Conditions: Bioavailability
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 7
Healthy volunteers: yes

Brief summary:
This research study is designed to measure the amount of medicine in blood over time after the patch is placed on the skin with and without external heat application.

Detailed description:

Arms:
arm 1: RLD rivastigmine patch (4.6 mg/24 hours); worn for 9 hours arm 2: generic rivastigmine patch (4.6 mg/24 hours); worn for 9 hours arm 3: RLD rivastigmine patch (4.6 mg/24 hours); worn for 9 hours; 90 min heat application arm 4: generic rivastigmine patch (4.6 mg/24 hours); worn for 9 hours; 90 min heat application

Interventions: intervention 1: Rivastigmine (RLD) transdermal patch intervention 2: Rivastigmine (generic) transdermal patch
Intervention descriptions: intervention 1: brand name patch intervention 2: generic patch

Protocol document:
Prot_SAP_000.pdf: 
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1 
Determination of Serum Rivastigmine Levels after Using Rivastigmine 
Transdermal Delivery Systems with and without Standardized Heat Application in 
Healthy Human Volunteers  
Short title: Effect of Heat on Rivastigmine TDS Products 
UMB IRB #:  HP-00076010 
 
Principal Investigator:  
Audra L. Stinchcomb (contact), PhD, RPh (PI) 
 
Medically Accountable Investigators: 
Jeffrey Fink, MD, MS (primary) 
Lee-Ann Wagner, MD (secondary) 
 
Sponsor: 
Food and Drug Administration 
Office of Generic Drugs 
 
Grant Number: 1U01FD004955 
NCT:  03915626 
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August 5, 2020 
 


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STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice E6 (ICH-GCP) and the applicable Food and Drug 
Administration 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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PROTOCOL SUMMARY 
Title:  
Determination of Serum Rivastigmine Levels after Using 
Rivastigmine Transdermal Delivery Systems with and without 
Standardized Heat Application in Healthy Human Volunteers 
Population: 
Healthy adults age 18 - 45 years 
Number of Sites: 
Single site: University of Maryland School of Medicine (GCRC) 
Study Duration: 
Approximately up to 1 year 
 
Subject Participation 
Duration: 
Approximately 10 weeks including the screening period 
 
Description of Study 
Product: 
Rivastigmine 
TDS 
(Exelon®, 
4.6 
mg/24 
h), 
Novartis 
Pharmaceutical Corporation; Rivastigmine TDS (generic, 4.6 
mg/24 h), Alvogen, Inc 
Objective: 
 
The aim of the present study is to generate human 
pharmacokinetic (PK) data in healthy subjects for the purpose of 
determining heat effect on Exelon® (RLD TDS) and rivastigmine 
(generic TDS).  
The pharmacokinetic data obtained in this study will be used in 
combination with in vitro data collected to develop an in vitro-in 
vivo correlation (IVIVC).    
Description of Study 
Design: 
The study will be an open-label, crossover study (n=12 healthy 
subjects) over ~10 weeks includes four study sessions with up to 
a 45 day screening period with one week washout period between 
study sessions. 
The study contains four study sessions: 
• 
Study Session 1:  Exelon® TDS containing 9 mg (4.6 mg/24 
h) of rivastigmine base to be worn for ~9 h. 
 
• 
Study Session 2:  Rivastigmine generic TDS containing 6.9 
mg (4.6 mg/24 h) of rivastigmine base to be worn for ~9 h. 
• 
Study Session 3: Exelon® TDS containing 9 mg (4.6 mg/24 
h) of rivastigmine base to be worn for ~9 h.  The heating pad 
will be set to induce a skin temperature of 42.0 ± 4°C and 
applied for 1 hour 30 minutes at 5 h after application of the 
TDS.   


