Clinical trial NCT04617782
Conditions: Healthy Subjects
Keywords: Donepezil, Transdermal Delivery System
Sponsor: Corium, Inc.
Start date: 2020-12-08; Completion date: 2021-04-05
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Phase 1, open-label, randomized, 3-period, 3-treatment, crossover pharmacokinetic study to evaluate the steady-state pharmacokinetics of 5 mg/day and 10 mg/day Corplex™ Donepezil TDS manufactured with the commercial process compared to 10 mg Aricept® in healthy volunteers.

Detailed description:
Screening Period:

Subjects will undergo a Screening Period up to 28 days prior to entering the Treatment Phase.

Treatment Phase consisting of 3 Treatment periods with 3 Treatments A, B, C.

Treatment Period 1: All Subjects will receive Treatment A; 5 mg/day Donepezil Transdermal Delivery System (TDS); 1-week wear and applied for 5 consecutive weeks.

Treatment Periods 2 and 3: Subjects will be randomized (by gender) to receive either sequences of Treatments B-C or Treatments C-B.

Treatment B: 10 mg/day Donepezil TDS 1-week wear and applied weekly for 5 consecutive weeks Treatment C: 10 mg/day Aricept® donepezil tablet administered daily (QD) for 5 weeks.

Blood samples for pharmacokinetics and safety assessments will be collected during the Treatment Phase.

Arms: arm 1: 5 mg/day Donepezil Transdermal Delivery System (TDS) 1-week wear and applied weekly for 5 consecutive weeks arm 2: 10 mg/day Donepezil TDS 1-week wear and applied weekly for 5 consecutive weeks arm 3: 10 mg/day Aricept® donepezil tablet administered QD for 5 consecutive weeks
Interventions: intervention 1: Donepezil TDS intervention 2: Aricept
Intervention descriptions: intervention 1: Transdermal Delivery System intervention 2: Oral

Protocol documents:
Prot_000.pdf: 
Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
This confidential information about the investigational product is provided for the exclusive 
use of investigators of this product and is subject to recall at any time. The information in this 
document may not be disclosed unless federal or state law or regulations require such 
disclosure. Subject to the foregoing, this information may be disclosed only to those persons 
involved in the study who have a need to know, with the obligation not to further disseminate 
this information. 
October 26, 2020 
A Phase 1, Open-Label, 3-Period, Randomized, 
Crossover Pharmacokinetic Study to Evaluate the 
Steady-State Pharmacokinetics of 5 mg and 10 mg 
Corplex™ Donepezil Transdermal Delivery Systems 
Compared to 10 mg Oral Administration of Aricept® in 
Healthy Volunteers
Protocol No: CL-P-20003 
Original Protocol dated: October 2, 2020 
Amendment #1 dated: 26Oct2020 
NCT - 04617782






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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 7 
PROTOCOL SYNOPSIS ............................................................................................................. 9 
1. 
SCHEDULE OF EVENTS ................................................................................................. 25 
2. 
TREATMENT PHASE SCHEMATIC ............................................................................. 29 
3. 
BACKGROUND ................................................................................................................. 30 
3.1. 
Alzheimer’s Disease (AD) ............................................................................................ 30 
3.2. 
Donepezil ...................................................................................................................... 30 
4. 
OVERVIEW OF CLINICAL STUDIES .......................................................................... 30 
5. 
STUDY RATIONALE ........................................................................................................ 33 
6. 
STUDY OBJECTIVES ....................................................................................................... 33 
6.1. 
Primary Objective ......................................................................................................... 33 
6.2. 
Secondary Objectives.................................................................................................... 33 
6.3. 
Safety Objective ............................................................................................................ 33 
7. 
INVESTIGATIONAL PLAN ............................................................................................ 33 
7.1. 
Study Design ................................................................................................................. 33 
7.2. 
Study Duration .............................................................................................................. 35 
8. 
SUBJECT SELECTION .................................................................................................... 35 
8.1. 
Number of Subjects....................................................................................................... 35 
8.2. 
Study Population ........................................................................................................... 35 
8.2.1. Inclusion Criteria ................................................................................................................... 35 
8.2.2. Exclusion Criteria .................................................................................................................. 36 
9. 
STUDY TREATMENTS .................................................................................................... 39 
9.1. 
Study Drug Treatments ................................................................................................. 39 
9.2. 
Treatment Assignment .................................................................................................. 41 
9.3. 
Blinding......................................................................................................................... 41 
9.4. 
Compliance ................................................................................................................... 41 
10. 
STUDY PROCEDURES ................................................................................................ 42 
10.1. Screening Procedures .................................................................................................... 42 
10.2. Check-In Procedures (Day -1) ...................................................................................... 43 
10.3. In-Clinic Procedures Treatment Phase .......................................................................... 44 
10.3.1. 
Study Drug Administration ............................................................................................... 44 
10.3.2. 
Procedures on Dosing Days (Days 1, 8, 15, 22, & 29) during Period 1 ........................... 46 
10.3.3. 
Procedures for In-Clinic Days during Period 1 ................................................................. 47 
10.4. Procedures on TDS Removal Days (Days 8, 15, 22, 29 & 36) during Period 1 ........... 48 
10.4.1. 
Study Drug Administration (Period 2 & 3) Treatment B .................................................. 49 
10.4.2. 
Procedures on In-Clinic Days Period 2 & 3 Treatment B & C ......................................... 50 
10.4.3. 
Procedures on TDS Removal Day Treatment B Periods 2 & 3 (Days 44, 51, 58, 65, 72, 
80, 87, 94, 101, 108): ......................................................................................................................... 50 
10.4.4. 
Procedures for Drug Administration Treatment C (Period 2 & 3).................................... 51 
10.4.5. 
End of Treatment (Day 109) ............................................................................................. 51 


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10.5. Unscheduled Assessments and Early Termination Visits ............................................. 52 
10.5.1. 
Unscheduled Assessments ................................................................................................ 52 
10.5.2. 
Early Termination (ET) .................................................................................................... 52 
10.6. Follow-Up Visit ............................................................................................................ 53 
10.7. End of Study (EOS) ...................................................................................................... 54 
11. 
CONCOMITANT MEDICATIONS AND RESTRICTIONS .................................... 54 
11.1. Concurrent Medication Restrictions ............................................................................. 54 
11.2. Dietary Restrictions ...................................................................................................... 55 
11.3. General Restrictions ...................................................................................................... 55 
12. 
INVESTIGATIONAL PRODUCT................................................................................ 56 
12.1. Active Pharmaceutical Ingredients ............................................................................... 56 
12.2. Pharmaceutical Treatments ........................................................................................... 56 
12.3. Supply of Study Drug ................................................................................................... 56 
12.4. Packaging and Labeling ................................................................................................ 57 
12.5. Materials Control .......................................................................................................... 57 
12.6. Storage of Study Drug .................................................................................................. 57 
12.7. Study Drug Accountability ........................................................................................... 57 
13. 
SAFETY ASSESSMENT ............................................................................................... 58 
13.1. Medical History ............................................................................................................ 58 
13.2. Physical Examination.................................................................................................... 58 
13.3. Columbia-Suicide Severity Rating Scale (C-SSRS) ..................................................... 58 
13.4. Vital Signs ..................................................................................................................... 58 
13.5. 12-Lead Electrocardiogram .......................................................................................... 58 
13.6. Clinical Laboratory Measurements ............................................................................... 59 
13.7. COVID-19 Testing........................................................................................................ 60 
13.8. Adverse Event Assessments ......................................................................................... 60 
14. 
PHARMACOKINETIC ASSESSMENTS.................................................................... 60 
14.1. Pharmacokinetic Plasma Sample Collection ................................................................ 60 
14.2. Pharmacokinetic Sample Shipment .............................................................................. 61 
14.3. Bioanalytical Methodology ........................................................................................... 62 
14.4. Subjects to Analyze....................................................................................................... 62 
15. 
ADHESION ASSESSMENTS AND PATCH PHOTOGRAPHY .............................. 62 
15.1. Patch Detachment ......................................................................................................... 63 
16. 
IRRITATION ASSESSMENTS/SKIN TOLERABILITY ......................................... 63 
16.1. Tolerability Scales (Dermal Response and Other Effects) ........................................... 63 
17. 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS .............................. 64 
17.1. Withdrawal of Subjects from the Study ........................................................................ 64 
17.2. Withdrawal of Subjects Post-Dose Study Drug ............................................................ 65 
17.3. Replacement of Subjects ............................................................................................... 65 
18. 
STATISTICAL METHODS .......................................................................................... 65 
18.1. Analysis Populations ..................................................................................................... 66 
18.2. Determination of Sample Size ...................................................................................... 66 
18.3. Pharmacokinetic Analysis ............................................................................................. 67 


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18.3.1. 
Pharmacokinetic Parameters ............................................................................................. 67 
18.3.2. 
Descriptive Statistics for Pharmacokinetics ...................................................................... 67 
18.3.3. 
Plasma Concentration-Time Plots ..................................................................................... 67 
18.3.4. 
Statistical PK Comparison between Treatments ............................................................... 68 
18.3.5. 
Time to Steady State Assessment ..................................................................................... 68 
18.3.6. 
Statistical Assessment of Relative Bioavailability............................................................ 68 
18.4. Adhesion Analysis ........................................................................................................ 69 
18.5. Subject Disposition and Demographic/Baseline Characteristics .................................. 69 
18.6. Safety Analysis ............................................................................................................. 70 
18.7. Interim Analysis ............................................................................................................ 70 
19. 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ................... 70 
19.1. Adverse Events ............................................................................................................. 70 
19.1.1. 
Recording and Monitoring of Adverse Events ................................................................. 70 
19.1.2. 
Definition .......................................................................................................................... 70 
19.1.3. 
AE Grading ....................................................................................................................... 71 
19.1.4. 
AE Relationship to Study Drug ........................................................................................ 71 
19.2. Serious Adverse Events ................................................................................................ 72 
19.2.1. 
Serious Adverse Event Reporting ..................................................................................... 72 
19.3. Adverse Event Treatment and Follow-up ..................................................................... 74 
20. 
PREGNANCY ................................................................................................................. 74 
21. 
PROTOCOL VIOLATIONS ......................................................................................... 74 
22. 
DATA MANAGEMENT AND RECORD KEEPING................................................. 75 
22.1. Data Management ......................................................................................................... 75 
22.2. Record Keeping ............................................................................................................ 75 
22.3. Access to Source Data/Documents ............................................................................... 75 
23. 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................ 75 
24. 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE ............................. 76 
25. 
PUBLICATION POLICY .............................................................................................. 76 
26. 
FINANCING AND INSURANCE ................................................................................. 76 
26.1. Finances ........................................................................................................................ 76 
26.2. Insurance Compensation ............................................................................................... 76 
27. 
COMPLETION OF STUDY .......................................................................................... 76 
28. 
STUDY ADMINISTRATIVE INFORMATION ......................................................... 77 
28.1. Protocol Amendments ................................................................................................... 77 
29. 
REFERENCES ................................................................................................................ 78 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ADL 
Activity of Daily Living 
ALT 
Alanine transaminase 
AST 
Aspartate aminotransferase, Aspartate transaminase 
AUC 
Area under the plasma concentration-time curve 
β-hCG 
Beta human chorionic gonadotropin 
BLQ 
Below the limit of quantification 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration estimated glomerular 
filtration rate (eGFR) 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration 
Ctau 
Plasma concentration at the end of a dosing interval at steady state 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOS 
End of Study  
ET 
Early Termination 
FDA 
Food and Drug Administration 
FLUCP 
Percent peak-to-trough fluctuation 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
LSGM 
Least squares geometric mean 
MedDRA 
Medical Dictionary of Regulatory Activities 
OTC 
Over the Counter 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 


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PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
Q1 
25th Percentile (1st Quartile) 
Q3 
75th Percentile (3rd Quartile) 
QTcF 
 
Time between the start of the Q wave and the end of the T wave (QT interval) in 
the heart's electrical cycle, corrected for heart rate with Fridericias’s formula 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOE 
Schedule of Events 
SS 
Steady State 
TDS 
Transdermal Delivery System 
TEAE 
Treatment-Emergent Adverse Event 
Tlag 
Lag time: time prior to the first measurable (non-zero) concentration 
Tmax 
Time to achieve the maximum observed plasma concentration 
ULN 
Upper Limit of Normal 
 
 


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PROTOCOL SYNOPSIS 
TITLE 
A Phase 1, Open-Label, 3-Period, Randomized, Crossover 
Pharmacokinetic Study to Evaluate the Steady-State 
Pharmacokinetics of 5 mg and 10 mg Corplex™ Donepezil 
Transdermal Delivery Systems Compared to 10 mg Oral 
Administration of Aricept® in Healthy Volunteers 
SPONSOR 
Corium, Inc. 
PROTOCOL NUMBER 
CL-P-20003 
INVESTIGATIONAL 
PRODUCT 
Corplex™ Donepezil Transdermal Delivery System (TDS) is 
a matrix type transdermal patch manufactured for a 7-day 
application. 
NAME OF ACTIVE 
INGREDIENT 
Donepezil 
ROUTE 
Oral/Transdermal (TDS) 
NUMBER OF SITES 
1 
STUDY DESIGN 
This is a Phase 1, open-label, randomized, 3-period, 3-
treament, crossover pharmacokinetic study to evaluate the 
steady-state pharmacokinetics of 5 mg and 10 mg Corplex™ 
Donepezil TDS manufactured with the commercial process 
compared to 10 mg oral administration of Aricept® in healthy 
volunteers. 
The study will consist of a Screening Period, a Treatment 
Phase with 3 treatment periods and a Follow-Up Visit, as 
follows: 
• Screening Period: Subjects will undergo a Screening 
Period up to 28 days prior to entering the Treatment 
Phase. 
• Treatment Phase: Eligible subjects will participate in 3 
treatment periods each consisting of 36 days, without 
a washout between treatments. 
o Treatment A: 5 mg/day Donepezil 
Transdermal Delivery System (TDS) for 
5 consecutive weeks (7-day wear for each of 
the 5 patches). In Period 1, all enrolled 
subjects will receive Treatment A. The last 
(5th) patch will be removed on the morning of 
Day 36 (168 hours after the last patch 
application). No study drug will be 
administered on Day 36. 
During Period 1, the 5 mg/day Donepezil TDS as the first 
treatment of the study allows subjects to get accustomed to 
the potential cholinergic effects (5 mg/day for 1 week is the 
recommended starting dose before titrating up, to 10 mg/day). 
In this study, the 5 mg/day Donepezil TDS is administered for 


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5 weeks to reach steady state in order to measure the steady 
state pharmacokinetics in Week 5 to be compared with those 
after oral Aricept®. 
 
During Treatment Periods 2 and 3, the subjects will be 
randomized to receive either sequences of Treatments B-C or 
Treatments C-B. Subjects will receive the following 
treatments according to the randomization schedule. 
o Treatment B: 10 mg/day Donepezil TDS 
applied weekly (within ±1 hour of application 
time on Day 1) for 5 consecutive weeks  
o Treatment C: 10 mg Aricept® donepezil tablet 
administered QD for 5 weeks (within ±1 hour 
of dosing time on Day 1). 
Randomization to the 2 treatment sequences will be stratified 
by gender. 
For all oral doses and TDS applications, subjects will receive 
a light meal 30 minutes prior to dosing. Standard meals will 
be provided at appropriate times thereafter. Blood samples for 
pharmacokinetics and safety assessments will be collected 
during the Treatment Phase. 
 
See Treatment Phase Schematic (Section 2). 
In each period wherein the treatment consists of a patch, the 
subjects will wear a total of 5 patches (1 per week) for a total 
of 35 days (5 weeks). The last (5th) patch in the period will be 
removed after the morning blood draw on Day 36 (168-hour 
time point after the last patch in the period). No treatment will 
be administered on Day 36 of the period; additional post-wear 
PK blood samples will be collected on Day 36 after any patch 
treatment. 
 
In each period (Period 2 or 3) wherein the treatment consists 
of oral Aricept®, the subjects will receive an oral dose daily 
for a total of 35 days (5 weeks). The last oral dose in the 
period will be administered on the morning of Day 35. No 
treatment will be administered on Day 36 of the period; a PK 
blood sample will be collected in the morning of Day 36 at 
24 hours after the last oral dose. 
 
In Period 1, all subjects will wear patches (Treatment A). In 
Periods 2 and 3, subjects will either wear patches 
(Treatment B) or receive once-per-day oral Aricept® 
(Treatment C).  
o The treatment in Period 2 will start on the morning of 
Study Day 37 after the pre-dose blood draw for 


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Period 2 is collected. No treatment will be 
administered on Study Day 72. For the patch treatment 
in Period 2, the patch will be removed on Study 
Day 72 after the 168-hour blood sample collection. 
o The treatment in Period 3 will start on the morning of 
Study Day 73 after the pre-dose blood draw for 
Period 3 is collected. No treatment will be 
administered on Study Day 108. For the patch 
treatment in Period 3, the patch will be removed on 
Study Day 108 after the 168-hour blood sample 
collection. 
 
• Follow-Up Visit: 5 ±2 days after the day of the last 
oral drug administration or last TDS removal during 
the Treatment Phase, subjects will enter a Follow-Up 
Visit to evaluate safety parameters. 
There will be no washout phase between treatment 
periods (with the exception of Day 36 within each period 
to collect post-treatment PK blood samples). 
PRIMARY OBJECTIVE 
To evaluate the bioequivalence of steady-state donepezil 
plasma exposure following once-weekly treatments with 
10 mg/day Corplex™ Donepezil TDS compared to once-daily 
oral administration of 10 mg Aricept®.  
SECONDARY  
OBJECTIVES 
 
• To evaluate the bioequivalence of steady-state 
donepezil plasma exposure (after dose-normalization) 
following once-weekly treatments with 5 mg/day 
Corplex™ Donepezil TDS compared to once-daily 
oral administration of 10 mg Aricept®. 
• To evaluate the adhesion to the skin during the wear 
period of each once-weekly 5 mg/day and 10 mg/day 
Corplex™ Donepezil TDS application. 
SAFETY OBJECTIVE 
To evaluate the safety and tolerability (including local skin 
tolerability, which consists of Dermal Response and Other 
Effects) of once-weekly Corplex™ Donepezil TDS.  
NUMBER OF SUBJECTS 
An appropriate number of subjects will enter the Screening 
Period to enroll approximately 60 subjects to complete with 
48 subjects during the Treatment Phase. 
SUBJECT SELECTION 
CRITERIA 
Inclusion Criteria 
1. Healthy males and females. 
2. Subject must be a male or non-pregnant, non-
breastfeeding female. 
3. Subject must be between 18 and 55 years of age 
(inclusive) at Screening. 
4. Subject's Body Mass Index (BMI) must be between 18 
and 32 kg/m2 (inclusive) and subject must weigh 


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between 60 and 100 kg (inclusive) at Screening. 
5. Subject must be continuous non-smokers and agree 
not to smoke during confinement from the time of 
screening and throughout the study. 
6. Subject must have a Fitzpatrick skin type of I, II or III 
or have skin colorimeter scores equivalent to the 
allowed Fitzpatrick skin type. 
7. Female subjects must agree to use one of the 
following forms of birth control from screening until 
14 days after the End-of-Study Visit, unless a different 
timeframe is listed below: 
a) Vasectomized partner (at least 6 months prior 
to Screening). 
b) Post-menopausal (at least 2 years prior to 
Screening). 
c) Surgically sterile (bilateral tubal ligation, 
hysterectomy, bilateral oophorectomy) at least 
6 months prior to Screening. 
d) Non-surgical sterilization (e.g., Essure® 
procedure) at least 3 months prior to 
Screening. 
e) Double barrier (diaphragm with spermicide; 
condoms with spermicide) 
f) Intrauterine device (IUD) 
g) Total abstinence (must agree to use a double 
barrier method if they become sexually active 
between Screening and 14 days after the End-
of-Study Visit). 
h) Implanted or intrauterine hormonal 
contraceptives in use for at least 3 consecutive 
months prior to Screening. 
i) Oral, patch, or injected contraceptives, or 
vaginal hormonal device (i.e., NuvaRing®), in 
use for at least 3 consecutive months prior to 
Screening. 
8. Subject must be able to speak, read and understand 
English or Spanish.  
9. Subject must voluntarily consent to participate in this 
study and provide their written informed consent prior 
to start of any study-specific procedures. 
10. Subject is willing and able to remain in the study unit 
for the entire duration of each confinement period and 
return for the Follow-Up Visit. 
Exclusion Criteria 
1. History or presence of clinically significant 
cardiovascular, pulmonary, hepatic, renal, 


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hematologic, gastrointestinal, endocrine, 
immunologic, dermatologic, neurologic, oncologic, or 
psychiatric disease or any other condition that, in the 
opinion of the Investigator, would jeopardize the 
safety of the subject or the validity of the study results. 
2. More specifically, subjects with a history of serious 
structural cardiac abnormalities, cardiomyopathy, 
serious heart rhythm abnormalities, coronary artery 
disease, or other cardiac problems.  
3. More specifically, at the discretion of the Investigator, 
subjects with preexisting hypertension, heart failure, 
myocardial infarction, or ventricular arrhythmia/prior 
EEG abnormalities in absence of seizure. 
4. At the discretion of the Investigator, a clinically 
significant abnormal finding in the physical 
examination, vital signs, medical history (including a 
family history of sudden death/ventricular 
arrhythmia), electrocardiogram (ECG), or clinical 
laboratory results at Screening. 
5. After resting seated for at least 3 minutes, subjects 
should be excluded from the study with the following 
vital signs at Screening: 
a) a confirmed systolic blood pressure outside the 
range of 90-145 mmHg, or 
b) a confirmed diastolic blood pressure outside 
the range of 50-90 mmHg, or 
c) a confirmed resting heart rate outside the range 
of 40-100 beats per minute. 
6. Has an isolated alanine aminotransferase (ALT) ≥1.5x 
the Upper Limit of Normal (ULN) or aspartate 
aminotransferase (AST) ≥1.5x the ULN at Screening; 
or both ALT and AST exceeding the ULN. 
7. Estimated creatinine clearance at screening 
<70 mL/min/1.73 m2 using the CKD-EPI equation 
calculator (Levey 2009). 
8. Prolonged corrected QT interval by Fridericia’s 
formula (QTcF) on screening electrocardiogram 
(ECG) (≥450 ms for both females and males). 
9. History of significant multiple and/or severe allergies 
(e.g., latex allergy, band aids, adhesive dressing, or 
medical grade adhesive tape), or has had an 
anaphylactic reaction or significant intolerability to 
prescription or nonprescription drugs. 
10. Major surgery that required general anesthesia within 
90 days prior to Screening. 
11. History or presence of hypersensitivity or 


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idiosyncratic reaction to the study drugs or related 
compounds (including piperidine derivatives and other 
cholinesterase inhibitors). 
12. At the discretion of the Investigator, on a significantly 
abnormal diet during the 4 weeks preceding Day -1. 
13. History or presence of excessive hairy skin on 
application sites as deemed by the Investigator to 
potentially interfere with patch adhesion or drug 
absorption. 
14. History or presence of significant skin damage, diffuse 
skin diseases (e.g., diffuse psoriasis or eczema), scars 
(flat scars, birth marks, moles, and stretch marks that 
do not affect skin surface are allowed), tattoos on the 
application sites or other skin disturbances (including 
sunburns, excessive tanning, and stretch marks) as 
deemed by the Investigator to potentially interfere 
with drug absorption or skin tolerability assessments 
15. Use of donepezil hydrochloride or related drugs within 
60 days prior to the first study drug administration 
(oral administration or TDS application, as 
appropriate). 
16. Has donated ≥500 mL blood within 30 days or 
donated ≥500 mL plasma within 14 days prior to 
Day -1. 
17. Inadequate peripheral venous access that would 
interfere with obtaining blood samples. 
18. Has participated in another clinical trial (randomized 
subjects only) within 30 days prior to Day -1. 
19. Has used any over the counter (OTC) medication, 
including vitamins, herbal products, and dietary 
supplements within 14 days prior to Day -1. 
20. Has used any prescription medication, except 
hormonal contraceptive or hormonal replacement 
therapy, within 14 days prior to Day -1. 
21. Has a history of substance abuse or treatment 
(including alcohol) within 1 year prior to Screening. 
22. Is a female with a positive pregnancy test. 
23. Has a positive urine screen for drugs of abuse at 
Screening or Day -1. 
24. Has a positive urine screen for alcohol on Screening or 
Day -1. 
25. Has a positive test for hepatitis B surface antigen, 
hepatitis C antibody, or human immunodeficiency 
virus (HIV) antibody at Screening or has been 
previously treated for hepatitis B, hepatitis C, or HIV 
infection. 


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26. Has an active COVID-19 test at Screening or Day -1. 
27. Has clinically significant gastrointestinal problems, 
including narrowing of the gastrointestinal tract, that 
may interfere with the gastrointestinal absorption of 
study drug. 
28. History of eating disorders within 3 months prior to 
Day -1. 
29. Has a history of unstable psychiatric illness requiring 
medications or hospitalization within 12 months prior 
to Day -1, or exhibits marked anxiety, tension, or 
agitation.  
30. Specifically, diagnosis of comorbid bipolar 
disorder/comorbid depressive symptoms. 
31. Has a history of unexplained syncope. 
32. Subject has any history of attempted suicide or 
clinically significant suicidal ideation based on the C-
SSRS assessment, in the opinion of the Investigator, at 
Screening or Day -1. 
33. Has smoked or used tobacco products within 6 months 
prior to Day -1 or is currently using nicotine products; 
is unable to abstain from the use of any nicotine-
containing products (including e-cigarettes, pipes, 
cigars, chewing tobacco, nicotine topical patches, 
nicotine gum, or nicotine lozenges). 
34. Subject is an employee or relative of any employee 
working for the CRO or Sponsor. 
TEST PRODUCT, DOSE, 
AND ROUTE OF 
ADMINISTRATION 
The study treatments are as follows: 
 
Treatment A (Test): 5 mg/day Donepezil TDS manufactured 
with the commercial process applied weekly (within ±1 hour 
of application time on Day 1) for 5 consecutive weeks (7-day 
wear each). All subjects will receive Treatment A in Period 1. 
The patch will be removed on the morning of Day 36. 
 
At the start of Period 2, subjects will be randomized to one of 
the following treatments in Period 2. Subjects will receive the 
alternate treatment in Period 3. Randomization to the 
2 treatment sequences will be stratified gender. 
 
Treatment B (Test): 10 mg/day Corplex™ Donepezil TDS 
manufactured with the commercial process applied weekly 
(within ±1 hour of application time on Day 1) for 
5 consecutive weeks (7-day wear each). 
 
