Clinical trial NCT03310970
Conditions: Healthy
Keywords: Peer Reviewed Research
Sponsor: Nicole K Brogden
Start date: 2018-03-14; Completion date: 2019-10-09
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study to be performed will utilize already FDA-approved marketed products in healthy adults for the purpose to generate data for establishing rate of drug delivery of Lidoderm® topical patch (manufactured by Endo Pharmaceuticals) and the lidocaine 5% patch (manufactured by Mylan Pharmaceuticals) in healthy adults, and to ensure the safety of individuals utilizing these types of products.

Detailed description:
Topical drug delivery systems in the form of patches are convenient, attractive, and easy to use. Lidocaine is a very popular patch available on the United States market today. Accurate determination of the rate and extent of drug release and absorption is crucial to ensure the safety of individuals using these and other types of patches. The drug delivery rate can be determined early in the development process by using in vitro skin flux permeation studies, and later in humans by accurately quantifying residual drug from patches post-wear and in pharmacokinetic studies. In this study the investigators will employ two types of evaluation to determine the rate and extent of drug release and absorption from lidocaine patches, namely residual drug analysis post-wear and pharmacokinetic analysis in healthy adult volunteers. In addition, the investigators will compare the serum drug concentrations following patch and intravenous administration in order to determine the absolute bioavailability of these patches. Positive outcomes of this project will identify appropriate methods to determine the rate and extent of drug release and absorption from topical patches, and will help regulatory agencies in the development of Guidances for Industry regarding the characterization of drug release and absorption kinetics to ensure the safety of individuals utilizing these types of products.

Arms: arm 1: Each subject will wear three generic Lidocaine 5% topical patches for 12 hours. arm 2: Each subject will wear three Lidoderm® topical patches for 12 hours. arm 3: A single intravenous dose of 0.5 mg/kg lidocaine hydrochloride will be administered to each subject.
Interventions: intervention 1: Lidocaine 5% patch intervention 2: Lidocaine hydrochloride intervention 3: Lidoderm 5% patch
Intervention descriptions: intervention 1: Each subject will wear three generic Lidocaine 5% topical patches for 12 hours. intervention 2: Each subject will receive a dose of 0.5 mg/kg intravenously over a period of 5 minutes. intervention 3: Each subject will wear three Lidoderm® topical patches for 12 hours.

Protocol documents:
Prot_SAP_000.pdf: 
i 
ABSOLUTE BIOAVAILABILITY/PHARMACOKINETIC AND RESIDUAL DRUG ANALYSIS 
OF TOPICAL LIDOCAINE SYSTEMs IN HEALTHY ADULTS 
Short title: Lidocaine Release from Topical Patches in Healthy Adults 
U01 Principal Investigator: 
Nicole K. Brogden (contact), PharmD, PhD 
Medically Accountable Investigator: 
Ken-ichi Ueda, MD 
Independent Safety Monitor: 
Srinivasan Rajagopal, MD 
Clinical Coordinator 
Jamie Carr, BA 
Sponsor: 
Food and Drug Administration 
Grant Number:5U01FD004275-03 
NCT03310970
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STATEMENT OF COMPLIANCE 
This study will be conducted in compliance with the protocol, International Conference on Harmonisation 
Good Clinical Practice E6 (ICH-GCP) and the applicable Food and Drug Administration (FDA) and other 
Department of Health and Human Services regulatory requirements. All key personnel (all individuals 
responsible for the design and conduct of this study) have completed Human Subjects Protection 
Training. 
 
 


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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this study will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable US federal regulations and ICH guidelines. 
 
Clinical Principal Investigator: Ken-ichi Ueda, MD 
(Medically Accountable Investigator)     
Signed: 
 
Date: 
 
 
U01 Principal Investigator: Nicole K. Brogden, PharmD, PhD 
(contact) 
 
Signed: 
 
Date: 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .............................................................................................................. ii 
SIGNATURE PAGE ................................................................................................................................... iii 
LIST OF ABBREVIATIONS .................................................................................................................... viii 
PROTOCOL SUMMARY ........................................................................................................................... ix 
1. KEY ROLES .......................................................................................................................................... 1 
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................................... 2 
2.1. Background Information ............................................................................................................... 2 
2.2. Rationale ....................................................................................................................................... 2 
2.3. Potential Risks and Benefits ......................................................................................................... 3 
2.3.1. Potential Risks ...................................................................................................................... 3 
2.3.2. Known Potential Benefits ..................................................................................................... 4 
3. OBJECTIVES ........................................................................................................................................ 5 
3.1. Study Objectives ........................................................................................................................... 5 
3.2. Study Outcome Measures ............................................................................................................. 5 
4. STUDY DESIGN ................................................................................................................................... 6 
5. STUDY ENROLLMENT AND WITHDRAWAL ................................................................................ 7 
5.1. Subject Inclusion Criteria ............................................................................................................. 7 
5.2. Subject Exclusion Criteria ............................................................................................................ 8 
5.3. Enrollment Procedures ................................................................................................................. 9 
5.3.1. Randomization Procedures ................................................................................................... 9 
5.3.2. Masking Procedures ............................................................................................................. 9 
5.3.3. Reasons for Withdrawal ....................................................................................................... 9 
5.3.4. Screen Failures ................................................................................................................... 10 
5.3.5. Termination of Study .......................................................................................................... 10 
5.3.6. Subject Discontinuations .................................................................................................... 10 
5.3.7. Handling of Withdrawals ................................................................................................... 10 
6. STUDY PRODUCT ............................................................................................................................. 11 
6.1. Study Product Description .......................................................................................................... 11 
6.1.1. Lidoderm® Patch 5% ......................................................................................................... 11 
6.1.2. Lidocaine HCl Injection, 20 mg/1 ml Preservative Free Single Dose Vials ...................... 11 
6.1.3. Lidocaine Patch 5% (Mylan) .............................................................................................. 11 
6.2. Acquisition.................................................................................................................................. 11 
6.3. Formulation, Packaging, and Labeling ....................................................................................... 11 
6.3.1. Lidoderm® Patch 5% ......................................................................................................... 11 


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6.3.2. Lidocaine HCl Injection, 20 mg/1 ml Preservative Free Single Dose Vials ...................... 12 
6.3.3. Lidocaine Patch 5% (Mylan) .............................................................................................. 13 
6.4. Product Stability ......................................................................................................................... 13 
6.5. Dosage, Preparation and Administration of Study Product ........................................................ 14 
6.5.1. Application of the Patch ..................................................................................................... 14 
6.5.2. Administration of the IV Injection of Lidocaine Hydrochloride ........................................ 14 
6.6. Accountability Procedures for the Study Product(s) .................................................................. 14 
6.7. Assessment of Subject Compliance with Study Product ............................................................ 15 
6.8. Patch System Adhesion Evaluation ............................................................................................ 15 
6.9. Concomitant Medications/Treatments ........................................................................................ 15 
7. STUDY SCHEDULE ........................................................................................................................... 16 
7.1. Screening 0 to 30 Days ............................................................................................................... 16 
7.2. Enrollment/Baseline ................................................................................................................... 17 
7.2.1. Prohibitions and Restrictions .............................................................................................. 17 
7.3. Study Visits and Procedures ....................................................................................................... 18 
7.3.1. Procedure Day 1: Lidocaine Patch 5% (Mylan) ................................................................. 18 
7.3.2. Procedure Day 2: Lidocaine Patch 5% (Mylan) ................................................................. 19 
7.3.3. Procedure Day 3: Lidocaine Patch 5% (Mylan) ................................................................. 19 
7.3.4. Procedure Day 4: Lidocaine HCl Injection, 20 mg/1 ml Preservative Free Single Dose 
Vials.................................................................................................................................... 20 
7.3.5. Procedure Day 5: Lidoderm® Patch 5% ............................................................................ 21 
7.3.6. Procedure Day 6: Lidoderm® Patch 5% ............................................................................ 22 
7.3.7. Procedure Day 7: Lidoderm® Patch 5% ............................................................................ 22 
7.3.8. Procedure Day 1: Lidoderm® Patch 5% ............................................................................ 22 
7.3.9. Procedure Day 2: Lidoderm® Patch 5% ............................................................................ 23 
7.3.10. Procedure Day 3: Lidoderm® Patch 5% ............................................................................ 24 
7.3.11. Procedure Day 4: Lidocaine HCl Injection, 20 mg/1 ml Preservative Free Single Dose 
Vials.................................................................................................................................... 24 
7.3.12. Procedure Day 5: Lidocaine Patch 5% (Mylan) ................................................................. 25 
7.3.13. Procedure Day 6: Lidocaine Patch 5% (Mylan) ................................................................. 26 
7.3.14. Procedure Day 7: Lidocaine Patch 5% (Mylan) ................................................................. 26 
7.4. Early Termination Visit .............................................................................................................. 26 
7.5. Unscheduled Visit ....................................................................................................................... 27 
8. STUDY PROCEDURES/EVALUATIONS ........................................................................................ 28 
8.1. Clinical Evaluations .................................................................................................................... 28 
8.2. Laboratory Evaluations ............................................................................................................... 28 


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8.2.1. Clinical Laboratory Evaluations ......................................................................................... 28 
8.2.2. Bioanalytical Methods ........................................................................................................ 28 
8.2.3. Method for Determining Drug Content in Worn and Unworn Transdermal Systems ........ 28 
8.2.3.1. Worn Systems .............................................................................................................. 28 
8.2.3.2. Unworn Systems .......................................................................................................... 29 
8.3. Specimen Preparation Handling and Shipping ........................................................................... 29 
8.3.1. Instructions for Specimen Preparation, Handling, and Storage .......................................... 29 
8.3.2. Specimen Shipment ............................................................................................................ 29 
9. ASSESSMENT OF SAFETY .............................................................................................................. 30 
9.1. Specification of Safety Parameters ............................................................................................. 30 
9.2. Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .................. 30 
9.2.1. Adverse Events ................................................................................................................... 30 
9.2.1.1. Adverse Event Definition ............................................................................................ 30 
9.2.2. Grading Scale for Severity of AEs ..................................................................................... 31 
9.2.3. Reactogenicity .................................................................................................................... 31 
9.2.4. Serious Adverse Events ...................................................................................................... 32 
9.3. Reporting Procedures ................................................................................................................. 33 
9.3.1. Serious Adverse Events ...................................................................................................... 33 
9.3.2. Reporting of Pregnancy ...................................................................................................... 34 
9.4. Type and Duration of Follow-up of Subjects after Adverse Events ........................................... 34 
9.5. Halting Rules .............................................................................................................................. 34 
9.6. Safety Oversight ......................................................................................................................... 34 
9.7. Clinical Monitoring .................................................................................................................... 35 
9.7.1. Site Monitoring Plan........................................................................................................... 35 
10. PHARMACOKINETICS AND STATISTICAL CONSIDERATIONS .............................................. 36 
10.1. Study Hypotheses ....................................................................................................................... 36 
10.2. Pharmacokinetic (PK) Analyses ................................................................................................. 36 
10.3. Sample Size Consideration ......................................................................................................... 37 
10.4. Statistical Analysis Plan ............................................................................................................. 37 
11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .............................. 38 
12. QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 39 
13. ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................ 40 
13.1. Ethical Standard .......................................................................................................................... 40 
13.2. Institutional Review Board ......................................................................................................... 40 
13.3. Informed Consent Process .......................................................................................................... 40 


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13.3.1. Informed Consent/Assent Process (in Case of a Minor) .................................................... 41 
13.4. Exclusion of Women, Minorities, and Children (Special Populations) ...................................... 41 
13.5. Subject Confidentiality ............................................................................................................... 41 
13.6. Study Discontinuation ................................................................................................................ 41 
13.7. Future Use of Stored Specimens................................................................................................. 41 
14. DATA HANDLING AND RECORD KEEPING ................................................................................ 43 
14.1. Data Management Responsibilities ............................................................................................ 43 
14.2. Data Capture Methods ................................................................................................................ 43 
14.3. Types of Data .............................................................................................................................. 43 
14.4. Timing/Reports ........................................................................................................................... 43 
14.5. Study Records Retention ............................................................................................................ 43 
14.6. Protocol Deviations .................................................................................................................... 43 
15. PUBLICATION POLICY .................................................................................................................... 45 
REFERENCES ........................................................................................................................................... 46 
APPENDIX A: SCHEDULE OF EVENTS ................................................................................................ 47 
APPENDIX B: ACCEPTABLE SCREENING VALUES & LABORATORY REFERENCE RANGES 49 
APPENDIX C: TOXICITY GRADING SCALES ..................................................................................... 50 
APPENDIX D: ADHESION ASSESSMENT SCORING ......................................................................... 52 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
AUC 
Area Under the Serum-Concentration Curve 
Cmax 
Maximum Serum Concentration 
Css 
Steady State Concentrations 
CFR 
Code of Federal Regulations 
CL 
Clearance 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
ICTS 
Institute for Clinical and Translational Science 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IV 
Intravenous 
Kel 
Elimination Rate Constant 
MAI 
Medically Accountable Investigator (i.e., licensed clinician) 
NBP 
Noninvasive Blood Pressure 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PSI 
Primary Skin Irritation 
QA 
Quality Assurance 
QC 
Quality Control 
QM 
Quality Management 
QMP 
Quality Management Plan 
RIHSC 
Research Involving Human Subjects Committee 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SpO2 
Oxygen Saturation 
Tmax 
Time of Maximum Serum Concentration 
UI 
University of Iowa 
UICOP 
University of Iowa College of Pharmacy 
UIHC 
University of Iowa Hospitals and Clinics 
US 
United States 
V 
Volume of Distribution 
 
 


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PROTOCOL SUMMARY 
 
Title:  
Absolute Bioavailability/Pharmacokinetic and Residual 
Drug Analysis of the Lidoderm® System in Healthy 
Adults 
Population: 
Healthy, non-smoking adults aged 18-65 years 
Number of Sites: 
Single site: University of Iowa College of Pharmacy/ 
University of Iowa Hospitals and Clinics 
Study Duration: 
Approximately up to 12 months 
Subject Participation Duration: 
Approximately 3-4 weeks, including the screening period 
Description of Study Products: 
Lidoderm® patch 5% (Endo Pharmaceuticals Inc.); 
lidocaine patch 5% (Mylan), lidocaine hydrochloride 20 
mg/1 ml preservative free single dose vials (Auromedics 
Pharma LLC) 
Objective: 
 
To determine the rate of lidocaine delivery after using a 
reference (Lidoderm®) topical drug delivery system in 
healthy adult volunteers. 
Description of Study Design: 
This will be a three arm, open-label, crossover clinical 
pharmacokinetic study; the three arms will include 
administration of intravenous (IV) lidocaine 
hydrochloride, topical administration of a single strength 
of the reference listed drug (RLD) Lidoderm® 5% topical 
patch manufactured by Endo Pharmaceuticals, and topical 
administration of a single strength lidocaine 5% patch 
manufactured by Mylan. 
A) Pharmacokinetic Determination of Strength 
The study will be a three arm, open-label, crossover 
clinical pharmacokinetic study (n=24 healthy adult 
subjects, or statistically suitable number) with a minimum 
48 hour washout period between each study arm. Each 
subject will be his/her own control.  
 