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Study Session 4: Rivastigmine generic TDS containing 6.9 mg 
(4.6 mg/24 h) of rivastigmine base to be worn for ~9 h.  The 
heating pad will be set to induce a skin temperature of 42.0 ± 4°C 
and applied for 1 hour 30 minutes at 5 h after application of the 
TDS.  
A)  Pharmacokinetics (PK) 
Each subject will be his/her own control (pre-dose blood sample) 
and each subject will sign an institutional review board–approved 
consent form explaining the purpose, nature, risks, benefits, and 
duration of the study. The study will be conducted in accordance 
with good clinical practice guidelines and with the ethical 
principles originating in the Declaration of Helsinki.  
The subject’s skin in the area of application (upper arm) will be 
relatively free of hair before TDS application. Blood samples 
(approximately 4 mL each) will be drawn in BD vacutainer tubes. 
Blood samples will be obtained as follows: 
• 
Within 60 min pre-application and then up to ~12 h after TDS 
application.   
 
B)  Residual Drug Analysis of Rivastigmine TDS  
In conjunction with the above described study, residual drug 
analysis will also be conducted for the previously worn Exelon® 
and rivastigmine generic TDS from Study Session 1-4.    
• 
Prior to administration to the subject as described in Part A, 
TDS will be weighed and the weight recorded. 
• 
The pouch, release liner and all items coming into contact with 
the TDS (gloves, forceps, etc..) applied in Part A will be 
retained for analysis. 
• 
The used TDS will be retained for drug content analysis. 
• 
All items coming into contact with the TDS during removal 
from the subject will be stored in a separate labeled sealable 
pouch until analyzed for drug content. 


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1 KEY ROLES 
U01 Principal Investigator: 
 
 
Audra L. Stinchcomb (contact), Ph.D., R.Ph. (PI) 
Professor 
Department of Pharmaceutical Sciences 
University of Maryland School of Pharmacy 
20 N Pine St, Room PHN521 
Baltimore, MD 21201 
Phone: 410-706-2646 
Fax: 410-706-0886 
Email: astinchc@rx.umaryland.edu  
 
 
 
 
Medically Accountable 
Investigators 
 
 
Jeffrey C Fink M.D., M.S.(primary) 
Professor 
Department of Medicine and Epidemiology (secondary) 
University of Maryland School of Medicine 
UMMC, Room NN3E03 
Baltimore, MD 21201 
Phone: 410-328-4822 
Fax: 410-328-5685 
Email:  jfink@medicine.umaryland.edu 
 
 
Lee-Ann Wagner, M.D. (secondary) 
University of Maryland Baltimore School of Medicine 
Department of Medicine  
Pediatrics 
22 South Greene Street, Room N13W46 
Baltimore, MD 21201 
Phone: 410-328-7605  
Email :  lwagner@medicine.umaryland.edu 
 
 


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2 BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
There are numerous transdermal delivery systems (TDS) that are currently available in 
the United States, the first of which was approved by the Food and Drug Administration 
(FDA) in 1979 (1). TDS are very attractive, convenient and easy to use systems and are 
available in various forms including TDSs (matrix or reservoir), sprays, gels, and 
ointments. Drug permeation from these TDS varies significantly and is dependent on a 
number of factors including system design, physicochemical properties of the drug, 
excipients, occlusion, sweat, skin condition, skin type and temperature. Investigating the 
influence of these factors on drug permeation from reference products that are often 
available in different forms is important to ensure that one formulation is not less safe than 
other formulations. In this proposal we will focus on investigating the influence of heat on 
drug permeation from rivastigmine RLD and generic TDS. Systemic absorption of drugs 
is dependent on cutaneous blood flow. Application of, or exposure to heat, allows gradual 
increase in cutaneous blood flow and an increase in the absorption rate and hence can 
increase drug permeation from TDSs.  Indeed, exposure to heat has been demonstrated 
to increase drug permeation from TDSs, which led to increased serum concentrations of 
numerous drugs (e.g., fentanyl and nicotine) and raised a number of safety concerns (2-7). 
As a result, almost all TDSs that are currently available have warnings against heat 
exposure.  
2.2 
Rationale 
The goal of this study is to conduct in vivo studies to compare the influence of heat on 
rivastigmine drug permeation from FDA approved products; Exelon® TDS versus 
rivastigmine generic TDS.  While there is data in the literature for heat effect on different 
active pharmaceutical ingredients (APIs), specifically RLD products, from exposure to 
external heating sources (heating pads, sauna, hot showers, exercising), there is no head-
to-head comparisons for heat effect on RLD versus generic during application.   Therefore, 
to help ensure that TDS are safe for patients, an in vitro setup is being developed to 
characterize the heat effect for these systems by correlating the in vivo data with in vitro 
data using the IVPT model with excised human skin.  This necessitates that a small number 
of human subject heat effect studies are performed under controlled and monitored 
conditions with selected products, to serve as an in vivo reference for parallel IVPT heat 
effect studies.  The rivastigmine heat effect studies described in this protocol are the final 
set in this series of studies. The intent of this research is to establish an IVIVC for the IVPT 
model in the specific context of heat effect studies, so that IVPT studies can be utilized to 