Treatment C (Reference): 10 mg Aricept® donepezil (1 x 
10 mg/day tablet) administered QD for 35 consecutive days 


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October 26, 2020 
 
(within ±1 hour of dosing time on Day 1). This is the 
Reference Listed Drug (RLD). 
 
See Treatment Phase Schematic (Section 2). 
In each period wherein the treatment consists of a patch, the 
subjects will wear a total of 5 patches for a total of 35 days 
(5 weeks). The last (5th) patch in the period will be removed 
after the morning blood draw on Day 36 (168-hour time 
point). No treatment will be administered on Day 36 of the 
period; additional post-wear PK blood samples will be 
collected on Day 36 after any patch treatment. 
 
In each period wherein the treatment consists of oral 
Aricept®, the subjects will receive an oral dose daily for a 
total of 35 days (5 weeks). The last oral dose in the period 
will be administered on the morning of Day 35. No treatment 
will be administered on Day 36 of the period; a PK blood 
sample will be collected in the morning of Day 36 at 24 hours 
after the last oral dose. 
 
In Period 1, all subjects will wear patches (Treatment A). In 
Periods 2 and 3, subjects will either wear patches (Treatment 
B) or receive once-per-day oral Aricept® (Treatment C).  
o The treatment in Period 2 will start on the morning of 
Study Day 37 after the pre-dose blood draw for 
Period 2 is collected. No treatment will be 
administered on Study Day 72. For the patch treatment 
in Period 2, the patch will be removed on Study 
Day 72 after the 168-hour blood sample collection. 
o The treatment in Period 3 will start on the morning of 
Study Day 73 after the pre-dose blood draw for Period 
3 is collected. No treatment will be administered on 
Study Day 108. For the patch treatment in Period 3, 
the patch will be removed on Study Day 108 after the 
168-hour blood sample collection. 
 
TDS Administration (Treatments A and B): 
• The pharmacy at the CRU will remove the TDS from 
refrigerated storage (2-8ºC) and place at room 
temperature storage (20-25ºC) on the day before 
application, no more than 24 hours prior to 
application. 
• The pharmacy at the CRU will prepare the Corplex™ 
Donepezil TDS for each subject (per the 
randomization and stratification scheme). Each TDS 
treatment will be applied to intact dry skin only on the 


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 17 of 78 
 
October 26, 2020 
 
subject’s back weekly for 5 consecutive weeks. The 
most ideal naïve location on the back (back area that 
avoids the bra area and is slightly above the waistline 
is preferred) should be reserved for the last 5th patch of 
the treatment sequence. If this is not possible Sponsor 
approval should be obtained and documented to apply 
the TDS to a previously used site. 
• It is recommended that the TDS is applied to the 
subject within 120 minutes of opening/removing from 
the packaging. 
• Subjects will be instructed to shower from 1 to 2 hours 
prior to each TDS application. No more than 1 shower 
a day is permitted and if showers are not taken, the 
following will be performed within 1 to 2 hours prior 
to each TDS application: the application area will be 
washed with room temperature water using a wet 
washcloth. The application site will be patted dry and 
will be checked for irritancy.  
• The application area will be identified with a template 
overlay. The TDS will be placed at the designated 
application site and firm pressure will be applied 
immediately over the TDS for approximately 
20 seconds using the palm of the hand on each TDS to 
ensure adhesion. A new TDS should not be applied to 
an area of skin where a TDS was just removed. The 
area selected should not be oily, damaged, or irritated 
and should not be exposed to sunlight. 
• No taping of the transdermal delivery systems will be 
allowed. 
• The exact clock time of TDS application and removal 
will be recorded for the start and end of TDS 
application. During each TDS treatment, the next TDS 
will be applied as soon as the previous TDS was 
removed. The change in TDSs should be performed 
within 15 minutes. 
 
Oral Drug Administration (Treatment C): 
Study drug will be given orally and be administered with 
approximately 240 mL of water. Subjects will be instructed 
not to crush, split, or chew the study drug tablets. 
EVALUATION CRITERIA 
The evaluation criteria of the study are based on 
pharmacokinetic assessments, TDS adhesion assessments, and 
safety evaluations. 
 
Pharmacokinetic Sampling (Days listed are days within each 
period. See Treatment Phase Schematic, Section 2): 


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 18 of 78 
 
October 26, 2020 
 
The blood PK samples will be collected at the nominal time 
points listed below ±5 minutes for the first 24 hours and 10 
minutes thereafter. 
Treatments A and B (patch applications): 
The following blood PK samples will be collected in 2 mL 
EDTA K2 lavender top tubes. 
• Week 1 (Days 1 to 7): Pre-TDS #1 application 
(Day 1), and at 2, 6, 12, 24, 48, 72, 96, 120, and 144 h 
after TDS #1 application. 
• Week 2 (Days 8 to 14): Pre-TDS #2 application 
(Day 8 at 168 h after TDS #1 application), and at 24, 
48, 72, 96, 120, and 144 h after TDS #2 application. 
• Week 3 (Day 15 to 21): Pre-TDS #3 application 
(Day 15 at 168 h after TDS #2 application). 
• Week 4 (Day 22 to 28): Pre-TDS #4 application 
(Day 22 at 168 h after TDS #3 application). 
The following blood PK samples will be collected in 4 mL 
EDTA K2 lavender top tubes. 
• Week 5 (Day 29 to 35): Pre-TDS #5 application 
(Day 29 at 168 h after TDS #4 application), and at 3, 
6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 
and 156 h after TDS #5 application 
• Week 6 (Day 36): Pre-TDS #5 removal (Day 36 at 
168 h after TDS #5 application), and at 2, 6, 8, 10, and 
12 h after TDS #5 removal 
 
Treatment C (oral donepezil): 
The following blood PK samples will be collected in 2 mL 
EDTA K2 lavender top tubes. 
• Week 1, Day 1: Pre-Dose, and at 1, 2, 3, 4, 6, 8, 12 
and 24 h after oral administration (before Day 2 oral 
administration) 
• Week 2: Day 8 Pre-Dose 
• Week 3: Day 15 Pre-Dose 
• Week 4: Day 22 Pre-Dose 
The following blood PK samples will be collected in 4 mL 
EDTA K2 lavender top tubes 
• Week 5: Day 29 Pre-Dose 
• Week 5: Day 35 Pre-Dose, and 1, 2, 3, 4, 6, 8, 12 and 
24 h after oral administration (the 24-h sample will be 
collected on Day 36) 
 
Adhesion: 
Trained observers will determine the adhesion of each TDS as 
the percentage of the total surface area that is adhered to the 
skin. 


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 19 of 78 
 
October 26, 2020 
 
 
Safety:  
The Investigator will assess safety using the following 
parameters: physical examinations, vital sign assessments, 
clinical laboratory evaluations, C-SSRS evaluations, 
electrocardiograms, and skin tolerability assessments (Dermal 
Response and Other Effects). Subjects will be monitored for 
any adverse events (AEs) from the time of first drug 
administration through the Follow-Up Visit. 
 
STUDY PARAMETERS  
Pharmacokinetic 
Pharmacokinetic parameters at steady state (Week 5) 
calculated for plasma concentrations of donepezil and 6-O-
desmethyl donepezil (active metabolite) will include AUC0-
24,SS (daily AUC), AUC0-168,SS, Cmax, Cmin, Cavg, Ctau, percent 
peak-to-trough fluctuation (FLUCP). After oral 
administration, AUC0-24,SS will be calculated and multiplied 
by 7 to obtain AUC0-168,SS. 
 
Safety 
Safety will be assessed through 12-lead ECGs, vital sign 
measurements, clinical laboratory tests, suicidality monitoring 
(as per the C-SSRS), AEs, and physical examinations. Skin 
tolerability assessments will be performed for each TDS 
treatment prior to the TDS application and after removal of 
the TDS application. 
 
Adhesion 
Adhesion assessments of each TDS will be collected every 12 
hours during TDS wear as the percentage of the total surface 
area that is adhered to the skin, assessed in person by trained 
observers. With each consecutive measurement, observers 
will record the percentage based upon the actual measurement 
at each time point with the observer blinded to the previous 
recorded percentage finding. Tactile pressure to the TDS must 
not be applied during the adhesion determinations.  A grid 
overlay with boxes will be used to assist with estimating the 
% adhesion.  No taping of the TDS will be allowed. 
The time of full detachment of any TDS and its 0% adherence 
will be recorded, and the 0% adhesion will be assigned to all 
remaining adhesion time points of the current wear period. 
At each adhesion assessment time point, a photograph will be 
taken as evidence of the extent of TDS adhesion to the skin 
(as support of the visual observation of the adhesion 
percentage but not to be used for automated or photometric 
analysis). 


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 20 of 78 
 
October 26, 2020 
 
Following removal of each TDS, the presence or absence of 
remaining adhesive residue will be recorded. 
 
Skin Tolerability 
Skin Tolerability assessments will be performed prior to the 
TDS application and after removal of the TDS application 
during each period. If application site score is other than a 0 
prior to TDS application, another site will need to be used. 
 
Residual Donepezil 
The used TDSs will be returned to Corium for residual drug 
analysis (inclusive of any TDS that will be replaced during 
the study). 
 
STATISTICAL 
ANALYSES 
Pharmacokinetics 
Plasma concentrations and PK parameters of donepezil and 6-
O-desmethyl donepezil will be tabulated using summary 
statistics. 
To examine the donepezil PK at steady state (Week 5 of 5 x 
1-week wear) after 5 and 10 mg/day TDS application 
compared to oral Aricept®, an analysis of variance (ANOVA) 
will be performed on the natural logarithms of AUC0-168,SS 
and Cmax. Dose-normalization will be applied as appropriate. 
Differences between each Test and Reference in the PK 
parameters will be tested at the 5% level of significance. 
 
Time to Steady State Assessment 
Assessment of time to achieve steady-state will be performed 
by a review of weekly donepezil trough levels (Ctau) at time 
points immediately prior to dosing on Days 15, 22, 29, and 36 
in each treatment period. The univariate analysis method 
described by Chow and Liu for examining when steady-state 
is attained will be implemented using log-transformed trough 
plasma concentrations. Modifications to the method for 
Treatment Periods 2 and 3 will be explained in the Statistical 
Analysis Plan (SAP),  to possibly adjust for the attainment of 
a new steady state after switching to a new treatment without 
a washout period after the previous treatment. 
 
Relative Bioavailability 
To examine the relative bioavailability at steady state of the 
5 and 10 mg/day TDS (Tests) relative to oral donepezil 
(Reference), plasma donepezil exposure as characterized by 
AUC0-168 at steady state will be assessed and compared 
utilizing bioequivalence criteria. 
Since the intention of the patch is to decrease the peak-to-


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 21 of 78 
 
October 26, 2020 
 
through fluctuations with lower Cmax after the patch 
application compared to daily oral Aricept dosing, rather than 
using the conventional bioequivalence criterion for Cmax, it is 
stipulated that  mean steady-state donepezil Cmax after patch 
administration should remain between the steady-state Cmax 
and Cmin after daily oral Aricept® administration. 
 
Safety 
Adverse events will be coded using the current version of 
Medical Dictionary for Regulatory Activities® (MedDRA). 
The numbers of subjects with AEs, serious AEs (SAEs), and 
AEs leading to withdrawal from the study will be summarized 
by Preferred Term and System Organ Class for each 
treatment. 
Continuous safety data will be summarized by observed value 
and by change from baseline at each scheduled assessment. 
Concomitant medications will be coded using the current 
version of World Health Organization drug dictionary and 
will be listed by subject. Columbia-Suicide Severity Rating 
Scale item responses will be listed and an overall summary of 
any suicidal ideation and behavior will be presented in tabular 
format. 
 
Adhesion 
TDS adhesion score results (percentage adhesion) for each 
TDS strength will be summarized separately for Weeks 1 
through 5 and across all wear periods (Weeks 1-5 combined) 
as follows: 
• Summary statistics (mean, SD, minimum, Q1, median, 
Q3, maximum) for the mean adhesion score, where 
the mean adhesion score for each patch is the average 
of the patch adhesion scores across the entire wear 
period.   
• Adhesion score distribution at each adhesion 
measurement time point post patch application (i.e., 
12, 24, …, and 168 hours) 
• Average adhesion score at each adhesion 
measurement time point post patch application 
• Number (%) of patches that are completely detached 
during the 7-day wear period 
• Number (%) of patches with adhesion <50% at any 
adhesion measurement time point during the 7-day 
wear period 
• Summary of frequency of time a patch was first 
observed with adhesion <50% during the 7-day wear 
period 


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 22 of 78 
 
October 26, 2020 
 
• Number (%) of patches with adhesion ≥75% at all 
adhesion assessment time points during the 7-day 
wear period 
  
To assess whether at least 80% of the TDS applied are at least 
75% adhered throughout the 7-day wear period, a one-sided 
95% confidence interval will be determined for the 
probability (p) that a randomly selected TDS maintains at 
least 75% adhesion throughout the entire wear period. If the 
95% lower confidence limit for p is greater than 80%, 
acceptable TDS adhesion will be concluded. The method for 
the calculation of the 95% lower confidence limit and the 
justification of the method will be provided in the SAP. 
 
To calculate the mean adhesion score and associated statistics, 
the lowest adhesion score at each time point after the baseline 
time point (t0) will be carried forward to subsequent time 
points until a lower score is observed. 
 
Patch Detachment: 
If a TDS partially or fully detaches from the skin, actions to 
reapply a detached area of the TDS, to apply pressure to the 
TDS, or to reinforce TDS adhesion with the skin (e.g., taping) 
must be avoided throughout the study. TDS detachment must 
not be inappropriately inhibited (e.g., by the constant pressure 
applied by a person or an object such as the back of a chair). 
 
If a TDS fully detaches from the skin, the TDS must not be 
reapplied and no fresh TDS will be applied for the remainder 
of the intended wear period. The time of full detachment of 
any TDS and its 0% adherence will be recorded, and the 0% 
adhesion will be assigned to all remaining adhesion time 
points of the current wear period. 
 
Skin Tolerability Assessments: 
Dermal response scores, other effects numerical scores, and 
the combined skin irritation score (calculated as the sum of 
the dermal response and other effects scores) will be 
summarized by post removal time point (0.5, 24, 48, 72 hours 
post removal).  The Dermal Response scale combined with 
the Other Effects scale is what defines the Local Skin 
Tolerability Assessment. Whole number scores will be used. 
When evaluating a dermal response, at least 25% or more of 
the patch area should demonstrate an observable response. 
When multiple observable dermal responses are present, each 
observable response shall represent at least 25% or more of 


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 23 of 78 
 
October 26, 2020 
 
the patch area. It is recommended when determining the 
percentage of patch area with an observable response, record 
each dermal response and determine if each one response 
represents at least 25% or more of the patch area. Skin 
irritation will be followed until skin tolerability scores are ≤1. 
Separate summaries by treatment and by post removal 
assessment time point will be provided.   
If a TDS detaches, the tolerability scores will be collected for 
the site from which the TDS was removed. 
 
Skin tolerability assessments will be performed prior to the 
TDS application and after removal of the TDS application 
during each period using the following scale: 
 
Dermal Response 
 
Skin Appearance 
Score 
No evidence of irritation 
0 
Minimal erythema that is barely perceptible 
1 
Definite erythema that is readily visible and 
minimal edema or minimal papular response 
2 
Erythema and papules 
3 
Definite edema 
4 
Erythema, edema, and papules 
5 
Vesicular eruption 
6 
Strong reaction spreading beyond the 
application site 
7 
 
Other Effects 
 
Observation 
Score 
(Numerical 
Equivalent) 
Slightly glazed appearance 
A (0) 
Markedly glazed appearance 
B (1) 
Glazing with peeling and cracking 
C (2) 
Glazing with fissures 
F (3) 
Film of dried serous exudates covering 
all or part of the TDS site 
G (3) 
Small petechial erosions and/or scabs 
H (3) 
Source: FDA Draft Guidance: Assessing the Irritation and 
Sensitization Potential of Transdermal and Topical Delivery 
Systems for ANDAs. 2018 


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Corium, Inc. 
 
Page 24 of 78 
 
October 26, 2020 
 
 
Residual Donepezil 
Results of the residual donepezil content from the used TDSs 
will be listed and an overall summary will be presented in a 
report. 
 
DURATION OF SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Subjects will participate in the study for up to 144 days, 
including up to 28 days of screening, a Treatment Phase with 
3 treatment periods of 36 days each, and a 5 ±2 day Follow-
Up Visit. Eligible subjects will stay in the research clinic for 
109 days (108 overnight stays) during the Treatment Phase 


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 25 of 78 
 
October 26, 2020 
 
1. SCHEDULE OF EVENTS 
 
STUDY PROCEDURES 
SCREENING 
Day -28 to Day -2 
Treatment Phase 
Period 1 
Day -1 through Day 36 
Period 2: Day 37 through Day 72 
Period 3 Day 73 through Day 108 
Discharge Day 109  
Period 3 
Early Term12 
Follow-Up 
Day -1 
Day 1,8, 15, 
22, 29 
Day 2, 9, 16, 
23, 30 
Day 3, 10, 17, 
24, 31 
Day 4, 11, 18, 
25, 32 
Day 5, 12, 19, 
26, 33 
Day 6, 13, 20, 
27, 34 
Day 7, 14, 21, 
28, 35 
Day 8, 15, 22, 
& 29  
Day 36 
Day 37, 44, 
51, 58, 65, 73, 
80, 87, 94, 
0
Day 38, 45, 
52, 59, 66, 
74 81 88 95
Day 39, 46, 
53, 60, 67, 75, 
82, 89, 96, 
Day 40, 47, 
54, 61, 68, 76, 
83, 90, 97, 
104
Day 41, 48, 
55, 62, 69, 77, 
84, 91, 98, 
Day 42, 49, 
56, 63, 70, 78, 
85, 92, 99, 
Day 43, 50, 
57, 64, 71, 79, 
86, 93, 100, 
Day 72 & 108 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin Type Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Height & BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
12-Lead ECG1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Vital Signs2 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Hem, Serum Chem, Coag, 
UA3 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
COVID-19 Test54 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (females 
only)  
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Urine Drug & Alcohol 
Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS5 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Drug Administration6 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PK Sampling7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adhesion Assessments8 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Skin Tolerability 
Assessments9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Skin Photography10 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
TDS Removal11 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 26 of 78 
 
October 26, 2020 
 
 
 
 
Abbreviations: , Chem = Chemistry, Coag = Coagulation, ConMeds = Concomitant medication, C-SSRS = Columbia-Suicide 
Severity Rating Scale, ECG = Electrocardiogram, Hem = Hematology, , PK = Pharmacokinetic, TDS = Transdermal Delivery System, 
UA = Urinalysis. 
 
 
1. ECG: A 12-lead ECG will be obtained after the subject has been in the supine position for at least 3 minutes. Abnormal 
ECGs may be repeated for confirmation in which case only the repeated ECG will be recorded. The QT interval corrected 
for heart rate will be calculated with Fridericia’s formula (QTcF). Vital sign measurements will be obtained after the 
subject has been seated for at least 3 minutes. Vital signs will include sitting blood pressure (systolic and diastolic 
measurements), pulse rate (beats per minute), respiratory rate (breaths per minute), and oral temperature.  
2. Vital signs will be collected prior to the first dose/application of each treatment period and weekly thereafter.  Temperature 
checks may be permitted daily. 
3. Hematology, Serum Chemistry, Coagulation Panel, and Urinalysis: Laboratory safety tests will be obtained at the 
Screening visit, Day -1, Day 36, Day 72, Day 109, and at the Early Termination visit. 
4. COVID-19 Testing: Subjects must have an inactive COVID-19 test at Screening and Day -1.  COVID-19 testing will occur 
weekly while subjects are housed in the clinic. Additional test may be conducted at the discretion of the Principle 
Investigator in consultation with the Medical Monitor. 
5. C-SSRS Columbia-Suicide Severity Rating Scale Assessments will be performed at Screening, Day -1, Day 37, Day 72, 
Day 109, and the Early Termination visit. 
6. Drug Administration: 
In Period 1, all subjects will wear patches (Treatment A). In Periods 2 and 3, subjects will either wear patches (Treatment 
B) or receive once-per-day oral Aricept (Treatment C). There is a treatment-free day on Day 36 of each period. 
In each period wherein the treatment consists of a patch, the subjects will wear a total of 5 patches for a total of 35 days 
(5 weeks). The last (5th) patch in the period will be removed after the morning blood draw on Day 36 (168 hour time 
point after the last patch in the period). No treatment will be administered on Day 36 of the period. 
In each period (Period 2 or 3) wherein the treatment consists of oral Aricept, the subjects will take an oral dose daily 
for a total of 35 days (5 weeks). The last oral dose in the period will be administered on the morning of Day 35. No 
treatment will be administered on Day 36 in each period. 
TDS Application: 
Adverse Event Monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ConMeds Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 27 of 78 
 
October 26, 2020 
 
• The pharmacy at the CRU will remove the TDS from refrigerated storage (2-8ºC) and place at room temperature 
storage (20-25ºC) on the day before application to the skin, no more than 24 hours prior to application. 
• It is recommended that the TDS is applied to the subject within 120 minutes of opening/removing from the packaging. 
• Subjects will be instructed to shower from 1 to 2 hours prior to each TDS application. No more than 1 shower a day is 
permitted and if showers are not taken, the following will be performed within 1 to 2 hours prior to each TDS 
application, the application area will be washed with room temperature water using a wet washcloth. The application 
site will be patted dry and will be checked for irritancy.  
• The application area will be identified with a template overlay. The TDS will be placed at the designated application 
site and firm pressure will be applied immediately over the TDS for approximately 20 seconds using the palm of the 
hand on each TDS to ensure adhesion. A new TDS should not be applied to an area of skin where a TDS was just 
removed. The area selected should not be oily, damaged, or irritated and should not be exposed to sunlight. 
The exact clock time of TDS application and removal will be recorded for the start and end of TDS application. During 
each TDS treatment period, the next TDS will be applied as soon as the previous TDS was removed. The change in 
TDSs should be performed within 15 minutes. No taping of the Transdermal Delivery Systems will be allowed. 
7. PK Sampling (Days listed are within each period) The blood PK samples will be collected at the nominal time points listed 
below ±5 minutes for the first 24 hours and 10 minutes thereafter: 
Treatments A and B (patch applications): 
The following blood PK samples will be collected in 2 mL EDTA K2 lavender top tubes: 
• Week 1 (Days 1 to 7): Pre-TDS #1 application (Day 1), and at 2, 6, 12, 24, 48, 72, 96, 120, and 144 h after TDS #1 
application. 
• Week 2 (Days 8 to 14): Pre-TDS #2 application (Day 8 at 168 h after TDS #1 application, prior to removal), and at 24, 
48, 72, 96, 120, and 144 h after TDS #2 application. 
• Week 3 (Day 15 to 21): Pre-TDS #3 application (Day 15 at 168 h after TDS #2 application, prior to removal). 
• Week 4 (Day 22 to 28): Pre-TDS #4 application (Day 22 at 168 h after TDS #3 application, prior to removal). 
The following blood PK samples will be collected in 4 mL EDTA K2 lavender top tubes 
• Week 5 (Day 29 to 35): Pre-TDS #5 application (Day 29 at 168 h after TDS #4 application, prior to removal), and at 3, 
6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, and 156 h after TDS #5 application 
• Week 6 (Day 36): Pre-TDS #5 removal (Day 36 at 168 h after TDS #5 application, prior to removal), and at 2, 6, 8, 10, 
and 12 h after TDS #5 removal 
Treatment C (oral dosing): 
The following blood PK samples will be collected in 2 mL EDTA K2 lavender top tubes: 
• Week 1, Day 1: Pre-Dose, and at 1, 2, 3, 4, 6, 8, 12 and 24 h after oral administration (before Day 2 oral administration) 
• Week 2: Day 8 Pre-Dose 


Protocol CL-P-20003 Amendment #1 CONFIDENTIAL 
Corium, Inc. 
 
Page 28 of 78 
 
October 26, 2020 
 
• Week 3: Day 15 Pre-Dose 
• Week 4: Day 22 Pre-Dose 
The following blood PK samples will be collected in 4 mL EDTA K2 lavender top tubes 
• Week 5: Day 29 Pre-Dose 
• Week 5: Day 35 Pre-Dose, and 1, 2, 3, 4, 6, 8, 12 and 24 h after oral administration (the 24-h sample will be collected 
on Day 36). 
8. Adhesion Assessments: Treatment A and B only - To be performed prior to TDS removal and at specified timepoints. 
Adhesion assessments will be performed at 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and 168 hour following 
TDS application. The 168-hour assessment will be conducted prior to the next TDS application. Adhesion assessments will 
be performed in all periods within ± 1 hour of scheduled assessment. 
9. Irritation Assessments: Treatment A and B only - The site receiving the TDS should be assessed for skin irritation prior to 
TDS application (if the score is greater than zero another site must be selected) for Period 1. For TDS applied in during 
period 2 or 3, the site receiving the TDS should be assessed prior to TDS application (if the score is greater than zero 
another site must be selected) and the previous week’s TDS site should be assessed at 0.5, 24, 48 and 72 hours following 
TDS removal. If the score is greater than 1 at 72 hours, assessments are to be performed at the following time points until 
the score returns to <1: 120 and 168 hours post-removal and then every 3 days. For TDS applied in Week 5, the site 
receiving the TDS should be assessed prior to TDS application (if the score is greater than zero another site must be 
selected) and the previous week’s TDS site should be assessed at 0.5, 24, 48 and 72 hours following TDS removal.  
10. Skin Photography: Treatment A & B only - A photograph of the TDS will be taken in conjunction with the adhesion 
assessments.  Adhesion assessments will be performed at baseline and every 12 hours during TDS wear, and when the TDS 
is removed (including patch removal at or before Early Termination). 
11. TDS Removal: Treatment A and B only – TDS removal will occur on Day 8, Day 15, Day 22, Day 29, and Day 36 of 
Period 1 and Days 44, 51, 58, 65, 72, 80, 87, 94, 101, and 108 for Period 2 and 3.  Immediately after removal, used TDSs 
will be collected and returned to the Sponsor. After TDS removal, the presence or absence of adhesive residue on the skin 
will be recorded. As soon as the TDS has been removed from the skin, the used TDS will be placed adhesive side down, on 
to a new release liner or folded in half and placed into a foil pouch. The sealed, labeled foil pouch and the corresponding 
original labeled patch pouch will then be inserted into a plastic bag and stored at approximately -20°C (-4°F) The used 
TDS will be shipped to the Sponsor, for residual drug determination. Additional instructions regarding application and 
removal of the TDS are provided in the Pharmacy Manual. 
12. Early Termination: Adhesion, tolerability and photos will be performed as needed if early termination occurs when the 
TDS is still being worn. 
 