The study products are: 
• 
Lidoderm® 5% patch (Endo                                
Pharmaceuticals Inc.) 
• 
Lidocaine 5% patch (Mylan) 
• 
Lidocaine hydrochloride 20 mg/1 ml preservative 
free single dose vials (Auromedics Pharma LLC) 
 
Blood samples will be obtained as follows (based on 
administration route): 


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• 
Patch studies: 60 min pre-application, during the 12 
hour patch wear, and up to 48 hour post patch 
application  
• 
60 min pre-IV injection and then up to 10 hour  post 
IV injection 
B) Residual Drug Analysis Determination of Strength  
In conjunction with the above described pharmacokinetic 
study, residual drug analysis will also be conducted for the 
lidocaine patches.  
• 
The worn patches are retained for drug content 
analysis.  
• 
Upon removal of the product after prescribed wear 
period, the skin (at site of application) is swabbed 
and the swabs are retained for drug content analysis 
 


1 
 
 
1. KEY ROLES 
U01 Principal Investigators: 
 
Nicole K. Brogden (contact), PharmD, PhD 
Assistant Professor, Department of Pharmaceutical Sciences and 
Experimental Therapeutics 
University of Iowa College of Pharmacy 
115 S. Grand Ave, S421 
Iowa City, IA 52242 
Phone: 319-335-8752 
Fax: 319-335-9349 
Email: nicole-brogden@uiowa.edu  
 
 
 
Medically Accountable 
Investigator: 
  
Ken-ichi Ueda, MD 
Clinical Associate Professor, Department of Anesthesia 
Co-Director, Anesthesia Workroom 
University of Iowa Hospitals and Clinics 
Iowa City, IA 52242  
Phone: 319-384-5718 
Email: kenichi-ueda@uiowa.edu   
 
 
Independent Safety Monitor 
Srinvisan Rajagopal, MD 
University of Iowa Hospitals and Clinics 
Department of Anesthesia 
200 Hawkins Drive, 6532 JCP 
Iowa City, IA 52242 
Phone: 319-356-2633 
Email: srinvisan-rajagopal@uiowa.edu 
 
 
Clinical study coordinator 
Jamie Carr, BA 
University of Iowa Hospitals and Clinics 
Institute for Clinical and Translational Science 
200 Hawkins Drive, C44-P GH 
Iowa City, IA 52242 
Phone: 319-678-8089 
Email: jamie-carr@uiowa.edu 
 
 
 
 


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2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1. Background Information 
There are numerous topical and transdermal drug delivery systems that are currently available in the 
United States; the first transdermal delivery system (Transderm Scōp®) was approved by the Food 
and Drug Administration (FDA) in 1979. Drug delivery systems in the form of patches are 
convenient, attractive, and easy to use. Lidocaine is a very popular topical patch available on the US 
market today, used for local relief of pain associated with post-herpetic neuralgia. 
Accurate determination of the rate and extent of drug release and absorption is crucial to ensure the 
safety of individuals using drug patches. Delivery rate and extent can be determined early in the 
development process by using in vitro skin flux permeation studies, the extent of absorption can be 
determined in humans by accurately quantifying residual drug from patches post-wear, and the 
delivery rate can be determined in pharmacokinetic studies. In this proposal, we will employ two 
types of evaluation to determine the rate and extent of drug release and absorption from two lidocaine 
patch products: residual drug analysis post-wear and pharmacokinetic analysis in healthy adult 
volunteers. In addition, we will compare the serum drug concentrations following patch and 
intravenous (IV) administration, in order to determine the absolute bioavailability of the patches. We 
will conduct residual drug analysis of the patches following in vivo wear using highly sensitive 
validated quantification methods. Positive outcomes of this project will identify appropriate methods 
to determine the rate and extent of drug release and absorption from topical drug patches, and will 
help regulatory agencies in the development of Guidances for Industry regarding the characterization 
of drug release and absorption kinetics to ensure the safety of individuals utilizing these types of 
products. 
2.2. Rationale 
The rationale of this study is to determine the absolute bioavailability and pharmacokinetics of topical 
lidocaine through development of an appropriately controlled and well-characterized methodology to 
quantify the exposure of healthy adults to lidocaine during wear, so that the rate of drug release and 
delivery can be defined in a manner that can help the regulatory agency (FDA) in developing 
Guidances for Industry regarding the characterization of drug release and absorption kinetics to 
ensure the safety of individuals utilizing these types of products.  
 
The project involves crossover pharmacokinetic (PK) studies using two lidocaine topical patch 
products made by different manufacturers, and IV injection of the corresponding drug (e.g. lidocaine 
hydrochloride). The IV data will be utilized to determine clearance (CL) of the drug from the 
systemic circulation. Different mathematical approaches including, but not limited to, deconvolution 
will then be utilized to determine the rate of drug delivery from the patch into the systemic circulation 
using PK parameters derived from non-compartmental and/or compartmental analyses of lidocaine 
serum concentrations measured using sensitive, validated bioanalytical methods. In order to compare 
the data obtained from this study to previously published data, a similar time course was selected for 
collecting the blood samples for serum analysis. As part of this study, appropriate methodologies will 
also be developed to precisely characterize the (residual) drug content in the selected products. 
Following the in vivo studies, residual drug content of the worn patches will be determined to 
calculate exposure from the patch (i.e. quantifying the amount of drug delivered in vivo over time 
based upon residual drug analysis data). 
 


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Since this will be a crossover study, all subjects will complete all three study arms. One of the patch 
systems will be applied first, followed by at least 48 hours of washout period. Then the IV injection 
will be administered followed by at least 48 hours of washout period. Last, the second patch system 
will be applied. Subjects will be assigned to one of two groups. Regardless of group, all subjects will 
receive the treatments in the same order of patch-IV-patch. In Group 1 the patch manufactured by 
Mylan will be applied first; in Group 2 the patch manufactured by Endo Pharmaceuticals will be 
applied first.  
2.3. Potential Risks and Benefits 
2.3.1. Potential Risks 
Lidocaine topical patches:  
Topical lidocaine 5% patches are approved by FDA for use in the United States and have been 
used for many years; the likelihood of unexpected frequent side effects is minimal. The major 
risks associated with topical lidocaine administration are reactions locally at site of patch 
application, including blisters, bruising, burning sensation, depigmentation, dermatitis, 
discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or 
abnormal sensation. The dose absorbed from the topical patches is small and so systemic adverse 
events are relatively unlikely. Systemic adverse effects, when they do occur, are expected to be 
similar in nature to those seen with other amide local anesthetic agents. This includes symptoms 
of central nervous system (CNS) excitation and/or depression, such as: light headedness, 
nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double 
vision, vomiting, sensations of heat, cold or numbness, twitching, tremor, convulsions, 
unconsciousness, respiratory depression, and arrest. Adverse events manifesting in the 
cardiovascular system may include bradycardia, hypotension, and cardiovascular collapse leading 
to arrest. Other miscellaneous adverse events that have been reported but causality has not been 
established include the following: asthenia, confusion, disorientation, dizziness, headache, 
hyperesthesia, hypoesthesia, lightheadedness, nausea, nervousness, exacerbation of pain, 
paresthesia, somnolence, taste alteration, vomiting, visual disturbances such as blurred vision, 
flushing, tinnitus, and tremor. 
The study has been designed to reduce these potential risks as follows. According to the FDA 
approved dosing, up to three patches may be applied once for up to 12 hours, in a 24 hour period. 
Thus, the proposed dosing regimen in this study is three patches, applied to the lower back. The 
skin will be carefully inspected prior to patch application and patches will not be applied to skin 
that is irritated or compromised in any way. The patches will be removed at the end of the 
approved 12-hour wear period. This dosing regimen will be used for both types of patches 
studied. The mean peak plasma concentrations obtained from this dosing regimen is expected to 
be approximately 0.13 μg/ml, which is ~1/10th of the concentration required for treatment of 
cardiac arrhythmias (0.4 ± 6.0 µg/mL are considered therapeutic for treatment of cardiac 
arrhythmias)1. 
Lidocaine hydrochloride IV injection: 
The major risks associated with the use of lidocaine hydrochloride IV injection include CNS 
effects and cardiovascular effects. CNS reactions may be excitatory and/or depressant and may 
include light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, 
tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, 
tremors, convulsions, unconsciousness, respiratory depression and arrest. Adverse effects of the 


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cardiovascular system are usually depressant and characterized by bradycardia, hypotension and 
cardiovascular collapse, which may lead to cardiac arrest. 
The study has been designed to reduce these potential side effects as follows. The dosing regimen 
in this study is 0.5 mg/kg IV lidocaine administered as a slow push over 5 minutes. This dose was 
selected based on previous studies in human subject in which IV lidocaine has been administered 
to humans in ranges from 0.5 mg/kg to 2.2 mg/kg1-5. We selected a low dose to reduce the risk of 
side effects but still allow detection of drug serum concentrations for calculating PK parameters. 
In a heart with normal conduction and normal sinus rhythm, therapeutic levels of lidocaine cause 
little or no decrease in A-V conduction, and minimal cardiac slowing1. Lidocaine also has 
minimal hemodynamic effects in normal subjects, and causes minimal to no decrease in 
ventricular contractility, cardiac output, arterial pressure, or heart rate. Rapid IV bolus injections 
would lead to very high blood levels very quickly, which would be more likely to cause 
depressed cardiac function than a slowly administered IV injection given over 1 – 5 min1. For this 
reason, the IV injection in this study will be administered slowly over 5 minutes. Subjects will be 
connected to a SureSigns VM4 portable bedside monitor during the injection and for one hour 
after, for continuous noninvasive monitoring. This monitor has a 3-lead electrocardiogram (ECG) 
to monitor heart rate and rhythm, a pulse oximeter to monitor oxygen saturation (SpO2,) and non-
invasive blood pressure monitoring (NBP) capability. This is similar to monitoring that has been 
described previously in human subjects receiving IV lidocaine4,6 and is also in agreement with the 
University of Iowa Hospitals and Clinics (UIHC) nursing committee protocol for monitoring with 
lidocaine injections. These parameters will be measured again prior to the subject leaving at the 
end of the procedure day. The Medically Accountable Investigator (MAI) (i.e., licensed clinician) 
will be in the hospital during all IV studies and will be available for consultation in the event that 
serious adverse events occur. 
Additional risks include:  
The standard risks of injection, including reactions which may occur because of the injection, 
excipients or administration include fever, local tenderness, abscess, tissue necrosis or infection at 
the site of injection, venous thrombosis or inflammation of the vein (phlebitis). These risks will 
be minimized by employing the expertise of the Clinical Research Unit (CRU) nursing staff for 
administering the IV injection. The injection site will be monitored for signs of infection during 
the study to minimize this risk. The standard risks of phlebotomy and venipuncture, including 
discomfort upon placement of an IV catheter, will consist of bruising at the site of blood draw, 
hypersensitivity to adhesive plasters or surgical tape, irritation at the catheter site, as well as a 
small risk of infection. These risks will be minimized by using sterile technique, as well as 
employing the expertise of the experienced nursing staff of the CRU. The catheter site will be 
monitored for signs of infection during the study to minimize this risk.  
2.3.2. Known Potential Benefits 
Participation in this study provides no direct benefit to the individual subjects. Society may 
benefit from the information obtained regarding the topical delivery of lidocaine, and how 
lidocaine patches compare to other topical reference products. This clinical protocol is part of an 
FDA U01 funded cooperative agreement, which is in response to the 5U01FD004275-03 “Critical 
Path Manufacturing Sector Research Initiative (U01). 
 
 


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3. OBJECTIVES 
3.1. Study Objectives 
The objectives of these studies are: 1) to determine the absolute bioavailability of lidocaine topical 
patches; 2) to determine the residual drug content in worn topical lidocaine patches; and 3) to apply 
mathematical models (e.g., deconvolution) to determine absorption rates from worn patches based on 
residual drug content and derived PK parameters. 
3.2. Study Outcome Measures 
The main outcome measure of the study is the determination of the pharmacokinetic parameters of 
lidocaine in healthy adult subjects; i.e., clearance (CL), volume of distribution (V), elimination rate 
constant (Kel), maximum serum concentration (Cmax), time of maximum serum concentration (Tmax) of 
lidocaine and area under the serum concentration-time curve (AUC). In addition, we will determine 
residual drug content from worn lidocaine patches to estimate total amount of absorbed lidocaine. 
 
 


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4. STUDY DESIGN 
This is a three arm, open-label, crossover clinical pharmacokinetic (PK) study in 24 healthy human 
volunteers. The study will consist of 8 – 9 procedure days with a minimum 48 hour washout period 
between study arms. Two study arms are based on topical administration of lidocaine patches, and a third 
arm is based on IV administration. A study arm is defined as the entire administration and PK assessment 
period of either lidocaine topical patches or lidocaine hydrochloride injection. 
  
The study products are: 
• 
Lidoderm® patch 5% (Endo Pharmaceuticals) 
• 
Lidocaine patch 5% (Mylan) 
• 
Lidocaine hydrochloride 20 mg/1ml preservative free single dose vials 
 
Each subject will be his/her own control and each subject will sign an Institutional Review Board (IRB) 
approved informed consent document explaining the purpose, nature, risks, benefits, and duration of the 
study. The study will be conducted in accordance with good clinical practice (GCP) guidelines and with 
the ethical principles originating in the Declaration of Helsinki.  
 
The subject’s skin in the area of application (skin of the lower back) will be relatively free of hair before 
patch application. Blood samples (approximately 5 mL each) will be drawn into vacutainer serum tubes. 
Blood samples will be obtained at the following time points (based on administration route):  
• 
Within 60 minutes pre-patch application and then 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 
12:00 (patch removal), 14:00, 24:00, 27:00, 30:00, 33:00, 36:00, 39:00, 48:00 hours post-patch 
wear. Total of 18 samples for each patch used. 
• 
Within 60 minutes pre-IV infusion and then 2, 5, 10, 20, 30, 45, 60 min, then 2:00, 3.00, 4:00, 
6:00, 8:00, and 10:00 hours post injection. Total of 14 samples. 
 
The total volume to be drawn from the subjects for the entire duration of the study will be approximately 
250 mL or 17 tablespoons.  
 