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evaluate whether all future generic products are similar in quality to the RLD in terms of 
heat effect.  In addition, the residual drug content of the used rivastigmine TDSs will be 
analyzed for the purpose of estimating the amount of drug absorbed. 
  
Rivastigmine Products 
Properties 
Exelon TDS 
Alvogen TDS 
Excipients 
Acrylic copolymer, 
poly(butylmethacrylate, methyl-
methacrylate), silicone adhesive 
applied to a flexible polymer backing 
film, silicone oil and vitamin E 
Colloidal silicon dioxide, light mineral oil, 
polyisobutylene adhesive, acrylate-vinylacetate 
pressure sensitive adhesive, aluminum coated 
polyester backing 
Drug load 
9 mg 
6.9 mg 
Delivery rate 
4.6 mg/24 h (0.19 mg/h) 
4.6 mg/24 h (0.19 mg/h) 
Size 
5 cm2 
4.6 cm2 
Manufacturer 
LTS Lohmann Therapie-Systeme AG 
Alvogen, Inc 
Distributor 
Novartis Pharmaceuticals Corp. 
Alvogen, Inc 
 
 
 


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3 OBJECTIVES 
3.1 
Study Objectives 
The present study aims to: 
 
1)   Determine serum rivastigmine concentrations after using Exelon® (matrix type TDS, 
Novartis Pharmaceuticals Corporation) and rivastigmine generic (matrix type TDS, 
Alvogen, Inc.) with and without standardized heat application in healthy adult 
subjects. 
 
2)  Determine residual drug content of TDSs for the purpose of estimating amount of drug 
absorbed. 
  
3) Generate human PK data for the purpose of establishing an IVIVC model by collecting 
data following the application of rivastigmine products: Exelon® and rivastigmine 
generic TDS. 
 
3.2 
Study Outcome Measures 
For the PK study the main outcome measure is the maximum serum concentration (Cmax); 
time of maximum serum concentration (Tmax) of rivastigmine and area under the curve 
(AUC) attained with and without heating for Exelon® TDS and rivastigmine generic TDS.  
In addition, we will determine residual drug content from worn TDSs to estimate total 
amount of absorbed rivastigmine.     
 
 


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4 
STUDY ENROLLMENT  
4.1 
Subject Inclusion Criteria 
Subjects are eligible for this study if they fulfill the inclusion criteria specified below: 
1. Men or non-pregnant, non-lactating women who are of any ethnic background 
between the age of 18 and 45 years old. 
2. Subjects must be non-smokers/tobacco users (must have refrained from the use 
of nicotine-containing substances, including tobacco products (e.g., cigarettes, 
cigars, chewing tobacco, snuff, gum, TDSs or electronic cigarettes) over the 
previous two months and are not currently using tobacco products. 
3. Provide written informed consent before initiation of any of the study procedures. 
4. Agree not to participate in another clinical trial/study or to participate in an 
investigational drug study for at least one month after the last study session. 
5. Able to adhere to the study restrictions and protocol schedule. 
6. Able to participate in all study sessions. 
7. Subjects deemed to be healthy as judged by the MAI and determined by medical 
history, physical examination and medication history. 
8. Negative urine drug screening test (cannabinoids, amphetamines, barbiturates, 
benzodiazepine, cocaine, methadone, opiates, PCP). 
9. Have normal screening laboratories for white blood cells (WBC), hemoglobin 
(Hgb), platelets, sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, alanine transaminase (ALT) and aspartate aminotransferase 
(AST). 
10. Have normal screening laboratories for urine protein and urine glucose.  
11. Female subjects must be of non-childbearing potential (as defined as surgically 
sterile [i.e., history of hysterectomy or tubal ligation] or postmenopausal for more 
than 1 year), or if of childbearing potential must be non-pregnant at the time of 
enrollment and on the morning of each procedure day, and must agree to use 
reliable hormonal or barrier birth control such as implants, injectables, condoms, 
combined oral contraceptives, some intrauterine devices (IUDs), sexual 
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12. Agree not to donate blood to a blood bank throughout participation in the study 
and for at least three months after the last procedure day. 
13. Have a normal ECG; must not have the following to be acceptable: pathologic Q 
wave abnormalities, significant ST–T wave changes, left ventricular hypertrophy, 
right bundle branch block, left bundle branch block. (sinus rhythm is between 55–
100 beats per minute). 
14. Have normal vital signs: 
• Temperature 35-37.9°C (95-100.3°F) 
• Systolic blood pressure 90-140 mmHg 
• Diastolic blood pressure 60-90 mmHg 
• Heart rate 55-100 beats per minute 
• Respiration rate 12-20 breaths per minute  
 
