: Each 
of the 2 anesthetics for a single cohort will be numbered 1 or 2. A randomized list of will 
be generated for each subject of the cohort as outlined in table 1 to determine which 
anesthetic (1 or 2) will be injected to which side of the chosen anatomic site (Left or 
Right). For each subject, a card will be created and held within a folder within the clinic 
space to guide KM in which anesthetic will be injected into which side. KM will not be 
blinded to the anesthetic choice and corresponding side, but the co-investigator 
 
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assessing for sensation will not have access to the list or card until study end, at which 
the data sheet will be corrected with the anesthetic choice for each side, thus blinding 
the co-investigator and participant to anesthetic choice during the study.
Table 1. An example of a randomized list of anesthetic choice and side of site 
association.
Subject ID
Right
Left
1
1
2
2
2
1
3
1
2
Cohorts: Each cohort has been outlined below..
Table 2. Outline of cohorts.
Cohort
Sample 
size (n)
Site
Route
Anesthetic A
Anesthetic B
1
25
Nasal ala
Subcutaneous 
local injection
Lidocaine + 
epinephrine
Ropivacaine
2
25
Nasal ala
Subcutaneous 
local injection
Lidocaine + 
epinephrine
Bupivacaine
3
25
Nasal ala
Subcutaneous 
local injection
Ropivacaine
Bupivacaine
4
25
Nasal ala
Subcutaneous 
local injection
0.5 ml 
Lidocaine+ 
epinephrine
1.0 ml 
Lidocaine+ 
epinephrine
Assessment of anesthesia: Subjects will be evaluated for duration of effect of anesthesia 
every 15 minutes on both sides of the face, until the patient reports return of a sharp 
sensation upon the pinprick test. The tester and the participants will be blinded to the 
laterality of the anesthetic. The return of the sensitivity will be measured by binary 
outcomes (yes/no) using a standardized template (see supporting documentation). The 
proposed local anesthetics have a quick onset (60 second-5 minutes), and a duration 
time of 60-400 mins. Thus, we will begin conducting the modified pinprick test prior to 
the injection (baseline response), immediately following injection, and at 15-minute 
intervals until return to baseline.
3.2 Scientific Rationale for Study Design
Perioperative anxiety, which can lead to elevated blood pressure and syncope, is a risk 
factor for intraoperative and postoperative bleeding. By delineating the duration of 
anesthesia by anatomical regions, we can intervene and provide additional anesthesia 
earlier before the patients experience pain. This will ensure patients will have maximal 
comfort and decreased anxiety throughout their surgical procedure by appropriately re-
anesthetizing areas in a site-specific manner, or using longer acting anesthetics. 
Characterizing and defining the duration of local anesthesia will allow clinicians to better 
 
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utilize the appropriate frequency of injection of lidocaine in different anatomical sites.  A 
better knowledge of the duration of action of local anesthetic would ensure patient 
comfort when operating at specific anatomical regions.
3.3 Justification for Dose 
We plan to use a minimal effective dose of 0.5mL of 1% lidocaine with epinephrine 
1:100,00, a common dose for local anesthesia as required for Mohs surgery. We will 
also use a dose 1.0 mL of 0.5% lidocaine with epinephrine in order to measure the 
difference that the volume of anesthetic used makes in a highly vascular area.
We plan to use a minimal effective dose of 0.5mL of 0.5% Marcaine (bupivacaine), a 
common dose for local anesthesia as required for Mohs surgery.
We plan to use a minimal effective dose of 0.5mL of 0.5% ropivacaine, a common dose 
for local anesthesia as required for Mohs surgery.  
3.4 End of Study Definition
Single visit study
4. Subject Selection
4.1 Study Population
Volunteers who meet the inclusion and exclusion criteria will be eligible for participation in 
this study. Current patients undergoing MMS will be eligible to participate in the study.
4.2 Inclusion Criteria
1.
Male or female ≥ 18 years of age
2. Normal skin sensation at both nasal ala assessed by pinprick
3. Ability to provide informed consent
4.3 Exclusion Criteria 
1.
Previous adverse reaction to local anesthetic or any components of the local anesthetics 
being evaluated
2.
Pregnant or breastfeeding volunteers (assessed by self-report)
3.
Patients taking monoamineoxidase inhibitors (MAOI) or antidepressants of the triptyline 
or imipramine types
4.4 Lifestyle Considerations
 