The half-life of topical lidocaine after patch removal is approximately 6 – 8 hours. Hence, 48 hours (i.e. 
~5 to 6 half-lives) will be sufficient for >95% of lidocaine to be eliminated from the body after topical 
administration. The half-life after IV administration is approximately 1.5 – 2 hours. Ten hours of 
sampling will be sufficient for >95% of lidocaine to be eliminated from the body. Each subject will be 
enrolled to complete all study arms and procedure days. The study is open-label and not blinded because 
PK assessment is not subject to participant and/or observer bias. After each study arm is completed, the 
available safety data will be reviewed by an Independent Safety Monitor (ISM) to determine whether or 
not the subject will proceed to the next study arm. 
 
A schedule of events is provided in Appendix A.  
 
This study will be conducted in the CRU outpatient unit of the Institute for Clinical and Translational 
Science (ICTS) in the University of Iowa Hospitals and Clinics (UIHC). Conducting studies in this well-
prepared research-oriented unit ensures that each subject is carefully observed throughout the study. If 
any adverse events occur, they can be properly documented and the subjects provided with the 
appropriate care. The CRU is a fully equipped research unit in UIHC, with inpatient and outpatient 
facilities, nursing staff on site and the MAI is available on- or offsite via the hospital pager system. The 
hospital code team is available to manage any unanticipated life-threatening emergency, and less urgent 
issues will be managed by the MAI. 
 


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5. STUDY ENROLLMENT AND WITHDRAWAL 
Only adult subjects who meet the inclusion/exclusion criteria will be eligible for enrollment into this 
study. Twenty-four subjects will be recruited, with ten additional alternates who could replace subjects 
who drop out from the study for any reason. The study population selected for this study includes healthy 
adult men and women ages 18 to 65, inclusive. Enrollment will continue until 24 subjects complete the 
study. The selection criteria are designed to exclude persons who might have medical conditions that 
could pose a safety risk and persons whose medical conditions might interfere with the objectives and 
results of the study. 
Subjects will be recruited by advertisements local to the study center. Potential subjects who are 
interested in the study will be informed of the study and if they wish to participate, will receive additional 
study information, including an informed consent document. Each of the 24 subjects enrolled will be 
expected to complete screening and all procedure days. 
5.1. Subject Inclusion Criteria 
Subjects are eligible for this study if they fulfill the inclusion criteria specified below:  
1. Men or non-pregnant women, of any ethnic background, between the age of 18 and 65 years old.  
2. Provide written informed consent before initiation of any study procedures. 
3. Available for follow-up for the planned duration of the study.  
4. Able to communicate well with the investigators.  
5. Demonstrate comprehension of the protocol procedures and knowledge of study, as demonstrated 
by a study member filling out a consent checklist form to verify that the subject understands all 
aspects of the study including the purpose, procedures, risks and benefits.  
6. Able to adhere to the study protocol schedule, study restrictions and examination schedule. 
7. Subjects must be non-smokers and not regular users of tobacco. They must have refrained from 
regular and habitual use of nicotine-containing substances, including tobacco products (e.g., 
cigarettes, cigars, chewing tobacco, gum, patch or electronic cigarettes) over the previous 12 
months and must have not used any nicotine-containing products in the previous 30 days.  
8. Subjects who are within their ideal body weight (BMI between 18-29.9 kg/m2). 
9. Subjects deemed to be healthy as judged by the Medically Accountable Investigator (MAI), as 
determined by medical history, physical examination, and medication history. 
10. Negative urine drug screening test.  
11. Have a normal blood pressure (systolic: 90-139 mmHg; diastolic: 60-89 mmHg) and heart rate 
(55-100 bpm). 
12. Have normal screening laboratories for WBC, Hgb, Hct, platelets, sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, ALT, AST. 
13. Female subjects must be of non-childbearing potential. This is defined as surgically sterile (i.e. 
history of hysterectomy or tubal ligation), or postmenopausal for more than 1 year (no bleeding 
for 12 consecutive months). If the person is of childbearing potential they must be non-pregnant 
at the time of enrollment and on the morning of the first day of each study treatment procedure 
day (a urine pregnancy test will be administered if it has been >30 days since serum pregnancy 
test for enrollment). The person must also agree to use hormonal or barrier birth control such as 
implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual 
abstinence, or a vasectomized partner.  
14. Agrees not to participate in another clinical study during the study period unless the study is in 
the follow-up phase and it has been one month since the subject received any experimental agents 


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or treatments. The subject also agrees not to participate in an investigational drug study for at 
least 30 days after last procedure day. 
15. Agrees not to donate blood to a blood bank throughout participation in the study and for at least 
60 days after last procedure day. 
16. Have a normal ECG; must not have any of the following: pathologic Q wave abnormalities, 
significant ST–T wave changes, left ventricular hypertrophy, right bundle branch block, left 
bundle branch block, advanced A-V heart block, non-sinus rhythm, excluding isolated premature 
atrial contractions (sinus rhythm is not between 55–100 beats per minute), or any other 
abnormality that, in the opinion of the MAI, makes it unsafe for the subject to participate in the 
study. 
5.2. Subject Exclusion Criteria 
Subjects will be excluded for any of the following conditions/reasons: 
1. Women who are pregnant or lactating or have a positive serum pregnancy test at enrollment or 
positive urine pregnancy test at any time during the study.  
2. Smokers. A “smoker”, for the purposes of the study, will be defined as an individual who has 
regularly and habitually used nicotine-containing substances, including tobacco products (e.g., 
cigarettes, cigars, chewing tobacco, gum, patch or electronic cigarettes) over the past 12 months. 
Occasional recreational use (less than once monthly) will not warrant exclusion unless the 
individual has used nicotine-containing substances in the previous 30 days before study 
enrollment. 
3. Participation in any ongoing investigational drug trial or clinical drug trial period unless the study 
is in the follow-up phase and it has been ≥ one month since the subject received any experimental 
agents or treatments. 
4. Abnormal vital signs, defined as:  
• 
Hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) at 
rest on two separate days. 
• 
Heart rate <55 at rest on two separate days 
• 
Respiratory rate ≤ 11 to ≥ 18 breaths per minute 
5. Temperature >38.0ºC (100.4ºF) or symptoms of an acute self-limited illness such as an upper 
respiratory infection or gastroenteritis within seven days of administration of a study product. 
6. History of chronic obstructive pulmonary disease. 
7. Positive urine drug screening test. 
8. Use of any prescription medication during the period 0 to 30 days or over-the counter medication 
during the period 0 to 3 days before entry to the study (vitamins, herbal supplements and birth 
control medications will be allowed).  
9. Use of medications or treatments that would significantly influence or exaggerate responses to the 
test product or that would alter inflammatory or immune response to the product. This includes  
antihistamines (within 72 hours prior to dosing), systemic or topical corticosteroids within four 
weeks prior to dosing, use of monoamine oxidase inhibitors 21 days prior to study, cyclosporine, 
tacrolimus, cytotoxic drugs, immune globulin, Bacillus Calmette-Guerin [BCG], monoclonal 
antibodies, or radiation therapy.  
10. Donation or loss of greater than one pint of blood within 60 days of entry to the study.  
11. Any prior serious adverse reaction or hypersensitivity to lidocaine administered by any route. 
12. Current diagnosis of any major psychiatric illness.  
13. Received an experimental agent (vaccine, drug, biologic, device, blood product or medication) 
within 30 days before enrollment in this study or expects to receive an experimental agent during 
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14. Medical history of a serious chronic condition, including (but not limited to): allergic conditions 
such as anaphylaxis to food or drugs; asthma; generalized drug reactions; any seizure disorder; 
any central nervous system disorder; glaucoma (open or closed angle); history of pyloric or 
urinary bladder neck obstruction; intestinal obstruction; difficulty swallowing; stomach or bowel 
problems (e.g, blockage, muscle weakness, ulcerative colitis, Crohn’s disease); bleeding 
disorders; acid reflux disease; myasthenia gravis; allergy to belladonna alkaloids; impaired 
hepatic or renal function. 
15. Any condition that would, in the opinion of the Principal Investigator (PI) or MAI, place the 
subject at an unacceptable risk of injury or render the subject unable to meet the requirements of 
the protocol.  
16. Inability to communicate or cooperate with the investigators.  
17. Medical history of significant dermatologic diseases or conditions, such as atopy, psoriasis, 
vitiligo or conditions known to alter skin appearance or physiologic response (e.g. diabetes, 
porphyria). 
18. History of significant dermatologic cancers (e.g. melanoma, squamous cell carcinoma), except 
basal cell carcinomas that were superficial and did not involve the investigative site. 
19. History of consumption of alcohol within 24 hours prior to dose administration.  
20. Subject has an obvious difference in skin color at patch sites (compared to neighboring skin), or 
the presence of a skin condition, excessive hair at the application site, sunburn, raised moles and 
scars, open sores at application site, scar tissue, tattoo, or coloration that would interfere with 
placement of test articles, or the assessment of the skin and/or reactions to drug. 
5.3. Enrollment Procedures 
5.3.1. Randomization Procedures 
When found eligible to participate, the subject will be enrolled in one of the two study groups. 
The group assignment will be assigned based on alternating Group 1 or 2 for every other subject.  
5.3.2. Masking Procedures 
Not applicable.  
5.3.3. Reasons for Withdrawal 
The primary reason for a subject’s discontinuation should be selected from the following standard 
categories:  
Adverse Event (AE) – Clinical or laboratory events that in the judgment of the PI or MAI 
require discontinuation from the study in the best interest of subject. All AEs must have their 
relationship to the patch or IV injection assessed using the following terms: Associated or 
Not Associated. Upon occurrence of a Serious Adverse Event (SAE) possibly requiring 
discontinuation of a subject, the PI will confer with the ISM. If a subject is discontinued due 
to an AE, the event will be followed until it is adequately resolved. 
 
Death  
 
Protocol Deviation – The subject’s findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements. The violation necessitated premature 
termination from the study as determined by the PI or MAI in consultation with the ISM. 


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Withdrawal of Consent – Subject desires to withdraw from further participation in the study 
in the absence of a medical need to withdraw as determined by the MAI. Subjects are free to 
withdraw from participating in the study at any time upon request.  
 
Pregnancy 
 
Other – Causes of premature termination from the study other than the above, such as 
suspension or termination of study, study site, or at investigator or Sponsor discretion. 
5.3.4. Screen Failures 
Subjects who signed an informed consent form and have undergone screening procedures, but 
who do not meet all entry criteria, will be considered screen failures and will not be enrolled. The 
reasons for screen failure will be documented. A screen failure also includes a screened subject 
who meets eligibility criteria but decides not to participate in the study. 
5.3.5. Termination of Study 
In the event that the study is discontinued, subjects will not progress on to the next procedure day. 
Enrolled subjects who have completed any procedure day will be followed for resolution of any 
ongoing AEs and will be contacted to evaluate the occurrence of any new AEs within 48 hours of 
the last procedure day completed.  
5.3.6. Subject Discontinuations 
The term "discontinuation" refers to a subject’s non-completion of a study whether by their own 
choice, the PI/MAI/ISM’s decision, or due to discontinuation of the study by the Sponsor. 
Subjects who discontinue prematurely after administration of the patch or IV injection will be 
replaced and their PK samples will be analyzed. Alternates will be recruited in the event study 
subjects are unavailable at the time of check in at the outpatient unit (CRU) or at any of the 
procedure days. It is expected that at least ten alternates will be recruited. An adequate number of 
alternates will be screened to ensure any dropouts can be replaced until a total of 24 subjects 
complete all study procedures.  
5.3.7. Handling of Withdrawals 
When handling withdrawals, every effort will be made to undertake protocol-specified safety 
follow-up procedures. However, should the subject decide to withdraw, the primary reason for 
withdrawal shall be recorded by a study team member in the subject’s data collection form. 
Written withdrawal will be requested if the subject decides to withdraw by his or her own choice. 
The study team will attempt to collect safety data on any subject who leaves the study. If 
voluntary withdrawal occurs due to an AE, the subject will be asked to continue scheduled 
evaluations and be given appropriate care under medical supervision until the symptoms of any 
AE resolve or for 48 hours after completion of any study arm. Subjects who fail to return for the 
second or third procedure day or arm of the crossover study will be contacted by the site in an 
attempt to have them comply with the protocol. At a minimum, two phone calls and a certified, 
return receipt letter should be employed in an attempt to contact every subject who discontinues 
prematurely due to an AE. 
 


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6. STUDY PRODUCT 
6.1. Study Product Description 
6.1.1. Lidoderm® Patch 5% 
Lidoderm® patch 5% is a prescription product that delivers approximately 3 ± 2% of the applied 
dose over a 12 hour wear time. At least 95% (665 mg) of lidocaine is expected to remain in the 
worn patch after removal. 
6.1.2. Lidocaine HCl Injection, 20 mg/1 ml Preservative Free Single Dose Vials 
Lidocaine hydrochloride injection is a prescription product that can be used for a variety of 
indications, including local anesthesia and treatment of ventricular arrhythmias. 
6.1.3. Lidocaine Patch 5% (Mylan) 
The Mylan lidocaine patch 5% is a prescription product that delivers approximately 11 ± 4% of 
the applied dose over a 12 hour wear time. At least 82% (115 mg) of lidocaine is expected to 
remain in the worn patch after removal. 
6.2. Acquisition 
All drug products will be acquired through direct purchase by the Investigational Drug Services (IDS) 
pharmacy at UIHC.  
 
Department of Pharmaceutical Care  
Investigational Drug Services 
University of Iowa Hospitals and Clinics 
01284 PFP  
200 Hawkins Drive 
Iowa City, IA 52242 
319-356-2577 
6.3. Formulation, Packaging, and Labeling 
6.3.1. Lidoderm® Patch 5% 
Active ingredient: lidocaine, 700 mg (50 mg per gram of adhesive). In addition to the active 
ingredient (lidocaine), the following inactive ingredients are present in the patch: 
dihydroxyaluminum aminoacetate, disodium edetate, gelatin, glycerin, kaolin, methylparaben, 
polyacrylic acid, polyvinyl alcohol, propylene glycol, propylparaben, sodium 
carboxymethylcellulose, sodium polyacrylate, D-sorbitol, tartaric acid, and urea. This is a 
hydrogel patch manufactured by Endo Pharmaceuticals.  


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6.3.2. Lidocaine HCl Injection, 20 mg/1 ml Preservative Free Single Dose Vials 
Active ingredient: lidocaine hydrochloride. Inactive ingredients: sodium chloride, sodium 
hydroxide, hydrochloric acid, and water. This injectable is manufactured by Auromedics Pharma 
LLC. 
 
 


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6.3.3. Lidocaine Patch 5% (Mylan) 
Active ingredient: lidocaine, 140 mg (50 mg per gram of adhesive). The patch contains a 
polyisobutylene adhesive matrix. This is a matrix type patch manufactured by Mylan 
Pharmaceuticals.  
 