 


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 TREATMENT PHASE SCHEMATIC 
 
 
 
Treatment A: 
5 mg/day TDS applied weekly, 7-day wear, removed in the morning of Period Day 36 
Treatment B: 
10 mg/day TDS applied weekly, 7-day wear, removed in the morning of Period Day 36 
Treatment C: 
10 mg oral Aricept® tablets, QD for 35 days (no dosing on Day 36 of the period) 
 
TDS Application: The first patch in each period with patch treatments (Treatment A or B) will be applied on Treatment Phase Days 
1, 37, and 73. For patches #2 to #4, at the end of each week of patch wear (168 h after application), the worn patch will be removed 
and a new patch will be applied. The 168-h post-dose PK blood samples will be collected before removal of the worn patch. 
The last (5th) patch in each period with patch treatments (Treatment A or B) will be removed after 168 hours of the last patch 
application, after the 168-h PK blood sample collection. 
Oral Dosing: In periods with oral Aricept (Treatment C), a single dose will be administered daily on Treatment Phase Days 37-71 
(Period 2) and 73-107 (period 3). 
Drug-Free Days: There is no study drug administration (neither patch wear nor oral dosing) on Treatment Phase Days 36, 72, and 
108. 


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2. BACKGROUND 
2.1. Alzheimer’s Disease (AD) 
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of unknown etiology, 
characterized by progressive cognitive decline. Due to the role of cholinergic forebrain projections 
in memory and learning, several researchers proposed a cholinergic hypothesis to explain at least 
some of the features of AD. In the cholinergic hypothesis, cholinergic neurons emanating from the 
basal forebrain (nucleus of Meynert) are selectively lost. A corollary of this hypothesis is that 
augmentation of available cholinergic input to the forebrain could ameliorate AD symptoms. One 
method to augment cholinergic input would be to increase the levels of acetylcholine (ACh) in the 
synaptic cleft by inhibiting its degradation by the enzyme acetylcholinesterase (AChE). 
 
2.2. Donepezil 
Donepezil HCl is one of 5 drugs approved for the treatment of AD. Aricept® (donepezil HCl) is 
approved for the treatment of mild to severe AD, and is available as 5, 10, and 23 mg tablets. 
Donepezil is a reversible inhibitor of the enzyme AChE. Donepezil is postulated to exert its 
therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the 
concentration of acetylcholine through reversible inhibition of its hydrolysis by AChE. While 
there is no evidence that donepezil alters the course of the underlying dementing process, 6 to 
12-month controlled studies have shown modest cognitive and/or behavioral benefits in patients 
with AD.  
 
Corium is developing CorplexTM Donepezil TDS, a matrix type transdermal patch that is 
designed for donepezil delivery over a 7-day wear period. A transdermal form of donepezil may 
benefit patients by potentially reducing gastrointestinal side effects (by bypassing the GI tract) 
and by improving treatment efficacy (through consistent, constant delivery, preventing missed 
doses and patient non-compliance). 
 
3. OVERVIEW OF CLINICAL STUDIES  
The clinical development program for CorplexTM Donepezil TDS consists currently of ten Phase 
1 studies in healthy volunteers as shown in Table 1. 
 
 
 
 
 
 


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Table 1 
List of Clinical Studies with CorplexTM Donepezil TDS 
Study 
Category 
Study 
Number 
Study Title 
Brief Objectives 
Early 
Development 
P-15007 
A Phase 1 Crossover Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics and Safety of Two Formulations of a 7 -Day 
Application of Donepezil Transdermal Delivery System 
Compared to Oral Administration of Aricept in Healthy 
Volunteers 
Assess initial TDS 
formulation performance 
P-15081 
A Phase 1 Parallel Study to Evaluate the Pharmacokinetics (PK), 
Pharmacodynamics (PD) and Safety of Formulations of a 7-Day 
Application Donepezil Transdermal Delivery System (TDS) in 
Healthy Female Volunteers 
Formulation Selection 
P-16007 
A Phase 1 Study to Evaluate the Adhesion, Pharmacokinetics 
(PK) and Safety of a Seven-Day Application of Donepezil 
Transdermal Delivery System (TDS) in Healthy Volunteers 
Adhesion Optimization 
Key – Pivotal P-15086 
A Phase 1, Randomized, Open-Label, 3-Way Crossover, Pilot, 
Pharmacokinetic Study to Evaluate the Steady State 
Pharmacokinetics of a Once-Weekly Application of Corplex™ 
Donepezil Transdermal Delivery System Compared to Daily 
Oral Administration of Aricept® in Healthy Adult Subjects 
Steady state 
Bioequivalence 
Key – 
Supportive 
P-16011 
A Randomized Double-Blind Study to Assess the Skin 
Irritation and Sensitization Potential of Once-Weekly 
Corplex™ Donepezil Transdermal Delivery System 
Skin Irritation/ 
Sensitization 
P-16012 
A Phase 1, Crossover Study to Evaluate the Pharmacokinetics 
of CorplexTM Donepezil 10 mg Transdermal Delivery System 
Applied to Different Body Locations 
Relative Bioavailability 
- Application Site (back, 
thigh, buttock) 
P-16039 
A Phase 1, 2-Way Crossover Study to Evaluate the Effect of 
Heat Application on the Pharmacokinetics of Corplex™ 
Donepezil 5 mg Transdermal Delivery System (TDS) in Healthy 
Volunteers 
Relative Bioavailability 
– Applied Heat 
Supportive 
P-16010 
A Study to Assess the Steady State Bioequivalence of Once-
Weekly Corplex™ Donepezil 10 mg Transdermal Delivery 
System Compared to Daily Oral Administration of Aricept® 
Safety/Tolerability and 
Adhesion 
P-15086 
Sub-
Study1 
A Phase 1, Randomized, Open-Label, 2-Way Crossover Study, 
to Compare the Relative Bioavailability of Two Corplex 
Donepezil Transdermal Delivery Systems’ Manufactured Using 
Active Pharmaceutical Ingredient from 2 Different Suppliers 
Relative Bioavailability 
- API Suppliers 
P-19005 
A Phase 1, Randomized, Blinded, 2-Way Crossover Study to 
Assess the Relative Bioavailability of Corplex™ Donepezil 
Transdermal Delivery Systems With and Without Crystals 
Relative Bioavailability 
– With vs Without 
Crystals 
API = Active Pharmaceutical Ingredient 
1 The P-15086 Sub-Study was conducted as an amendment to Protocol No. P-15086. 
 
Across all Phase 1 studies conducted to date with Donepezil and CorplexTM Donepezil TDS (any 
formulation), no safety concerns specific to Donepezil or CorplexTM Donepezil TDS have been 
identified. Most systemic adverse effects have been consistent with those described in the package 
insert for Aricept. Application site-related AEs accounted for the greatest differences in AEs 
reported with CorplexTM Donepezil TDS versus those reported with Aricept (due to the nature of 
transdermal delivery system). The most frequently reported AEs considered related to the TDS were 
nausea, headache, application site pruritus, application site erythema, and nightmare. Headache and 


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nausea were also observed following treatment with oral Aricept. Application site-related AEs were 
largely mild in severity and skin irritation assessments demonstrated that most application site 
irritation was scored as not detected or mild and decreased over wear duration. In studies of 
CorplexTM Donepezil TDS there were not apparent differences in the incidence and quality of AEs 
reported for subjects using regimens that titrated doses (5 mg/day initial dose) upward to the 10 
mg/day target dose and those that did not titrate (initial dose was 10 mg/day). Both regimens yielded 
comparable adverse event profiles. 
With regard to the pharmacokinetics of donepezil after CorplexTM Donepezil TDS application, of 
note is Study P-15086 wherein bioequivalence was demonstrated between the registration batch of 
the CorplexTM Donepezil TDS (TDS A) and oral Aricept®. The mean steady state donepezil plasma 
concentration-time profiles after weekly donepezil TDS application (TDS A, 10 mg/day) and daily 
oral 10 mg/day Aricept are shown in Figure 1. In accordance with the long donepezil half-life of 
approximately 70 hours, steady state was reached by Day 29, at the beginning of Week 5 during 
which the steady state exposure was evaluated. In line with the intension of the TDS application to 
also decrease the peak-to-through fluctuations of plasma donepezil concentrations, a lower 
donepezil Cmax after the TDS application was observed compared to daily oral Aricept dosing. The 
mean steady-state donepezil concentrations after TDS application fell between the steady-state Cmax 
and Cmin after daily oral Aricept administration at most time points. 
Corium has made changes to the intended commercial manufacturing process including changes to 
increase the bond strength between the active layer and the overlay portion of the patch. Since these 
and other changes may be considered major differences compared to the process used for the clinical 
batch used in Study P-15086, the purpose of the current study is to demonstrate bioequivalence at 
steady state between the highest strength (10 mg/day) TDS manufactured with the new 
manufacturing process and oral 10 mg/day Aricept®. 
In clinical practice, some patients are taking 5 mg/day Aricept®, and donepezil-naïve patients 
typically receive 5 mg/day oral Aricept doses as a lead-in before safely escalating to a 10 mg/day 
dose. Therefore, Corium had also developed a 5 mg/day CorplexTM Donepezil TDS by using half 
the patch size as in the 10 mg/day TDS. The current study will therefore also evaluate the 
bioequivalence of steady-state donepezil plasma exposure (after dose-normalization) following 
once-weekly treatments with 5 mg/day CorplexTM Donepezil TDS compared to once-daily oral 
administration of 10 mg Aricept®. Bioequivalence is expected since it has been demonstrated that 
the pharmacokinetics of donepezil are linear over a dose range of 1-10 mg given once daily 
(Aricept® label, Eisai Inc, 2012). In addition, the 5-mg/day TDS application in the first study period 
for all subjects of the current study will allow safe escalation to 10 mg/day in the next study period. 
Refer to the Investigator’s Brochure (IB) for detailed background information on CorplexTM 
Donepezil TDS, and to the prescribing information for oral Aricept® (Aricept® label, Eisai Inc, 
2018). 


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4. STUDY RATIONALE 
The study is being conducted to evaluate the steady-state pharmacokinetics of 5 mg/day and 10 
mg/day Corplex™ Donepezil TDS manufactured with the commercial process compared to 10 mg 
oral administration of Aricept® in healthy volunteers. 
5. STUDY OBJECTIVES 
5.1. Primary Objective 
To evaluate the bioequivalence of steady-state donepezil plasma exposure following once-weekly 
treatments with 10 mg/day Corplex™ Donepezil TDS compared to once-daily oral administration 
of 10 mg Aricept®. 
5.2. Secondary Objectives 
• To evaluate the bioequivalence of steady-state donepezil plasma exposure (after dose-
normalization) following once-weekly treatments with 5 mg/day Corplex™ Donepezil TDS 
compared to once-daily oral administration of 10 mg Aricept®.  
• To evaluate the adhesion to the skin during the wear period of each once-weekly 5 mg/day 
and 10 mg/day Corplex™ Donepezil TDS application 
5.3. Safety Objective 
To evaluate the safety and tolerability, including local skin tolerability (Dermal Response and Other 
Effects) of once-weekly Corplex™ Donepezil TDS. 
6. INVESTIGATIONAL PLAN 
6.1. Study Design 
This is a Phase 1, open-label, randomized, 3-period, 3-treament, crossover pharmacokinetic study 
to evaluate the steady-state pharmacokinetics of 5 mg/day and 10 mg/day Corplex™ Donepezil 
TDS manufactured with the commercial process compared to 10 mg oral administration of Aricept® 
in healthy volunteers.  
The study will consist of a Screening Period, a Treatment Phase with 3 treatment periods and a 
Follow-Up Visit, as follows: 
• Screening Period: Subjects will undergo a Screening Period up to 28 days prior to 
entering the Treatment Phase. 
 
• Treatment Phase: Eligible subjects will participate in 3 treatment periods each consisting 
of 36 days, without a washout between treatments. 


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o Treatment A: 5 mg/day Donepezil Transdermal Delivery System (TDS) for 5 
consecutive weeks (7-day wear for each of the 5 patches). In Period 1, all enrolled 
subjects will receive Treatment A. The last (5th) patch will be removed on the 
morning of Day 36 (168 hours after the last patch application). No study drug will 
be administered on Day 36. The 5 mg/day Donepezil TDS as the first treatment of 
the study allows subjects to get accustomed to the potential cholinergic effects (5 
mg/day for 1 week is the recommended starting dose before titrating up, to 10 
mg/day). In this study, the 5 mg/day Donepezil TDS is administered for 5 weeks to 
reach steady state in order to measure the steady state pharmacokinetics in Week 5 
to be compared with those after oral Aricept®. 
During Treatment Periods 2 and 3, the subjects will be randomized to receive either sequences of 
Treatments B-C or Treatments C-B. Subjects will receive the following treatments according to the 
randomization schedule. 
o Treatment B: 10 mg/day Donepezil TDS applied weekly (within ±1 hour of 
application time on Day 1) for 5 consecutive weeks  
 
o Treatment C: 10 mg Aricept® donepezil tablet administered QD for 5 weeks 
(within ±1 hour of dosing time on Day 1). 
 
Randomization to the 2 treatment sequences will be stratified by the subject’s gender.  For all oral 
doses and TDS applications, subjects will receive a light meal 30 minutes prior to dosing. Standard 
meals will be provided at appropriate times thereafter. Blood samples for pharmacokinetics and 
safety assessments will be collected during the Treatment Phase. 
In each period wherein the treatment consists of a patch, the subjects will wear a total of 5 patches 
for a total of 35 days (5 weeks). The last (5th) patch in the period will be removed after the morning 
blood draw on Day 36 (168-hour time point after the last patch in the period). No treatment will be 
administered on Day 36 of the period; additional post-wear PK blood samples will be collected on 
Day 36 after any patch treatment.  Because of the lag time of donepezil plasma concentrations after 
TDS application, the Cmax and Tmax values at steady state. in some subjects, may be observed after 
removal of the TDS (past 168 hours after TDS application). This is the reason why an additional 
day (Day 36 in each treatment period) was added to the PK sampling schedule, after TDS removal 
at the end of the TDS dosing interval (168 hours). 
In each period (Period 2 or 3) wherein the treatment consists of oral Aricept®, the subjects will an 
oral dose daily for a total of 35 days (5 weeks). The last oral dose in the period will be administered 
on the morning of Day 35. No treatment will be administered on Day 36 of the period; a PK blood 
sample will be collected in the morning of Day 36 at 24 hours after the last oral dose. 
In Period 1, all subjects will wear patches (Treatment A). In Periods 2 and 3, subjects will either 
wear patches (Treatment B) or receive once-per-day oral Aricept® (Treatment C). 


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o The treatment in Period 2 will start on the morning of Study Day 37 after the pre-
dose blood draw for Period 2 is collected. No treatment will be administered on 
Study Day 72. For the patch treatment in Period 2, the patch will be removed on 
Study Day 72 after the 168-hour blood sample collection. 
 
o The treatment in Period 3 will start on the morning of Study Day 73 after the pre-
dose blood draw for Period 3 is collected. No treatment will be administered on 
Study Day 108. For the patch treatment in Period 3, the patch will be removed on 
Study Day 108 after the 168-hour blood sample collection. 
 
• Follow-Up Visit: 5 ±2 days after the day of the last oral drug administration or last TDS 
removal during the Treatment Phase, subjects will enter a Follow-Up Visit to evaluate safety 
parameters. 
There will be no washout phase between treatment periods (with the exception of Day 36 within 
each period to collect post-treatment PK blood samples). 
6.2. Study Duration 
Subjects will participate in the study for up to 144 days, including up to 28 days of screening, a 
Treatment Phase with 3 treatment periods of 36 days each, and a 5 ±2 day Follow-Up Visit. Eligible 
subjects will stay in the research clinic for 109 days (108 overnight stays) during the Treatment 
Phase 
7. SUBJECT SELECTION 
7.1. Number of Subjects 
An appropriate number of subjects will enter the Screening Period to enroll approximately 60 
subjects to complete with 48 subjects during the Treatment Phase.  
7.2. Study Population 
Healthy male and female subjects who meet the inclusion/exclusion criteria listed below. 
7.2.1. Inclusion Criteria 
A subject will be eligible for inclusion in the study if all the following criteria apply: 
1. Healthy males and females. 
2. Subject must be a male or non-pregnant, non-breastfeeding female. 
3. Subject must be between 18 and 55 years of age (inclusive) at Screening. 


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4. Subject's Body Mass Index (BMI) must be between 18 and 32 kg/m2 (inclusive) and subject 
must weigh between 60 and 100 kg (inclusive) at Screening. 
5. Subject must be continuous non-smokers and agree not to smoke during confinement and 
from the time of screening and throughout the study. 
6. Subject must have a Fitzpatrick skin type of I, II or III or have skin colorimeter scores 
equivalent to the allowed Fitzpatrick skin type. 
7. Female subjects must agree to use one of the following forms of birth control from screening 
until 14 days after the End-of-Study Visit, unless a different timeframe is listed below: 
a) Vasectomized partner (at least 6 months prior to Screening). 
b) Post-menopausal (at least 2 years prior to Screening). 
c) Surgically sterile (bilateral tubal ligation, hysterectomy, bilateral oophorectomy) at least 
6 months prior to Screening. 
d) Non-surgical sterilization (e.g., Essure® procedure) at least 3 months prior to Screening. 
e) Double barrier (diaphragm with spermicide; condoms with spermicide) 
f) Intrauterine device (IUD) 
g) Total abstinence (must agree to use a double barrier method if they become sexually 
active between Screening and 14 days after the End-of-Study Visit). 
h) Implanted or intrauterine hormonal contraceptives in use for at least 3 consecutive 
months prior to Screening. 
i) Oral, patch, or injected contraceptives, or vaginal hormonal device (i.e., NuvaRing®), in 
use for at least 3 consecutive months prior to Screening. 
8. Subject must be able to speak, read and understand English or Spanish.  
9. Subject must voluntarily consent to participate in this study and provide their written 
informed consent prior to start of any study-specific procedures 
10. Subject is willing and able to remain in the study unit for the entire duration of each 
confinement period and return for the Follow-Up Visit. 
 
7.2.2. Exclusion Criteria 
A subject who meets any of the following exclusion criteria will not be enrolled into the study: 


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1. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, 
hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, 
oncologic, or psychiatric disease or any other condition that, in the opinion of the 
Investigator, would jeopardize the safety of the subject or the validity of the study results. 
2. More specifically, subjects with a history of serious structural cardiac abnormalities, 
cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other 
cardiac problems.  
3. More specifically, at the discretion of the Investigator, subjects with preexisting 
hypertension, heart failure, myocardial infarction, or ventricular arrhythmia/prior EEG 
abnormalities in absence of seizure. 
4. At the discretion of the Investigator, a clinically significant abnormal finding in the physical 
examination, vital signs, medical history (including a family history of sudden 
death/ventricular arrhythmia), electrocardiogram (ECG), or clinical laboratory results at 
Screening. 
5. After resting seated for at least 3 minutes, subjects should be excluded from the study with 
the following vital signs at Screening: 
a) a confirmed systolic blood pressure outside the range of 90-145 mmHg, or 
b) a confirmed diastolic blood pressure outside the range of 50-90 mmHg, or 
c) a confirmed resting heart rate outside the range of 40-100 beats per minute. 
6. Has an isolated alanine aminotransferase (ALT) ≥1.5x the Upper Limit of Normal (ULN) 
or aspartate aminotransferase (AST) ≥1.5x the ULN at Screening; or both ALT and AST 
exceeding the ULN. 
7. Estimated creatinine clearance at screening <70 mL/min/1.73 m2 using the CKD-EPI 
equation calculator (Levey 2009). 
8. Prolonged corrected QT interval by Fridericia’s formula (QTcF) on screening 
electrocardiogram (ECG) (≥450 ms for both females and males). 
9. History of significant multiple and/or severe allergies (e.g., latex allergy, band aids, adhesive 
dressing, or medical grade adhesive tape), or has had an anaphylactic reaction or significant 
intolerability to prescription or nonprescription drugs. 
10. Major surgery that required general anesthesia within 90 days prior to Screening. 
11. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related 
compounds (including piperidine derivatives and other cholinesterase inhibitors). 


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12. At the discretion of the Investigator, on a significantly abnormal diet during the 4 weeks 
preceding Day -1. 
13. History or presence of excessive hairy skin on application sites as deemed by the 
Investigator to potentially interfere with patch adhesion or drug absorption. 
14. History or presence of significant skin damage, diffuse skin diseases (e.g., diffuse psoriasis 
or eczema), scars (flat scars, birth marks, moles, and stretch marks that do not affect skin 
surface are allowed), tattoos on the application sites or other skin disturbances (including 
sunburns, excessive tanning, and stretch marks) as deemed by the Investigator to potentially 
interfere with drug absorption or skin tolerability assessments 
15. Use of donepezil hydrochloride or related drugs within 60 days prior to the first study drug 
administration (oral administration or TDS application, as appropriate). 
16. Has donated ≥500 mL blood within 30 days or donated ≥500 mL plasma within 14 days 
prior to Day -1. 
17. Inadequate peripheral venous access that would interfere with obtaining blood samples. 
18. Has participated in another clinical trial (randomized subjects only) within 30 days prior to 
Day -1. 
19. Has used any over the counter (OTC) medication, including vitamins, herbal products, and 
dietary supplements within 14 days prior to Day -1. 
20. Has used any prescription medication, except hormonal contraceptive or hormonal 
replacement therapy, within 14 days prior to Day -1. 
21. Has a history of substance abuse or treatment (including alcohol) within 1 year prior to 
Screening. 
22. Is a female with a positive pregnancy test. 
23. Has a positive urine screen for drugs of abuse at Screening or Day -1. 
24. Has a positive urine screen for alcohol on Screening or Day -1. 
25. Has a positive test for hepatitis B surface antigen, hepatitis C antibody, or human 
immunodeficiency virus (HIV) antibody at Screening or has been previously treated for 
hepatitis B, hepatitis C, or HIV infection. 
26. Has an active COVID-19 test at Screening or Day -1.  
27. Has clinically significant gastrointestinal problems, including narrowing of the 


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gastrointestinal tract, that may interfere with the gastrointestinal absorption of study drug. 
28. History of eating disorders within 3 months prior to Day -1. 
29. Has a history of unstable psychiatric illness requiring medications or hospitalization within 
12 months prior to Day -1, or exhibits marked anxiety, tension, or agitation.  
30. Specifically, diagnosis of comorbid bipolar disorder/comorbid depressive symptoms. 
31. Has a history of unexplained syncope. 
32. Subject has any history of attempted suicide or clinically significant suicidal ideation based 
on the C-SSRS assessment, in the opinion of the Investigator, at Screening or Day -1. 
33. Has smoked or used tobacco products within 6 months prior to Day -1 or is currently using 
nicotine products; is unable to abstain from the use of any nicotine-containing products 
(including e-cigarettes, pipes, cigars, chewing tobacco, nicotine topical patches, nicotine 
gum, or nicotine lozenges). 
34. Subject is an employee or relative of any employee working for the CRO or the Sponsor. 
8. STUDY TREATMENTS 
8.1. Study Drug Treatments 
On Day -1, eligible subjects will be checked into the research clinic to enter the Treatment Phase.  
The study treatments are as follows: 
Treatment A (Test): 5 mg/day Donepezil TDS manufactured with the commercial process applied 
weekly (within ±1 hour of application time on Day 1) for 5 consecutive weeks (7-day wear each). 
All subjects will receive Treatment A in Period 1. The patch will be removed on the morning of 
Day 36. 
At the start of Period 2, subjects will be randomized to one of the following treatments in Period 2. 
Subjects will receive the alternate treatment in Period 3. Randomization to the 2 treatment 
sequences will be stratified by gender. 
Treatment B (Test): 10 mg/day Corplex™ Donepezil TDS manufactured with the commercial 
process applied weekly (within ±1 hour of application time on Day 1) for 5 consecutive weeks (7-
day wear each). 
Treatment C (Reference): 10 mg Aricept® donepezil (1 x 10 mg/day tablet) administered QD for 
35 consecutive days (within ±1 hour of dosing time on Day 1). This is the Reference Listed Drug 


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(RLD).See Section 2 for a treatment phase schematic. 
TDS Application: The first patch in each period with patch treatments (Treatment A or B) will be 
applied on Treatment Phase Days 1, 37, and 73. For patches #2 to #4, at the end of each week of 
patch wear (168 h after application), the worn patch will be removed and a new patch will be 
applied. The 168-h post-dose PK blood samples will be collected before removal of the worn patch. 
The last (5th) patch in each period with patch treatments (Treatment A or B) will be removed after 
168 hours of the last patch application, after the 168-h PK blood sample collection. 
Oral Dosing: In periods with oral Aricept (Treatment C), a single dose will be administered daily 
on Treatment Phase Days 37-71 (Period 2) and 73-107 (Period 3). 
Drug-Free Days: There is no study drug administration (neither patch wear nor oral dosing) on 
Treatment Phase Days 36, 72, and 108. 
In each period wherein the treatment consists of a patch, the subjects will wear a total of 5 patches 
for a total of 35 days (5 weeks). The last (5th) patch in the period will be removed after the morning 
blood draw on Day 36 (168-hour time point). No treatment will be administered on Day 36 of the 
period; additional post-wear PK blood samples will be collected on Day 36 after any patch 
treatment. 
In Period 1, all subjects will wear patches (Treatment A). In Periods 2 and 3, subjects will either 
wear patches (Treatment B) or receive once-per-day oral Aricept® (Treatment C).  
The treatment in Period 2 will start on the morning of Study Day 37 after the pre-dose blood draw 
for Period 2 is collected. No treatment will be administered on Study Day 72. For the patch 
treatment in Period 2, the patch will be removed on Study Day 72 after the 168-hour blood sample 
collection. 
The treatment in Period 3 will start on the morning of Study Day 73 after the pre-dose blood draw 
for Period 3 is collected. No treatment will be administered on Study Day 108. For the patch 
treatment in Period 3, the patch will be removed on Study Day 108 after the 168-hour blood sample 
collection. 
TDS Administration (Treatments A and B): 
The pharmacy at the CRU will remove the TDS from refrigerated storage (2-8ºC) and place at room 
temperature storage (20-25ºC) on the day before application, no more than 24 hours prior to 
application. The pharmacy at the CRU will prepare the Corplex™ Donepezil TDS for each subject 
(per the randomization and stratification scheme). Each TDS treatment will be applied to intact dry 
skin only on the subject’s back weekly for 5 consecutive weeks. The most ideal naïve location on 
the back (back area that avoids the bra area and is slightly above the waistline is preferred) should 


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be reserved for the last TDS application of each period. If this is not possible Sponsor approval 
should be obtained and documented to apply the TDS to a previously used site. 
• It is recommended that the TDS is applied to the subject within 120 minutes of 
opening/removing from the packaging. 
• Subjects will be instructed to shower from 1 to 2 hours prior to each TDS application. No 
more than 1 shower a day is permitted and if showers are not taken, the following will be 
performed within 1 to 2 hours prior to each TDS application, the application area will be 
washed with room temperature water using a wet washcloth. The application site will be 
patted dry and will be checked for irritancy.  
• The application area will be identified with a template overlay. The TDS will be placed at 
the designated application site and firm pressure will be applied immediately over the TDS 
for approximately 20 seconds using the palm of the hand on each TDS to ensure adhesion. 
A new TDS should not be applied to an area of skin where a TDS was just removed. The 
area selected should not be oily, damaged, or irritated and should not be exposed to sunlight. 
• No taping of the transdermal delivery systems will be allowed. 
• The exact clock time of TDS application and removal will be recorded for the start and end 
of TDS application. During each TDS treatment, the next TDS will be applied as soon as 
the previous TDS was removed. The change in TDSs should be performed within 15 
minutes. 
Oral Drug Administration (Treatment C): 
Study drug will be given orally and be administered with approximately 240 mL of water. Subjects 
will be instructed not to crush, split, or chew the study drug tablets. 
8.2. Treatment Assignment 
At the start of Period 2, subjects will be randomized to one of the following treatments in Period 2. 
Subjects will receive the alternate treatment in Period 3. Randomization to the 2 treatment 
sequences will be stratified by gender using a computer-generated randomization scheme.  Study 
drug will be assigned to each subject on each dosing day based on the randomization scheme.  
8.3. Blinding 
This is an open-label pharmacokinetic study; therefore, study treatments will not be blinded. 
8.4. Compliance 
Each dose of study drug will be administered in the research clinic by a pharmacy staff member or 


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Investigator-delegated employee. A record of the dosing event will be prepared and kept by the 
clinical site. 
9. STUDY PROCEDURES 
The study will consist of a Screening Period, a Treatment Phase and a Follow-Up Visit. A table 
with the Schedule of Events (SOE) representing the required testing procedures to be performed is 
included in Section 1. Following is a list of these procedures and assessments:  
9.1. Screening Procedures 
Subjects will complete the screening visit within 28 days (Day -28 to Day -1) of admission to the 
in-clinic visit of the Treatment Phase (Day -1). Prior to conducting any study-related activities 
including screening procedures, written Informed Consent and the Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be signed and dated by the subject. 
The following information collection/assessments will be performed at the Screening Visit: 
1. Informed Consent and HIPAA authorization by the subject. 
2. Subject demographics including date of birth, sex, race, and ethnicity. 
3. Review of inclusion/exclusion criteria to determine study eligibility. 
4. Record medical history including skin type assessment, chronic conditions, relevant 
surgical procedures (with start date) history of alcohol and recreational drug use, 
smoking status,  evaluation of drug and alcohol use and personal habits affecting the 
skin (example: tanning, hair removal, and application of tattoos). 
5. Fitzpatrick skin type score: Type I - always burns, never tans, Type II - usually burns, 
tans with difficulty, or Type III - may burn initially, but tans easily. 
6. A complete physical examination with back evaluation and personal habits affecting the 
skin (example: tanning, hair removal, and application of tattoos). 
7. Body weight, height, and BMI. 
8. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). 
9. 12-lead electrocardiogram (ECG) after subject has been in supine position for a 
minimum of 3 minutes. Abnormal ECGs may be repeated for confirmation in which 
case only the repeated ECG will be recorded. The QT interval corrected for heart rate 
will be calculated with Fridericia’s formula (QTcF). 