4.2 
Subject Exclusion Criteria 
Subjects will be excluded for any of the following conditions/reasons: 
1. Women who are pregnant, lactating, breast feeding or have a positive serum 
pregnancy test at enrollment or positive urine pregnancy test on the morning of 
any study session. 
2. Smokers/tobacco users (current use or use over the previous two months of 
nicotine-containing substances, including tobacco products (e.g., cigarettes, 
cigars, chewing tobacco, snuff, gum, TDS or electronic cigarettes). 
3. Participation in any ongoing investigational drug trial/study or clinical drug 
trial/study. 
4. History of chronic obstructive pulmonary disease or cor pulmonale, or substantially 
decreased respiratory reserve, hypoxia, hypercapnia or pre-existing respiratory 
depression. 
5. Active positive Hepatitis B, C and/or HIV serologies (see Appendix B). 
6. Positive urine drug screening test. 
7. Use of chronic prescription medications during the period 0 to 30 days; or over-
the-counter medications (e.g. cholinomimetic drugs [used to treat diseases like 
acid reflux in children, glaucoma, dry mouth associated with Sjögren’s Syndrome], 
anticholinergics [used to treat diseases like asthma, incontinence, gastrointestinal 
cramps, and muscular spasms], antihistamines, topical corticosteroids) and short 
term (<30 days) prescription medications during the period 0-3 days before a study 
session [vitamin, herbal supplements and birth control medications not included)]. 


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8. Donation or loss of greater than one pint of blood within 60 days of entry to the 
study. 
9. Any prior adverse reaction or hypersensitivity to rivastigmine, other carbamate 
derivatives, other ingredients in the TDS tested, to medical tape products or other 
skin TDSs. 
10. Subject has problems with urinary retention, gastric retention or gastrointestinal 
obstruction.   
11. Subject has continuous spasms, muscle contractions, motor restlessness, rigidity, 
slowness of movement, tremors or irregular jerky movements. 
12. Subject has ulcers or gastrointestinal bleeding. 
13. Subject has history of asthma or blocked airflow making it hard to breathe (COPD). 
14. Received an experimental agent (vaccine, drug, biologic, device, blood product or 
medication) within one month before enrollment in this study or expects to receive 
an experimental agent during the study. 
15. Any condition that would, in the opinion of the Medically Accountable Investigator 
(MAI), place the subject at an unacceptable risk of injury or render the subject 
unable to meet the requirements of the protocol. 
16. History as either reported by the subject or evident to the investigator of infectious 
disease or skin infection or of chronic skin disease (e.g., psoriasis, atopic 
dermatitis). 
17. History of diabetes.  
18. Hereditary skin disorders or any skin inflammatory conditions as reported by the 
subject or evident to the MAI. 
19. History of significant dermatologic cancers (e.g., melanoma, squamous cell 
carcinoma) except basal cell carcinomas that were superficial and did not involve 
the investigative sites. 
20. At application site (upper arms), subject has an obvious difference in skin color 
between arms or the presence of a skin condition, excessive hairand refuses to 
clip hair , sunburn, raised moles and scars, open sores, scar tissue, tattoo or 
coloration that would interfere with placement of products, skin assessment or 
reactions to rivastigmine. 