 
 
 
 
 
 
 
 
 
 
6.4. Product Stability 
Lidoderm® should be should be stored between 15-30°C (59-86 °F). The Mylan lidocaine 5% patch 
should be stored between 20-25°C (68-77°F). Lidocaine HCl injection should be stored at 15°-30°C 
(59°-86°F). 


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6.5. Dosage, Preparation and Administration of Study Product 
6.5.1. Application of the Patch 
The application site will be the skin of the mid to lower back. The subject’s skin in the area of 
patch application will be healthy, clean, dry and relatively free of hair before patch application. 
Hair may be clipped (but not shaved) at the application site prior to patch application dosing, if 
necessary. A study team member will cleanse the site with water and carefully dry the skin prior 
to patch application. The patches will be applied to the skin and held firmly in place for 15 – 20 
seconds after application. During the 12 hour patch wear time, the subjects will be asked to sit/lay 
quietly for the majority of their time, so as not to affect patch adhesion. 
6.5.2. Administration of the IV Injection of Lidocaine Hydrochloride 
A catheter will be inserted into the subject’s arm, contralateral to the arm of the IV catheter that 
will be used for blood sampling. The site of the insertion for the catheter to administer lidocaine 
hydrochloride will be either near the elbow or the wrist depending on the identification of the 
vein in the subject. The IV will be injected over 5 minutes using an Alaris Guardrails pump with 
syringe pump cassette. 
6.6. Accountability Procedures for the Study Product(s) 
All drug products will be acquired through the University of Iowa IDS pharmacy. The products will 
be stored in the IDS pharmacy at the conditions noted in the package inserts. The IDS pharmacy will 
dispense the drug product to a study team member on the morning of, or the business day 
immediately before, a subject starts a new study arm. If the product is dispensed on the business day 
before a study, then it will be stored in a locked cabinet in the locked medication room in the CRU. 
Authorized badge access is required to access the medication room. 
 
Department of Pharmaceutical Care  
Investigational Drug Services 
University of Iowa Hospitals and Clinics 
01284 PFP  
200 Hawkins Drive 
Iowa City, IA 52242 
Phone: 319-356-2577 
Prior to dispensing the patch, the lot number on both the patch pouch and the product box will be 
recorded. Prior to dispensing the IV injection, the lot number of the product will be recorded. After 
removal, the used patches will be stored in sealable foil pouches labeled with subject ID number and 
shipped to Long Island University.  
 
Ken Morris 
Lachman Institute for Pharmaceutical Analysis 
Long Island University – Brooklyn Campus 
75 DeKalb Avenue, Room WL 313B  
Brooklyn, New York 11201  


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6.7. Assessment of Subject Compliance with Study Product 
Subjects will be directly observed at the time of patch application or IV administration by a member 
of the clinical research team. Administration will be documented on the clinical notes.  
6.8. Patch System Adhesion Evaluation 
Patch adhesion (for each patch being worn) will be evaluated and scored by study site personnel. The 
recommended scoring system for adhesion of patches will be adopted as described in the FDA draft 
Guidance included in Appendix D. 
0 = ≥ 90% adhered (essentially no lift off the skin) 
1 = ≥ 75% to < 90% adhered (some edges only lifting off the skin) 
2 = ≥ 50% to < 75% adhered (less than half of the patch lifting off the skin) 
3 = > 0% to < 50% adhered but not detached (more than half of the patch lifting off the skin 
without falling off) 
4 = 0% adhered - patch detached (patch completely off the skin) 
6.9. Concomitant Medications/Treatments 
Any concomitant medication deemed necessary for the welfare of the subject during any arm of the 
study may be given at the discretion of the MAI. It is the responsibility of the PI to ensure that details 
regarding the medication are recorded in full in the subject’s data collection forms, along with the 
routine documentation of any changes in concomitant medication that may have occurred during the 
study. Within four weeks prior to enrollment, use of medications or treatments that would 
significantly influence or exaggerate responses to the test product or that would alter inflammatory or 
immune response to the product or agents deemed to be immunosuppressive as determined by 
physician investigator is prohibited. 
 
 


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7. STUDY SCHEDULE 
Study schedule is summarized in Appendix A. 
7.1. Screening 0 to 30 Days 
This study will be advertised through the UI campus-wide email system and through the University of 
Iowa Health Care “Noon News”, a daily announcement flier printed for community and faculty 
members within UIHC. Individuals who call the study site will be provided with a brief overview of 
the purpose and study procedures. Prospective participants may be pre-screened through a telephone 
survey, if applicable. A copy of the informed consent document will be emailed to the prospective 
subject for them to review on their own time. If a subject is interested in study participation and 
passes pre-screening procedures, they will be invited to sign the informed consent document with a 
study team member (where they will again be provided overview of the study rationale, procedures, 
risks, and benefits). The individual must make the initiative to call the study center and schedule a 
meeting to sign the informed consent document. If the prospective participant cannot receive an 
informed consent document by email, the individual will be invited to review the document with a 
study team member, but must schedule a separate meeting to sign the document. This ensures that the 
individual has the chance to review the material in the informed consent on their own time. 
It is recognized that the consent process must be carried out in an environment where no coercion is 
applied and where subjects can be adequately informed of the purpose, nature, procedures, risks and 
hazards of the study. One of the important features of our screening process is the ability for the 
prospective participant to leave the study site for review of the informed consent on his/her own time. 
This additionally demonstrates the reliability of the subject if they schedule a follow-up meeting to 
sign the informed consent. To assess and document comprehension of the material presented, the 
study member obtaining consent will complete a consent checklist to verify that the subject 
understands all aspects of the study including the purpose, procedures, risks and benefits. Checklists 
are signed by a member of the research team and made part of the permanent record. Prospective 
subjects will be carefully screened to ensure that they are in excellent physical and mental health. All 
women of childbearing potential will have a serum pregnancy test performed during screening. 
 
After signing of the informed consent document a screening visit will be scheduled. It is possible for 
the screening visit to take place on the same day as the informed consent visit if scheduling allows. 
Screening evaluations will include: 
• 
Questions about demographic information, medical history, and medication history 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate 
• 
Height and weight 
• 
ECG 
• 
A brief physical exam, performed by the MAI or his designee 
• 
Primary Skin Irritation (PSI) assessment for the site of patch application, completed by a study 
team member 
• 
Urine drug of abuse screen 
• 
Approximately 40 mL of blood will be collected from an arm or hand vein to test for the 
following: 
− 
Hematology parameters including Hgb, Hct, WBC and platelets  
− 
Chemistry parameters including sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
AST, ALT 
− 
Serum pregnancy test (if female of childbearing potential) 
 


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Subjects will satisfy all inclusion/exclusion requirements. All screening results will be evaluated 
against the inclusion/exclusion criteria to confirm subject eligibility (as defined in section 5.1 and 
5.2). Laboratory results must be within the acceptable ranges in Appendix B; abnormal values may 
be repeated if believed to be a transient and non-clinically significant value. Any clinically significant 
abnormal laboratory will be shared with the subject and the subject will be advised to follow-up with 
their physician. 
 
Subjects will be compensated for their time which is calculated as follows: 
 
 
 
 
 
 
 
 
Screening visit:  
 
 
$50 
 
 
 
 
Procedure Day 1: 
 
 
$175 
 
 
 
 
Procedure Day 2: 
 
 
$75 
 
 
 
 
Procedure Day 3:  
 
 
$25 
 
 
 
 
Procedure Day 4:  
 
 
$175 
 
 
 
Procedure Day 5:  
 
 
$175 
Procedure Day 6: 
 
 
$100 
Procedure Day 7:  
 
 
$25 
 
 
 
Bonus completion of all visits:  
$100 
 
 
 
Total compensation: 
 
 
$900.00 
 
 
 
The money will be mailed directly from Accounts Payable to the subject in the form of a check for a 
total of $900.00. This payment schedule is based on the volunteer completing all study procedures. 
Failure to meet study requirements will result in a prorated payment determined by subject 
completion. This payment schedule will be followed for subjects in both groups. 
7.2. Enrollment/Baseline 
Total Planned Enrollment: 24 subjects and at least 10 alternates; however, enough alternates will be 
recruited to ensure 24 subjects complete screening and all seven procedure days. After eligible 
subjects are enrolled; they will be contacted to return to the CRU on the first procedure day. A 
washout period of a minimum of 48 hours after conclusion of each study arm will be ensured. Meals 
and snacks will be provided to the subjects during their stay at the CRU for the first day of each study 
arm. 
7.2.1. Prohibitions and Restrictions 
Potential subjects must be willing to adhere to the following prohibitions and restrictions during 
the course of the study to be eligible for participation. 
1. Must have a negative urine pregnancy test on Day 1 of each study arm (pregnancy test will be 
administered only if it has been >30 days since the serum pregnancy test obtained as part of 
the screening procedures). 
2. It is not recommended to consume food or beverages containing alcohol or caffeine for 24 
hours prior to each PK sample collection day and until after the last PK sample is collected in 
each study arm.  
3. Subjects should not be under the influence of alcohol, opiates, cocaine, amphetamines, 
benzodiazepines, hallucinogens, cannabinoids or barbiturates throughout the study. A 
positive urine drug test will exclude a subject from participating in the study.  


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4. If a subject has had a recent febrile illness within seven days of scheduled dosing, the start of 
study drug intake should be postponed until the body temperature is normal for at least 72 
hours.  
5. Subjects will be advised not to donate blood to a blood bank throughout participation in the 
study and for at least 60 days after the last procedure day or to participate in an 
investigational drug study for at least 30 days after completion of the study.  
6. Must refrain from sunbathing and tanning for 48 hours prior to beginning of study and 
throughout the duration of the procedure days.  
7.3. Study Visits and Procedures 
Pivotal study (n = 24 subjects) 
Since this is a crossover study, subjects will be divided into two groups (n = 12/group). The only 
difference between groups is the order in which they go through the study arms. There will be a 
minimum 48 hour washout period between study arms.  
 
 
Group 1 study schedule    
7.3.1. Procedure Day 1: Lidocaine Patch 5% (Mylan) 
• 
Study staff will review any changes in medical history, medication history, and other study 
qualifications. All inclusion/exclusion criteria must continue to be met. 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate will be 
performed within the 60 minutes prior to the application of the three patches.  
• 
Urine pregnancy test will be obtained from women of childbearing potential if it has been 
more than 30 days since their last pregnancy test; the test must be negative. 
• 
PSI assessment (as explained in section 9.2.3.) will be performed prior to patch application.  
• 
The IV catheter will be placed under aseptic technique by an experienced nurse in the CRU. 
• 
Approximately 5 mL of blood will be drawn within the 60 minutes prior to patch application.  
• 
Time 0: Three lidocaine 5% patches (Mylan) will be applied by a member of the study team 
to the subject’s lower back. 
• 
Each pouch will be numbered with a marker, and the patch corresponding to that pouch 
and release liner will be numbered the same. The pouches and release liners will be 
retained. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse in the CRU at the 
following time points after patch application: 
• 
1:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
2:00 hours ± 5 minutes after patch application  
• 
3:00 hours ± 5 minutes after patch application  
• 
4:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
5:00 hours ± 5 minutes after patch application  
• 
6:00 hours ± 5 minutes after patch application  
Group 1 
Study arm 1: Lidocaine 5% patches (Mylan) 
Study arm 2: Lidocaine injection 
Study arm 3: Lidoderm® 5% patches 
Group 2 
Study arm 1: Lidoderm® 5% patches 
Study arm 2: Lidocaine injection 
Study arm 3: Lidocaine 5% patches (Mylan) 


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• 
8:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
10:00 hours ± 5 minutes after patch application  
• 
12:00 hours ± 5 minutes after patch application (vital signs obtained, patches removed, 
and PSI recorded) 
• 
14:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
Adhesion assessment (as explained in Appendix B) will be performed at all time points while 
the subject is wearing the patches. 
• 
If a patch has an adhesion score ≥2 at any time, a member of the study team may apply a 
small piece of medical tape to the corners of the patch in order to keep the patch in contact 
with the skin. Great care will be taken that the smallest area possible on the patch is covered 
by tape, so as not to alter drug absorption in any way.  
• 
The patches will be removed at 12 hours. A PSI assessment will be recorded for each patch 
site. 
• 
Upon removal, each patch will be placed back on its release liner (care will be taken to put 
the patch on the correct side of the release liner) and inserted into its original pouch. All three 
pouches will be placed together into a sealable foil pouch. Subject ID and date will be labeled 
on the outside of the foil pouch.  
• 
The area of the skin where the patches were applied will be wiped with alcohol swabs (a 
different swab for each different patch site); the swabs will be numbered and placed into a 
second sealable foil pouch with the Subject ID and date.  
• 
The day after removal, the patches will be shipped to Long Island University to be analyzed 
for residual drug content. 
• 
Subjects are free to leave the facility but must arrive at the facility in time for scheduled 
blood draws the following day. 
7.3.2. Procedure Day 2: Lidocaine Patch 5% (Mylan) 
• 
A brief symptom-directed physical exam, if indicated. 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate. 
• 
PSI assessment (as explained in section 9.2.3.) at patch application sites will be performed at 
the 24 and 39 hour time points. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse or phlebotomist in 
the CRU at: 
• 
24:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
27:00 hours ± 30 minutes after patch application 
• 
30:00 hours ± 30 minutes after patch application 
• 
33:00 hours ± 30 minutes after patch application 
• 
36:00 hours ± 30 minutes after patch application 
• 
39:00 hours ± 30 minutes after patch application (vital signs obtained) 
Subjects are free to leave the facility between these visits and at the end of the day, but must 
arrive at the facility in time for scheduled blood draw the following day. 
7.3.3. Procedure Day 3: Lidocaine Patch 5% (Mylan) 
• 
A brief symptom-directed physical exam, if indicated.  
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate. 
• 
PSI assessment (as explained in section 9.2.3.) at patch application sites will be performed. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse or phlebotomist in the 
CRU at:  


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• 
48:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
Subjects are free to leave the facility as this completes Arm 1 of the study. 
• 
A total of 18 blood draws will be completed over a period of 48 hours (total blood volume 
drawn = approximately 90 mL). 
7.3.4. Procedure Day 4: Lidocaine HCl Injection, 20 mg/1 ml Preservative Free Single Dose 
Vials 
• 
Subject will return to the CRU after a minimum washout period of 48 hours from the last 
blood draw from Arm 1 of the study. 
• 
Study staff will review any changes in medical history, medication history, and other study 
qualifications. All inclusion/exclusion criteria must continue to be met. 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate will be 
performed within the 60 minutes prior to injection of lidocaine HCl.  
• 
Urine pregnancy test will be obtained from women of childbearing potential if it has been 
more than 30 days since their last pregnancy test; the test must be negative. 
• 
The IV catheter will be placed under aseptic technique by an experienced nurse in the CRU.  
• 
Approximately 5 mL of blood will be drawn within the 60 minutes prior to the injection 
of lidocaine HCl. 
• 
The SureSigns VM4 monitor will be setup and attached to the subject for continuous 
monitoring of ECG, SpO2, and blood pressure. Monitoring will start 5 minutes before 
administration of the IV lidocaine and will continue during and for one hour after the 
injection. 
• 
Time 0: Using aseptic technique, an experienced nurse in the CRU will place an intravenous 
catheter in the opposite arm from the IV catheter used for blood sampling; this second 
catheter will be used for the IV lidocaine injection. Lidocaine HCl injection, 20 mg/1 ml 
preservative free single dose vials, dose 0.5 mg/kg, will be intravenously administered over 5 
minutes using an Alaris Guardrails pump with syringe pump cassette. The catheter will be 
removed immediately upon completion of the injection. 
• 
Blood sample collection will begin after the full injection has been administered. 
Approximately 5 mL of blood will be drawn by an experienced nurse in the CRU at the 
following time points after injection of the lidocaine HCl: 
• 
2 minutes after the lidocaine HCl injection 
• 
5 minutes after the lidocaine HCl injection 
• 
10 minutes after the lidocaine HCl injection 
• 
20 minutes after the lidocaine HCl injection 
• 
30 ± 5 minutes after the lidocaine HCl injection 
• 
45 ± 5 minutes after the lidocaine HCl injection 
• 
1:00 hour ± 5 minutes after the lidocaine HCl injection (SureSigns VM4 monitor 
removed) 
• 
2:00 hours ± 5 minutes after the lidocaine HCl injection (vital signs obtained) 
• 
3:00 hours ± 5 minutes after the lidocaine HCl injection 
• 
4:00 hours ± 5 minutes after the lidocaine HCl injection (vital signs obtained. 
• 
6:00 hours ± 5 minutes after the lidocaine HCl injection 
• 
8:00 hours ± 5 minutes after the lidocaine HCl injection (vital signs obtained) 
• 
10:00 hours ± 5 minutes after the lidocaine HCl injection (SureSigns VM4 monitor used 
to monitor ECG, SpO2, and blood pressure for 5 minutes) 
• 
Subjects are free to leave the facility as this completes Arm 2 of the study. 