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10. Clinical laboratory tests (chemistry, hematology, coagulation, and urinalysis) obtained 
under fasted conditions. During the Screening Period, Clinical Laboratory 
Measurements may be repeated at the discretion of the Investigator. 
11. Blood samples for Serology (HIV antibody, hepatitis B surface antigen and hepatitis C 
virus antibody). 
12. Urine samples will be tested for alcohol, drugs of abuse (amphetamines, 
methamphetamines, benzodiazepines, barbiturates, cannabinoids, cocaine, and opioids) 
If the test is positive for any of the tested analytes, the subject will be excluded from 
study participation. 
13. Coronavirus (COVID-19) test.  A diagnostic test to determine if an active coronavirus 
infection is present. 
14. A serum β-hCG pregnancy test will be performed. A positive pregnancy test will 
exclude a subject from enrollment into the study. 
15. Perform the Columbia Suicide Severity Rating Scale (C-SSRS), “Baseline” version. 
Subjects with a history of attempted suicide or clinically significant suicidal ideation 
based on the C-SSRS assessment, in the opinion of the Investigator, will be excluded 
from enrollment in the study, and further evaluation and/or preventive intervention steps 
for suicidal behavior will be taken, at the discretion of the Investigator. 
16. Review of concomitant medications, treatment and/or therapies.  
After subjects complete the screening procedures and are considered eligible to take part in the 
clinical study, they will be instructed to return to the clinic to begin the Treatment Phase. 
9.2. Check-In Procedures (Day -1) 
Subjects who meet the inclusion/exclusion criteria during Screening, will be checked into the 
research clinic on Day -1, the day before treatment with study drug. Subjects will undergo the 
following procedures upon check-in: 
1. Review of inclusion/exclusion criteria to determine whether subjects continue to meet 
study eligibility. 
2. Update medical history. 
3. Back application site evaluation and clip application site hair as needed. 
 
4. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). Vital signs will be taken at least 12 hours prior to the 


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subject receiving their first dose of study drug on Day 1. 
5. 12-lead electrocardiogram (ECG) after subject has been in supine position for a 
minimum of 3 minutes. Abnormal ECGs may be repeated for confirmation in which 
case only the repeated ECG will be recorded. The QT interval corrected for heart rate 
will be calculated with Fridericia’s formula (QTcF). 
6. Perform the Columbia Suicide Severity Rating Scale (C-SSRS) “Since Last Visit” 
version. Subjects with clinically significant suicidal ideation based on the C-SSRS 
assessment, in the opinion of the Investigator, will be excluded from further participation 
in the study, and further evaluation and/or preventive intervention steps for suicidal 
behavior will be taken, at the discretion of the Investigator. 
7. Clinical laboratory tests (chemistry, hematology, coagulation, and urinalysis) will be 
obtained. 
8. Urine samples will be tested for alcohol, cotinine, drugs of abuse: (amphetamines, 
methamphetamines, benzodiazepines, barbiturates, cannabinoids, cocaine, and opioids) 
If the test is positive for any of the tested analytes, the subject will be excluded from 
study participation. 
9. Coronavirus (COVID-19) test.  A diagnostic test to determine if an active coronavirus 
infection is present.   If the test is for the virus is detected, the subject will be excluded 
from study participation 
10. A urine pregnancy test will be performed. A positive pregnancy test will exclude a 
subject from enrollment into the study.  
11. Review of concomitant medications, treatment and/or therapies.  
 
9.3. In-Clinic Procedures Treatment Phase 
Subjects will stay in the research clinic during the Treatment Phase for 109 days (108 overnight 
stays) starting on Day -1. The Treatment Phase will consist of 3 treatment periods of 36 days each, 
and a 5 ±2 day Follow-Up Visit.  Subjects will be discharged from the clinical unit on Day 109. 
9.3.1. Study Drug Administration  
On Day 1 of Period 1 during the Treatment Phase, subjects will receive the following treatment: 
Treatment A (Test): 5 mg/day Donepezil TDS manufactured with the commercial process applied 
weekly (within ±1 hour of application time on Day 1) for 5 consecutive weeks (7-day wear each). 
All subjects will receive Treatment A in Period 1. The patch will be removed on the morning of 


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Day 36. 
At the start of Period 2, subjects will be randomized to one of the following treatments in Period 2. 
Subjects will receive the alternate treatment in Period 3. Randomization to the 2 treatment 
sequences will be stratified by gender.   
Treatment B (Test): 10 mg/day Corplex™ Donepezil TDS manufactured with the commercial 
process applied weekly (within ±1 hour of application time on Day 1) for 5 consecutive weeks (7-
day wear each). 
Treatment C (Reference): 10 mg Aricept® donepezil (1 x 10 mg/day tablet) administered QD for 
35 consecutive days (within ±1 hour of dosing time on Day 1). This is the Reference Listed Drug 
(RLD). 
In each period wherein the treatment consists of a patch, the subjects will wear a total of 5 patches 
for a total of 35 days (5 weeks). The last (5th) patch in the period will be removed after the morning 
blood draw on Day 36 (168-hour time point). No treatment will be administered on Day 36 of the 
period; additional post-wear PK blood samples will be collected on Day 36 after any patch 
treatment. 
In each period wherein the treatment consists of oral Aricept®, the subjects will an oral dose daily 
for a total of 35 days (5 weeks). The last oral dose in the period will be administered on the morning 
of Day 35. No treatment will be administered on Day 36 of the period; a PK blood sample will be 
collected in the morning of Day 36 at 24 hours after the last oral dose. In Periods 2 and 3, subjects 
will either wear patches (Treatment B) or receive once-per-day oral Aricept® (Treatment C).  
• The treatment in Period 2 will start on the morning of Study Day 37 after the pre-dose blood 
draw for Period 2 is collected. No treatment will be administered on Study Day 72. For the 
patch treatment in Period 2, the patch will be removed on Study Day 72 after the 168-hour 
blood sample collection. 
• The treatment in Period 3 will start on the morning of Study Day 73 after the pre-dose blood 
draw for Period 3 is collected. No treatment will be administered on Study Day 108. For the 
patch treatment in Period 3, the patch will be removed on Study Day 108 after the 168-hour 
blood sample collection. 
TDS Administration (Treatments A and B): 
• The pharmacy at the CRU will remove the TDS from refrigerated storage (2-8ºC) and place 
at room temperature storage (20-25ºC) on the day before application, no more than 24 hours 
prior to application. 
• The pharmacy at the CRU will prepare the Corplex™ Donepezil TDS for each subject (per 


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the randomization and stratification scheme). Each TDS treatment will be applied to intact 
dry skin only on the subject’s back weekly for 5 consecutive weeks. The most ideal naïve 
location on the back (back area that avoids the bra area and is slightly above the waistline is 
preferred) should be reserved for the last TDS application. If this is not possible Sponsor 
approval should be obtained and documented to apply the TDS to a previously used site. 
• It is recommended that the TDS is applied to the subject within 120 minutes of 
opening/removing from the packaging. 
• Subjects will be instructed to shower from 1 to 2 hours prior to each TDS application. No 
more than 1 shower a day is permitted and if showers are not taken, the following will be 
performed within 1 to 2 hours prior to each TDS application, the application area will be 
washed with room temperature water using a wet washcloth. The application site will be 
patted dry and will be checked for irritancy.  
• The application area will be identified with a template overlay. The TDS will be placed at 
the designated application site and firm pressure will be applied immediately over the TDS 
for approximately 20 seconds using the palm of the hand on each TDS to ensure adhesion. 
A new TDS should not be applied to an area of skin where a TDS was just removed. The 
area selected should not be oily, damaged, or irritated and should not be exposed to sunlight. 
• No taping of the transdermal delivery systems will be allowed. 
• The exact clock time of TDS application and removal will be recorded for the start and end 
of TDS application. During each TDS treatment, the next TDS will be applied as soon as 
the previous TDS was removed. The change in TDSs should be performed within 15 
minutes. 
Oral Drug Administration (Treatment C): 
Study drug will be given orally and be administered with approximately 240 mL of water. Subjects 
will be instructed not to crush, split, or chew the study drug tablets 
The pharmacy manual will provide further application information. 
9.3.2. Procedures on Dosing Days (Days 1, 8, 15, 22, & 29) during Period 1 
The following assessments will be performed on dosing days during Period 1 of Treatment Phase: 
1. Subjects will be instructed to shower from 1 to 2 hours prior to each TDS application.  If 
showers are not taken, the following will be performed within 1 to 2 hours prior to each 
TDS application, the application area will be washed with room temperature water using a 
wet washcloth. The application site will be patted dry and will be checked for irritancy.  


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2. Subjects will receive a light meal approximately 30 minutes prior to TDS application or oral 
Aricept administration. 
3. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood pressure, 
oral temperature) will be collected at times listed in Section 13.4. 
4. Blood samples for pharmacokinetics will be collected at times listed in Section 14.1. 
5. The site receiving the TDS should be assessed for skin irritation prior to TDS application 
(if the score is greater than zero another site must be selected). 
6. The TDS is applied to the subject within 120 minutes of opening/removing from the 
packaging and the application area will be identified with a template overlay. The TDS will 
be placed at the designated application site and firm pressure will be applied immediately 
over the TDS for approximately 20 seconds using the palm of the hand on each TDS to 
ensure adhesion. The area selected should not be oily, damaged, or irritated and should not 
be exposed to sunlight.  The exact clock time of TDS application will be recorded for the 
start of TDS application.  No taping of the Transdermal Delivery Systems will be allowed. 
7. A photograph of the TDS will be taken immediately after application and at all adhesion 
timepoints. 
8. Patch Adhesion Assessments will be performed at times listed in Section 15.1. 
9. Review of concomitant medications, treatment and/or therapies. 
10. Assessment of adverse events. While subjects are in the research clinic, AEs will be 
monitored continuously and solicited using a non-leading question at times listed in Section 
13.8. The inquiry using non-leading questions will be performed after all other procedures 
are conducted for the specified time points. 
The PK samples will be collected at the nominal time points ±5 minutes.  
9.3.3. Procedures for In-Clinic Days during Period 1 
The following assessments will be performed during the in-clinic days of period 1: 
1. Blood samples for pharmacokinetics will be collected at times listed in Section 14.1. 
2. TDS Adhesion Assessments will be performed at times listed in Section 15.0. 
3. A photograph of the TDS will be taken at adhesion timepoints. 
4. Review of concomitant medications, treatment and/or therapies 


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5. Assessment of adverse events. While subjects are in the research clinic, AEs will be 
monitored continuously and solicited using a non-leading question at times listed in Section 
13.8. The inquiry using non-leading questions will be performed after all other procedures 
are conducted for the specified time points. 
9.4. Procedures on TDS Removal Days (Days 8, 15, 22, 29 & 36) during Period 1 
1. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood pressure, 
oral temperature) will be collected at times listed in Section 13.4. 
2. Immediately after removal, used TDSs will be collected and returned to the Sponsor. As 
soon as the TDS has been removed from the skin, the used TDS will be placed, adhesive 
side down, on to a new release liner or folded in half and placed into a foil pouch. The 
sealed, labeled foil pouch and the corresponding original labeled patch pouch will then be 
inserted into a plastic bag and stored at approximately -20°C (-4°F) The used TDS will be 
shipped to the Sponsor, for residual drug determination. Additional instructions regarding 
application and removal of the TDS are provided in the Pharmacy Manual. 
3. TDS site Irritation Assessments will be obtained at times listed in Section 16.1. 
4. Blood samples for pharmacokinetics will be collected at times listed in Section 14.1. 
5. Obtain blood sample for chemistry, hematology, coagulation, and urinalysis tests. (Day 36). 
6. Urine pregnancy tests for females only (Day 36). 
 
7. Perform the Columbia Suicide Severity Rating Scale (C-SSRS) “Since Last Visit” version. 
Subjects with clinically significant suicidal ideation based on the C-SSRS assessment, in 
the opinion of the Investigator, will be excluded from further participation in the study, 
and further evaluation and/or preventive intervention steps for suicidal behavior will be 
taken, at the discretion of the Investigator (Day 36). 
 
8. Patch Adhesion Assessments and photographs will be performed at times listed in Section 
15.0 
9. Review of concomitant medications, treatment and/or therapies 
10. Assessment of adverse events. While subjects are in the research clinic, AEs will be 
monitored continuously and solicited using a non-leading question at times listed in Section 
13.8. The inquiry using non-leading questions will be performed after all other procedures 
are conducted for the specified time points.  


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9.4.1. Study Drug Administration (Period 2 & 3) Treatment B 
The following assessments will be performed on dosing days during Period 2 & 3 of Treatment B 
Phase (Study Days 37, 44, 51, 58, 65, 73, 80, 87, 94, & 101): 
1. Subjects will be instructed to shower from 1 to 2 hours prior to each TDS application.  If 
showers are not taken, the following will be performed within 1 to 2 hours prior to each 
TDS application, the application area will be washed with room temperature water using a 
wet washcloth. The application site will be patted dry and will be checked for irritancy.  
2. Subjects will receive a light meal approximately 30 minutes prior to TDS application 
3. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood pressure, 
oral temperature) will be collected at times listed in Section 13.4. 
4. Blood samples for pharmacokinetics will be collected at times listed in Section 14.1. 
5. The site receiving the TDS should be assessed for skin irritation prior to TDS application 
(if the score is greater than zero another site must be selected). 
6. The TDS is applied to the subject within 120 minutes of opening/removing from the 
packaging and the application area will be identified with a template overlay. The TDS will 
be placed at the designated application site and firm pressure will be applied immediately 
over the TDS for approximately 20 seconds using the palm of the hand on each TDS to 
ensure adhesion. The area selected should not be oily, damaged, or irritated and should not 
be exposed to sunlight.  The exact clock time of TDS application will be recorded for the 
start of TDS application.  No taping of the Transdermal Delivery Systems will be allowed. 
7. A photograph of the TDS will be taken immediately after application and at adhesion 
timepoints listed in Section 15.0. 
8. Patch Adhesion Assessments will be performed at times listed in Section 15.0 
9. Review of concomitant medications, treatment and/or therapies. 
10. Assessment of adverse events. While subjects are in the research clinic, AEs will be 
monitored continuously and solicited using a non-leading question at times listed in Section 
13.8. The inquiry using non-leading questions will be performed after all other procedures 
are conducted for the specified time points. 
The PK samples will be collected at the nominal time points ±5 minutes.  


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9.4.2. Procedures on In-Clinic Days Period 2 & 3 Treatment B & C 
The following assessments will be performed during the in-clinic days of Periods 2 &3: 
1. Blood samples for pharmacokinetics will be collected at times listed in Section 14.1. 
2. TDS Adhesion Assessments will be performed at times listed in Section 15.0 Treatment B 
only.  A photograph of the TDS will be taken at adhesion timepoints listed in Section 15.0 
Treatment B only 
3. Review of concomitant medications, treatment and/or therapies 
4. Assessment of adverse events. While subjects are in the research clinic, AEs will be 
monitored continuously and solicited using a non-leading question at times listed in Section 
13.8. The inquiry using non-leading questions will be performed after all other procedures 
are conducted for the specified time points. 
9.4.3. Procedures on TDS Removal Day Treatment B Periods 2 & 3 (Days 44, 51, 58, 65, 72, 
80, 87, 94, 101, 108): 
1. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood pressure, 
oral temperature) will be collected at times listed in Section 13.4. 
2. Immediately after removal, used TDSs will be collected and returned to the Sponsor. As 
soon as the TDS has been removed from the skin, the used TDS will be placed, adhesive 
side down, on to a new release liner or folded in half and placed into a foil pouch. The 
sealed, labeled foil pouch and the corresponding original labeled patch pouch will then be 
inserted into a plastic bag and stored at approximately -20°C (-4°F). The used TDS will be 
shipped to the Sponsor, for potential residual drug determination. Additional instructions 
regarding application and removal of the TDS are provided in the Pharmacy Manual. 
3. TDS site Irritation Assessments will be obtained at times listed in Section 16.0 
4. Blood samples for pharmacokinetics will be collected at times listed in Section 14.1. 
5. Obtain blood sample for chemistry, hematology, coagulation, and urinalysis tests. (Day 72). 
6. Urine pregnancy tests for females only (Day 72). 
7. Perform the Columbia Suicide Severity Rating Scale (C-SSRS) “Since Last Visit” version. 
Subjects with clinically significant suicidal ideation based on the C-SSRS assessment, in 
the opinion of the Investigator, will be excluded from further participation in the study, and 
further evaluation and/or preventive intervention steps for suicidal behavior will be taken, 
at the discretion of the Investigator (Day 72). 


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8. Patch Adhesion Assessments and photographs will be performed at times listed in Section 
15.0. 
9. Review of concomitant medications, treatment and/or therapies 
10. Assessment of adverse events. While subjects are in the research clinic, AEs will be 
monitored continuously and solicited using a non-leading question at times listed in Section 
13.8. The inquiry using non-leading questions will be performed after all other procedures 
are conducted for the specified time points 
9.4.4. Procedures for Drug Administration Treatment C (Period 2 & 3) 
The following assessments will be performed for drug administration for during Period 2 & 3): 
1. Subjects will receive a light meal approximately 30 minutes prior to drug administration. 
2. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood pressure, 
oral temperature) will be collected at times listed in Section 13.4. 
3. Blood samples for pharmacokinetics will be collected at times listed in Section 14.1. 
4. Randomized subjects will receive 10 mg Aricept® donepezil (1 x 10 mg/day tablet) 
administered QD for 35 consecutive days during either Period 2 or Period 3.  Study drug 
will be given orally and be administered with approximately 240 mL of water. Subjects will 
be instructed not to crush, split, or chew the study drug tablets. 
5. Water will be allowed ad libitum up to 1 hour prior to dose administration. No water maybe 
consumed for 1-hour prior through 1 hour after dosing (except for water needed to 
administer study drug). After 1 hour following dose administration, subjects may drink 
water ad libitum. 
6. Review of concomitant medications, treatment and/or therapies. 
7. Assessment of adverse events. While subjects are in the research clinic, AEs will be 
monitored continuously and solicited using a non-leading question at times listed in Section 
13.8. The inquiry using non-leading questions will be performed after all other procedures 
are conducted for the specified time points. 
9.4.5. End of Treatment (Day 109) 
The end of the treatment phases of the study is Day 109. After all procedures during the Treatment 
Phase are conducted including the collection of the 168-hour blood sample after the last dose of 
study drug, the following End-of-Treatment procedures will be conducted: 


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1. Complete physical examination. 
2. Body weight. 
3. Clinical laboratory tests (chemistry, hematology, coagulation, and urinalysis). Samples for 
clinical laboratory tests at the end of treatment can be collected under non-fasted conditions. 
4. Urine pregnancy test (females only). 
5. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood pressure, 
oral temperature). 
6. 12-lead ECG will be obtained after the subject has been in the supine position for at least 3 
minutes. 
7. Assessment of the Columbia Suicide Severity Rating Scale (C-SSRS), “Since Last Visit” 
version. If a subject has a clinically significant suicidal ideation based on the C-SSRS 
assessment, in the opinion of the Investigator, further evaluation and/or preventive 
intervention steps for suicidal behavior will be taken, at the discretion of the Investigator. 
8. Review of concomitant medications, treatment and/or therapies. 
9. Assessment of adverse events. 
Subjects will be discharged from the research clinic when the Investigator determines that the 
subjects are medically stable, and all end-of-treatment procedures are completed. 
9.5. Unscheduled Assessments and Early Termination Visits 
9.5.1. Unscheduled Assessments 
Unscheduled visits occur at any unplanned subject evaluation during study conduct not specified 
in the Schedule of Events or overall protocol and will be documented and recorded in the database 
and listings. Unscheduled assessments during study conduct will be inclusive of, but not limited 
to TDS removals, TDS applications, adhesion assessments, adhesion photographs, and skin 
tolerability assessments. 
9.5.2. Early Termination (ET) 
Early Termination (ET) from the study is defined as withdrawal during the Treatment Phase after 
at least one dose of study drug is administered. The ET Visit is not required for subjects who 
screen fail before the administration of the first dose of study drug. 
If possible, subjects who terminate early will complete all study procedures post-dose study drug 
(including PK sample collections) before starting ET procedures. The following procedures will 


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be performed at ET visits: 
1. Complete physical examination. 
 
2. Vital signs (respiratory rate, pulse rate, blood pressure, and oral temperature) after subject 
has been sitting for a minimum of 3 minutes. 
 
3. 12-lead ECG after subject has been in supine position for a minimum of 3 minutes. 
 
4. Clinical laboratory tests (chemistry, hematology coagulation, and urinalysis). Samples for 
clinical laboratory tests at Early Termination can be collected under non-fasted 
conditions. 
 
5. Urine pregnancy tests (for females only) 
 
6. Assessment of the Columbia Suicide Severity Rating Scale (C-SSRS), “Since Last Visit” 
version. If a subject has a clinically significant suicidal ideation based on the C-SSRS 
assessment, in the opinion of the Investigator, further evaluation and/or preventive 
intervention steps for suicidal behavior will be taken, at the discretion of the Investigator. 
 
7. If applicable, perform skin irritation/tolerability assessments, adhesion assessments and 
adhesion photographs. 
 
8. Review of concomitant medications, treatment and/or therapies. 
 
9. Assessment of adverse events. 
Subjects will be discharged from the study clinic when the Investigator determines that the subjects 
are medically stable and, if possible, after all ET procedures are completed. 
At the discretion of the Investigator, ensuring the safety of the subjects, any ET procedures that 
were already performed on the same day as part of the procedures of the current treatment phase, 
do not need to be repeated.  
Subjects who withdraw early from the study and complete the above ET procedures will not return 
for a Follow-Up Visit. Therefore, the ET Visit is the EOS for these subjects. 
9.6. Follow-Up Visit 
Subjects who complete the Treatment Phase will return in 5 ±2 days after the administration of the 
last dose of study drug for the Follow-Up Visit. 
The following procedures will be completed during the Follow-Up Visit: 
1. Complete physical examination. 
2. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood pressure, 
and oral temperature). 


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3. 12-lead ECG after the subject has been supine at least 3 minutes. 
4. If applicable, perform skin irritation/tolerability assessments. 
5. Review of concomitant medications, treatment and/or therapies. 
6. Assessment of adverse events. 
The Follow-Up Visit is the EOS for subjects who will undergo the Follow-Up procedures. 
9.7. End of Study (EOS) 
The End of Study (EOS) is either the Follow-Up Visit for subjects who complete the Treatment 
Phase, or the Early Termination Visit for subjects who withdraw early from the study. 
10. CONCOMITANT MEDICATIONS AND RESTRICTIONS 
Subjects will be instructed not to consume any of the below products; however, allowance for an 
isolated single incidental consumption may be evaluated and approved by the study Investigator 
based on the potential for interaction with the study drug, and impact on subject safety and the 
validity of the study results. 
10.1. Concurrent Medication Restrictions 
Restricted Medications: 
1. Any OTC medication use within 14 days prior to Day -1 until the End-of-Study Visit 
without evaluation and approval by the study Investigator. With approval of the 
Investigator, acetaminophen may be given as needed during the study as rescue 
medication to treat headaches or other adverse events. 
2. Subject must not take any prescription medication, with the exception of female 
hormonal contraceptives, from 14 days prior to Day -1 until the End-of-Study Visit 
without evaluation and approval by the Investigator. 
All other concomitant medications will be prohibited unless its use is deemed necessary in a medical 
emergency. Concomitant use of prescription or nonprescription medications, including reasons for 
use, will be reviewed, and recorded on the eCRF from the Screening Period through the Follow-up 
Period. 
Allowed concurrent medications can be taken with water if needed, irrespective of the water 
restrictions before and after administration of study drug. 