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21. BMI  30 kg/m2. 


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5 
PHARMACOKINETICS AND STATISTICAL 
CONSIDERATIONS 
5.1 
Analyses 
Rivastigmine concentrations will be measured in serum samples collected from each 
subject. Blood samples (approximately 4 mL or 5 mL (~1 tsp)) will be collected within 60 
min of pre-application and then at 2 h, 3 h, 4 h, 5 h, 5 h 15 min, 5 h 30 min, 5 h 45 min, 6 
h, 6 h 15 min, 6 h 30 min, 7 h, 7 h 30 min, 8 h, 8 h 30 min, 9 h, 9 h 15 min, 9 h 30 min, 10 
h, 11 h and 12 h post-TDS application.   
 
Non compartmental analyses (NCA) will be conducted to estimate the  PK parameters 
such as: maximum serum concentration (Cmax), apparent elimination rate constant (k); 
apparent half-life (t1/2), calculated as 0.693/k; AUC0-last of the serum concentration–time 
determined by the linear trapezoidal method (TDS);and AUC value extrapolated to infinity 
(AUCinf), calculated as the sum of AUC0-last and the area extrapolated to infinity: AUCinf = 
AUC0-last + Clast/k where Clast would be the last quantifiable concentration. All NCA analyses 
will be conducted using Phoenix® WinNonlin® 6.4 (Pharsight, a Certara Company, CA). 
5.2 
Sample Size Considerations 
 
To calculate the sample size required to achieve an 80% power, we considered a 
parameter estimate (area under the curve (AUC)) with a maximum error within 25% of the 
reported value to be acceptable.  The sample size calculation used was reported by 
Panetta et al. and is as follows (9): 
n =
(𝑍α +  𝑍β )2 ∗ ς 2
ε 2
 
where n represents the sample size required, 𝑍α represents the z score for the type 1 
error, 𝑍β represents the z score for the type 2 error, ς represents the standard deviation of 
the parameter and ε represents the predicted error of the parameter estimate.  The type 
1 error was fixed to 5% and the type 2 error was fixed to 20%.   
 
For Exelon®, assuming a mean ± SD AUC24h of 166 ± 50 ng*h/mL (30% CV), the sample 
size calculations using the above formula indicated that n=12 subjects would provide a 
power of 82% for a predicted error of 25% on the AUC (8).  
5.3 
Final Analysis Plan 
An objective of this study is to investigate the influence of heat application on the PK 
parameters of rivastigmine after using a RLD or generic TDS.  The primary PK parameters 


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to be compared are 1) Cmax, before and after heat application; 2) AUC before and after 
heat application consistent with similar PK studies(6,7).  Determine PK parameters (Cmax, 
AUC) of rivastigmine in healthy adults after using Exelon® and rivastigmine generic TDS 
for the purpose of IVIVC by collecting data. Complimentary in vitro data will be collected 
using human skin. 
 
IVIVC will be conducted comparing PK parameters and profiles to predicted PK 
parameters and profiles using IVPT results.  Multiple methods will be implemented to 
develop an IVIVC.  The first method is to compare the steady state concentrations.  The 
predicted steady state concentration using our current IVPT data will employ the following 
formula: 
𝐶𝑠𝑠= 𝐽𝑠𝑠 ∗𝐴
𝐶𝐿
 
 
Css=steady state serum concentration; Jss=steady state flux; A=area; CL=clearance 
  
The second method will compare the PK profiles of the clinical and IVPT study by 
predicting rivastigmine concentrations at each time point in the IVPT study and comparing 
it to the PK profile.  The third method will be to determine and compare residual TDS 
analysis between in vitro and in vivo.     
 
Intra-procedure comparisons: 
 
For Study Session 1-4: 
• 
Cmax will be compared among the following time periods:  0-5 h, 5 h-6 h 30 min, 6 
h 30 min-9 h and 9-12 h post TDS application 
• 
AUC: will be compared among the following time periods: 0-5 h, 5 h-6 h 30 min, 6 
h 30 min-9 h and 9-12 h post TDS application 
 
Inter-procedure comparisons: 
For Study Session 1-4: Both Cmax and AUC will be compared among procedure groups for 
the following time periods:  5 h -6 h 30 min.