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• 
A total of 14 blood draws will be completed over a period of 10 hours (total blood volume 
drawn = approximately 70 mL). 
7.3.5. Procedure Day 5: Lidoderm® Patch 5% 
• 
Subject will return to the CRU after a minimum washout period of 48 hours from the last 
blood draw from Arm 2 of the study. 
• 
Study staff will review any changes in medical history, medication history, and other study 
qualifications. All inclusion/exclusion criteria must continue to be met. 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate will be 
performed within the 60 minutes prior to the application of the three patches.  
• 
Urine pregnancy test will be obtained from women of childbearing potential if it has been 
more than 30 days since their last pregnancy test; the test must be negative. 
• 
PSI assessment (as explained in section 9.2.3.) will be performed prior to patch application.  
• 
The IV catheter will be placed under aseptic technique by an experienced nurse in the CRU. 
• 
Approximately 5 mL of blood will be drawn within the 60 minutes prior to patch application.  
• 
Time 0: Three Lidoderm® patches will be applied by a member of the study team to the 
subject’s lower back. 
• 
Each pouch will be numbered with a marker, and the patch corresponding to that pouch 
and release liner will be numbered the same. The pouches and release liners will be 
retained. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse in the CRU at the 
following time points after patch application: 
• 
1:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
2:00 hours ± 5 minutes after patch application  
• 
3:00 hours ± 5 minutes after patch application  
• 
4:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
5:00 hours ± 5 minutes after patch application  
• 
6:00 hours ± 5 minutes after patch application  
• 
8:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
10:00 hours ± 5 minutes after patch application  
• 
12:00 hours ± 5 minutes after patch application (vital signs obtained, patches removed, 
and PSI recorded) 
• 
14:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
Adhesion assessment (as explained in section Appendix B) will be performed at all time 
points while the subject is wearing the patches. 
• 
If a patch has an adhesion score ≥2 at any time, a member of the study team may apply a 
small piece of medical tape to the corners of the patch in order to keep the patch in contact 
with the skin. Great care will be taken that the smallest area possible on the patch is covered 
by tape, so as not to alter drug absorption in any way.  
• 
The patches will be removed at 12 hours. A PSI assessment will be recorded for each patch 
site. 
• 
Upon removal, each patch will be placed back on its release liner (care will be taken to put 
the patch on the correct side of the release liner) and inserted into its original pouch. All three 
pouches will be placed together into a sealable foil pouch. Subject ID and date will be labeled 
on the outside of the foil pouch.  
• 
The area of the skin where the patches were applied will be wiped with alcohol swabs (a 
different swab for each different patch site); the swabs will be numbered and placed into a 
second sealable foil pouch with the Subject ID and date.  


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• 
The day after removal, the patches will be shipped to Long Island University to be analyzed 
for residual drug content. 
• 
Subjects are free to leave the facility but must arrive at the facility in time for scheduled 
blood draws the following day. 
7.3.6. Procedure Day 6: Lidoderm® Patch 5% 
• 
A brief symptom-directed physical exam, if indicated. 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate. 
• 
PSI assessment (as explained in section 9.2.3.) at patch application sites will be performed at 
the 24 and 39 hour time points. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse or phlebotomist in 
the CRU at: 
• 
24:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
27:00 hours ± 30 minutes after patch application 
• 
30:00 hours ± 30 minutes after patch application 
• 
33:00 hours ± 30 minutes after patch application 
• 
36:00 hours ± 30 minutes after patch application 
• 
39:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
Subjects are free to leave the facility between these visits and at the end of the day, but must 
arrive at the facility in time for scheduled blood draw the following day. 
7.3.7. Procedure Day 7: Lidoderm® Patch 5% 
• 
A brief symptom-directed physical exam, if indicated.  
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate. 
• 
PSI assessment (as explained in section 9.2.3.) at patch application sites will be performed. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse or phlebotomist in the 
CRU at:  
• 
48:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
Subjects are free to leave the facility as this completes the study. 
• 
A total of 18 blood draws will be completed over a period of 48 hours (total blood volume 
drawn = approximately 90 mL). 
Group 2 study schedule 
7.3.8. Procedure Day 1: Lidoderm® Patch 5% 
• 
Study staff will review any changes in medical history, medication history, and other study 
qualifications. All inclusion/exclusion criteria must continue to be met. 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate will be 
performed within the 60 minutes prior to the application of the three patches.  
• 
Urine pregnancy test will be obtained from women of childbearing potential if it has been 
more than 30 days since their last pregnancy test; the test must be negative. 
• 
PSI assessment (as explained in section 9.2.3.) will be performed prior to patch application.  
• 
The IV catheter will be placed under aseptic technique by an experienced nurse in the CRU. 
• 
Approximately 5 mL of blood will be drawn within the 60 minutes prior to patch application.  
• 
Time 0: Three Lidoderm® patches will be applied by a member of the study team to the 
subject’s lower back. 


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• 
Each pouch will be numbered with a marker, and the patch corresponding to that pouch 
and release liner will be numbered the same. The pouches and release liners will be 
retained. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse in the CRU at the 
following time points after patch application: 
• 
1:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
2:00 hours ± 5 minutes after patch application  
• 
3:00 hours ± 5 minutes after patch application  
• 
4:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
5:00 hours ± 5 minutes after patch application  
• 
6:00 hours ± 5 minutes after patch application  
• 
8:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
10:00 hours ± 5 minutes after patch application  
• 
12:00 hours ± 5 minutes after patch application (vital signs obtained, patches removed, 
and PSI recorded) 
• 
14:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
Adhesion assessment (as explained in Appendix B) will be performed at all time points while 
the subject is wearing the patches. 
• 
If a patch has an adhesion score ≥2 at any time, a member of the study team may apply a 
small piece of medical tape to the corners of the patch in order to keep the patch in contact 
with the skin. Great care will be taken that the smallest area possible on the patch is covered 
by tape, so as not to alter drug absorption in any way.  
• 
The patches will be removed at 12 hours. A PSI assessment will be recorded for each patch 
site. 
• 
Upon removal, each patch will be placed back on its release liner (care will be taken to put 
the patch on the correct side of the release liner) and inserted into its original pouch. All three 
pouches will be placed together into a sealable foil pouch. Subject ID and date will be labeled 
on the outside of the foil pouch.  
• 
The area of the skin where the patches were applied will be wiped with alcohol swabs (a 
different swab for each different patch site); the swabs will be numbered and placed into a 
second sealable foil pouch with the Subject ID and date.  
• 
The day after removal, the patches will be shipped to Long Island University to be analyzed 
for residual drug content. 
• 
Subjects are free to leave the facility but must arrive at the facility in time for scheduled 
blood draws the following day. 
7.3.9. Procedure Day 2: Lidoderm® Patch 5% 
• 
A brief symptom-directed physical exam, if indicated. 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate. 
• 
PSI assessment (as explained in section 9.2.3.) at patch application sites will be performed at 
the 24 and 39 hour time points. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse or phlebotomist in 
the CRU at: 
• 
24:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
27:00 hours ± 30 minutes after patch application 
• 
30:00 hours ± 30 minutes after patch application 
• 
33:00 hours ± 30 minutes after patch application 
• 
36:00 hours ± 30 minutes after patch application 


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• 
39:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
Subjects are free to leave the facility between these visits and at the end of the day, but must 
arrive at the facility in time for scheduled blood draw the following day.  
7.3.10. Procedure Day 3: Lidoderm® Patch 5% 
• 
A brief symptom-directed physical exam, if indicated.  
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate will be 
performed 
• 
PSI assessment (as explained in section 9.2.3.) will be performed. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse or phlebotomist at the 
CRU at:  
• 
48:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
Subjects are free to leave the facility as this completes Arm 1 of study. 
• 
A total of 18 blood draws will be completed over a period of 48 hours (total blood volume 
drawn = approximately 90 mL). 
7.3.11. Procedure Day 4: Lidocaine HCl Injection, 20 mg/1 ml Preservative Free Single 
Dose Vials 
• 
Subject will return to the CRU after a minimum washout period of 48 hours from the last 
blood draw from Arm 1 of the study. 
• 
Study staff will review any changes in medical history, medication history, and other study 
qualifications. All inclusion/exclusion criteria must continue to be met. 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate will be 
performed within the 60 minutes prior to injection of lidocaine HCl.  
• 
Urine pregnancy test will be obtained from women of childbearing potential if it has been 
more than 30 days since their last pregnancy test; the test must be negative. 
• 
The IV catheter will be placed under aseptic technique by an experienced nurse in the CRU.  
• 
Approximately 5 mL of blood will be drawn within the 60 minutes prior to the injection 
of lidocaine HCl. 
• 
The SureSigns VM4 monitor will be setup and attached to the subject for continuous 
monitoring of ECG, SpO2, and blood pressure. Monitoring will start 5 minutes before 
administration of the IV lidocaine and will continue during and for one hour after the 
injection. 
• 
Time 0: Using aseptic technique, an experienced nurse in the CRU will place an intravenous 
catheter in the opposite arm from the IV catheter used for blood sampling; this second 
catheter will be used for the IV lidocaine injection. Lidocaine HCl injection, 20 mg/1 ml 
preservative free single dose vials, dose 0.5 mg/kg, will be intravenously administered over 5 
minutes using an Alaris Guardrails pump with syringe pump cassette. The catheter will be 
removed immediately upon completion of the injection. 
• 
Blood sample collection will begin after the full injection has been administered. 
Approximately 5 mL of blood will be drawn by an experienced nurse in the CRU at the 
following time points  after injection of the lidocaine HCl: 
• 
2 minutes after the lidocaine HCl injection 
• 
5 minutes after the lidocaine HCl injection 
• 
10 minutes after the lidocaine HCl injection 
• 
20 minutes after the lidocaine HCl injection 
• 
30 ± 5 minutes after the lidocaine HCl injection 


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• 
45 ± 5 minutes after the lidocaine HCl injection 
• 
1:00 hour ± 5 minutes after the lidocaine HCl injection (SureSigns VM4 monitor 
removed) 
• 
2:00 hours ± 5 minutes after the lidocaine HCl injection (vital signs obtained) 
• 
3:00 hours ± 5 minutes after the lidocaine HCl injection 
• 
4:00 hours ± 5 minutes after the lidocaine HCl injection (vital signs obtained) 
• 
6:00 hours ± 5 minutes after the lidocaine HCl injection 
• 
8:00 hours ± 5 minutes after the lidocaine HCl injection (vital signs obtained) 
• 
10:00 hours ± 5 minutes after the lidocaine HCl injection (SureSigns VM4 monitor used 
to monitor ECG, SpO2, and blood pressure for 5 minutes) 
• 
Subjects are free to leave the facility as this completes Arm 2 of the study. 
• 
A total of 14 blood draws will be completed over a period of 10 hours (total blood volume 
drawn = approximately 70 mL). 
7.3.12. Procedure Day 5: Lidocaine Patch 5% (Mylan) 
• 
Subject will return to the CRU after a minimum washout period of 48 hours from the last 
blood draw from Arm 2 of the study. 
• 
Study staff will review any changes in medical history, medication history, and other study 
qualifications. All inclusion/exclusion criteria must continue to be met. 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate will be 
performed within the 60 minutes prior to the application of the three patches.  
• 
Urine pregnancy test will be obtained from women of childbearing potential if it has been 
more than 30 days since their last pregnancy test; the test must be negative. 
• 
PSI assessment (as explained in section 9.2.3.) will be performed prior to patch application.  
• 
The IV catheter will be placed under aseptic technique by an experienced nurse in the CRU. 
• 
Approximately 5 mL of blood will be drawn within the 60 minutes prior to patch application.  
• 
Time 0: Three lidocaine 5% patches (Mylan) will be applied by a member of the study team 
to the subject’s lower back. 
• 
Each pouch will be numbered with a marker, and the patch corresponding to that pouch 
and release liner will be numbered the same. The pouches and release liners will be 
retained. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse in the CRU at the 
following time points after patch application: 
• 
1:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
2:00 hours ± 5 minutes after patch application  
• 
3:00 hours ± 5 minutes after patch application  
• 
4:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
5:00 hours ± 5 minutes after patch application  
• 
6:00 hours ± 5 minutes after patch application  
• 
8:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
10:00 hours ± 5 minutes after patch application  
• 
12:00 hours ± 5 minutes after patch application (vital signs obtained, patches removed, 
and PSI recorded) 
• 
14:00 hours ± 5 minutes after patch application (vital signs obtained) 
• 
Adhesion assessment (as explained in Appendix B) will be performed at all time points while 
the subject is wearing the patches. 
• 
If a patch has an adhesion score ≥2 at any time, a member of the study team may apply a 
small piece of medical tape to the corners of the patch in order to keep the patch in contact 