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10.2. Dietary Restrictions 
While subjects are in the research clinic, the following dietary restrictions will be followed: 
1. Subjects must not take any herbal or dietary supplements (e.g., St. John’s Wort, Milk 
Thistle, etc.) within 14 days prior to Day -1 until the End-of- Study Visit. 
2. Subjects must not consume beverages and foods containing alcohol or caffeine/xanthine 
from 48 hours prior to Day -1 until after discharge on Day 109. Alcohol and caffeinated 
beverages will not be available while in the research clinic. 
3. Water Consumption: Water will be allowed ad libitum up to 1 hour prior to dose 
administration. For Treatment C (Aricept 10 mg), after 1 hour following dose 
administration, subjects may drink water ad libitum.  Fluids during the predose light meal 
are allowed.  
4. Food Consumption: While housed in the research clinic, subjects will receive meals at 
regularly scheduled times. No food sharing will be permitted. Standard meals will be 
provided at appropriate times. Calories will be spread across the day. Mealtimes may be 
adjusted to not interfere with study procedures such as blood draws for pharmacokinetics.  
10.3. General Restrictions 
1. Subject must not engage in strenuous activities such as exercise or sports within 24 hours 
prior to Day -1 until the End-of-Study Visit. 
2. No more than 1 shower a day is permitted.  Subjects must avoid having the water spray 
directly on the patch. Water running over the patch is allowed. The patch should be patted 
dry after the shower. 
3. Subject must not donate blood (one pint or more) from 30 days or plasma from 14 days 
prior to Day -1 until the End-of-Study Visit. It is recommended that blood/plasma donations 
not be made for at least 30 days after the End-of-Study Visit. 
4. Subjects must not smoke or use tobacco products from 6 months prior to Day -1 until the 
End-of-Study Visit. Subjects must refrain from use of all nicotine products (including e-
cigarettes, pipes, cigars, chewing tobacco, nicotine topical patches, nicotine gum, or nicotine 
lozenges) from Screening until the End-of-Study Visit. 
5. Female subjects must utilize one of the allowed forms of birth control listed in the Inclusion 
Criteria (Section 8.2.1). 
6. Following all TDS applications, subjects will remain seated in chairs without the following 
back support: pillows, soft padding, blankets, or similar; for at least the first 2 hours, except 


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when they are supine or standing for study procedures. Subjects will then resume normal 
activity. During the first 2 hours post dose, subjects may be allowed to rise for brief periods 
under supervision (e.g., in order to use the toilet facilities). However, should AEs occur at 
any time, subjects may be placed in an appropriate position or will be permitted to lie down 
on their side. 
7. Following oral drug administration (Treatment C) subjects will remain seated, except as 
otherwise required for study procedures or personal needs, for the first 4 hours after dosing. 
Subjects will not be allowed to lie down, except as directed by clinical staff secondary to 
adverse events, for the first 4 hours after dosing. 
11. INVESTIGATIONAL PRODUCT 
11.1. Active Pharmaceutical Ingredients 
Corplex™ Donepezil Transdermal Delivery System (TDS) is a matrix type transdermal patch 
manufactured for a 7-day application. 
11.2. Pharmaceutical Treatments 
Treatment A (Test): 5 mg/day Donepezil TDS manufactured with the commercial process 
applied weekly (within ±1 hour of application time on Day 1) for 5 consecutive weeks (7-day 
wear each). All subjects will receive Treatment A in Period 1. The patch will be removed on the 
morning of Day 36. 
 
At the start of Period 2, subjects will be randomized to one of the following treatments in Period 
2. Subjects will receive the alternate treatment in Period 3. Randomization to the 2 treatment 
sequences will be stratified by gender. 
 
Treatment B (Test): 10 mg/day Corplex™ Donepezil TDS manufactured with the commercial 
process applied weekly (within ±1 hour of application time on Day 1) for 5 consecutive weeks 
(7-day wear each). 
 
Treatment C (Reference): 10 mg Aricept® donepezil (1 x 10 mg/day tablet) administered QD 
for 35 consecutive days (within ±1 hour of dosing time on Day 1). This is the Reference Listed 
Drug (RLD). 
 
11.3. Supply of Study Drug 
The Sponsor (or designee) will ship study drug to the investigational site. The study drug 
shipment(s) will be shipped after site activation. All other drug products needed for the conduct of 
the study (such as medications to treat Adverse Events) will be commercially available products 
obtained by the research clinic. 


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11.4. Packaging and Labeling 
The investigation product will be packaged and labeled appropriately, according to the appropriate 
FDA regulations. See the Pharmacy Manual for details of packaging and labeling. 
11.5. Materials Control 
Once received and labeled by the onsite pharmacist or designee for use in the study, the drugs will 
be considered study drug material. The pharmacist or designee will maintain adequate records of 
the receipt, dispensing, return or other disposition of the drug, including dates, quantity, serial 
numbers, expiration dates, as appropriate. Reasons for any departure from the expected regimen 
will be documented. These documents will be made available to regulatory agency inspectors upon 
request. The Investigator will not supply study drug to anyone other than those named as sub-
investigators on FDA Form 1572, designated site staff, and subjects in the study. 
11.6. Storage of Study Drug 
Study drug for Treatment A and B will be stored at a controlled; refrigerated temperature (2-8ºC).  
The pharmacy will remove the TDS from 2-8ºC refrigerated storage on the day before application 
and no more than 24 hours prior to application, and stored at controlled room temperature of 20-
25°C (68-77°F) with excursions allowed between 15° and 30°C (59° and 86°F). Transient spikes 
up to 40°C are permitted as long as they do not last for more than 24 hours. Study drug will be 
stored in a safe, secure area with limited, controlled access in accordance with all local, state, and 
federal regulations.  Investigational products must not be frozen. The Investigator will ensure that 
adequate precautions are taken, including storage of the study drug in a securely locked, 
substantially constructed cabinet, or other securely locked, substantially constructed enclosure, 
access to which is limited, to prevent theft or diversion of the substance into illegal channels of 
distribution. 
The investigational product(s) must be stored as indicated. Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the Sponsor. Once 
a deviation is identified, the investigational product must be quarantined and not used until the 
Sponsor provides documentation of permission to use the investigational product. 
11.7. Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each subject will 
be maintained on an ongoing basis by a member of the study site staff. The number of study drug 
dispensed will be recorded on the Investigational Drug Accountability Record. The study monitor 
will verify these documents throughout the course of the study. 


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12. SAFETY ASSESSMENT 
12.1. Medical History 
A complete medical history will be obtained at the Screening Visit including the recording of 
demographic data (date of birth, sex, age, race, ethnicity), collection of previous surgeries, 
medications and chronic conditions, past or present illnesses or dysfunctions, substance/drug abuse, 
and history of allergies or idiosyncratic responses to drugs. 
12.2. Physical Examination 
A complete physical examination including body weight will be completed for all subjects at 
Screening, at End-of-Treatment or Early Termination, and at the Follow-Up visits. The complete 
physical examination will include a review of the subject’s general appearance, skin, head and neck 
(eyes, ears, nose, mouth, and throat), lymph nodes, thyroid, musculoskeletal/extremities, 
cardiovascular system, lungs, abdomen and a brief examination of the neurological system. 
Height will be recorded in centimeters (cm) with the subject’s shoes removed. Body weight will be 
measured in kilograms (kg); subjects will remain in their normal clothing with shoes and jacket 
(and/or outer clothing) removed. 
12.3. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a brief questionnaire that provides for the 
identification, quantification and standardized assessment of the occurrences and severity of 
suicidal ideation and behavior (see http://cssrs.columbia.edu) (Posner 2011). The typical 
administration time is a few minutes. The “Baseline Version” of the C-SSRS will be assessed at 
Screening. The C-SSRS “Since Last Visit” version will be assessed at Day -1, Day 36, Day 72, Day 
109, and Early Termination. 
12.4. Vital Signs 
Vital sign measurements will be obtained after the subject has been seated for 3 minutes. Vital signs 
will include sitting blood pressure (systolic and diastolic measurements), pulse rate (beats per 
minute), respiratory rate (breaths per minute), and oral temperature. In order to ensure accuracy, 
out-of-range vital signs may be repeated once, at least 2 minutes after an abnormal finding. 
Vital signs will be collected at prior to the first dose/application and weekly thereafter.  Temperature 
checks may be permitted daily. 
12.5. 12-Lead Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be obtained after the subject has been in a supine position 
for a minimum of 3 minutes. Abnormal ECGs may be repeated for confirmation in which case only 


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the repeated ECG will be recorded. The QT interval corrected for heart rate will be calculated with 
Fridericia’s formula (QTcF). 
ECGs will be obtained at Screening, Day -1, ET and EOS visit. 
12.6. Clinical Laboratory Measurements 
All clinical laboratory samples will be sent to a local laboratory for analysis. Up to approximately 
40 mL of blood will be collected for clinical chemistries, hematology, and pregnancy test (if 
applicable) from each subject during the study. During the Screening Period, Clinical Laboratory 
Measurements may be repeated at the discretion of the Investigator. 
The Clinical Laboratory evaluations will consist of the following: 
• Total Hematology as well as differential and Coagulation: red blood cell count, white 
blood cell count with differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils), hemoglobin, hematocrit and platelets, Prothrombin Time (PT) and Partial 
Thromboplastin Time (PTT). 
• Serum Chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
albumin, alkaline phosphatase, bicarbonate, total bilirubin, blood urea nitrogen, 
phosphorus (inorganic) calcium, chloride, creatine phosphokinase, creatinine, gamma 
glutamyl transferase, glucose, lactate dehydrogenase, potassium, sodium, total protein, 
and uric acid. 
• Urinalysis: microanalysis for specific gravity, pH, protein, glucose, ketones, blood, 
nitrites, leukocytes. If positive for blood, protein or nitrites, a microscopic examination 
will be performed. 
• Serology: hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency 
virus antibody. 
• Pregnancy Tests: will be performed for all female subjects. A serum β-hCG pregnancy 
test will be performed at Screening. A urine pregnancy test will be performed at check-
in, Day 36, Day 72, Day 109, and the Early Termination visit,. A positive pregnancy test 
will exclude a subject from enrollment into the study. A positive urine pregnancy test will 
be confirmed with a serum β-hCG pregnancy test. 
• Urine Screen for Alcohol, Drugs of Abuse: Urine samples will be tested for alcohol, drugs 
of 
abuse 
(amphetamines, 
methamphetamines, 
benzodiazepines, 
barbiturates, 
cannabinoids, cocaine, and opioids) at Screening and at check-in of the Treatment Phase. 
If the test is positive for any of the tested analytes the subject will be excluded from further 
study participation. 


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• Laboratory safety tests will be obtained at the Screening visit, Day -1, Day 36, Day 72, 
Day 109, and at the Early Termination visit. In addition, laboratory safety tests may be 
performed at various unscheduled time points if deemed necessary by the investigator. 
12.7. COVID-19 Testing 
Subjects must have a negative COVID-19 viral test at Screening and Day -1 in order to be eligible 
for enrollment.  COVID-19 testing will be performed weekly while subjects are housed in the clinic. 
Other reasons for testing could include but are not limited to: 
• If a subject displays COVID-19 symptoms (fever, cough, loss of taste or smell, or 
diarrhea). 
• If any subject is suspected of coming in contact with a confirmed COVID-19 positive 
person. 
• At the discretion of the Principle Investigator/in consultation with the Medical Monitor. 
A detailed site COVID-19 Continuity Plan could be provided to include guidance for testing 
frequency and related safety precautions. 
12.8. Adverse Event Assessments 
Adverse events (AEs) shall be monitored continuously from the administration of the first dose of 
study drug until either the Follow-Up or Early Termination visits as noted on the Schedule of 
Events.  AEs will be monitored continuously and solicited using a non-leading question 
immediately after dosing and at 1, 3, 5, 10, 24 hours post-dose, after all other procedures at each 
specified time are performed. Definitions and details of AE reporting and documentation are listed 
in Section 19. 
13. PHARMACOKINETIC ASSESSMENTS 
13.1. Pharmacokinetic Plasma Sample Collection 
Pharmacokinetic Sampling for Treatments A and B (TDS application): 
The blood PK samples will be collected at the nominal time points listed below ±5 minutes for the 
first 24 hours and 10 minutes thereafter. 
The following blood PK samples will be collected in 2 mL EDTA K2 lavender top tubes: 
• Week 1 (Days 1 to 7): Pre-TDS #1 application (Day 1), and at 2, 6, 12, 24, 48, 72, 96, 
120, and 144 h after TDS #1 application. 
• Week 2 (Days 8 to 14): Pre-TDS #2 application (Day 8 at 168 h after TDS #1 
application), and at 24, 48, 72, 96, 120, and 144 h after TDS #2 application. 
• Week 3 (Day 15 to 21): Pre-TDS #3 application (Day 15 at 168 h after TDS #2 
application). 
• Week 4 (Day 22 to 28): Pre-TDS #4 application (Day 22 at 168 h after TDS #3 


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application). 
The following blood PK samples will be collected in 4 mL EDTA K2 lavender top tubes: 
• Week 5 (Day 29 to 35): Pre-TDS #5 application (Day 29 at 168 h after TDS #4 
application), and at 3, 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, and 156 h after 
TDS #5 application 
• Week 6 (Day 36): Pre-TDS #5 removal (Day 36 at 168 h after TDS #5 application), and at 
2, 6, 8, 10, and 12 h after TDS #5 removal. 
The 168-h post-dose PK blood samples will be collected before removal of the worn TDS. 
Pharmacokinetic Sampling for Treatment C (oral dosing): 
The blood PK samples will be collected at the nominal time points listed below ±5 minutes for the 
first 24 hours and 10 minutes thereafter. 
The following blood PK samples will be collected in 2 mL EDTA K2 lavender top tubes: 
• Week 1, Day 1: Pre-Dose, and at 1, 2, 3, 4, 6, 8, 12 and 24 h after oral administration 
(before Day 2 oral administration) 
• Week 2: Day 8 Pre-Dose 
• Week 3: Day 15 Pre-Dose 
• Week 4: Day 22 Pre-Dose 
The following blood PK samples will be collected in 4 mL EDTA K2 lavender top tubes: 
• Week 5: Day 29 Pre-Dose 
• Week 5: Day 35 Pre-Dose, and 1, 2, 3, 4, 6, 8, 12 and 24 h after oral administration (the 24-
h sample will be collected on Day 36. 
One hundred and four (104) blood samples will be collected during the entire treatment period. A 
total of approximately 316 mL blood per subject will be drawn for PK analysis. 
Detailed instructions for the collection, processing, storage and shipment of the plasma PK samples 
will be included in the Laboratory Manual. The date and time of collection of each PK sample will 
be recorded. 
13.2. Pharmacokinetic Sample Shipment 
The plasma samples will be transferred to the analytical laboratory after completion of the study or 
at mutually agreed upon time points during the clinical conduct of the study. Prior to shipment, the 
samples will be appropriately packed in a Styrofoam cooler containing dry ice. Sufficient dry ice 
will be added to ensure that the samples will remain frozen for at least 24 hours for local shipments 
and for at least 48 hours for remote shipments. The shipment will be accompanied by documentation 
containing the following information: name of the study drug product, protocol number, number of 
patients, and number of samples included in the shipment. 
All frozen PK samples will be transferred with accompanying documentation to: 




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be recorded, and the 0% adhesion will be assigned to all remaining adhesion time points of the 
current wear period. No taping of the TDS will be allowed. 
At each adhesion assessment time point, a photograph will be taken as evidence of the extent of 
TDS adhesion to the skin (as support of the visual observation of the adhesion percentage but not 
to be used for automated or photometric analysis). 
Following removal of each TDS, the presence or absence of remaining adhesive residue will also 
be recorded. 
14.1. Patch Detachment 
If a TDS partially or fully detaches from the skin, actions to reapply a detached area of the TDS, to 
apply pressure to the TDS, or to reinforce TDS adhesion with the skin (e.g., taping) must be avoided 
throughout the study. TDS detachment must not be inappropriately inhibited (e.g., by the constant 
pressure applied by a person or an object such as the back of a chair). 
If a TDS fully detaches from the skin, the TDS must not be reapplied, and no fresh TDS will be 
applied for the remainder of the intended wear period. The time of full detachment of any TDS and 
its 0% adherence will be recorded, and the 0% adhesion will be assigned to all remaining adhesion 
time points of the current wear period. 
15. IRRITATION ASSESSMENTS/SKIN TOLERABILITY 
Dermal response scores, other effects numerical scores, and the combined skin irritation score 
(calculated as the sum of the dermal response and other effects scores) will be summarized by post 
removal time point (0.5, 24, 48, 72 hours post removal). Skin irritation will be followed until skin 
tolerability scores are ≤1. Separate summaries by treatment and by post removal assessment time 
point will be provided. Whole number scores will be used. When evaluating a dermal response, at 
least 25% or more of the patch area should demonstrate an observable response. When multiple 
observable dermal responses are present, each observable response shall represent at least 25% or 
more of the patch area. It is recommended when determining the percentage of patch area with an 
observable response, record each dermal response and determine if each one response represents at 
least 25% or more of the patch area. 
Skin tolerability assessments will be performed prior to the TDS application and after removal of 
the TDS application during each period using the following scale: 
15.1. Tolerability Scales (Dermal Response and Other Effects) 
Skin Appearance 
Score 
No evidence of irritation 
0 


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Minimal erythema that is barely perceptible 
1 
Definite erythema that is readily visible and minimal edema or
minimal papular response 
2 
Erythema and papules 
3 
Definite edema 
4 
Erythema, edema, and papules 
5 
Vesicular eruption 
6 
Strong reaction spreading beyond the application site 
7 
 
 
Other Effects 
Observation 
Score 
(Numerical 
Equivalent) 
Slightly glazed appearance 
A (0) 
Markedly glazed appearance 
B (1) 
Glazing with peeling and cracking 
C (2) 
Glazing with fissures 
F (3) 
Film of dried serous exudates covering all or
part of the TDS site 
G (3) 
Small petechial erosions and/or scabs 
H (3) 
Source: FDA Draft Guidance: Assessing the Irritation and Sensitization Potential of Transdermal 
and Topical Delivery Systems for ANDAs. 2018. 
16. DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
16.1. Withdrawal of Subjects from the Study 
A subject may be discontinued or choose to withdraw from study treatment at any time if the subject, 
the Investigator, or the Sponsor feels that it is not in the subject’s best interest to continue. The 
following is a list of possible reasons for study treatment discontinuation: 
• 
Subject withdrawal of consent. 


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• 
Subject is not compliant with study procedures. 
• 
Adverse event that in the opinion of the Investigator would be in the best interest of the 
subject to discontinue study treatment. 
• 
Protocol violation requiring discontinuation of study treatment. 
• 
Lost to follow-up. 
• 
Sponsor request for early termination of the study. 
• 
Positive pregnancy test (females). 
• 
Out-of-range vital signs, at the discretion of the Investigator. In order to ensure accuracy, 
out-of-range vital signs may be repeated once, at least 2 minutes after an abnormal 
finding. 
• 
For other reasons (e.g., Investigator/Sponsor request, inappropriate behavior, social 
reasons). 
 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed and 
treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
16.2. Withdrawal of Subjects Post-Dose Study Drug 
If a subject meets withdrawal criteria post-dose during the Treatment Phase, the subject will 
complete, if possible, all study procedures after the current (last) administration of study drug 
(including PK sample collections) before starting Early Termination procedures. The subject will 
be withdrawn and Early Termination procedures will be completed prior to the subject’s discharge 
from the clinic. 
At the discretion of the Investigator, ensuring the safety of the subjects, any ET procedures that 
were already performed on the same day as part of the procedures of the current treatment phase, 
do not need to be repeated. 
The Sponsor may be contacted if clarification is required on a case-by-case basis. 
16.3. Replacement of Subjects  
Treated subjects who discontinue treatment or withdraw early from the study will not be 
replaced.  
17. STATISTICAL METHODS 
More details of the statistical analyses will be defined in the Statistical Analysis Plan (SAP). Prior 
to the analysis of the final study data, a detailed SAP will be written describing all analyses that will 
be performed. 


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17.1. Analysis Populations 
There are 5 populations in this study: 
Randomized Population: all subjects who signed the informed consent form and are assigned a 
randomization number on Day 1 of Treatment Period 1, prior to the first dose of study drug. 
Intent-to-Treat (ITT) Population: all randomized subjects who take a least 1 dose of study drug. 
Demographics and baseline characteristics will be summarized for the ITT population. 
Pharmacokinetic Per-Protocol (PK-PP) Population: all ITT subjects for a particular treatment 
without any major protocol deviations that could affect the pharmacokinetic endpoint for that 
particular treatment, who received adequate treatment to reach steady state for donepezil in the 
particular treatment (for example, adequate TDS wear), and who provide the plasma concentrations 
required to calculate the donepezil AUC0-168,SS after a particular treatment. Detailed criteria for the 
PK-PP Population will be listed in the SAP. Demographics and baseline characteristics will be 
summarized for the PK-PP Population by treatment. Data from the PK-PP Population will be used 
for PK data listings, with descriptive statistics, and for statistical comparison between the treatments 
in the Test Products and the Reference. 
Safety Population: all randomized subjects who receive at least one dose of study drug and who 
have at least one safety assessment. Safety measures will be analyzed for all subjects in the Safety 
Population. 
Adhesion Per-Protocol (ADH-PP) Population: The ADH-PP population will be based on the 
number of TDSs applied (instead of the number of subjects). All TDSs applied will be part of the 
ADH-PP Population except those that were intentionally removed early in the trial (e.g., because of 
unacceptable irritation) or from subjects who discontinued use of a TDS before the end of the 7-day 
wear period for reasons unrelated to adhesion (e.g., because of a protocol violation or an adverse 
event). Individual case reports describing any subjects/TDS who were excluded from the ADH-PP 
Population, and the reasons for their exclusion, will be included in the clinical study report. The 
ADH-PP Population will be used for the summaries and statistics of adhesion data. 
17.2. Determination of Sample Size 
An adequate number of subjects (approximately 60 subjects) will be enrolled in the study to plan 
for 48 subjects to complete all study periods. This sample size was based on results of a previous 
steady-state study comparing 10 mg/day donepezil TDS to oral 10 mg/day donepezil (Study CL-P-
15086) that showed an AUC geometric mean ratio of 1.04 and a coefficient of variation of 29.3%. 
The calculated sample size of 48 subjects is estimated to show at least 90% power to assess 
bioequivalence within the limits of 80 to 125% for the geometric mean ratio if the true expected 
geometric mean ratio is 1.05 (assuming a coefficient of variation of 29%) for AUC. 


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Based on adhesion scores from previous studies with the donepezil TDS, the planned sample size 
of the current study should be more than adequate to demonstrate, based on a one-sided lower 95% 
confidence interval created with 80% power, that >80% of patches are adhered for at least 75% 
throughout the wear period. 
17.3. Pharmacokinetic Analysis 
17.3.1. Pharmacokinetic Parameters 
PK parameters will be calculated for the PP population from plasma concentrations of donepezil 
and 6-O-desmethyl donepezil (active metabolite) using standard, non-compartmental methods 
using Phoenix® WinNonlin® (Version 8.3 or higher, Certara USA, Inc., Princeton, NJ). 
Pharmacokinetic parameters at steady state (Week 5) will include AUC0-24,SS (daily AUC), AUC0-
168,SS, Tlag, Cmax, Cmin, Cavg, Ctrough, Ctau, percent peak-to-trough fluctuation (FLUCP). After oral 
administration, AUC0-24,SS will be calculated and multiplied by 7 to obtain AUC0-168,SS. In some 
subjects, because of the lag time, the Cmax and Tmax values at steady state may be observed after 
removal of the TDS (past 168 hours after TDS application). Additional PK parameters will be 
reported (see SAP for details). 
Area under the plasma concentration versus time curve will be calculated by the linear trapezoidal 
rule. Concentrations that are below the limit of quantification (BLQ) will be treated as zero in the 
data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations 
will be treated as zero from time zero up to the time at which the first quantifiable concentration is 
observed; embedded and/or terminal BLQ concentrations will be treated as “missing. 
17.3.2. Descriptive Statistics for Pharmacokinetics 
For the plasma concentrations at each time point and for each PK parameter, parametric and 
nonparametric descriptive statistics will be calculated. Parametric descriptive statistics include 
number of subjects (n), arithmetic mean and standard deviation (SD), and percent coefficient of 
variation (%CV). Nonparametric descriptive statistics include minimum, Q1 (25th percentile), 
median, Q3 (75th percentile), and maximum. Individual plasma concentrations and PK parameters 
and descriptive statistics by treatment will be listed. 
PK parameters of exposure (concentrations and AUCs) after the 5 mg/day TDS application will be 
multiplied by 2 to adjust for the lower dose (dose-normalization) before comparison to the 
10 mg/day treatments. 
17.3.3. Plasma Concentration-Time Plots 
Individual subject and mean plasma concentration-time profiles will be plotted for donepezil by 
treatment on linear and logarithmic concentration axes. 


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17.3.4. Statistical PK Comparison between Treatments  
Statistical comparison of the PK parameters of exposure (AUC0-24,SS, AUC0-168,SS, Cmax, Cmin, Ctau, 
percent peak-to-trough fluctuation (FLUCP).) at steady state for donepezil among the 3 treatments 
will be performed using an Analysis of Variance (ANOVA) model for a 3-way crossover design on 
the ln-transformed data with sequence, period and treatment as the fixed effects and subject within 
sequence as a random effect. A statistically significant difference is defined as p <0.05. Intersubject, 
intrasubject and total variability (coefficient of variation in percent, CV%) of the PK parameters 
will be reported. 
PK parameters of exposure (concentrations and AUCs) after the 5 mg/day TDS application will be 
multiplied by 2 to adjust for the lower dose (dose-normalization) before statistical comparison to 
the 10 mg/day treatments. 
17.3.5. Time to Steady State Assessment 
Assessment of time to achieve steady-state will be performed by a review of weekly donepezil 
trough levels (Ctau) at time points immediately prior to dosing on Days 15, 22, 29, and 36 in each 
treatment period. The univariate analysis method described by Chow and Liu for examining when 
steady-state is attained will be implemented using log-transformed trough plasma concentrations. 
Modifications to the method for Treatment Periods 2 and 3 will be explained in the SAP,  to possibly 
adjust for the attainment of a new steady state after switching to a new treatment without a washout 
period after the previous treatment. 
17.3.6. Statistical Assessment of Relative Bioavailability 
To examine the relative bioavailability at steady state of the 5 and 10 mg/day TDS (Tests) relative 
to oral donepezil (Reference), plasma donepezil exposure as characterized by AUC0-168,SS will be 
assessed and compared utilizing bioequivalence criteria. The least squares geometric means 
(LSGM) of the PK parameters for each treatment will be reported. Point estimates and 90% 
Confidence Intervals (CI) for the Test to Reference ratios of geometric means will be provided. 
Similar bioavailability for donepezil will be concluded if the 90% CIs of the LSGMs lie within the 
acceptable range of 0.80 to 1.25 for AUC0-168,SS. Forest plots presenting the point estimate and 90% 
confidence intervals for AUC0-168,SS will be constructed for the comparisons between the 5 mg/day 
and 10 mg/day donepezil TDS applications (Tests) and oral Aricept® (Reference). 
Since the intention of the patch is to decrease the peak-to-through fluctuations with lower Cmax 
after the patch application compared to daily oral Aricept dosing, rather than using the conventional 
bioequivalence criterion for Cmax, it is stipulated that mean steady-state donepezil Cmax after patch 
administration should remain between the steady-state Cmax and Cmin after daily oral Aricept® 
administration. 