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Not applicable
4.5 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently randomly assigned to the study intervention or entered in the study. A 
minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) will not be 
rescreened.
4.6 Strategies for Recruitment and Retention
•Anticipated accrual rate will be 50%. The target sample size will include both women 
and men, regardless of the race and ethnicity. 
•We will recruit at 1 site only (Department of Dermatology, Weill Cornell Medicine) and 
we anticipate a total of 75 patients will be recruited.  Each patient will be randomized to 
one of 3 cohorts in which the following local anesthetics will be compared: 1) Lidocaine + 
epinephrine vs. Ropivacaine, 2) Lidocaine + epinephrine vs. Bupivacaine, 3) 
Ropivacaine vs. Bupivacaine.  There will be 25 patients in each cohort following 
randomization.  
•Print advertisement (local recruitment flyers), online advertisement and word of mouth 
will be used to recruit participants. 
•The source of participants will be the general public, previous and current MMS patients 
who will agree to participate in the study. 
•Potential participants will be approached by the study PI and research assistants. The 
research team will explain the purpose of the study, and convey that the participation is 
voluntary and will not influence future treatments directly. 
•Patients will be consented in the clinic after recruitment and screening. They will be 
provided with a copy of the consent to review and take with them. 
•Vulnerable participants, such as those who lack consent capacity, including the 
mentally ill, prisoners, cognitively impaired participants, children, will not be recruited or 
enrolled in the study.
5. Registration Procedures
5.1 Subject Registration (WCM only)
 
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Subjects will be registered within the WRG-CT as per the standard operating procedure 
for Subject Registration. 
5.2 Subject Registration (Sub-sites)
Not applicable
6. Study Procedures
6.1 Schedule of Assessments
Table 3. Schedule of trial events
Visit 
1
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
Vital signs
X
Height
X
Weight
X
Baseline pinprick  
evaluation
X
Confirm 
eligibility/random
ization
Study product 
administration
X
Adverse event 
evaluation 
   
X
Outcome 
evaluation: 
Pinprick test 
X
 
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during the 
procedure 
7. Study Intervention
7.1 Study Intervention/Device Description  
The agents utilized in the study intervention include 3 local anesthetics.  Xylocaine + 
epinephrine 1:100,000 (lidocaine + epinephrine 1:100,000), buffered 1/10 with sodium 
bicarb, Marcaine (bupivacaine) 0.5% and Naropin (ropivacaine) 0.5%. All anesthetics will 
be drawn up using 18-gauge syringe needles into 1cc syringes.  All injections will be 
done with 30-gauge needs.
7.2 Availability
The agents used in this study are available in the PI’s dermatology practice, supplied by 
WCM Department of Dermatology.
7.3 Acquisition and Accountability 
Agent Inventory Records/Device Logs – The investigator, or a responsible party 
designated by the investigator, will maintain a careful record of the inventory of study 
medications and adhere to relevant policies regarding storage of medications. 
7.4 Formulation, Appearance, Packaging, and Labeling 
This study will utilize existing supply channels to obtain drug.  These are generally 
multiuse vials. The specific brand and manufacturer may vary over the course of the 
study.
7.5 Product Storage and Stability
All agents should be stored at room temperature, approximately 25C (77F) and 
protected from light.
7.6 Preparation
0.5 mL in syringes of each anesthetic will be prepared by practice staff. Xylocaine + 
epinephrine 1:100,000 (lidocaine + epinephrine 1:100,000) is buffered with sodium 
bicarbonate (1/10). Otherwise 0.5 mL of each anesthetic will be drawn directly from 
manufacturing bottle.  All anesthetics will be drawn up using 18-gauge syringe needles 
 