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with the skin. Great care will be taken that the smallest area possible on the patch is covered 
by tape, so as not to alter drug absorption in any way.  
• 
The patches will be removed at 12 hours. A PSI assessment will be recorded for each patch 
site. 
• 
Upon removal, each patch will be placed back on its release liner (care will be taken to put 
the patch on the correct side of the release liner) and inserted into its original pouch. All three 
pouches will be placed together into a sealable foil pouch. Subject ID and date will be labeled 
on the outside of the foil pouch.  
• 
The area of the skin where the patches were applied will be wiped with alcohol swabs (a 
different swab for each different patch site); the swabs will be numbered and placed into a 
second sealable foil pouch with the Subject ID and date.  
• 
The day after removal, the patches will be shipped to Long Island University to be analyzed 
for residual drug content. 
• 
Subjects are free to leave the facility but must arrive at the facility in time for scheduled 
blood draws the following day. 
7.3.13. Procedure Day 6: Lidocaine Patch 5% (Mylan) 
• 
A brief symptom-directed physical exam, if indicated. 
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate. 
• 
PSI assessment (as explained in section 9.2.3.) at patch application sites will be performed at 
the 24 and 39 hour time points. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse or phlebotomist in 
the CRU at: 
• 
24:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
27:00 hours ± 30 minutes after patch application 
• 
30:00 hours ± 30 minutes after patch application 
• 
33:00 hours ± 30 minutes after patch application 
• 
36:00 hours ± 30 minutes after patch application 
• 
39:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
Subjects are free to leave the facility between these visits and at the end of the day, but must 
arrive at the facility in time for scheduled blood draw the following day.  
7.3.14. Procedure Day 7: Lidocaine Patch 5% (Mylan) 
• 
A brief symptom-directed physical exam, if indicated.  
• 
Vital signs to determine blood pressure, pulse, temperature, and respiratory rate. 
• 
PSI assessment (as explained in section 9.2.3.) at patch application sites will be performed. 
• 
Approximately 5 mL of blood will be drawn by an experienced nurse or phlebotomist in the 
CRU at:  
• 
48:00 hours ± 30 minutes after patch application (vital signs obtained) 
• 
Subjects are free to leave the facility as this completes the study. 
• 
A total of 18 blood draws will be completed over a period of 48 hours (total blood volume 
drawn = approximately 90 mL). 
7.4. Early Termination Visit 
An Early Termination Visit should be performed for any subject who discontinues their participation 
in the study prior to completing all procedure days. If a subject leaves the study before the last 


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procedure day, the subject will be asked about his/her reasons for termination. This may occur via 
telephone call or by email from a member of the study team. If the subject identifies one or more 
adverse events as their reason, then a brief physical exam should be performed. All withdrawals will 
be documented on a subject withdrawal form for study records. 
7.5. Unscheduled Visit 
If an unscheduled visit occurs, a member of the study team will interview and evaluate the subject to 
determine the cause of the visit and provide care as needed and information documented on a 
supplemental visit form. 
 
 


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8. STUDY PROCEDURES/EVALUATIONS 
8.1. Clinical Evaluations 
Serum pregnancy tests will be performed at the screening visit before enrollment for all women of 
childbearing potential. Urine pregnancy tests will be performed on the morning of the first day of 
each of the three study arms if it has been more than 30 days since the subject’s negative serum 
pregnancy test. If any test is positive, the subject will be excluded from further participation, 
counseled, and referred to a clinical facility. 
On each of the procedure days, the subjects will be interviewed about any new, continuing, or 
worsening symptoms. Vital signs will be recorded before patch application or IV injection and at 
specified times in each procedure day (as indicated in section 7.3.). A CRU nurse or member of the 
study team will determine if the subject has any reportable symptoms. If appropriate, the MAI will be 
contacted and a symptom-directed physical exam will be completed. Results of the physical 
examinations and vital sign assessments will be reported to the ISM to determine if there is evidence 
of immediate safety concerns or for changes in values that indicate a potential danger to the subject 
should the subject continue in the study. After conclusion of each study arm and discharge from the 
CRU, subjects will be asked to report all adverse events (AE) for up to 48 hours. Subjects will be 
interviewed by telephone daily for two consecutive days (up to 48 hours) after the last procedure day 
of each study arm to determine if any AE occurred in the 48 hours post-discharge. If an event is 
judged to be a Serious Adverse Event (SAE), an SAE data collection form will be completed and 
SAE reporting procedures followed. 
8.2. Laboratory Evaluations 
8.2.1. Clinical Laboratory Evaluations 
In the event of an AE (of moderate severity or more) or SAE, safety laboratory data will be 
drawn, including hematology and chemistry parameters and provided to the MAI and ISM. 
Chemistry parameters include sodium, potassium, chloride, bicarbonate, BUN, creatinine, AST, 
ALT. Hematology parameters include Hgb, Hct, WBC and platelets. All tests are considered 
normal if the parameters are within normal limits or acceptable ranges, according to Appendix B. 
8.2.2. Bioanalytical Methods 
Serum samples will be analyzed using validated quantitation methods, which will be developed 
and performed by Ken Morris, PhD, and his laboratory members at Long Island University. Dr. 
Morris’ group will meet conditions in the FDA guidance for Bioanalytical Method Validation 
2012. 
8.2.3. Method for Determining Drug Content in Worn and Unworn Transdermal Systems 
8.2.3.1. Worn Systems 
For the determination of residual content, the used patches will be sent to Ken Morris’ 
laboratory at Long Island University on the day after the patches are removed from the 
subject using expedited, temperature-controlled, next day delivery service. The appropriate 
extraction technique will be determined and developed by Dr. Morris’ group.  


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8.2.3.2. Unworn Systems 
A minimum of 10 unworn systems from the same lot number worn by the subjects will be 
analyzed for drug content.  
The amount of drug absorbed will be calculated as follows:  
Amount of drug absorbed=mean amount of drug in unworn systems – amount of drug in 
worn system 
8.3. Specimen Preparation Handling and Shipping 
8.3.1. Instructions for Specimen Preparation, Handling, and Storage 
Blood samples will be collected during the procedures days at the time points specified in section 
4. The CRU has a small well-equipped laboratory on site with a trained laboratory technician 
available to process the samples as required for this study, and the study coordinator/study team 
members will be available to assist with sample processing. The PI also has a well-equipped 
laboratory with appropriate equipment for sample processing. After processing, all samples will 
be stored in Dr. Brogden’s lab at -80°C until shipped to Long Island University. During sample 
processing, the sera will be separated into two aliquots. One set of aliquots will be analyzed using 
an LC-MS validated method at Long Island University while the other set will be stored 
separately at the UI College of Pharmacy as a back-up set of samples. 
8.3.2. Specimen Shipment 
Serum samples will be shipped to Long Island University for analysis using expedited 
temperature-controlled, next-day delivery service. 
 
 


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9. ASSESSMENT OF SAFETY 
9.1. Specification of Safety Parameters 
Assessment of AEs throughout each of the procedure days will be monitored and vital signs (blood 
pressure, temperature, pulse, and respiratory rate) for each subject will be periodically monitored. 
AEs at the patch application site (e.g., erythema, edema, itching) will be assessed subjectively by 
each subject and also examined by a member of the study team at study visits following patch 
removal. Subjects will be interviewed by telephone daily for two consecutive days (up to 48 hours) 
after completing each study arm to determine if any AEs occurred in the 48 hours following study 
arm completion. If any skin changes are noted by the subject, (s)he will be instructed to return to the 
CRU for evaluation. If any skin changes are seen on exam they will be defined as topical AEs. In 
addition, the MAI will be available to assess and treat (where indicated). When medically indicated, 
the subject will be admitted to UIHC for emergency and/or continued care. All adverse effects will be 
reviewed by the ISM, and all SAEs will be immediately reported to the IRB. 
 
The administration of lidocaine is not anticipated to cause clinical problems. If a clinical problem 
would occur the subject will be discontinued from the study. If AEs occur, clinical judgment will be 
used with the results recorded as part of the PI or MAI’s judgment of the probability that an event is 
linked to the procedure. Subjects will be followed until all AEs are resolved or until they become 
medically stable.  
9.2. Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
9.2.1. Adverse Events 
AEs are qualified by expectedness, grade of severity, relationship of causality, and as serious or 
non-serious based on the definitions provided (Appendices B and C). All events will be recorded 
on appropriate clinical report forms with notation of duration, severity, and outcome. The PI is 
responsible for recording all AEs that are observed or reported during the study, regardless of 
their relationship to investigational product or their clinical significance. 
9.2.1.1. 
Adverse Event Definition 
Any untoward medical occurrence in a subject administered a study product, which does not 
necessarily have a causal relationship with this procedure. An AE is defined as any noxious, 
pathologic, or unintended change in anatomic, physiologic, or metabolic functions, as 
indicated by physical signs, symptoms, and/or laboratory changes occurring in any phase of 
the clinical study, regardless of their relationship to study product. The occurrence of an AE 
may come to the attention of study personnel during study visits or interviews of a subject 
presenting for medical care, or upon review by a study monitor. AEs include: 
• 
An exacerbation of a pre-existing condition  
• 
A concurrent illness 
• 
Any drug interaction  
• 
Any event related to a concomitant medication  
An AE can be any unfavorable and unintended sign (including an abnormal finding), 
symptom or disease temporarily associated with the use of a study product, whether or not 
related to the study product. This includes any occurrence that is new in onset or aggravated 


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in severity or frequency from the baseline condition, abnormal results of diagnostic 
procedures (including laboratory test abnormalities) which are considered AEs if they: 
• 
Result in discontinuation from the study 
• 
Require treatment or any other therapeutic intervention 
• 
Require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality) 
• 
Are associated with clinical signs or symptoms judged by the investigator to have a 
significant clinical impact 
All AEs including local and systemic reactions not meeting the criteria for “serious adverse 
events” should be captured on the appropriate case report form (CRF). Information to be 
collected includes event description, time of onset, assessment of severity, relationship to 
study product (assessed only by the PI or MAI), and time of resolution/stabilization of the 
event. All AEs occurring during the study must be documented appropriately regardless of 
relationship. All AEs will be followed until the subject becomes medically stable. Elective 
hospitalizations for pre-study conditions (e.g., elective cosmetic procedures) are not AEs. 
9.2.2. Grading Scale for Severity of AEs 
AEs are to be graded according to the standard criteria in Appendix B and C. The definitions 
provided in this section will be applied if there are no standard criteria given for that particular 
event. 
• 
Mild: events require minimal or no treatment and do not interfere with the subject’s daily 
activities. 
• 
Moderate: events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe: events interrupt a subject’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
• 
Life Threatening: any adverse drug experience that places the subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that had it occurred in a more severe form, might have caused death. 
Changes in the severity of an AE should be documented to allow an assessment of the duration of 
the event at each level of intensity to be performed. Adverse events characterized as intermittent 
require documentation of onset and duration of each episode. 
9.2.3. Reactogenicity 
Adverse events associated with topical administration will vary based on formulation and extent 
of systemic absorption. Dermatology reactions from the topical patch include blisters, bruising, 
burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, 
irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. Other 
possible systemic reactions include bradycardia, apprehension, confusion, dizziness, drowsiness, 
paresthesia, nausea, vomiting, bruising, methemoglobinemia, weakness, and angioedema or 
anaphylactic hypersensitivity reactions. Also please refer to the attached package inserts.  
The adverse events associated with systemic lidocaine administration may be cardiovascular, 
central nervous system, gastrointestinal, neuromuscular and skeletal, respiratory, or 
miscellaneous in nature. The majority of these reactions do not have a defined frequency of 
occurrence, and many will vary with route of administration and are dose-related. Cardiovascular 


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effects may include bradycardia, cardiac arrhythmia, circulatory shock, coronary artery 
vasospasm, edema, flushing, heart block, hypotension, or local thrombophlebitis. Central nervous 
system effects may include agitation, anxiety, apprehension, coma, confusion, disorientation, 
dizziness, drowsiness, euphoria, hallucination, hyperesthesia, hypoesthesia, intolerance to 
temperature, lethargy, loss of consciousness, metallic taste, nervousness, paresthesia, psychosis, 
seizure, slurred speech, and twitching. Respiratory reactions include bronchospasm, dyspnea, 
respiratory depression. Other/miscellaneous possible adverse events include nausea, vomiting, 
tremor, weakness, tinnitus, and anaphylaxis or hypersensitivity reactions. Asystole and 
methemoglobinemia have occurred in less than 1% of patients. 
 
If an event has not been experienced previously and is not listed here, it will be categorized as an 
“Unexpected” AE. 
Primary Skin Irritation (PSI) Assessment 
PSI will be performed pre-dose, and at 12:00 hours (after patch removal), 24:00 hours, 39:00 and 
48:00 hours. The skin site will be graded according to the following irritation grading scale:  
0 - No evidence of irritation.  
1 - Faint but definite erythema, no eruptions or broken skin or no erythema but definite 
dryness; may have epidermal fissuring.  
2 - Moderate erythema, may have a few papules or deep fissures, moderate-to-severe 
erythema in the cracks. 
3 - Severe erythema (beet redness), may have generalized papules or moderate-to-severe 
erythema with slight edema (edges well defined by raising).  
4 - Generalized vesicles or eschar formations or moderate-to-severe erythema and/or edema 
extending beyond the area of the patches. 
A CRU nurse or member of the study team will evaluate each subject for the occurrence of 
reactogenicity symptoms by assessing signs and reported symptoms by the subject and by 
reviewing the subject’s vital signs. A physical examination by the MAI will be conducted when 
appropriate. 
9.2.4. Serious Adverse Events 
A SAE is defined as an AE that results in any of the following outcomes: 
• 
Death 
• 
Life-threatening event 
• 
Inpatient hospitalization (>24 hrs) or prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity 
• 
Any other important medical event that may not result in death, be life-threatening (any 
adverse drug experience that places the subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred, i.e. it does not include a reaction 
that had it occurred in a more severe form, might have caused death), or require 
hospitalization, may be considered a SAE when, based upon appropriate medical judgment, 
the event may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above.  
 
Additionally, the occurrence of the following reactogenicity symptoms is defined as an SAE: 
• 
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9.3. Reporting Procedures 
9.3.1. Serious Adverse Events 
The PI must report to the FDA Sponsor and the Research Involving Human Subject Committee 
(RIHSC) any unanticipated problems involving risk to human subjects or others according to 21 
CFR 312.32(c)(2). Anticipated adverse events may be reported to the RIHSC in the annual report 
for continuing review.  
 