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17.4. Adhesion Analysis 
TDS adhesion score results (percentage adhesion) for each TDS strength will be summarized 
separately for Weeks 1 through 5 and across all wear periods (Weeks 1-5 combined) as follows: 
• Summary statistics (mean, SD, minimum, Q1, median, Q3, maximum) for the mean 
adhesion score, where the mean adhesion score for each patch is the average of the patch 
adhesion scores across the entire wear period. 
• Adhesion score distribution at each adhesion measurement time point post patch application 
(i.e., 12, 24, …, and 168 hours). 
• Average adhesion score at each adhesion measurement time point post patch application. 
• Number (%) of patches that are completely detached during the 7-day wear period. 
• Number (%) of patches with adhesion <50% at any adhesion measurement time point during 
the 7-day wear period. 
• Summary of frequency of time a patch was first observed with adhesion <50% during the 
7-day wear period. 
• Number (%) of patches with adhesion ≥75% at all adhesion assessment time points during 
the 7-day wear period 
To assess whether at least 80% of the TDS applied are at least 75% adhered throughout the 7-day 
wear period, a one-sided 95% confidence interval will be determined for the probability (p) that a 
randomly selected TDS maintains at least 75% adhesion throughout the entire wear period. If the 
95% lower confidence limit for p is greater than 80%, acceptable TDS adhesion will be concluded. 
The method for the calculation of the 95% lower confidence limit and the justification of the method 
will be provided in the SAP. 
To calculate the mean adhesion score and associated statistics, the lowest adhesion score at each 
time point after the baseline time point (t0) will be carried forward to subsequent time points until a 
lower score is observed. 
17.5. Subject Disposition and Demographic/Baseline Characteristics 
The numbers of subjects screened, the number of subjects randomized overall (Randomized 
Population) and per treatment sequence group, and the number of subjects in the ITT and PP 
populations overall and by treatment sequence group will be listed. Differences between the number 
of subjects in the analysis populations will be explained. For randomized subjects who discontinue 
from the study, the primary reason for discontinuation will be listed and summarized by treatment 
after which they discontinued. 
Summary statistics will be provided by treatment sequence and overall for demographic 
characteristics (e.g., age, sex, race, and ethnicity) and baseline characteristics (e.g., body weight, 
height, BMI) in the ITT and PP populations. Demographic data and baseline characteristics will be 


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compared among treatment sequence groups for the ITT and PP population. 
17.6. Safety Analysis 
All analyses of safety will be conducted on the Safety Population. The safety assessment will be 
based on adverse events, physical exams, vital signs, ECG parameters, C-SSRS, safety laboratory 
tests, and irritation scores (for treatments with TDS). 
Adverse events will be coded in accordance with the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events with new onset during the study between the initiation of study drug 
and 5 days after the last dose of study drug will be considered treatment-emergent (TEAEs). This 
will include any AE with onset prior to initiation of study drug and increased severity after the 
treatment initiation. 
Treatment-emergent adverse events will be summarized by system organ class and preferred term, 
and by treatment. This will include overall incidence rates (regardless of severity and relationship 
to study drug), and incidence rates for moderate or severe adverse events. A summary of serious 
adverse events, and adverse events leading to early discontinuation from the study will be presented 
through data listings. 
Safety laboratory tests and vital signs will be summarized by post-treatment change from baseline 
for each of the parameters using descriptive statistics by treatment group. Those subjects with 
significant laboratory abnormalities will be identified in data listings. Additional safety parameters 
will be summarized in data listings. 
17.7. Interim Analysis 
No interim analysis is planned for this study. 
18. ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
18.1. Adverse Events 
18.1.1. Recording and Monitoring of Adverse Events 
For the purpose of this clinical trial, all Adverse Events will be recorded and monitored for all 
enrolled subjects from the moment they receive the dose of study drug until they complete the study 
at the EOS (the Follow-Up visit or the Early Termination Visit). 
18.1.2. Definition 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship with 
the treatment. An AE is therefore any unfavorable and unintended sign (including an abnormal 


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laboratory finding), symptom or disease temporally associated with the administration of an 
investigational product, whether or not related to that investigational product. An unexpected AE is 
one of a type not identified in nature, severity, or frequency in the current Investigator’s Brochure 
or of greater severity or frequency than expected based on the information in the Investigator’s 
Brochure. 
The Investigator or designee will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents. Adverse events 
will be recorded in the patient CRF. Adverse events will be described by duration (start and stop 
dates and times), severity, outcome, treatment and relation to study drug, or if unrelated, the cause. 
18.1.3. AE Grading  
The severity of each AE will be graded by the investigator using the following categories: 
Mild 
Does not interfere with subject’s usual function (awareness of symptoms or signs, but 
easily tolerated [no specific medical intervention required]). 
Moderate 
Interferes to some extent with subject’s usual function (enough discomfort to interfere 
with usual activity [minimal intervention; local intervention; noninvasive 
intervention]). 
Severe 
Interferes significantly with subject’s usual function (incapacity to work or to do usual 
activities [significant symptoms requiring hospitalization or invasive intervention]). 
 
If there is a change in severity of an AE, only the maximum severity of the AE should be 
recorded. 
The investigator will describe the action taken in the appropriate section of the eCRF, as follows: 
• None 
• Study product stopped 
• Study product temporarily interrupted 
• Concomitant medication 
• Other, specify 
18.1.4. AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following: 
1. Definitely - Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or expected 
response pattern to the suspected drug; that is confirmed by stopping or reducing the dosage 


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of the drug; and that is not explained by any other reasonable hypothesis. 
2. Probably - An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
3. Possibly - An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but that 
could readily have been produced by a number of other factors. 
4. Unrelated - An event that can be determined with certainty to have no relationship to the 
study drug. 
18.2. Serious Adverse Events 
A Serious Adverse Event (SAE) is defined as any AE occurring at any dose that results in any of 
the following outcomes: 
• Death 
• A life-threatening adverse experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention 
to prevent one of the outcomes listed. 
 
Other important medical events may also be considered an SAE when, based on appropriate medical 
judgment, they jeopardize the subject or require intervention to prevent one of the outcomes listed. 
Note that AEs of Grade 3 due to hospitalization or prolongation of a hospitalization, and Grade 4 
and Grade 5 per CTCAE grading criteria are classified as SAEs. 
18.2.1. Serious Adverse Event Reporting 
Within 24 hours after a SAE detection, observation, or report of occurrence (regardless of the 
relationship to test article), the Investigator or designee will enter the SAE into the electronic 
database. The investigator/qualified designee will enter the required information regarding the SAE 
into the appropriate module of the eCRF, which will automatically result in distribution of the 
information to the appropriate sponsor contact. If the EDC system is temporarily unavailable, the 
event, including the investigator-determined causality to study drug, should be reported via a paper 
back-up SAE form to the appropriate sponsor contact. Upon return of the availability of EDC 




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the alert reports per FDA regulations. 
18.3. Adverse Event Treatment and Follow-up 
All AEs, including SAEs, will be followed to resolution when possible. All AEs and treatment 
administered will be recorded on the case report form (eCRF). Treatment may be rendered on site 
under the direction of the Investigator as appropriate. Events requiring diagnostic evaluation or 
treatment beyond the scope of what is available and appropriate within the clinical research unit 
shall be referred in a timely basis to other care providers. Records of diagnostic and therapeutic 
interventions shall be requested in compliance with HIPAA requirements, and those received shall 
be retained in the subject’s file. 
SAE assessment, treatment, and follow up shall be performed up to at least 30 days after last dose 
for events considered definitely, probably, or possibly related to study drug, and continue until 
resolved or clinically stable. 
19. PREGNANCY 
Females with a positive pregnancy test will terminate the study early (Section 10.5). The initial 
report of a pregnancy during the study will be provided to the sponsor within 24 hours of the incident 
identification and to the IRB within a time frame after the incident identification as required by the 
IRB. 
All pregnancies will be followed to at least the completion/termination of the pregnancy. The 
Investigator will document the subject visits accordingly and record the information in the clinical 
site’s source documents. If the pregnancy continues to delivery, the outcome (health of the infant), 
in addition to the maternal health status, must be included in the report. 
Pregnancy will not be considered an AE or SAE; any pregnancy complication or termination of a 
pregnancy for medical reasons will be recorded as an AE or SAE. 
20. PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, Investigator, or Sponsor fails to adhere to significant 
protocol requirements that materially (a) reduces the quality or completeness of the data, (b) makes 
the Informed Consent Form inaccurate, or (c) impacts a subject's safety, rights, or welfare. 
Examples of protocol violations may include the following: 
1. Inadequate or delinquent Informed Consent 
2. Inclusion/exclusion criteria not met 
3. Unreported serious adverse events 
4. Multiple visits missed or outside permissible windows 
5. Materially inadequate record keeping 
6. Intentional deviation from protocol, Good Clinical Practice, or regulations by study 


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personnel 
7. Subject repeated non-compliance with study requirements 
 
It is the Investigator’s responsibility to report to the IRB of any Protocol Violation(s) according to 
the IRBs policy. Copy of the IRB submission will be filed in the site’s regulatory binder and in the 
Sponsor’s files. 
21. DATA MANAGEMENT AND RECORD KEEPING 
21.1. Data Management 
Data will be recorded at the site on CRFs. All entries on a CRF are ultimately the responsibility of 
the Investigator, who is expected to review each form for completeness, accuracy and legibility 
before signing. All forms must be filled out by using black ink. Errors should be lined out but not 
obliterated and the correction inserted, initialed and dated. A CRF must be completed for each 
participant who has given informed consent. The CRFs and source documents must be made 
available to Sponsor and/or its representatives. 
21.2. Record Keeping 
The Investigator must maintain all documents and records, originals or certified copies of original 
records, relating to the conduct of this trial, and necessary for the evaluation and reconstruction of 
the clinical trial. This documentation includes, but is not limited to protocol, CRFs, AE reports, 
subject source data (including records of subjects, subject visit logs, clinical observations and 
findings), correspondence with health authorities and IRB, consent forms, inventory of study 
product, Investigator’s curriculum vitae, monitor visit logs, laboratory reference ranges and 
laboratory certification or quality control procedures and laboratory director curriculum vitae. 
The Investigator and affiliated Institution should maintain the trial documents as required by the 
applicable regulations. The Investigator and affiliated Institution should take measures to prevent 
accidental or premature destruction of documents. Clinical trial documents must be kept in the 
clinical site’s archives indefinitely, unless written authorization is obtained from the Sponsor. 
21.3. Access to Source Data/Documents 
The Investigator and research Institution agree that the Sponsor, their representatives, the IRB, and 
representatives from worldwide regulatory agencies will have the right, both during and after the 
clinical trial, to review and inspect pertinent medical records related to the clinical trial. 
22. QUALITY CONTROL AND QUALITY ASSURANCE 
By signing the protocol, the Institution and the Sponsor agree to be responsible for implementing 
and maintaining quality control and quality assurance systems with written standard operating 
procedures to ensure that trials are conducted and data are generated, documented, and reported in 


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compliance with the protocol, accepted standards of Good Clinical Practice. (GCP), ICH and other 
applicable regulations. 
23. ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting trials that involve human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and wellbeing of trial subjects are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical trial data are credible. In this study, the 2008 version of the Declaration of Helsinki 
will be adhered to. It can be found on the website of The World Medical Association: 
http://www.wma.net/en/30publications/10policies/b3/17c.pdf 
24. PUBLICATION POLICY 
Confidentiality, presentation, and publication of manuscripts containing the study data, and patent 
applications related to unpublished study-related information and unpublished information given to 
the Investigator by the Sponsor and/or its representatives shall be handled as set forth in a mutual 
written agreement between the Sponsor and the Institution. The publication or presentation of any 
study results shall comply with all applicable privacy laws, including, but not limited to, the Health 
Insurance Portability and Accountability Act of 1996. 
25. FINANCING AND INSURANCE 
25.1. Finances 
Prior to starting the study, the Principal Investigator and/or Institution will sign an agreement with 
the Sponsor related to conducting the clinical trial. This agreement will include the financial 
information agreed upon by the parties. 
25.2. Insurance Compensation 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. The 
insurance of the Sponsor does not relieve the Investigator and the other collaborators from 
maintaining their own liability insurance policy. An insurance certificate will be provided to the 
IRB according to regulatory requirements. 
26. COMPLETION OF STUDY 
The end of the study will be at the time of the last subject, last visit. The IRB will be notified about 
the end of the study according to regulatory requirements. 


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27. STUDY ADMINISTRATIVE INFORMATION 
27.1. Protocol Amendments 
Any amendments to the study protocol considered to be a substantial amendment will be 
communicated to the Investigator by the Sponsor. All substantial protocol amendments will 
undergo the same review and approval process as the original protocol and may be implemented 
after it has been approved by the IRB, unless immediate implementation of the change is necessary 
for subject safety. In this case, the situation must be documented and reported to the IRB according 
to all relevant regulatory requirements. 
A protocol amendment is considered to be a substantial amendment if it is likely to affect the safety, 
physical, or mental integrity of subjects in the study; the scientific value of the study; the conduct 
or management of the study; or the quality or safety of any Investigational Medicinal Product used 
in the study. 
Any other minor changes to the protocol not considered to be substantial amendments will not need 
prior approval of the IRB and will be communicated to the Investigator by the Sponsor. 
 
 


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28. REFERENCES 
Aricept® US Prescribing Information. Eisai R&D Management Co., Ltd. Last updated 
2018 
Assessing Adhesion with Transdermal and Topical Delivery Systems for ANDAs. Guidance for 
Industry. Rockville, MD: Food and Drug Administration; Oct 2018. Available at: 
https://www.fda.gov/media/98634/download 
Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems 
for ANDAs Guidance for Industry. Rockville, MD: Food and Drug Administration; Oct 2018. 
Available at https://www.fda.gov/media/117569/download 
Chow SC, Liu JL. 2009. Design and Analysis of Bioavailability and Bioequivalence Studies. 
Chapman & Hall, Boca Raton, FL. Pages 574-575. 
Corplex™ Donepezil Transdermal Delivery System (donepezil HCl patch). Investigator’s 
Brochure Edition 8.0. Menlo Park, CA: Corium International, Inc; 23 Sep 2020. 
Coyle JT, Price DL, DeLong MR. Alzheimer's disease: a disorder of cortical cholinergic 
innervation. Science. 1983;219(4589):1184-90. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity 
and internal consistency findings from three multisite studies with adolescents and adults. Am J 
Psychiatry. 2011;168(12):1266-77. 
 

SAP_001.pdf: 
Corium, Inc. 
CL-P-20003
Statistical Analysis Plan 
Version 2.0 
Issue Date 15-JUL-2021 
Page 1 of 61 
Confidential 
Statistical Analysis Plan 
A Phase 1, Open-Label, 3-Period, Randomized, Crossover Pharmacokinetic Study 
to Evaluate the Steady-State Pharmacokinetics of 5 mg and 10 mg Corplex™ 
Donepezil Transdermal Delivery Systems Compared to 10 mg Oral Administration 
of Aricept® in Healthy Volunteers 
Protocol Number: CL-P-20003 
Final Version, dated 28-SEP-2020 
Amendment #1 dated: 26-OCT2020 
Protocol Clarification Memo #1, dated 30-OCT-2020 
SAP Version 2.0 
Issue Date: 15-JUL-2021 
Authors: 
Previous SAP Version 
1.0 
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Table of Contents 
1 
INTRODUCTION ............................................................................................... 4 
2 
STUDY OBJECTIVES ....................................................................................... 6 
2.1 
Primary Objective ........................................................................................................... 6 
2.2 
Secondary Objective ....................................................................................................... 6 
2.3 
Safety Objective .............................................................................................................. 6 
3 
ENDPOINTS ....................................................................................................... 6 
3.1 
Primary Endpoints .......................................................................................................... 6 
3.2 
Secondary Endpoints ...................................................................................................... 7 
3.3 
Safety Endpoints ............................................................................................................. 7 
4 
SAMPLE SIZE .................................................................................................... 7 
5 
RANDOMIZATION ........................................................................................... 8 
6 
PLANNED ANALYSES ..................................................................................... 8 
6.1 
Analysis Populations ....................................................................................................... 8 
6.1.1 
Randomized Population ............................................................................................ 8 
6.1.2 
Pharmacokinetic (PK) Population............................................................................. 8 
6.1.3 
Relative Bioavailability (BA) Population ................................................................. 8 
6.1.4 
Safety Analysis Population ....................................................................................... 9 
6.1.5 
Skin Irritation Population .......................................................................................... 9 
6.1.6 
Adhesion Population ................................................................................................. 9 
6.2 
Derived Data ................................................................................................................. 10 
6.2.1 
Race......................................................................................................................... 10 
6.2.2 
Baseline ................................................................................................................... 10 
6.2.3 
Early Terminations Assessments ............................................................................ 10 
6.2.4 
Study Day................................................................................................................ 10 
6.2.5 
Conventions for Missing and Partial Dates ............................................................ 11 
6.2.6 
Inexact Values ......................................................................................................... 11 
6.2.7 
Unscheduled Visits ................................................................................................. 11 
6.2.8 
TDS Adhesion Assessment Scale ........................................................................... 11 
6.2.9 
Skin Irritation Assessment Scale ............................................................................ 11 
6.2.10 
Columbia-Suicide Severity Rating Scale ................................................................ 13 
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6.2.11 
PK Parameters ......................................................................................................... 14 
6.3 
Conventions .................................................................................................................. 20 
6.3.1 
Decimal Places ........................................................................................................ 22 
6.4 
Subject Disposition ....................................................................................................... 23 
6.5 
Protocol Deviations ....................................................................................................... 24 
6.6 
Baseline Comparability ................................................................................................. 24 
6.7 
Medical History ............................................................................................................ 25 
6.8 
Prior and Concomitant Medications ............................................................................. 25 
6.9 
TDS Application Data................................................................................................... 25 
6.10 
Statistical Analysis of PK Data ..................................................................................... 25 
6.10.1 
Statistical PK Comparison between Treatments ..................................................... 26 
6.10.2 
Assessment of Steady-State Achievement .............................................................. 27 
6.10.3 
Statistical Assessment of Bioequivalence at Steady-State ...................................... 29 
6.10.4 
Subgroup Analyses ................................................................................................. 29 
6.11 
Safety Analyses ............................................................................................................. 33 
6.11.1 
Adverse Events ....................................................................................................... 33 
6.11.2 
Laboratory Data ...................................................................................................... 35 
6.11.3 
Vital Signs ............................................................................................................... 35 
6.11.4 
Electrocardiogram Data .......................................................................................... 36 
6.11.5 
Physical Examination.............................................................................................. 37 
6.11.6 
C-SSRS ................................................................................................................... 37 
6.11.7 
Skin Tolerability Assessments ................................................................................ 37 
6.11.8 
Skin Photography .................................................................................................... 37 
6.12 
Adhesion Assessments .................................................................................................. 37 
6.13 
Duration of Patch Wear and Patch Detachment ..................................................... 43 
7 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................43 
8 
REFERENCES ..................................................................................................44 
9 
LIST OF TABLES, FIGURES AND LISTINGS .............................................45 
 
 
 