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into 1cc syringes.  All injections will be done with 30-gauge needs. 
7.7 Dosing and Administration
7.7.1
Dosing Delays/Dose Modifications
NA
7.8 General Concomitant Medication and Supportive Care Guidelines
NA
7.9 Duration of Therapy and Criteria for Removal from Study
In this section, please describe the duration of study therapy and reasons for 
discontinuation from therapy. 
Example text provided as a guide, customize as needed:  
This study will require a single visit. The study termination guidelines are as follows:
Subject’s voluntary withdrawal
•
Return to normal sensation of both sides
7.10  Duration of Follow Up
NA
7.11 Measures to Minimize Bias: Randomization and Blinding 
For this study, there will be two different investigators taking part in the intervention and 
assessment. KM will inject the local anesthetic in each patient, while the co-investigator 
will assess for sensation and administer surveys. The anesthetics of interest include 
lidocaine + epinephrine, ropivacaine, and bupivacaine. For each cohort, 2 of 3 
anesthetics will be utilized and the duration compared to one another at a single site. As 
each anesthetic is injected to the mirror opposite side at each site, the side at which a 
single anesthetic will be injected will be randomized as follows: Each of the 2 anesthetics 
for a single cohort will be numbered 1 or 2. A randomized list of will be generated for 
each subject of the cohort as outlined in table 1 to determine which anesthetic (1 or 2) 
will be injected to which side of the chosen anatomic site (Left or Right). For each 
subject, a card will be created and held within a folder within the clinic space to guide 
KM in which anesthetic will be injected into which side. KM will not be blinded to the 
anesthetic choice and corresponding side, but the co-investigator assessing for 
sensation will not have access to the list or card until study end, at which the data sheet 
will be corrected with the anesthetic choice for each side, thus blinding the co-
investigator and participant to anesthetic choice during the study. 
Each patient will be randomized to one of 3 cohorts in which the following local 
anesthetics will be compared: 1) Lidocaine + epinephrine vs. Ropivacaine, 2) Lidocaine 
+ epinephrine vs. Bupivacaine, 3) Ropivacaine vs. Bupivacaine.  There will be 25 
patients in each cohort following randomization. See table 2.
 
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7.12 Study Intervention/Follow-up Compliance
Not applicable.
8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal
8.1 Discontinuation of Study Intervention
Each participant will receive 2 injections as the intervention, which will take place during 
a single visit without further intervention. If the participant discontinues from the study 
intervention, such as refusing the second injection, they will not be included in the study 
as the primary endpoint will not be obtainable/measurable.
8.2 Participant Discontinuation/Withdrawal from the Study
Participants are free to withdraw from participation in the study at any time upon request.
An investigator may discontinue or withdraw a participant from the study for the following 
reasons:
•
Participant unable to receive the second injection or refuses the second injection
The reason for participant discontinuation or withdrawal from the study will be recorded 
on the Case Report Form (CRF). Subjects who sign the informed consent form and are 
randomized but do not receive the study intervention may be replaced.  Subjects who 
sign the informed consent form, and are randomized and receive the study intervention, 
and subsequently withdraw, or are withdrawn or discontinued from the study, will be 
replaced.
8.3 Lost to Follow Up
Not applicable.
9. Correlative/Special Studies 
Not applicable
10.  Measurement of Effect
10.1 Response Criteria
The primary aim of this study is to determine whether the time to return to baseline 
sensation (in minutes) differs significantly between each pair of anesthetics.  Since each 
 
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patient will receive two anesthetics, we will calculate the difference in anesthetic 
durations measured by pin-prick test in minutes for each patient and perform a paired t-
test within each cohort to assess whether time to return to baseline sensation 
significantly differed.  
10.2 Duration of Response 
Not applicable.
10.3 Progression-Free Survival 
Not applicable.
10.4 Other Response Parameters
None
11. Data Reporting / Regulatory Considerations
11.1 Data Collection
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, efficacy, and adverse event data for all enrolled subjects.  
11.1.1 REDCap
REDCap (Research Electronic Data Capture) is a free data management 
software system that is fully supported by the Weill-Cornell Medical Center 
CTSC.  It is a tool for the creation of customized, secure data management 
systems that include Web-based data-entry forms, reporting tools, and a full 
array of security features including user and group based privileges, 
authentication using institution LDAP system, with a full audit trail of data 
manipulation and export procedures.  REDCap is maintained on CTSC-owned 
servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported 
through a multi-institutional consortium led by the Vanderbilt University CTSA.
11.2 Regulatory Considerations
11.2.1 Institutional Review Board/Ethics Committee Approval 
As required by local regulations, the Investigator will ensure all legal aspects are covered, 
and approval of the appropriate regulatory bodies obtained, before study initiation. 
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be 
submitted to the appropriate Ethics Committee. Written approval of the study and all 
relevant study information must be obtained before the study center can be initiated or the 
IP is released to the Investigator. Any necessary extensions or renewals of IRB approval 
must be obtained for changes to the study, such as amendments to the protocol, the ICF, 
 