However, certain adverse events must be reported to the RIHSC within 7 working days of the 
discovery of the event. The RIHSC defines these adverse events as including, but not limited to 
the following:  
• 
An adverse event that is not expected, i.e. not listed in the informed consent document or 
the investigator’s brochure;  
• 
An expected adverse event that occurs at a greater frequency or duration than expected;  
• 
Any adverse event that would require modification of the protocol and/or informed consent 
document. 
The following procedures will occur if in the opinion of the PI, MAI or ISM the event meets the 
criteria of a SAE: 
• 
All SAEs will be: 
− 
reviewed by a study physician 
− 
recorded on the appropriate AE and SAE form 
− 
followed by the MAI until satisfactory resolution or until the MAI deems the event to 
be chronic or the subject to be stable 
Any AE considered serious by the PI, MAI, or ISM or which meets the aforementioned criteria 
must be submitted on an SAE form to the FDA at the following address: 
 
Caroline Strasinger, PhD 
Branch Chief – Chemistry, Manufacturing and Controls at FDA 
FDA / CDER / Office of Pharmaceutical Quality / Office of Lifecycle Drug Product  
301-796-3776 (Office) 
502-249-1839 (Cell) 
caroline.strasinger@fda.hhs.gov 
 
 
 
In addition, such events will be reported to the IRB in accordance with IRB policy. The PI will 
complete an SAE form within the following timelines:  
• 
All deaths and immediately life-threatening events, whether related or unrelated, will be 
recorded on an SAE Form and sent by email to the FDA within 24 hours of site awareness. 
• 
SAEs other than death and immediately life-threatening events, regardless of relationship, 
will be reported via email by the site within 24 hours of becoming aware of the event. 
 
Other supporting documentation of the event may be requested by the FDA Pharmacovigilance 
Group and should be provided as soon as possible. All SAEs will be followed until satisfactory 
resolution or until the MAI deems the event to be chronic or the subject to be stable. The FDA 
Clinical Project Manager will be notified of the SAE by the FDA Pharmacovigilance Group. The 
FDA Medical Monitor will review and assess the SAE for regulatory reporting and potential 
impact on study subject safety and protocol conduct.  


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9.3.2. Reporting of Pregnancy 
Subjects must be of non-childbearing potential, or if of childbearing potential (as determined by 
the MAI or PI) must be practicing abstinence or using an effective licensed method of birth 
control (e.g., use hormonal or barrier birth control such as implants, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), condoms with spermicidal agents; or have a 
vasectomized partner). Female subjects will undergo serum pregnancy tests during the Screening 
Period. Pregnant or lactating women will be excluded from the study. If an eligible female subject 
has a positive urine pregnancy test on any of the procedure days, she will not be permitted to 
participate that day and will be discontinued from the study.  
9.4. Type and Duration of Follow-up of Subjects after Adverse Events 
The administration of lidocaine is not anticipated to cause significant clinical problems. If a clinical 
problem would occur the subject will be discontinued from the study. If AEs occur, clinical judgment 
will be used with the results recorded as part of the PI or MAI judgment of the probability that an 
event is linked to the lidocaine procedure. 
9.5. Halting Rules 
The ISM will review reports on protocol progress, side effects and AEs after each study arm. The PI 
will be informed of all SAE reports within 24 hours of their occurrence. All SAEs will be reported by 
the PI to the MAI, ISM, the University of Iowa IRB, and the appropriate FDA program officer. The 
PI will provide an initial SAE report within 24 hours of their occurrence to the ISM, University of 
Iowa IRB, and FDA program officer, or as soon as required by each entity, with a final report to 
follow.  
 
Dosing will be halted and the data reviewed by the ISM if any of the following are observed: 
• 
3 or more subjects develop Grade 2 or higher of the major side-effects known to be related to 
lidocaine 
• 
2 or more subjects develop Grade 3 or higher of the major side-effects known to be related to 
lidocaine 
• 
Any single SAE 
 
When the study is halted then the PI, MAI, and ISM will determine whether further procedure days or 
study arms should be stopped, and/or if protocol or informed consent is modified. 
9.6. Safety Oversight 
The ISM is a physician at the enrollment site with relevant expertise whose primary responsibility is 
to provide independent safety monitoring in a timely fashion at each site. The primary focus of the 
ISM is to independently review all SAEs, thoroughly investigate those events considered unexpected, 
and provide an independent assessment to the FDA. Participation is for the duration of the study. The 
ISM will review available safety data provided for each subject after each study arm prior to making a 
recommendation to proceed to the next study arm. A “study arm” encompasses the administration of 
the product (patches or IV) and all associated procedure days. Ad hoc meetings with the FDA and 
MAI/PI may be required if a halting rule occurs. The ISM should be able to readily access all subject 
records in real time. This is accomplished by review of SAEs, immediately after they occur, with 
follow-up through resolution, or until the MAI/ISM deems the subject medically stable. 


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The ISM may be a faculty member at the clinical site, but will not be under the direct supervision of 
the PI. It is the responsibility of the PI to ensure that the ISM is appraised of all new safety 
information relevant to the study product and the study. This includes providing the ISM with all 
safety reports issued by the sponsor. The ISM should receive all protocol revisions and may receive 
other documents related to the study. The ISM will review all SAEs which occur during the course of 
the study. The ISM may transiently halt enrollment. The ISM will contact the MAI and PI, and the 
medical officer at the FDA for any event that needs further evaluation. 
9.7. Clinical Monitoring 
9.7.1. Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subject protection, study procedures, 
laboratory, study product administration and data collection processes are of high quality and 
meet sponsor, ICH E6, and other appropriate, regulatory guidelines and that the study is 
conducted in accordance with the protocol and sponsor standard operating procedures. Site visits 
may be conducted by an authorized representative of the FDA or other regulatory agencies to 
inspect study data, subjects’ medical records and CRFs in accordance with ICH guidelines, Good 
Clinical Practice (GCP) and the respective local and national government regulations and 
guidelines. The investigator will permit authorized representatives of the FDA and the respective 
local and national health or regulatory authorities to inspect facilities and records relevant to this 
study if needed. The PI and MAI will provide direct access to all study-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor, and 
inspection by local and regulatory authorities.  
 
FDA-designated clinical monitors will verify that the clinical study is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements. Clinical monitoring reports will be submitted to the FDA. 
 
 
 


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10. PHARMACOKINETICS AND STATISTICAL CONSIDERATIONS 
10.1. Study Hypotheses 
The main objective of this study is to determine the absolute bioavailability and PK parameters (e.g., 
AUC, Cmax, Tmax, CL, V) of lidocaine in healthy adults after using lidocaine 5% patches manufactured 
by Endo Pharmaceuticals and Mylan. The secondary objective is to determine residual drug content in 
worn patches.  
10.2. Pharmacokinetic (PK) Analyses 
Lidocaine concentrations will be measured in serum samples collected from each subject. Blood 
samples (approximately 5 mL each) will be collected at the time points list in section 4. Actual 
sampling times will be used to estimate PK parameters. 
 
Non compartmental and compartmental analyses will be conducted to estimate the primary PK 
parameters such as clearance (CL), volume of distribution (V), elimination rate constant (Kel), 
maximum serum concentration (Cmax), time of maximum serum concentration (Tmax) and area under 
the serum concentration-time curve (AUC). Absolute bioavailability will be calculated as follows:   
 
 
𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝑏𝑖𝑜𝑎𝑣𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦= 
𝐴𝑈𝐶𝑝𝑎𝑡𝑐ℎ/𝐷𝑜𝑠𝑒𝑝𝑎𝑡𝑐ℎ
𝐴𝑈𝐶𝐼𝑉/𝐷𝑜𝑠𝑒𝐼𝑉
 
Equation 1: For determination of the absolute bioavailability for the Lidoderm® 5% patches 
(Endo Pharmaceuticals) and the lidocaine 5% patches (Mylan). The patch refers to the topical 
lidocaine patch systems. The geometric means for AUC0-∞ will be obtained by exponentiating the 
log transformed AUC0-∞ for the two treatments to determine the absolute bioavailability.  
Different mathematical approaches including, but not limited to, deconvolution will then be utilized 
to determine secondary objectives and the rate of drug delivery from the patches. The secondary 
objective to determine residual drug content in worn patches would provide a surrogate method to 
determine the amount of drug delivered in vivo after wearing the patch. The following equation will 
be used to determine the amount of drug delivered in vivo: 
𝐿𝑖𝑑𝑜𝑐𝑎𝑖𝑛𝑒 𝑟𝑒𝑙𝑒𝑎𝑠𝑒𝑑= 𝑇𝑜𝑡𝑎𝑙 𝑙𝑖𝑑𝑜𝑐𝑎𝑖𝑛𝑒−𝑟𝑒𝑠𝑖𝑑𝑢𝑎𝑙 𝑙𝑖𝑑𝑜𝑐𝑎𝑖𝑛𝑒 
 
Equation 2: The cumulative amount of lidocaine released by Lidoderm® 5% patches (Endo 
Pharmaceuticals) or lidocaine 5% patches (Mylan) at the end of the study arm will be obtained by 
subtracting residual lidocaine still remaining in the patch at the end of the study arm from the 
total amount of the drug present in an unused patch. 
 
Further calculation will determine the rate of drug release from the patches using the following 
equation: 
 
𝑅𝑒𝑙𝑒𝑎𝑠𝑒 𝑟𝑎𝑡𝑒= 𝐿𝑖𝑑𝑜𝑐𝑎𝑖𝑛𝑒 𝑟𝑒𝑙𝑒𝑎𝑠𝑒𝑑 
𝐴𝑝𝑝𝑙𝑖𝑐𝑎𝑡𝑖𝑜𝑛 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 
 
Equation 3: Determination of lidocaine release rate using the amount of lidocaine released from 
the patches. 


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Finally, the lidocaine absorption rate will be calculated using steady state concentrations (Css) and the 
clearance (CL) as predicted from the IV bolus data: 
 
𝐴𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒= 𝐶𝑠𝑠×  𝐶𝐿 
 
Equation 4: Determination of the absorption rate from lidocaine patches using the steady state 
concentrations and the clearance. 
 
A detailed explanation of the statistics to be performed on the PK analysis is presented in Section 
10.4.  
10.3. Sample Size Consideration 
A power analysis determined a sample size of 24 as sufficient for an alpha ≤ .05 to reject the null 
hypothesis and establish statistical significance. This analysis assumed a 22% within subject 
variability in the pharmacokinetic parameters, CMax and AUC0-∞, with 80% power. The analysis also 
assumed that the test and reference formulation vary by 5% and a type-I error rate of 5%. 
10.4. Statistical Analysis Plan 
Primary statistical analysis will be performed on the natural log transformed AUC0-t, AUC0-∞ and Cmax 
of lidocaine from the two treatments. The following will be obtained: 
• 
A linear mixed effects model will be used to assess the effects of treatment, period, sequence, 
and subject within sequence on the natural log transformed AUC0-t, AUC0-∞ and Cmax of 
lidocaine. For this, the treatment, period, and sequence effect will be treated as fixed effects 
(assessed at a significance level of 0.05) while the subject within sequence will be treated as a 
random effect. 
• 
Intra- and inter-individual variabilities will be obtained. 
• 
The least squares mean estimates for the adjusted differences between treatment means (the log 
transformed AUC0-t, AUC0-∞ and Cmax) and the standard error associated with these differences 
will be obtained. 
• 
The 95% confidence intervals for absolute bioavailability of the lidocaine patches will be 
obtained. 
 
 


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11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
The PI, clinical coordinator, and investigational site will maintain appropriate medical and research 
records for this study, in compliance with ICH E6 GCP, Section 4.9 and regulatory and institutional 
requirements for the protection of confidentiality of subjects. The PI and investigational site will permit 
authorized representatives of the Sponsor and regulatory agencies to examine (and when required by 
applicable law, to copy) clinical records for the purposes of quality assurance (QA) reviews, audits, and 
evaluation of the study safety and progress. 
 
Data collection forms will be used to collect source data. Source data are all information, original records 
of clinical findings, observations, or other activities in a study. Examples of these original documents and 
data records include, but are not limited to, data collection forms, laboratory notes, memoranda, recorded 
data from automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, photographic negatives, microfilm or magnetic media, and subject files and records kept at the 
pharmacy and at the laboratories involved in the clinical study. 
 
Research records generated in this study will be stored in file cabinets in a locked room and on a secure 
electronic database. Only authorized personnel at the sites will have access to the data. 
 
 


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12. QUALITY CONTROL AND QUALITY ASSURANCE 
The investigational site is responsible for conducting routine QA and quality control (QC) activities to 
internally monitor study progress and protocol compliance. The PI will ensure all study personnel are 
appropriately trained and applicable documentations are maintained on site. The combined processes of 
QC and QA form the basis of quality management (QM) and will be applied to this clinical study. QM 
activities will be guided by each site’s Quality Management Plan (QMP). The QMP identifies key 
indicators (i.e., eligibility, informed consent, concomitant medications, study product, AE/SAE, missed 
visits, missed labs, etc.) that will be reviewed during quality control checks and quality assurance audits 
to assess adherence to the IRB-approved protocol, generate quality data, protect data integrity, and 
safeguard the safety and well-being of study participants. 
 
The study product and accountability records will be maintained at the site and will include the study 
product shipping receipts, preparation, dispensing, administration, accountability, and destruction records 
(as applicable).  
All staff will have completed the Human Subjects Protection and HIPAA training required by the IRB.  
 
 


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13. ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1. Ethical Standard 
The PI will ensure that this study is conducted in full conformity with the principles set forth in The 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research 
of the US National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 
25691 (1997). 
13.2. Institutional Review Board 
The IRB of record for the protocol and consent covered by this grant is the University of Iowa IRB, 
and approval will be obtained prior to subject enrollment and study initiation. All participating 
research staff will have undergone documented Human Subjects Protection and HIPAA training. As 
previously stated, all laboratory data and records will be identified only by code numbers and kept in 
a locked cabinet.  
The study will not be initiated until the IRB provides written or electronic approval of the research 
plan and the informed consent, and until the PI has provided copies of all appropriate approval 
documents to the Sponsor. Site activation cannot begin until the Research Involving Human Subjects 
Committee (RIHSC), the FDA’s IRB, has reviewed and approved the study and the approval letter is 
forwarded to the PI. Appropriate reports on the progress of this study by the PI will be made available 
to their IRBs and the Sponsor in accordance with applicable government regulations and in agreement 
with policy established by the Sponsor. The address and contact information for the participating IRB 
is listed below: 
 
University of Iowa 
Hardin Library for the Health Sciences 
600 Newton Road, Suite 105 
Iowa City, IA 52242 
Phone: 319-335-6564 
Email: irb@uiowa.edu 
13.3. Informed Consent Process 
Informed consent is a process that is initiated before the individual’s agreeing to participate in the 
study and continuing throughout the individual’s study participation. Consent forms describing in 
detail the study products, study procedures, and risks are given to the subject and written 
documentation of informed consent is required before administering any drug product. Consent forms 
will be IRB-approved and the subject will be asked to read and review the document. Upon reviewing 
the document, a member of the research team will explain the research study to the subject and 
answer any questions that the subject has. The subjects will sign the consent document before any 
study procedures are performed. The subjects will have the opportunity to discuss the study with their 
surrogates and consider participation before agreeing to enroll in the study.  
 