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1 INTRODUCTION 
This document details the planned statistical analyses for the Corium, Inc., protocol “CL-P-
20003” study titled “A Phase 1, Open-Label, 3-Period, Randomized, Crossover Pharmacokinetic 
Study to Evaluate the Steady-State Pharmacokinetics of 5 mg and 10 mg Corplex™ Donepezil 
Transdermal Delivery Systems Compared to 10 mg Oral Administration of Aricept® in Healthy 
Volunteers”. 
The proposed analyses are based on the contents of the final version of the protocol (dated 2-
OCT-2020), the protocol amendment #1 (dated 26-OCT-2020), and the protocol clarification 
memo #1 (dated 30-OCT-2020). 
This is a Phase 1, open-label, randomized, 3-period, 3-treatment, crossover pharmacokinetic 
study to evaluate the steady-state pharmacokinetics of 5 mg/day and 10 mg/day Corplex™ 
Donepezil TDS manufactured with the commercial process compared to 10 mg oral 
administration of Aricept® in healthy volunteers.  
The study will consist of a Screening Period, a Treatment Phase with 3 treatment periods and a 
Follow-Up visit as follows: 
• Screening Period: Subjects will undergo a Screening Period up to 28 days prior to 
entering the Treatment Phase. 
• Treatment Phase: Eligible subjects will participate in 3 treatment periods each 
consisting of 36 days, without a washout between treatments: 
o Treatment A: 5 mg/day Donepezil Transdermal Delivery System (TDS) for 5 
consecutive weeks (7-day wear for each of the 5 patches). In Period 1, all enrolled 
subjects will receive Treatment A. The last (5th) patch will be removed on the 
morning of Day 36 (168 hours after the last patch application). No study drug will 
be administered on Day 36. The 5 mg/day Donepezil TDS as the first treatment of 
the study allows subjects to get accustomed to the potential cholinergic effects 
(5 mg/day for 1 week is the recommended starting dose before titrating up, to 
10 mg/day). In this study, the 5 mg/day Donepezil TDS is administered for 
5 weeks to reach steady state in order to measure the steady state 
pharmacokinetics in Week 5 to be compared with those after oral Aricept®. 
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During Treatment Periods 2 and 3, the subjects will be randomized to receive either sequences 
of Treatments B-C or Treatments C-B. Subjects will receive the following treatments 
according to the randomization schedule. 
o Treatment B: 10 mg/day Donepezil TDS applied weekly (within ±1 hour of 
application time on Day 1) for 5 consecutive weeks. 
o Treatment C: 10 mg Aricept® donepezil tablet administered QD for 5 weeks 
(within ±1 hour of dosing time on Day 1). 
Randomization to the 2 treatment sequences will be stratified by the subject’s gender.  For all oral 
doses and TDS applications, subjects will receive a light meal 30 minutes prior to dosing. Standard 
meals will be provided at appropriate times thereafter. Blood samples for pharmacokinetics and 
safety assessments will be collected during the Treatment Phase. 
In each period wherein the treatment consists of a patch, the subjects will wear a total of 5 patches 
for a total of 35 days (5 weeks). The last (5th) patch in the period will be removed after the morning 
blood draw on Day 36 (168-hour time point after the last patch in the period). No treatment will 
be administered on Day 36 of the period; additional post-wear PK blood samples will be collected 
on Day 36 after any patch treatment.  Because of the potential for continued drug absorption after 
TDS removal, an additional non-treated PK sampling day (Day 36 in each treatment period) was 
added to the PK sampling schedule after TDS removal at the end of the TDS dosing interval (168 
hours) to evaluate the presence of this phenomenon.  These samples at the very beginning of the 
terminal phase will not be used for any terminal-phase assessments due to their truncated nature. 
In each period (Period 2 or 3) wherein the treatment consists of oral Aricept®, the subjects will an 
oral dose daily for a total of 35 days (5 weeks). The last oral dose in the period will be administered 
on the morning of Day 35. No treatment will be administered on Day 36 of the period; a PK blood 
sample will be collected in the morning of Day 36 at 24 hours after the last oral dose. 
In Period 1, all subjects will wear patches (Treatment A). In Periods 2 and 3, subjects will either 
wear patches (Treatment B) or receive once-per-day oral Aricept® (Treatment C). 
o The treatment in Period 2 will start on the morning of Study Day 37 after the pre-
dose blood draw for Period 2 is collected. No treatment will be administered on 
Study Day 72. For the patch treatment in Period 2, the patch will be removed on 
Study Day 72 after the 168-hour blood sample collection. 
o The treatment in Period 3 will start on the morning of Study Day 73 after the pre-
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dose blood draw for Period 3 is collected. No treatment will be administered on 
Study Day 108. For the patch treatment in Period 3, the patch will be removed on 
Study Day 108 after the 168-hour blood sample collection. 
• Follow-Up: 5 ±2 days after the day of the last oral drug administration or last TDS 
removal during the Treatment Phase, subjects will enter a Follow-Up Visit to evaluate 
safety parameters. 
There will be no washout phase between treatment periods (with the exception of Day 36 within 
each period to collect post-treatment PK blood samples). 
Subjects will participate in the study for up to 144 days, including up to 28 days of screening, a 
Treatment Phase with 3 treatment periods of 36 days each, and a 5 ±2 day Follow-Up Visit. 
Eligible subjects will stay in the research clinic for 109 days (108 overnight stays) during the 
Treatment Phase. 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
• To evaluate the bioequivalence of steady-state donepezil plasma exposure following 
once-weekly treatments with 10 mg/day Corplex™ Donepezil TDS compared to once-
daily oral administration of 10 mg Aricept®.   
2.2 Secondary Objective 
• To evaluate the bioequivalence of steady-state donepezil plasma exposure (after dose-
normalization) following once-weekly treatments with 5 mg/day Corplex™ Donepezil 
TDS compared to once-daily oral administration of 10 mg Aricept® 
• To evaluate the adhesion to the skin during the wear period of each once-weekly 5 
mg/day and 10 mg/day Corplex™ Donepezil TDS application. 
2.3 Safety Objective 
• To evaluate the safety and tolerability, including local skin tolerability (Dermal Response 
and Other Effects) of once-weekly Corplex™ Donepezil TDS. 
3 ENDPOINTS 
3.1 Primary Endpoints 
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• Primary pharmacokinetic parameters at steady state (Week 5) calculated for plasma 
concentrations of donepezil will include: AUC0-168,ss and Cmax,ss 
3.2 Secondary Endpoints 
• Secondary pharmacokinetic parameters on Week 1 after the first TDS application 
calculated for plasma concentrations of donepezil will include: AUC0-168, AUC0-24 (daily 
AUC), Cmax, Tmax, and Tlag. 
• Secondary pharmacokinetic parameters at steady state (Week 5) calculated for plasma 
concentrations of donepezil will include: AUC0-24,ss (daily AUC), Tlag, Tmax,ss; Cmin,ss; 
Tmin,ss; Cavg,ss; Ctrough; and percent peak-to-trough fluctuation (FLUCP).  
• Trough donepezil levels (Ctau) reported at the end of each dosing interval (taken predose 
on Days 8, 15, 22, 29, and 36 after TDS treatments and on Days 8, 15, 22, 29, and 35 
after Aricept oral treatment) 
• Skin adhesion assessments for each TDS will be evaluated every 12 hours during wear as 
the percentage of the total surface area that is adhered to the skin, assessed in person by 
trained observers. 
• All PK parameters and trough levels for 6-O-desmethyl donepezil (active metabolite) 
3.3 Safety Endpoints 
• Adverse events (AEs), physical examinations, vital signs assessments, clinical laboratory 
evaluations, C-SSRS evaluations, electrocardiograms (ECGs), and skin tolerability 
assessments 
4 SAMPLE SIZE 
An adequate number of subjects (approximately 60 subjects) will be enrolled in the study to plan 
for 48 subjects to complete all study periods. This sample size was based on results of a previous 
steady-state study comparing 10 mg/day donepezil TDS to oral 10 mg/day donepezil (Study CL-
P-15086) that showed an AUC0-168,ss geometric mean ratio of 1.04 and a coefficient of variation of 
29.3%. The calculated sample size of 48 subjects is estimated to show at least 90% power to assess 
bioequivalence within the limits of 80 to 125% for the geometric mean ratio if the true expected 
geometric mean ratio is 1.05 (assuming a coefficient of variation of 29%) for AUC0-168,ss. 
Based on adhesion scores from previous studies with the donepezil TDS, the planned sample size 
of the current study should be more than adequate to demonstrate, based on a one-sided lower 
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95% confidence interval created with 80% power, that >80% of patches are adhered for at least 
75% throughout the wear period. 
5 RANDOMIZATION 
At the start of Period 2, subjects will be randomized to one of the following treatments in Period 
2. Subjects will receive the alternate treatment in Period 3. Randomization to the 2 treatment 
sequences will be stratified by gender using a computer-generated randomization scheme.  Study 
drug will be assigned to each subject on each dosing day based on the randomization scheme. 
This is an open-label study. Study treatments will not be blinded.
6 PLANNED ANALYSES 
The final clinical study report (CSR) may contain additional tables or statistical tests if warranted 
by the data obtained.  The justification for any such additional analyses will be fully documented 
in the final CSR. 
6.1 Analysis Populations 
Subjects excluded from the analysis populations and the reason for their exclusion will be listed 
in Appendix 16.2. 
6.1.1 
Randomized Population 
The Randomized Population includes all subjects who signed the informed consent form and are 
assigned a randomization number on Day 1 of Treatment Period 1, prior to the first dose of study 
drug. 
6.1.2 
Pharmacokinetic (PK) Population 
The PK Population includes all subjects without major protocol deviations that could affect 
pharmacokinetics and who have at least one PK parameter derived. Subjects that are withdrawn 
from the study prior to study completion (early termination, ET) will be excluded from the PK 
population for the period during which ET occurred. Additionally, subjects with 100% patch 
detachment occurring in Weeks 3, 4, or 5 will be excluded from the PK population and 
subsequent analyses. The PK population will be used in the PK analysis and to generate 
summary statistics for PK endpoints. 
6.1.3 
Relative Bioavailability (BA) Population 
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The Relative Bioavailability Population includes all PK Population subjects that have AUC0-168,ss 
and/or Cmax,ss for TDS 10 mg and Aricept treatments.  
Demographics and baseline characteristics will be summarized for the Relative Bioavailability 
Population by treatment. Data from the PK Population will be used for PK parameter data 
listings, with descriptive statistics.  Statistical comparison of the test and reference products will 
be based on the Relative Bioavailability Population. 
All protocol deviations will be assessed and documented on a case-by-case basis before database 
lock, and deviations considered to have a potentially serious impact on the PK results will lead to 
the relevant subject being excluded from the Relative Bioavailability Population.  Before 
database lock, potential subject exclusions from the PK and Relative Bioavailability Populations 
will be reviewed by the Sponsor and documented in a subject evaluability document. 
6.1.4 
Safety Analysis Population 
The Safety Analysis Population includes all randomized subjects who receive at least one dose of 
study drug and who have at least one safety assessment. Safety measures will be analyzed for all 
subjects in the Safety Analysis Population. 
6.1.5 
Skin Irritation Population 
The skin irritation population includes all TDSs except those removed prior to the end of the 7-
day wear period (e.g., dropouts) for reasons unrelated to skin tolerability, or those that became 
detached due to lack of adhesion. TDSs that are removed due to irritation or other skin effects 
will be retained in the Skin Irritation Population.  The Skin Irritation Population will be used for 
summaries of skin irritation data. 
6.1.6 
Adhesion Population 
The Adhesion Population will be based on the TDS patches (instead of subjects). All TDSs 
applied will be part of the Adhesion Population except those that removed before the end of the 
7-day wear period for reasons unrelated to adhesion (e.g., due to unacceptable skin irritation,
because of a protocol violation, an adverse event, or subject dropout). Individual subject case
reports for any subject with a TDS excluded from the Adhesion Population, and the reasons for
the TDS’s exclusion, will be included in the clinical study report. TDSs that became detached for
reasons related to adhesion will not be excluded from the Adhesion Population. The Adhesion
Population will be used for the summaries and statistics of adhesion data.
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Demographics and baseline characteristics will be summarized for the Safety Analysis 
Population by treatment. Data from the PK Population will be used for PK data tables with 
descriptive statistics by treatment. Data from the Relative Bioavailability Population will be used 
for statistical comparisons between TDS 10 mg and Aricept treatments. 
All protocol deviations will be assessed and documented on a case-by-case basis before the 
database lock, and deviations considered to have a serious impact on the efficacy results will lead 
to the relevant subject being excluded from the PK and Relative Bioavailability Populations. 
Prior to database lock, blinded adhesion data will be reviewed by the Sponsor and 
pharmacokinetics to identify any potential subject exclusions from the PK and Relative 
Bioavailability Populations.  
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 
Race 
Where more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple Race” in the summary tables. The listings will 
reflect the original selected categories.  
6.2.2 
Baseline 
For variables that will be summarized by treatment, the baseline for each period is defined as the 
last non-missing value (either scheduled, unscheduled or repeat) that is collected before dosing, 
in the relevant period.  
6.2.3 
Early Terminations Assessments 
Early Termination (ET) from the study is defined as withdrawal during the Treatment Phase after 
a Donepezil TDS has been applied.  
ET assessments will be summarized alongside the Follow-Up assessments as the End of Study 
(EoS) visit. 
6.2.4 
Study Day  
Study day will be calculated as the number of days from first dose of study drug. 
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•
date of event – date of first dose of study drug + 1
6.2.5 
Conventions for Missing and Partial Dates 
It is not expected that there will be any missing dates, however in the rare case that an AE start 
date or time is missing and it is unclear whether the AE is treatment emergent or not then a 
conservative approach will be taken and it will be assumed that the AE occurred after first 
dosing.  
All dates presented in the individual subject listings will be as recorded on the eCRF. 
6.2.6 
Inexact Values 
In the case where a safety laboratory variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value 
of x will be taken for analysis purposes. 
6.2.7 
Unscheduled Visits 
Only scheduled post-baseline laboratory and vital signs values will be tabulated. Post-baseline 
repeat/unscheduled assessments will not be included in summary statistics.  However, these 
repeat/unscheduled post-baseline assessments will be included in the relevant listings. 
6.2.8 
TDS Adhesion Assessment Scale 
TDS adhesion will be assessed every 12 hours (h) after application throughout the wear period. 
Each time point will be assessed in person by a trained observer based on the percentage of total 
surface area of skin attachment. 
The time of full detachment of any TDS and its 0% adherence will be recorded, and the 0% 
adhesion will be assigned to all remaining adhesion time points of the current wear period. 
At each adhesion assessment time point, a photograph will be taken as evidence of the extent of 
TDS adhesion to the skin (as support of the visual observation of the adhesion percentage but not 
to be used for automated or photometric analysis). 
Following removal of each TDS, the presence or absence of remaining adhesive residue will be 
recorded. 
6.2.9 
Skin Irritation Assessment Scale 
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Skin irritation at the patch site will be assessed prior to each TDS application and following TDS 
removal at 0.5, 24, 48, and 72 h. If the score is greater than 1 at 72 h post-removal, assessments 
will continue until a score < 1 is reported.  
Application sites will be graded using the following two scales: 
•
an 8-point categorical Dermal Response Scale (see Table 6.2.9.1 below) 
Table 6.2.9.1 Dermal Response Scale 
Skin Appearance 
Numeric Score 
No evidence of irritation 
0 
Minimal erythema that is barely perceptible 
1 
Definite erythema that is readily visible and minimal edema 
or minimal popular response 
What was present: 
•
Definite Erythema
•
Minimal Edema
•
Minimal Papular Response
2 
Erythema and Papules 
What was present: 
•
Erythema
•
Papules
3 
Definite Edema 
4 
Erythema, edema, and papules 
What was present: 
•
Erythema
•
Edema
•
Papules
5 
Vesicular Eruption 
6 
Strong reaction spreading beyond the application site 
7 
•
a 6-point categorical Other Effects Scale (see Table 6.2.9.2 below). site will be assessed
for skin irritation
Table 6.2.9.2 Other Effects Scale
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Observation 
Score (Numeric Equivalent) 
No other effects observed 
None (0) 
Slightly glazed appearance 
A (0) 
Marked glazed appearance 
B (1) 
Glazing with peeling and cracking 
C (2) 
Glazing with fissures 
F (3) 
Film of dried serous exudate covering 
all or part of the TDS site 
G (3) 
Small petechial erosions and/or scabs 
What was present: 
• Small petechial erosions 
• Scabs 
H (3) 
 
Combined scores will be calculated as: 
𝐶𝑜𝑚𝑏𝑖𝑛𝑒𝑑 𝑆𝑘𝑖𝑛 𝐼𝑟𝑟𝑖𝑡𝑎𝑡𝑖𝑜𝑛 𝑆𝑐𝑜𝑟𝑒= (𝐷𝑒𝑟𝑚𝑎𝑙 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒 𝑆𝑐𝑜𝑟𝑒) + (𝑂𝑡ℎ𝑒𝑟 𝐸𝑓𝑓𝑒𝑐𝑡𝑠 𝑆𝑐𝑜𝑟𝑒) 
Only whole number scores will be used. 
6.2.10 
Columbia-Suicide Severity Rating Scale 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a brief questionnaire that provides for 
the identification, quantification, and standardized assessment of the occurrence and severity of 
suicidal ideation and behavior (see http://cssrs.columbia.edu) (Posner 2011).  The “Baseline” 
version of the C-SSRS will be assessed at Screening.  The C-SSRS “Since Last Visit” version 
will be assessed on all other study days [Day -1 and End of Treatment (EoT)/ET visit]. 
The following outcomes are C-SSRS categories and have binary responses (yes/no). The 
categories have been re-ordered from the actual scale to facilitate the definition of composite 
endpoints: 
Category 1  
Wish to be Dead 
Category 2  
Non-specific Active Suicidal Thoughts 
Category 3  
Active Suicidal Ideation with Any Methods (Not Plan) without 
Intent to Act 
Category 4 
Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan 
Category 5 
Active Suicidal Ideation with Specific Plan and Intent 
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Category 6 
Preparatory Acts or Behavior 
Category 7  
Aborted Attempt 
Category 8 
Interrupted Attempt 
Category 9 
Actual Attempt (non fatal) 
Category 10 
Completed Suicide 
 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome which also has a binary 
outcome (yes/no).  
Composite endpoints based on the above categories are defined below: 
• Suicidal Ideation since baseline – A “yes” answer at any time during treatment phase to 
any one of the 5 suicidal ideation questions (categories 1-5) on the C-SSRS. 
• Suicidal Behavior since baseline – A “yes” answer at any time during treatment phase to 
any one of the 5 suicidal behavior questions (categories 6-10) on the C-SSRS. 
There will be no imputation of missing data for C-SSRS. 
6.2.11 
PK Parameters 
6.2.11.1 Concentration-Time Data 
Blood samples will be collected for plasma donepezil and 6-O-desmethyl donepezil (active 
metabolite) concentration assessments at the following timepoints (please note, “Day” refers to 
the day relative to Week 1 dosing in each study period): 
Treatments A and B (patch applications): 
• Week 1 (Days 1 to 7): Pre-TDS #1 application (Day 1), and at 2, 6, 12, 24, 48, 72, 
96, 120, and 144 h after TDS #1 application. 
• Week 2 (Days 8 to 14): Pre-TDS #2 application (Day 8 at 168 h after TDS #1 
application, prior to removal), and at 24, 48, 72, 96, 120, and 144 h after TDS #2 
application. 
• Week 3 (Day 15 to 21): Pre-TDS #3 application (Day 15 at 168 h after TDS #2 
application, prior to removal). 
• Week 4 (Day 22 to 28): Pre-TDS #4 application (Day 22 at 168 h after TDS #3 
application, prior to removal). 
• Week 5 (Day 29 to 35): Pre-TDS #5 application (Day 29 at 168 h after TDS #4 
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application, prior to removal), and at 3, 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 
132, 144, and 156 h after TDS #5 application 
• Week 6 (Day 36): Pre-TDS #5 removal (Day 36 at 168 h after TDS #5 
application, prior to removal), and at 170, 174, 176, 178, and 180  h after TDS #5 
removal 
Treatment C (oral dosing): 
• Week 1, Day 1: Pre-Dose 
• Week 2: Day 8 Pre-Dose 
• Week 3: Day 15 Pre-Dose 
• Week 4: Day 22 Pre-Dose 
• Week 5: Day 29 Pre-Dose 
• Week 6: Day 35 Pre-Dose, and 1, 2, 3, 4, 6, 8, 12 and 24 h after oral 
administration (the 24-h sample will be collected on Day 36). 
Concentration-time data prior to Week 5 will be presented by week and nominal time relative to 
the time of TDS application for that particular week. 
For PK analysis and presentation of concentration-time data on Week 5, nominal and actual 
times will be expressed relative to the time of TDS # 5 application (beginning on Day 29): 0, 3, 
6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 (prior to patch removal), 170, 176, 
174, 178, and 180 h.  
Concentrations that are below the limit of quantification (BLQ) will be treated as zero in the data 
summarization and descriptive statistics. Individual plasma concentration-time data of donepezil 
and 6-O-desmethyl donepezil will be plotted on both linear concentration scales and on 
logarithmic (log10) concentration (semi-log) scales. Mean plasma concentration-time data will 
be presented by nominal times. For summarizing concentration and linear plots of individual 
time-concentration profiles, BLQ values will be set to 0. For semi-logarithmic plots of individual 
concentration-time profiles, BLQ values will be set to missing. Spaghetti plots (all subjects per 
treatment) and individual plots (comparing treatments for each subject) of the concentration-time 
data will be presented using actual times on both linear and semi-log scales.  
The following plots will be created for donepezil and metabolite 6-O-desmethyl donepezil: 
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1. Mean concentration-time profiles over the entire collection period (Days 1 through 35) 
for Treatments A, B, and C (nominal times relative to Day 1, Week 1 dosing) 
2. Mean concentration-time profiles for Treatments A, B, and C for Week 5 (Days 29 
through 36, predose to 180 h relative to TDS #5 application; Day 35, predose to 24 h for 
oral dosing) 
3. Mean trough concentration-time profiles for Treatments A, B, and C (predose on Days 1, 
8, 15, 22, 29, and 36). 
4. Spaghetti plots over the entire collection period (Days 1 through 35) for Treatments A, B, 
and C (actual times relative to Day 1, Week 1 dosing) 
5. Spaghetti concentration-time profiles for Treatments A, B, and C for Week 5 (Days 29 
through 35, predose to 180 h relative to TDS #5 application; Day 35, predose to 24 h for 
oral dosing) 
6. Spaghetti concentration-time profiles for Treatments A, B, and C for trough 
concentration-time data (predose on Days 1, 8, 15, 22, 29, and 36) 
7. Individual subject concentration-time profiles over the entire collection period (Days 1 
through 35) for Treatments A, B, and C (nominal times relative to Day 1, Week 1 dosing) 
8. Individual subject concentration-time profiles for Treatments A, B, and C for Week 5 
(Days 29 through 35, predose to 180 h relative to TDS #5 application; Day 35, predose to 
24 h for oral dosing) 
9. Individual subject concentration-time profiles for Treatments A, B, and C for trough 
concentration-time data (predose on Days 1, 8, 15, 22, 29, and 36) 
The PK population will be used to summarize concentration-time data (concentration-time 
summary tables, mean plots, and individual plots) and for creating concentration-time listings. 
6.2.11.2 PK Parameters and Methodology 
Concentration-time data for donepezil and active metabolite 6-O-desmethyl donepezil and will 
be analyzed using noncompartmental methods in Phoenix™ WinNonlin® (Version 8.1 or higher, 
Certara, L.P.) in conjunction with the internet-accessible implementation of Pharsight® 
Knowledgebase ServerTM (PKSO; Version 4.0.4, Certara, L.P.). PKSO provides protected and 
structured storage, audit trails, and version control for clinical study data, analyses, and related 
files, supporting Food and Drug Administration (FDA) 21 CFR Part 11 compliance. The PK 
population will be used to calculate PK parameters. 
In the PK analysis, BLQ concentrations will be treated as zero from time-zero up to the time at 
which the first quantifiable concentration is observed; embedded and/or terminal BLQ 
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concentrations will be treated as “missing”. Actual time relative to TDS #5 application (Days 29 
through 35) will be used in the PK analysis. If actual time is missing, nominal (scheduled) time 
will be used. Actual predose sample times will be set to zero prior to PK analysis. 
The following PK parameters will be calculated for Weeks 1 and 5 for donepezil and 6-O-
desmethyl donepezil for TDS: 
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Parameter 
Description 
Week 1 (Single Dose) 
AUC0-24 
The area under the plasma concentration versus time curve, from time 
zero to 24 h post TDS #1 application, calculated by the linear 
trapezoidal rule for 24 h intervals within Week 1 (i.e., there will be a 
total of 7 values for AUC0-24 for Day 1 to Day 7 in Week 1) 
These will be calculated using the partial area function in WinNonlin 
(ie, AUC0-24, AUC24-48, AUC48-72, AUC72-96, AUC96-120, AUC120-144, and 
AUC144-168) 
AUC0-168 
 
The area under the plasma concentration versus time curve during a 1 
week period (AUC during the wear period for Week 1), calculated by 
the linear trapezoidal rule. 
Cmax 
The maximum observed plasma concentration over a dosage interval 
following the first TDS application (Week 1)  
Tmax, 
Time to reach Cmax after first TDS application on Week 1. If the 
maximum value occurs at more than one time point, Tmax is defined as 
the first time point with this value. 
Tlag 
Lag time: time for the drug to appear in the systemic circulation after 
the first TDS application on Week 1  
Week 5 (Steady-State) 
AUC0-24 
The area under the plasma concentration versus time curve, from time 
zero to 24 h post TDS #5 application, calculated by the linear 
trapezoidal rule for 24 h intervals within Week 5 (i.e., there will be a 
total of 7 values for AUC0-24 for Day 1 to Day 7 in Week 5). 
These will be calculated using the partial area function in WinNonlin 
(ie, AUC0-24, AUC24-48, AUC48-72, AUC72-96, AUC96-120, AUC120-144, and 
AUC144-168) 
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AUC0-168,ss 
(AUCtau) 
The area under the plasma concentration versus time curve during a 1 
week period at steady-state (AUC during the wear period for Week 5), 
calculated by the linear trapezoidal rule. 
Cmax,ss 
The maximum observed plasma concentration over a dosage interval at 
steady-state (Week 5)  
Tmax,ss 
Time to reach Cmax,ss. If the maximum value occurs at more than one 
time point, Tmax,ss is defined as the first time point with this value. 
Cmin,ss 
Minimum observed non-zero plasma concentration over a dosage 
interval at steady state (Week 5) 
Tmin,ss 
The time to reach Cmin,ss at steady-state (Week 5) 
Cavg,ss 
The average plasma concentration over the dosing interval at steady-
state (Week 5), calculated as: Cavg,ss=AUCtau/tau, with 
AUCtau=AUC0-168,SS and tau = 168 h 
FLUCPss 
Percent peak-to-trough fluctuation within the 168 h wear period at 
steady-state on Week 5, calculated as: 
FLUCP=(Cmax,ss-Cmin,ss)/Cavg x 100, where Cmin,ss and Cmax,ss are 
obtained between 0 and tau (168 h) 
Ctrough,ss 
 
The plasma concentration at the end if the steady-state dosing interval 
(Day 35) 
Ctau 
The plasma concentration at the end of each dosing interval, taken on 
Days 8, 15, 22, 29, and 35 
 
 
 
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The following PK parameters will be calculated for Week 5 for donepezil and 6-O-desmethyl 
donepezil for orally-administered Aricept: 
Parameter 
Description 
AUC0-24,ss 
(AUCtau) 
The area under the plasma concentration versus time curve at steady-state, 
from time zero to 24 h after Day 35 administration, calculated by the linear 
trapezoidal rule. 
AUC0-168,ss 
 
The area under the plasma concentration versus time curve at steady-state; 
this will be estimated by multiplying AUC0-24,ss on Day 35 by 7. 
Cmax,ss 
The maximum observed plasma concentration at steady-state on Day 35 
Tmax,ss 
The time to reach Cmax,ss on Day 35 
Cmin,ss 
Minimum observed non-zero plasma concentration over a dosage interval at 
steady state (Day 35) 
Tmin,ss 
The to reach Cmin,ss at steady-state (Day 35) 
Cavg,ss 
The average plasma concentration at steady-state on Day 35, calculated as: 
Cavg,ss=AUCtau/tau, with tau = 24 h 
FLUCPss 
Percent peak-to-trough fluctuation on Day 35, calculated as: 
FLUCP=(Cmax,ss-Cmin,ss)/Cavg,ss x 100, where Cmin,ss and Cmax,ss are obtained 
between 0 and tau (24 h) 
Ctrough,ss 
 
The plasma concentration at the end if the steady-state dosing interval (Day 
36) 
Ctau 
The plasma concentration at the end of each dosing interval, taken on Days 
8, 15, 22, 29, and 36 
6.3 Conventions 
All safety and clinical data listings, summaries, figures and statistical analyses will be generated 
using SAS (Version 9.4 or higher)2. 
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Summaries of the clinical data will be presented by treatment/sequence and/or overall as 
depicted in the TFL shells.  
PK data listings, summaries, figures, and statistical analyses will be generated using Phoenix™ 
WinNonlin® (Version 8.1 or higher) or SAS (Version 9.4 or higher).  PK concentration data and 
PK parameter data will be summarized by analyte and treatment at each nominal sample time.  
Treatment labels will be displayed as follows:  
 
Treatment A 
 
 
Treatment B 
 
 
Treatment C 
 
A: 5 mg/day TDS applied weekly, 7-day wear 
B: 10 mg/day TDS applied weekly, 7-day wear 
C: 10 mg oral Aricept® tablets, QD for 35 days  
 
Treatment sequence labels will be displayed as follows:  
 