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or other study documentation. The written approval of the IRB together with the approved 
ICF must be filed in the study files. 
The Investigator will report promptly to the IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. The Investigator will submit 
written summaries of the study status to the IRB as required. On completion of the study, 
the IRB will be notified that the study has ended. 
All agreed protocol amendments will be clearly recorded on a protocol amendment form 
and will be signed and dated by the original protocol approving signatories. All protocol 
amendments will be submitted to the relevant institutional IRB for approval before 
implementation, as required by local regulations. The only exception will be when the 
amendment is necessary to eliminate an immediate hazard to the trial participants. In this 
case, the necessary action will be taken first, with the relevant protocol amendment 
following shortly thereafter. 
Once protocol amendments or consent form modifications are implemented at the lead 
site, Weill Cornell Medicine, updated documents will be provided to participating sites, as 
applicable. Weill Cornell Medicine must approve all consent form changes prior to local 
IRB submission. 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the regulatory authorities 
will be notified that the study has ended. 
11.2.2 Ethical Conduct of the Study 
The Investigators and all parties involved should conduct this study in adherence to the 
ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines and the 
applicable national and local laws and regulatory requirements. 
This study will be conducted under a protocol reviewed and approved by the applicable 
ethics committees and investigations will be undertaken by scientifically and medically 
qualified persons, where the benefits of the study are in proportion to the risks.
11.2.3 Informed Consent
The investigator or qualified designee must obtain documented consent according to ICH-
GCP and local regulations, as applicable, from each potential subject or each subject’s 
legally authorized representative prior to participating in the research study. Subjects who 
agree to participate will sign the approved informed consent form and will be provided a 
copy of the signed document.  
The initial ICF, any subsequent revised written ICF and any written information provided 
to the subject must approved by IRB prior to use. The ICF will adhere to IRB requirements, 
applicable laws and regulations.Consent will not be remote or electronic, but instead by 
signature on paper record kept on file in a secure location within the PI’s office.
 
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11.2.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to http://www.clinicaltrials.gov. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.
11.2.5 Record Retention
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced.  After completion of the study, all 
documents and data relating to the study will be kept in an orderly manner by the 
Investigator in a secure study file.  Essential documents should be retained for 2 years 
after the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the IP. In addition, all subjects medical records 
and other source documentation will be kept for the maximum time permitted by the 
hospital, institution, or medical practice.  
12. Statistical Considerations
12.1 Study Design/Endpoints
Eligible participants will be randomized into one of three cohorts and receive two 
different local anesthetics (Lidocaine + epinephrine vs Ropivacaine, Lidocaine + 
epinephrine vs Bupivacaine or Ropivacaine vs Bupivacaine) administered to both [sides 
of the nose].  We will assay the duration of local anesthetic at 15-minute increments 
using a modification of the previously published non-invasive pinprick testing. The co-
investigator and participant will be blinded to the side (left or right) to which each 
anesthetic is injected. The primary endpoint will be the time to return to baseline 
sensation (in minutes), as measured by a modification of the previously published non-
invasive pin-prick testing method, and recorded by the questionnaire.
12.2 Sample Size/Accrual Rate
We anticipate recruiting 75 participants for this study.  This sample size is based on patient 
census and other logistical factors.  We will randomize each patient to one of three 
anesthetic comparison cohorts (as shown in Table 2), resulting in 25 patients per cohort.  
Within each cohort, the laterality of each anesthetic will also be randomized for each patient. 
We will aim to recruit all participants by 5 months. In previous work, we’ve recruited a cohort 
of 25 participants in 4-5 weeks.     
12.3 Stratification Factors 
 