All subjects must be judged to be capable of signing informed consent by the research team. They 
must give their written consent to participate in the study. Subjects’ questions and concerns will be 
adequately addressed by the experienced research team prior to signing the consent form. A signed 
copy of the consent form will be given to the subject for their records, and a signed copy will be 
placed in their research file. In addition, to assess and document comprehension of the material 


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presented, a study member will complete a consent checklist to verify that the subject understands all 
aspects of the study including the procedures and risks. This checklist is IRB-approved and dated and 
signed by the research staff and made part of the research file. 
 
The subjects may withdraw consent at any time throughout the course of the study. The rights and 
welfare of the subjects will be protected by emphasizing to them that the quality of their medical care 
will not be adversely affected if they decline to participate in this study or choose to withdraw consent 
at any time. 
 
With the exception of students, employees and women of childbearing potential who take precautions 
against pregnancy as defined in the eligibility criteria, special populations will not be enrolled in this 
study. Examples of special populations are non-English speakers, children, illiterate or non-writing 
individuals, and prisoners. No individual group will be targeted for enrollment. Every effort will be 
made to ensure that subjects do not feel there is any secondary gain for themselves from participation.  
13.3.1. Informed Consent/Assent Process (in Case of a Minor) 
 
Not applicable. 
13.4. Exclusion of Women, Minorities, and Children (Special Populations) 
Children under age 18 will be excluded from participation because existing data is insufficient to 
judge risks in children. Women and minorities will not be excluded. We expect the racial composition 
of the volunteers in this study to be similar to that in prior recent studies at the University of Iowa. 
13.5. Subject Confidentiality 
All records of the research will be kept in locked files with subjects' evaluation study materials 
identified by code only. A separate file will hold the code key. Subjects will not be personally 
identified in any publications or reports of the study. All blood specimens drawn for research 
purposes will be identified by code only. The highest standards of subject confidentiality will be kept. 
Electronic records of data will be kept on password-only accessible computers. Appropriate firewalls 
and protections of computerized data are maintained to ensure that entry by those other than research 
personnel is not possible. The study monitor or other authorized representatives of the Sponsor may 
inspect all documents and records required to be maintained by the PI, including but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the subjects in this study. The 
FDA regulatory authorities may also access subject records. The clinical study site will permit access 
to such records. 
13.6. Study Discontinuation 
If the study is discontinued, subjects will not continue with the procedure days or arms. If the study is 
discontinued, follow-up visits for safety would continue as needed. 
13.7. Future Use of Stored Specimens 
Back-up serum samples will be stored at the UI College of Pharmacy immediately after collection 
during the study, and will remain there until after the study is completed. These back-up samples will 
be aliquots of unused sera collected during the study, and will be stored frozen at -80°C and may be 
used for future studies. Subjects can decide if they want their samples to be retained for future 
research or have their samples destroyed at the end of the study. The site may have an option for 


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subjects to consent to store their specimens with their identification linked or they may choose to de-
identify their stored specimens. All future research performed on these specimens must obtain 
Sponsor authorization and will be approved by the IRB at the University of Iowa. All samples will 
remain confidential within the extent of state and federal laws. Genetic testing will not be performed.  
 
There are no benefits to subjects in the collection, storage and subsequent research use of specimens. 
Reports about future research done with subject’s samples will NOT be kept in their health records, 
but subject’s samples may be kept with the study records or in other secure areas. 
 
 


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14. DATA HANDLING AND RECORD KEEPING 
The PI is responsible to ensure the accuracy, completeness, legibility, and timeliness of the data reported. 
All data collection forms will be completed in a neat, legible manner to ensure accurate interpretation of 
data. Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, 
cross out the original entry with a single line, and initial and date the change. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. Data collection forms 
will be used and maintained for recording data for each subject enrolled in the study.  
14.1. Data Management Responsibilities 
The PI and clinical team are responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported. AEs must be graded and assessed for severity and causality, and 
reviewed by the PI or MAI. 
Data collection is the responsibility of the clinical study staff at the site under the supervision of the 
PI. During the study, the PI will maintain complete and accurate documentation for the study. 
14.2. Data Capture Methods 
All data will be entered into an electronic spreadsheet (Microsoft Excel®) and will be reviewed to 
ensure accuracy and completion prior to data analysis. 
14.3. Types of Data 
Data for this study will include subject demographic data, safety, and laboratory (lidocaine levels in 
serum) and drug concentrations in patches post-wear.  
14.4. Timing/Reports 
After all subjects have completed the procedure days, and laboratory data analyzed, the final report 
will be prepared. 
14.5. Study Records Retention 
Records and documents pertaining to the conduct of this study, including case report forms (CRF), 
data collection forms, and consent forms, must be retained by the PI for at least three years following 
conclusion of the study or until the FDA authorizes transfer or destruction of study records. No study 
records will be destroyed without prior authorization from the Sponsor. It is the responsibility of the 
Sponsor to inform the PI when these documents no longer need to be retained. 
14.6. Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or GCP requirements. The 
noncompliance may be either on the part of the subject, the PI, or the study site staff. As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly. All 
deviations from the protocol must be addressed in study subject data collection forms. Protocol 
deviations must be sent to the IRB per their guidelines. The site PI/study staff is responsible for 
knowing and adhering to their IRB requirements. The Sponsor will identify personnel who will 
monitor the protocol and identify protocol deviations in addition to the ongoing efforts of study staff. 
A protocol deviation form will be completed for all deviations. This form will identify the subject by 


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study ID, the deviation, and possible reasons for the deviation. For deviations that are not subject-
specific (e.g. study product, laboratory procedure and storage temperature anomalies) a Non-Subject 
Specific Protocol Deviation data collection form should be completed. 
 
 


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15. PUBLICATION POLICY 
All investigators funded by a government agency must submit to the National Library of Medicine’s 
PubMed Central an electronic version of their final, peer-reviewed manuscripts upon acceptance for 
publication, to be made publicly available no later than 12 months after the official date of publication. 
This Public Access Policy ensures the public has access to the published results of the funded research. It 
requires investigators to submit final peer-reviewed journal manuscripts to the digital archive PubMed 
Central upon acceptance for publication. Further, the policy stipulates that these papers must be accessible 
to the public on PubMed Central no later than 12 months after publication. All publications resulting from 
this study shall be reviewed by the Sponsor prior to submittal for publication. FDA support will be 
acknowledged in all publications. 
 
 


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REFERENCES 
1. 
Collinsworth KA, Kalman SM, Harrison DC. The clinical pharmacology of lidocaine as an 
antiarrhythymic drug. Circulation 1974;50:1217-30. 
2. 
Adinoff B, Devous MD, Sr., Cooper DC, Best SE, Harris TS, Williams MJ. Neural response to 
lidocaine in healthy subjects. Psychiatry Res 2009;173:135-42. 
3. 
Hamp T, Krammel M, Weber U, Schmid R, Graf A, Plochl W. The effect of a bolus dose of 
intravenous lidocaine on the minimum alveolar concentration of sevoflurane: a prospective, randomized, 
double-blinded, placebo-controlled trial. Anesthesia and analgesia 2013;117:323-8. 
4. 
Baik HJ, Kim YJ, Kim JH. Lidocaine given intravenously improves conditions for laryngeal 
mask airway insertion during propofol target-controlled infusion. Eur J Anaesthesiol 2009;26:377-81. 
5. 
Rowland M, Thomson PD, Guichard A, Melmon KL. Disposition kinetics of lidocaine in normal 
subjects. Annals of the New York Academy of Sciences 1971;179:383-98. 
6. 
Wallace MS, Laitin S, Licht D, Yaksh TL. Concentration-effect relations for intravenous 
lidocaine infusions in human volunteers: effects on acute sensory thresholds and capsaicin-evoked 
hyperpathia. Anesthesiology 1997;86:1262-72. 
 
 


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SUPPLEMENTS/APPENDICES 
APPENDIX A: SCHEDULE OF EVENTS 
Schedule → 
Arm 1: first 
patch study 
Arm 2: 
Lidocaine   
hydrochloride  
injection 
Arm 3: second 
patch study 
Events ↓ 
Screen¹ Day 
1 
Day 
2 
Day 
3 
Day 4 
Day 
5 
Day 
6 
Day 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Medical History Review 
 
X 
 
 
X 
X 
 
 
Physical Exam, weight, height 
X 
 
 
 
 
 
 
 
Targeted physical exam, if indicated 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs² 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
3-lead ECG 
 
 
 
 
X 
 
 
 
Laboratory tests 
X 
 
 
 
 
 
 
 
Pregnancy serum test³ 
X 
 
 
 
 
 
 
 
Pregnancy urine test ⁴ 
 
X 
 
 
X 
X 
 
 
Urine drug of abuse screen 
X 
 
 
 
 
 
 
 
Review of all inclusion and 
exclusion criteria and all laboratory 
results to ensure subject continued 
eligibility for the study 
 
X 
 
 
X 
X 
 
 
Administration of Lidocaine 
(Topical or Injection) 
 
X 
 
 
X 
X 
 
 
Concomitant medications review 
 
X 
X 
X 
X 
X 
X 
X 
Patch adhesion assessment 
 
X 
 
 
 
X 
 
 
Pharmacokinetic blood samples ⁵ 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events monitoring - 
systemic 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events monitoring - local: 
Primary Skin Irritation (PSI) 
 
X 
X 
X 
 
X 
X 
X 
¹ Screening will be conducted for every volunteer to ensure eligibility 
² Vital signs include blood pressure, temperature, pulse, and respiration rate 
³ Serum pregnancy test for all women of childbearing potential 
⁴ Urine pregnancy test for all women of childbearing potential if it has been >30 days since serum 
pregnancy test.  


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⁵ For each patch study arm: A pre-dose sample will be obtained within 60 min pre-patch application and 
then at 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 14:00, 24:00, 27:00, 30:00, 33:00, 36:00, 
39:00, and 48:00 hr post-patch application 
For IV study arm: 5 A blood sample will be collected within 60 minutes pre-IV injection and then at 
00:02, 00:05, 00:10, 00:20, 00:30, 00:45, 1:00, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00 hours post IV injection 
 
 


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APPENDIX B: ACCEPTABLE SCREENING VALUES & LABORATORY REFERENCE 
RANGES 
Laboratory Test 
Acceptable Value per University 
of Iowa Pathology Handbook 
Units 
White Blood Cell count (WBC) 
3.7 – 10.5 
k/mm3 
Hemoglobin 
13.2-17.7 (males) 
g/dL 
 
11.9-15.5 (Females) 
g/dL 
Hematocrit 
40-52 (Males) 
Percent 
 
35-47 (Females) 
Percent 
Platelet count 
150-400 
k/mm3 
Sodium 
135–145 
meq/L 
Potassium 
3.5 – 5.0 
meq/L 
Creatinine 
0.6 – 1.2 (Males) 
mg/dL 
 
0.5 – 1.0 (Females) 
mg/dL 
AST  
0 – 40 (Males) 
Unit/L 
 
0 – 32 (Females) 
Unit/L 
ALT  
0 – 41(Males) 
Unit/L 
 
0 – 33 (Females) 
Unit/L 
Chloride 
95 – 107 
mEq/L 
Bicarbonate 
22 – 29 
mEq/L 
BUN 
10 – 20 
mEq/L 
Serum β-HCG 
Negative 
n/a 
Urine pregnancy test 
Negative 
n/a 
Urine Drug (toxicology) 
Must be negative for cocaine, opiates, and barbiturates 
Electrocardiogram (ECG) 
Must not have any of the following, in order to be acceptable: 
Pathologic Q wave abnormalities 
Significant ST-T wave changes 
Left ventricular hypertrophy 
Right bundle branch block 
Left bundle branch block 
Advanced A-V heart block 
Non-sinus rhythm, excluding isolated premature atrial 
contractions 
n/a, not applicable 
 
 
 


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APPENDIX C: TOXICITY GRADING SCALES 
Vital Signs* 
Reference 
Range of 
Normal 
Values 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-
Threatening 
(Grade 4) 
Fever  (C)** 
            (F) 
35-37.9 
95-100.3 
38.0-38.4 
100.4-101.1 
38.5- 38.9 
101.2-102.0 
39.0-40 
102.1-104 
>40 
>104 
Tachycardia - 
beats per minute 55-100 
101-115 
116-130 
>130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - 
beats per minute 55-100 
50- 54 
45- 49 
<45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension 
(systolic) - mm 
Hg  
90 – 139  
140 – 159  
160 – 179  
>180 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension 
(diastolic) - mm 
Hg 
60 – 89  
90 – 99  
100 – 110  
>110 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension 
(systolic) – mm 
Hg *** 
90-139 
85-89 
80-84 
< 80 
Mean arterial pressure  
<60mm/ Hg or end 
organ damage 
or shock; 
requires 
hospitalization 
and vasopressor 
treatment 
Respiratory 
Rate 
- breaths per 
minute 
12-17 
18-20 
21- 25 
>25 
Intubation 
*Subject should be at rest for all vital sign measurements 
**Oral temperature; no recent (30 min) hot or cold beverages 
***A low diastolic blood pressure reading will be assessed to determine whether there are associated 
signs and symptoms 
 
 


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APPENDIX C: TOXICITY GRADING SCALE (CON’T) 
 
 
 
TOXICOLOGY GRADING SCALE – SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic 
Reaction 
Pruritus without rash 
Localized urticaria 
Generalized 
urticaria; 
angioedema 
 
Anaphylaxis 
Headache 
Mild discomfort that is 
brief or easily 
tolerated 
Discomfort that 
causes mild to 
moderate limitation 
in activity 
Symptom prevents 
all normal activity 
for 24 hours or 
more 
ER visit or 
hospitalization 
Fatigue 
Normal activity 
reduced 
 Normal activity 
decreased 25-0% 
Can’t go to work or 
school 
ER visit or 
hospitalization 
Any other 
illness or 
clinical 
adverse event  
No interference with 
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 


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APPENDIX D: ADHESION ASSESSMENT SCORING 
Score Condition 
0 
≥ 90% adhered (essentially no lift off the skin) 
1 
≥ 75% to < 90% adhered (some edges only lifting off the skin) 
2 
≥ 50% to < 75% adhered (less than half of the patch lifting off the skin) 
3 
> 0% to < 50% adhered but not detached (more than half of the patch lifting off the skin 
without falling off) 
4 
0% adhered - transdermal system detached (patch completely off the skin)