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Not applicable.
 12.4 Analysis of Endpoints
12.4.1 Analysis of Primary Endpoints
The primary aim of this study is to determine whether the time to return to baseline 
sensation (in minutes) differs significantly between each pair of anesthetics.  Since each 
patient will receive two anesthetics, we will calculate the difference in anesthetic 
durations for each patient and perform a paired t-test within each cohort to assess 
whether time to return to baseline sensation significantly differed.  Our hypothesis is that 
none of the cohorts will show a significant difference in duration between anesthetics.   
The maximum difference in anesthetic duration that we consider “not different” from 
a clinical standpoint is 15 minutes.  Using this as an estimate of the mean of paired 
differences in a paired t-test with a sample size of N=25 and 5% alpha level, we can 
expect 82% power or greater if the standard deviation of the paired differences is 25 
minutes or less.  We will consider the treatments not different if the 95% confidence 
interval for the absolute difference is contained within (-15 minutes to +15 minutes). We 
will not adjust for multiple comparisons.
12.4.2 Analysis of Secondary Endpoints
The secondary aim of this study is to examine which patient characteristics are 
associated with the duration of each local anesthetic.  We will use Pearson’s correlation 
coefficient, or a non-parametric equivalent, to examine the association between patient 
characteristics measured on a continuous scale (e.g., age, BMI, etc.) and anesthetic 
duration, and we will perform independent samples t-tests, ANOVAs, or their non-
parametric equivalents, to examine the association between categorical patient 
characteristics (e.g., gender, hair color, etc.).
Descriptive statistics (mean/SD for continuous variables and frequency/percent for 
categorical variables) will be calculated for all patient characteristics, and for anesthetic 
durations and paired differences in each cohort.  All tests will be two-sided, assuming a 
5% alpha level, and 95% confidence intervals will be computed, where appropriate, to 
show the precision of the obtained estimates.  All analyses will be performed in SAS 
Version 9.4 (SAS Institute, Inc., Cary, NC)
Note: The statistical considerations section was written in conjunction with Debra 
D’Angelo, MS, in the Division of Biostatistics, Department of Population Health Sciences 
at Weill Cornell Medicine.
12.5 Interim Analysis
Not Applicable. All analysis will be conducted at the completion of the study. 
 12.6 Reporting and Exclusions
 
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12.6.1 Evaluation of Toxicity
All subjects will be evaluable for toxicity from the time of their first treatment with the 
local anesthetics. 
12.6.2 Evaluation of Response
All subjects included in the study will be assessed for response to treatment if they have 
received both injections of local anesthetic. 
13. Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug or device under investigation.  Safety will be monitored by evaluation of adverse 
events reported by subjects or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc.
13.1 Adverse Event Definition
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about 
causality. An adverse event can arise with any use of the drug (e.g., off-label use, use in 
combination with another drug) and with any route of administration, formulation, or 
dose, including an overdose. 
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events)
We do not anticipate any side effects or anesthetic toxicity. As such, the study poses 
minimal risk to the patients. Subjects will experience pain with the injection. There may 
be a small risk of ecchymosis at the injection site, however we will use a small quantity 
of injection and a 30-gauge needle to minimize this risk. The risk of infection will be 
minimal due to appropriate skin preparation with antiseptic. We do not anticipate any 
adverse reactions in this study.
13.1.2 Adverse Event Characteristics and Related Attributions
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov).
•
Attribution of the AE:
-Definite – The AE is clearly related to the study treatment.
-Probable – The AE is likely related to the study treatment.
 
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-Possible – The AE may be related to the study treatment.
-Unlikely – The AE is doubtfully related to the study treatment.
-Unrelated – The AE is clearly NOT related to the study treatment.
13.1.3 Recording of Adverse Events
All adverse events grade 3 or greater and any serious adverse events will be recorded 
on a subject specific AE log. The AE log will be maintained by the research staff and 
kept in the subject’s research chart.   
13.1.4 Reporting of AE to WCM IRB
All AEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf. 
13.1.5 Reporting Events to Participants
NA
13.1.6 Events of Special Interest
Not applicable.
13.1.7 Reporting of Pregnancy
Not applicable.
13.2 Definition of SAE
SAEs include death, life threatening adverse experiences, hospitalization or 
prolongation of hospitalization, disability or incapacitation, overdose, congenital 
anomalies and any other serious events that may jeopardize the subject or require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
13.2.1 Reporting of SAE to IRB
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf. 
13.2.2 Reporting of SAE to FDA [For Protocols Where WCMC is the Sponsor-
Investigator]
IND application sponsor must report any suspected adverse reaction or adverse 
reaction to study treatment that is both serious and unexpected. Unexpected fatal 
or life-threatening suspected adverse reactions represent especially important 
 
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safety information and must be reported to FDA as soon as possible but no later 
than 7 calendar days following the sponsor’s initial receipt of the information.
i.
death,
ii.
a life-threatening adverse event,  
iii.
in-patient hospitalization or prolongation of existing hospitalization,
iv.
a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, or  
v.
a congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or research subject and may 
require medical or surgical intervention to prevent one of the outcomes listed as 
serious
13.3 AE/SAE Follow Up
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. 
This requirement indicates that follow-up may be required for some events after the 
subject discontinues participation from the study. 
13.4 Time Period and Frequency for Event Assessment and Follow Up
AEs will be assessed through the end of study participation in this one visit study.
14. Unanticipated Problems Involving Risks to Subjects or Others
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO)
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied;
•
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and
•
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized.
14.1.2 Unanticipated Problem Reporting
 
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The investigator will report unanticipated problems (UPIRTSOs) to the reviewing 
Institutional Review Board (IRB) and to the Data Coordinating Center (DCC)/lead 
principal investigator (PI). The UPIRTSO report will include the following information:
•
Protocol identifying information: protocol title and number, PI’s name, and the 
IRB project number;
•
A detailed description of the event, incident, experience, or outcome; 
•
An explanation of the basis for determining that the event, incident, experience, 
or outcome represents an UPIRTSO; 
•
A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UPIRTSO.
To satisfy the requirement for prompt reporting, UPIRTSOs will be reported using the 
following timeline:  
•
UPIRTSOs that are serious adverse events (SAEs) will be reported to the IRB 
and to the DCC/study sponsor within <insert timeline in accordance with policy> 
of the investigator becoming aware of the event. 
•
Any other UPIRTSO will be reported to the IRB and to the DCC/study sponsor 
within <insert timeline in accordance with policy> of the investigator becoming 
aware of the problem. 
•
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or 
designee), Food and Drug Administration (FDA), and the Office for Human 
Research Protections (OHRP) within <insert timeline in accordance with policy> 
of the IRB’s receipt of the report of the problem from the investigator.]
15. Data and Safety Monitoring Plan (DSMP)
This study will be monitored by the study team only.  The agents being study are being used on 
label and pose minimal risk to the participant. If a single Grade 4 or SAE occurs, the study will 
halt until an external advisory group can be convened and the IRB has reviewed the event.
Data and events that will be captured and submitted:
All Grade 3 or greater AEs  and SAEs will be recorded. This includes but is not limited to 
local and systemic reactions to both tissue trauma (needle injection) and/or the agent 
used. The capturing template is outlined in table 5. 
Table: Monitoring entity reporting and review
Data type
Frequency of review
Reviewer
Subject accrual (including 
compliance with protocol 
enrollment criteria)
Quarterly
PI, study team 
Status of all enrolled subjects, 
as of date of reporting 
Quarterly
PI, study team 
 
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Data type
Frequency of review
Reviewer
Adherence data regarding 
study visits and intervention
Quarterly
PI, study team
AEs 
Quarterly
PI, study team
SAEs
Per occurrence
PI, study team, external 
advisory group
Study stopping rules:
This study will be stopped prior to its completion if: (1) the intervention is associated with 
adverse effects that call into question the safety of the intervention; (2) difficulty in study 
recruitment or retention will significantly impact the ability to evaluate the study endpoints; 
(3) any new information becomes available during the trial that necessitates stopping the 
trial; or (4) other situations occur that might warrant stopping the trial
Protection of subject privacy:
During this study, all of the data collected are for research purposes only and data will be 
kept in strict confidence. No information will be given to anyone without permission from 
the participant. The consent form includes the informed consent statement required by 
the IRB and Weill Cornell Medicine for interventional studies. This statement guarantees 
confidentiality and identifies the participant as the owner of the data gathered. 
Confidentiality will be ensured by use of deidentification. All data, whether generated in 
the laboratory or at the bedside, will be identified with a randomly generated 
identification code unique to the participant.
The only risk of this study is a breach of confidentiality, which will be avoided by the 
following methods. No published data will be associated with participant names, or other 
elements of PHI. Unique study identifiers will be used in place of participant names and 
medical record numbers. All deidentified data will be saved electronically on a password 
protected computer that has been tagged by WCM. Only the PI and study personnel will 
have access to this data. After completion of this research, all data will be deleted.
Database protection:
The database will be secured with password protection. The informatics manager will 
receive only coded information that is entered into the database under those 
identification numbers. Electronic communication with outside collaborators will involve 
only unidentifiable information.
Confidentiality during Adverse Event (AE) Reporting:
AE reports and annual summaries will not include subject-identifiable data. Each report 
will only include the participant identification code.
 
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16. References
Please provide the citations for all publications referenced in the text.
1.
Administration FaD. Xylocaine (lidocaine HCl and epinephrine Injection, USP) 2010 
[Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/006488s074lbl.pdf.
2.
Iowa Uo. Maximum Recommended Doses and Duration of Local Anesthetics  [updated 
October 13, 2019. Available from: https://medicine.uiowa.edu/iowaprotocols/maximum-
recommended-doses-and-duration-local-anesthetics.
3.
Administration FaD. Marcaine. 2011.
4.
Administration FaD. Naropin. 2018.
5.
Chen P, Smith H, Vinciullo C. Bupivacaine as an Adjunct to Lidocaine in Mohs 
Micrographic Surgery: A Prospective Randomized Controlled Trial. Dermatol Surg. 
2018;44(5):607-10.
6.
Sorenson E, Chesnut C. Liposomal Bupivacaine: A Review and Applications to 
Dermatologic Surgery. Dermatol Surg. 2019;45(1):68-73.
7.
Yadlapati S, Kaul S, Jakhar D. Liposomal bupivacaine infiltration as an effective option 
for postoperative pain management after Mohs surgery. Int J Dermatol. 2021.
8.
Drugs.com Drugs.com [Available from: https://www.drugs.com/.
9.
Collins JB, Song J, Mahabir RC. Onset and duration of intradermal mixtures of 
bupivacaine and lidocaine with epinephrine. Can J Plast Surg. 2013;21.
10.
Boen M, Alhaddad M, Goldman MP, Kollipara R, Hoss E, Wu DC. A Randomized, 
Evaluator-Blind, Split-Face Study Evaluating the Safety and Efficacy of Calcium Hydroxylapatite 
for Jawline Augmentation. Dermatol Surg. 2022;48(1):76-81.
11.
Weiss R, Bank D, Brandt F. Randomized, Double-Blind, Split-Face Study of Small-Gel-
Particle Hyaluronic Acid with and without Lidocaine During Correction of Nasolabial Folds. 
Dermatol Surg. 2010;36(1):750-9.
12.
Alexanian CC, Zhuang AR, Crispin MK, Armstrong AW, Eisen DB. Wound eversion 
versus planar closure for wounds on the face or neck: A randomized split-wound comparative 
effectiveness trial. J Am Acad Dermatol. 2020;83(5):1439-40.
13.
Kouba DJ, LoPiccolo MC, Alam M, Bordeaux JS, Cohen B, Hanke CW, et al. Guidelines 
for the use of local anesthesia in office-based dermatologic surgery. J Am Acad Dermatol. 
2016;74(6):1201-19.
 
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