Sequence ABC 
 
Sequence ACB 
 
Listings will be sorted in the following order treatment sequence (ABC then ACB), subject, 
treatment, parameter (where applicable), and visit/timepoint (where applicable) unless otherwise 
stated.  
For safety and clinical data continuous variables will be summarized by the number of non-
missing observations, mean, median, standard deviation, and minimum and maximum. 
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented. 
PK data (concentration-time data and PK parameter data) will be summarized by the number of 
non-missing observations (n), arithmetic mean (mean), standard deviation (SD), median, 
minimum (min), maximum (max), and coefficient of variation (CV%), geometric mean, 
geometric CV%, Q1 (25th percentile), and Q3 (75th percentile). The geometric CV% will be 
calculated as 100*sqrt[exp(σ2)-1], where σ2 was the variance of the log-transformed data. 
Summaries for PK parameters Tlag and Tmax,ss will not include the geometric mean or geometric 
CV%.    
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6.3.1 
Decimal Places 
Non-PK Data 
Decimal places for derived data described in section 6.2 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated value is ≥ 100; 1 decimal place will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement.  
Derived data where it is known in advance the result will be an integer for example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal 
places.  
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the 
minimum and maximum will be displayed to the same number of decimal places as reported in 
the raw data. Percentages will be displayed with one decimal place.  
PK Data 
Individual donepezil and 6-O-desmethyl donepezil concentrations, PK parameters, and summary 
statistics will be presented to the precision described in the table below. Time will be presented 
to 2 decimal places in tables and listings. 
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Parameter 
Individual 
Values 
(Table/Listing) 
Arithmetic 
Mean, 
Geo Mean 
(Table) 
SD 
(Table) 
CV%, 
Geo 
CV% 
(Table) 
Median, 
Max, 
Min, 
Q1, Q3 
(Table) 
Donepezil or 6-O-desmethyl 
donepezil concentrations 
3 sf 
2 dp 
3 dp 
1 dp 
3 sf 
Time-based parameters (Tmax, Tlag, 
Tmax,ss, Tmin,ss)a 
2 dp 
3 dp 
4 dp 
1 dp 
2 dp 
Cmax, Cmax,ss, Cmin,ss,  Cavg,ss, Ctrough,ss, 
Ctau 
3 sf 
2 dp 
3 dp 
1 dp 
3 sf 
AUC parameters (AUC0-24, AUC0-168, 
AUC0-168,ss AUC0-24,ss) 
2 dp 
3 dp 
4 dp 
1 dp 
2 dp 
FLUCPss 
3 sf 
2 dp 
3 dp 
1 dp 
3 sf 
Note: sf=significant figure, dp=decimal place.  
aSummaries for PK parameters Tmax,ss and Tmin,ss will not include the geometric mean or 
geometric CV%.    
Number of subjects (n) will be reported as a whole number. Percent ratios of the geometric least 
squares means and associated 90% confidence intervals will be reported to 2 decimal places, p-
values will be reported to 4 decimal places.   
6.4 Subject Disposition 
Subject and patch disposition data will be summarized as follows:  
• Subject level summaries will include: 
o The number of subjects screened 
o The number of subjects who are in each analysis population will be summarized 
by treatment sequence and overall for the Randomized Population.  
o The number of subjects who completed the study by treatment sequence for the 
Randomized Population 
o The number of early terminations, the primary reason for termination will be 
tabulated by treatment (last treatment received prior to discontinuing from the 
study) and overall for the Randomized Population.  
• Patch level summaries will include: 
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o
The number of patches applied for each treatment
o
The number of patches in each population (i.e. Adhesion Population and Skin
Irritation Population) by treatment
o
The number of patches excluded and the reason for exclusion from each TDS-
based population
All subject and patch level disposition data will be listed separately. 
6.5 Protocol Deviations 
A summary (number, %) of all major and minor protocol deviations will be provided by category 
reported overall for all subjects.  Additionally, a listing of all protocol deviations will be 
provided within Appendix 16.2. 
6.6 Baseline Comparability 
Demographics and baseline characteristics will be assessed by treatment sequence and overall in 
a descriptive manner using the Safety and PK populations, but no formal statistical testing will 
be performed. 
Standard continuous (n, mean, median, SD, Q1 (25th percentile), Q3 (75th percentile) and 
minimum and maximum values) or categorical variable (number, %) summaries will be 
presented for the following: 
•
Demographic data
o
Age at informed consent (IC)
o
Sex – M/F
o
Race (White, Black or African American, Asian, American Indian or Alaska
Native, Native Hawaiian or Other Pacific Islander, Mixed Race)
o
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
•
Baseline characteristics
o
Height at Screening (cm)
o
Weight at Screening (kg)
o
Body Mass Index (BMI) at Screening (kg/m2)
o
Skin type
Individual subject listings of all demographic, medical history, COVID-19 data and baseline 
characteristics data will be provided. 
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6.7 Medical History 
A complete listing of subject medical history including previous/ongoing conditions and relevant 
surgical procedures will be presented for the Safety Population.  
Medical history data will be coded using the Medical Dictionary of Regulated Activities 
(MedDRA version 23.1) primary system organ class (SOC) and preferred term (PT). 
6.8 Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHODDE), version September 2020. Medications entered on the eCRF will be mapped to 
Anatomic Therapeutic Chemical (ATC) drug class (level 3) and drug name. If ATC drug class 
level 3 is not available, then ATC drug class level 2 will be utilized. If ATC drug class levels 3 
and 2 are not available, then ATC drug class level 1 will be utilized.  
The study phase during which each medication was received (e.g., prior, concomitant, or both) 
will be presented in a subject data listing. The study phase of each medication, determined 
programmatically based on medication start and end dates, will be presented in the listing. A 
prior medication is defined as any medication administered prior to the date of the first dose of 
study drug. A concomitant medication is defined as any medication administered on or after the 
date of the first dose of study drug. A medication may be defined as both prior and concomitant. 
If it cannot be determined whether a medication was received prior to the start of study drug 
dosing due to partial or missing medication start and/or end dates, it will be considered a prior 
medication. Likewise, if it cannot be determined whether a medication was received after the 
start of study drug dosing, it will be considered concomitant.  
For concomitant medications, the number and percentage of subjects receiving any medication 
will be summarized as will the number and percentage receiving any medication by ATC drug 
class and generic drug name. Subjects reporting use of more than one medication at each level of 
summarization (any medication received, ATC class, and generic drug name) will be counted 
only once. ATC class terms will be displayed by descending order of incidence, as will generic 
drug names within each ATC class. 
6.9 TDS Application Data 
All TDS application and removal data will be listed. 
6.10 Statistical Analysis of PK Data 
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The Relative Bioavailability population will be used in the statistical analyses. 
6.10.1 
Statistical PK Comparison between Treatments 
Statistical comparison of the PK parameters of donepezil and 6-O-desmethyl donepezil exposure 
(AUC0 24,ss, AUC0-168,ss, Cmax,ss, Cmin,ss, Ctau,ss, Cavg,ss, and FLUCP,ss) at steady-state will be 
performed using an Analysis of Variance (ANOVA) model for a 2-way crossover design for the 
comparison of 10 mg TDS vs. Aricept (Treatment B vs. Treatment C) on the ln-transformed data 
with sequence, period and treatment as the fixed effects and subject within sequence as a random 
effect. For comparison of 5 mg/day TDS vs. Aricept (Treatment A vs. Treatment C) the analysis 
will be performed using a ANOVA model with treatment as fixed effect and subject as random 
effect with Treatment A being dose normalized (PK parameter values multiplied by 2) before the 
analysis.  A statistically significant difference is defined as p <0.05.  
Geometric means. inter-subject and intra-subject variability (coefficient of variation in percent, 
CVintra% and CVinter%, respectively), and intraclass correlation (Chow and Liu, 2009)4 of the PK 
parameters will be calculated based on the mixed model results (Proc Mixed of SAS) as indicated 
below: 
  
 
 
 
Where  
 
 
 
 
  
 
 
 
 
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run; 
 
Where  
 
 
 
 
 
 
 
 
 
 
6.10.2 
Assessment of Steady-State Achievement 
Assessment of time to achieve steady-state for the 3 treatments will be performed by a review of 
weekly donepezil trough levels (Ctau).  
In the current study, TDS Ctau levels of interest are the plasma concentrations measured 
immediately prior to TDS removal on Days 8, 15, 22, 29, and 36 . For Aricept, Ctau levels of 
interest are the plasma concentrations measured immediately prior to dosing on Days 8, 15, 22, 
29, and 36 following dosing in each period (i.e., Study Days 8, 15, 22, 29, and 36 in Period 1, 
Study Days 44, 51, 58, 65, 72 in Period 2, and Study Days 80, 87, 94, 101, and 108 in Period 3). 
 
Separate mixed effect models will be used to assess the steady-state of each treatment with 
consideration of potentially significant sequence effect on Treatments B and C due to lack of 
washout between periods.  For Treatment A the mixed effect model will include Day (Days 8, 
15, 22, 29, and 36) as the fixed effect and subject as the random effect.  For Treatments B and C 
two mixed effect models will be used to assess the steady-state: 
1. Assess the steady-state of each treatment by period (i.e. Treatment B in Period 2, 
Treatment B in Period 3, Treatment C in Period 2, and Treatment C in Period 3 using a 
mixed effect model with Day (Days 8, 15, 22, 29, and 36 in periods 2 or 3) as the fixed 
effect and subject as the random effect. 
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2.  Assess the steady-state of each treatment combining both periods using a mixed effect 
model with Day (Days 8, 15, 22, 29, and 36) and sequence as the fixed effects and 
subject as the random effect. 
The least squares means (LSMs) of the log-transformed Ctau (pre-dose concentrations) for 
Treatments A through C will be estimated from the mixed-effect models with Day being treated 
as a repeated measure within a subject. An unstructured covariance structure will initially be 
used. If problems with convergence arise, an AR(1) covariance structure will be used. 
The Ctau concentrations observed on Day 15 through Day 36 will be compared with the average 
Ctau levels for the rest of the period to determine the time at which steady state was achieved. The 
following orthogonal Helmert transformation contrasts that compare each day (8, 15, 22, 29 and 
36) to the mean Ctau concentrations over all subsequent time points will be tested for each 
treatment group: 
• Day 8 Ctau value vs. the average of Day 15 through Day 36: C′1 = (1, -1/4, -1/4, -1/4, -1/4) 
• Day 15 Ctau value vs. the average of Day 22 through Day 36: C′2 = (0, 1, -1/3, -1/3, -1/3) 
• Day 22 Ctau value vs. the average of Day 29 through 36: C′3 = (0, 0, 1, -1/2, -1/2) 
• Day 29 Ctau value vs. Day 36: C′4 = (0, 0, 0, 1, -1) 
Testing of the contrasts will proceed in the order shown. The first non-significant comparison (p 
>0.05) will be interpreted as the day (8, 15, 22, or 29) at which steady-state concentrations were 
attained. 
The LS mean estimate associated with the contrasts and their corresponding 90% confidence 
intervals, the p-value for the difference of the least squares means (LSMs) (ln transformed scale), 
and the geometric mean ratios and their 90% confidence intervals will be provided for each 
treatment group. The LSM estimates and CI limits for the natural log values will be 
exponentiated. For the geometric mean ratio and its CI limits, the natural log values will be 
exponentiated and multiplied by 100. 
 
Example SAS code for the steady-state assessment of Treatment A in Period 1 or Treatments B 
or C in a specific period: 
 
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Where  
 
 
 
 
 
 
 
Example SAS code for the steady-state assessment of Treatments B or C with data from both 
Period 2 and Period 3: 
 
Where  
 
 
 
 
 
 
 
 
 
6.10.3 
Statistical Assessment of Bioequivalence at Steady-State 
To examine the relative bioavailability at steady state of the  5  and 10 mg/day TDS (Tests) 
relative to Aricept (Reference), plasma donepezil exposure as characterized by AUC0-168,ss and 
Cmax,ss will be assessed and compared utilizing bioequivalence criteria. The least squares 
geometric means (LSGM) of the PK parameters for each treatment will be reported. Point 
estimates and 90% Confidence Intervals (CI) for the Test to Reference ratios of geometric means 
will be provided. Similar bioavailability for donepezil will be concluded if the 90% CIs of the 
LSGMs lie within the acceptable range of 0.80 to 1.25 for AUC0-168,SS and Cmax,ss (Cmax,ss for 
informational purposes). Forest plots presenting the point estimate and 90% confidence intervals 
for AUC0-168,ss and Cmax,ss will be constructed for the comparisons between the 5 mg/day and 10 
mg/day donepezil TDS applications (Tests) and oral Aricept® (Reference). 
6.10.4 
Subgroup Analyses 
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Assessment of exposure across gender, ethnicity and age will be explored using the steady state 
PK parameters AUC0-168,ss and Cmax,ss. Subset analyses will include treatments B and C only. 
 
Gender Analysis 
To assess exposure across gender, adding gender and gender by treatment interaction to the 
bioequivalence models allows for testing gender effects across and within the study treatment. In 
the model, gender and gender by treatment interaction effects will be estimated using least 
squares means and tested using a significant level of alpha = 0.05. The following SAS code 
details the testing approach within the standard BE models: 
 
Where  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In addition, box-plots of the parameters will be generated for each treatment by gender. 
 
Ethnicity Analysis 
Similar to gender above, effects of ethnicity (Hispanic or Latino vs. Not-Hispanic or Latino) will 
be explored. 
 
Age Analysis 
To examine the potential effect of age on donepezil steady-state PK for the B and C treatments, a 
three-step assessment procedure will be undertaken: 
 
1. Test slopes-equal-to-zero hypothesis for each treatment: This is designed to determine if 
a model without the covariate of age can be used to adequately describe the PK 
parameters (i.e. test the slopes-equal-to-zero hypothesis for each treatment).  To achieve 
this objective an additional fixed effect (age*treatment) will be added to the Treatment B 
vs. Treatment C ANOVA model described in Section 6.10.1.  If the hypothesis that all 
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slopes are zero is accepted, a common slope model will be fit to the data and the slope-
equal-to-zero hypothesis will be tested (Step 3 below).  
2.  If the hypothesis that all slopes are equal to zero was rejected in Step 1 (i.e. 1 or more of 
the slopes were not 0), the hypothesis that the slopes are equal will be tested. An 
ANCOVA will be performed on the natural logarithms of the PK parameters with age 
being added to the model used in Step 1.  If the slopes are determined to be unequal, the 
treatment-specific slopes and intercepts from the unequal slopes model (Step 1) will be 
used to describe the relationship between age and the natural log transformed PK 
parameter for each treatment. 
3.  If the null hypothesis of slopes equal to zero is not rejected (Step 1) or if the test of the 
equal slopes hypothesis indicates insufficient evidence to reject the assumption of equal 
slopes (Step 2), then a common slope model will be fit to the data and the hypothesis that 
the common slope is 0 will be tested. ANCOVA will be performed on the natural 
logarithms of the PK parameters with age being added as a covariate to the Treatment B 
vs. Treatment ANOVA model described in Section 6.10.1. If the common slope is 
determined to not be 0, the intercept for each treatment and the common slope will bebe 
reported. If the treatment-by-age effect in Step 2 shows the slopes can be assumed to be 
equal (i.e., non-significant treatment-by-age interaction), then a simplified common slope 
model will be fitted where the age contribution can be assessed (testing the hypothesis 
that the age coefficient, common slope, is zero).  
 
The following outlines the testing process.  
 
For Step 1, the following SAS code is provided to clarify the approach for determining if any of 
the treatment specific slopes are not equal to zero:  
 
Where  
 
 
 
 
 
 
 
 
 
 
 
 
 
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For a given natural log transformed PK endpoint, if the age*trt effect is significant then it can be 
concluded that at least one treatment specific slope is not equal to zero and Step 2 of the process 
is implemented. If the test is not significant then all slopes can be assumed as zero, a common 
slope model will be fit to the data (Step 3), and the hypothesis that the common slope is zero will 
be tested.   
 
For Step 2, if the one or more of the slopes are non-zero in Step 1, the following code sets up the 
test to determine whether the slopes are equal: 
 
 
Where  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If the age*trt effect is significant, then it will be concluded that the relative effect of age on the 
natural log transformed PK endpoint differs by treatment (i.e., the slopes are not equal); in this 
case the treatment-specific slopes and intercepts from the unequal slopes model (Step 1) will be 
used to describe the relationship between age and the natural log transformed PK parameter for 
each treatment.  
 
For Step 3, if the slopes equal to zero is not rejected (Step 1) or if the age contributions across 
treatments, slopes, are concluded to be equal (Step 2), then the following code fits the common 
slope model: 
 
For the ANOVA (Treatment B vs  Treatment C): 
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Where  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scatter plots of the PK results by treatment and age, with regression lines displayed, will be 
provided. 
For effects of gender or ethnicity on exposure the least squares geometric means (LSGM) of the 
PK parameters for each gender or each ethnicity group will be reported. Point estimates and 90% 
Confidence Intervals (CI) for the ratios of geometric means (Female vs. Male or Hispanic or 
Latino vs. Not-Hispanic or Latino) will be provided.  The results from Type 3 Tests of Fixed 
Effects will also be reported with p-values to indicate if significant effects from gender, 
ethnicity, or age for each treatment exist. 
 
6.11 Safety Analyses 
The safety analyses will be presented by the treatment received for the Safety Population. 
6.11.1 
Adverse Events 
A treatment emergent adverse event (TEAE) is defined as: 
• Any AE that has a new onset during the study between the initiation of study drug and 
the follow-up visit.  
• Any pre-existing AE that has worsened in severity on or after the initiation of study drug 
till the follow-up visit.  
The following rules will be used to assign a TEAE to a treatment: 
• A TEAE will be assigned to the treatment received immediately before onset. 
• Any TEAE reported within Period 1, Day 36, when no treatment is administered, will be 
attributed to the last treatment received before Day 36 began.  
• If the severity of a TEAE increases in a later period the TEAE at the increased severity 
also will be assigned to the treatment received immediately before the increase in 
severity. 
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All TEAEs are defined as being definitely, probably, possibly related or unrelated to the study 
drug. If an AE has missing relationship it is assumed to be definitely related to the study drug for 
analysis purposes. Additionally, any SAE considered definitely, probably, or possibly related to 
the study drug will also be classified by the Sponsor as either “expected” or “unexpected” upon 
review by the medical monitor. 
Adverse event severity will be graded as Grade 1: Mild, Grade 2: Moderate, or Grade 3: Severe 
or Medically Significant but not immediately life-threatening. Maximum severity will be 
assumed for an AE with missing severity.  
All AEs will be coded using the most current version of the Medical Dictionary for Regulatory 
Activities (MedDRA version 23.1, updated to include activities related to COVID-19) by SOC and 
PT. 
The following tables will be presented for AEs by treatment and overall using the Safety 
Population: 
• Overall incidence and the number of AEs, SAEs, TEAEs leading to withdrawal. 
• TEAE by system organ class and preferred term, incidence and number of events 
• Treatment related TEAE by system organ class and preferred term, incidence and number 
of events 
• Serious TEAE by system organ class and preferred term, incidence and number of events 
and “expected or unexpected” classification 
• TEAE by system organ class and preferred term by nearest relationship to study drug, 
incidence and number of events 
• TEAE by system organ class, preferred term and maximum severity, incidence 
• TEAEs leading to early withdrawal by system organ class and preferred term, incidence 
• Listing of Serious TEAEs (presented in the Table section of the appendices) 
• Listing of Deaths (produced only if necessary and presented in the Table section of the 
appendices) 
• Listing of TEAEs leading to early termination by system organ class and preferred term, 
incidence  
In counting the number of AEs reported, a continuous event (i.e. reported more than once and 
which did not cease), will be counted only once; non-continuous AE reported several times by 
the same subject will be counted as multiple events.  
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If more than one AE is coded to the same preferred term for the same subject, the subject will be 
counted only once for that preferred term using the most severe and most related occurrence for 
the summarization by severity and by relationship to the study drug. 
All AEs will be listed. 
6.11.2 
Laboratory Data 
Samples for clinical laboratory tests will be collected at screening, prior to start of Period 1 
treatment (Treatment A), at the end of treatment within each study period, and in the event of 
premature study termination. Descriptive statistics for the the observed values and change from 
baseline (continuous data) will be presented by treatment for hematology, serum chemistry, 
coagulation, and urinalysis parameters at the following time points: 
• Screening,  
• Baseline (last available measurement prior to start of Period 1 treatment),  
• End of treatment (Day 36 after TDS application/first dose within study period),  
• Early termination (last available sample collected for subjects who prematurely 
terminated from the study).  
Each measurement (continuous data) will be classed as below (low), within (normal), or above 
(high) normal range, based on ranges supplied by the laboratory used. Shift tables in relation to 
the normal range from Screening visit to the End of Treatment (EoT) or ET visit will be 
presented. 
A listing of any abnormal laboratory measurements recorded throughout the study will be 
presented. 
All laboratory data, including serology, urine drug screening tests, COVID-19 testing data and 
pregnancy test data will be listed. 
6.11.3 
Vital Signs 
Vital signs will be collected at screening, prior to start of Period 1 treatment (Treatment A), on 
the day of first TDS application/first dose within study period, and weekly thereafter (i.e., on 
Days 1, 8, 15, 29, and 36 within study period).  Additionally, vital signs will be collected in the 
event of premature study termination.  Vital signs include the following endpoints: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
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• Pulse rate (bpm)  
• Respiration rate (breath/min) 
• Oral temperature (C) 
Descriptive statistics will be presented for observed values and changes from baseline by 
treatment at the following time points for subjects in the Safety Analysis Population: 
• Screening,  
• Baseline (last available measurement prior to start of Period 1 treatment),  
• Day of first TDS application (Treatments A and B)/first dose (Treatment C) within study 
period) 
• Days 1, 8, 15, 22, 29, and 36 within study period 
• Early Termination (last available on-treatment vital signs collected for subjects who 
prematurely terminate from the study) 
All vital signs data will be listed. 
6.11.4 
Electrocardiogram Data 
Twelve-lead electrocardiograms (ECGs) will be obtained at screening, prior to start of Period 1 
treatment (Treatment A), and at the end of treatment (Day 109).  Additionally, ECGs will be 
obtained in the event of premature study termination.   Descriptive statistics for observed values 
and changes from baseline in the following ECG variables will be tabulated overall at the end of 
treatment (Study Day 109):  
• Heart rate (bpm) 
• PR interval (ms) 
• RR interval (ms)  
• QRS duration (ms)   
• QT interval (ms)  
• QTcB interval (ms) [Bazett’s formula]  
• QTcF interval (ms) [Fridericia’s formula]  
If an ECG measurement was repeated, only the repeated measurement was recorded. 
Shift tables in relation to the overall interpretation (Normal, Abnormal NCS, and Abnormal CS) 
from baseline to end of treatment (Study Day 109) will be presented. 
All ECG data, including details of any abnormalities, will be listed. 
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6.11.5 
Physical Examination 
All physical examination data will be listed, including any clinically significant findings. 
6.11.6 
C-SSRS 
All C-SSRS data will be listed. 
6.11.7 
Skin Tolerability Assessments 
Skin tolerability assessments will be summarized descriptively by treatment using the Skin 
Irritation Population for each post removal assessment time point as follows: 
• The frequency distribution of Dermal Response and Other Effects scores (number, % by 
category) will be summarized by post removal time point (0.5, 24, 48, and 72 hours post 
removal)   
• The frequency distribution (number, % by score category) of the combined skin irritation 
score will be summarized by post removal time point (0.5, 24, 48, and 72 hours post 
removal). The combined skin irritation score at a given time point can range from 0 to 10 
and is calculated as the sum of: 
o Dermal Response score which ranges from 0 (none or no evidence of irritation) to 
7 (strong reaction spreading beyond the application site 
o Other Effects scores which ranges from 0 (slightly glazed appearance) to 3 
(glazing with fissures, film of dried serous exudate covering all or part of the TDS 
site, or small petechial erosions and/or scabs) 
• Number (%) of subjects with a combined irritation score of ≥3 at 30 minutes after TDS 
removal 
• Number (%) of subjects with one or more combined skin irritations scores of ≥3 at any 
time point between 30 minutes and 72 hours after TDS removal) 
• Number (%) of TDS that were removed due to an unacceptable degree of skin irritation 
All skin tolerability assessment data will be listed. 
6.11.8 
Skin Photography 
All skin photography data collected in the CRF will be listed, including the assessment date/time 
and any recorded comments. 
6.12 Adhesion Assessments 
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TDS observed adhesion score results (i.e., observed percent adhesion with 0% adhesion assigned 
to all remaining time points during the wear period in the event of complete detachment) for each 
TDS will be summarized by treatment as follows using the Adhesion Population: 
• Summary statistics (mean, SD, minimum, Q1, median, Q3, maximum) for the mean 
adhesion score, where the mean adhesion score for each patch is the average of the patch 
adhesion scores across the entire wear period. 
• Adhesion score distribution at each adhesion measurement time point post patch 
application (i.e., 12, 24, …, and 168 hours). 
• Average adhesion score at each adhesion measurement time point post patch application. 
• Number (%) of patches that are completely detached during the 7-day wear period. 
• Number (%) of patches with adhesion <50% at any adhesion measurement time point 
during the 7-day wear period. 
• Summary of time a patch was first observed with adhesion <50% during the 7-day wear 
period. 
• Number (%) of patches with adhesion ≥75% at all adhesion assessment time points 
during the 7-day wear period 
In addition to the observed adhesion score, a modified adhesion score will be calculated as 
follows: the lowest observed adhesion score at each time point after the baseline time point (t0) 
will be carried forward to subsequent time points until a lower score is observed.  The modified 
adhesion score results for each TDS will be summarized as follows for the Adhesion Population: 
• Summary statistics (mean, SD, minimum, Q1, median, Q3, maximum) for the mean 
adhesion score computed based on the modified adhesion scores. 
• Adhesion score distribution at each adhesion measurement time point post patch 
application. 
• Average modified adhesion score at each adhesion measurement time point post patch 
application. 
All adhesion assessment data (observed adhesion scores as well as the modified adhesion scores 
as described previously) will be listed. 
Within each treatment, to assess whether at least 80% of the TDS applied are at least 75% 
adhered throughout the 7-day wear period,  a one-sided 95% confidence interval (CI) will be 
determined for the probability (p) that a randomly selected TDS maintains at least 75% adhesion 
throughout the entire wear period.   If the 95% lower confidence limit exceeds 80%,  then it will 
be concluded that at least 80% of patches are at least 75% adhered throughout the wear period.   
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The 95% lower confidence limit will be determined using the Jeffreys prior method.  The 
Jeffreys interval has a Bayesian derivation, and has good frequentist properties (Brown, Cai, 
Dasgupta 2001; Cai 2005).  It is obtained using the non-informative Jeffreys prior for the 
binomial proportion p, namely a Beta distribution with parameters (½, ½). It is a conjugate prior 
with a posterior distribution for p that is Beta (X+½, n-X+½), where n is the number of TDS in 
the Adhesion Population for the treatment and X is the number of TDS with at least 75% 
adhesion throughout the wear period. The 95% lower confidence limit (CL) will be formed as 
follows: 
CL = Beta(0.05; X + ½, n – X + ½) 
where in the event that x=0, the lower limit is defined to be 0. 
The Jeffreys one-sided CI has been recommended by Cai (2005).  It is one of the few CI methods 
with the advantage of being equal-tailed (i.e., the probabilities of the interval lying above or 
below the true value are equal). The Wilson score interval, for example, has good coverage 
probabilities as a method for constructing two-sided confidence intervals for p, but has a 
systematic bias in that it is centered too close to p=0.5 making it unsuitable for construction of a 
one-sided interval.  Similarly, the one-sided Wald interval and the likelihood ratio interval 
(formed by inversion of the likelihood ratio test) also have pronounced systematic bias (Cai 
2005; Newcombe 1998).   
Adhesion results from 3 previous studies are available (Table 1).  In Study P-15086 (Periods 2 
and 3 where the incidence of patch taping and smoothing was extremely low), point estimates of 
the probability that a randomly selected TDS remains at least 75% adhered during the 7-day 
wear period were 0.94 (32/34) for the 5 mg/day TDS and .96 (126/135) for the 10 mg/day TDS.  
In study P-16010, estimates that patches were at least 80% adhered throughout the 7-day wear 
period were 0.94 (80/85) and 0.91 (307/338) for the 5 mg/day and 10 mg/day TDS, respectively.  
The estimate (at least 80% adhered throughout the wear period) for the 10 mg/day TDS applied 
to the back in Study P=15086 was 0.85 (51/60).  
Subjects received 5 mg/day TDS during Week 1 and a 10 mg/day TDS weekly during Weeks 2-5 
in studies P-15086 and P-16010. Adhesion results show some indication of clustering within 
subject in Study P-16010 but not in Study P-15086.  Individual subjects that had adhesion <75% 
(<80% in Study P-16010) during the TDS wear period are listed by week in Table 2.   In Study 
P-15086, 5 TDS (10 mg/day) from 5 different subjects had 10 mg/day patches that were <75% 
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adhered at some point during the wear period. In contrast, there were 31 TDS (10 mg/day) from 
19 subjects that were <80% adhered during the wear period in Study P-16010.  
Table 1. Adhesion Results from Studies P-15086, P-16010, and P-16012 
TDS 
Application 
Week 
P-15086 (Periods 2 and 3) 
[1] 
Study P-16010 [2] 
Study P-16012 [2] 
Adhered 
>75% 
𝑝̂0.75 
Adhered 
>80% 
𝑝̂0.80 
Adhered 
>80% 
𝑝̂0.80 
Week 1 
32/34 
0.94 
80/85 
0.94 
51/60 
0.85 
Week 2 
33/34 
0.97 
76/85 
0.89 
 
 
Week 3 
31/33 
0.94 
75/85 
0.88 
 
 
Week 4 
31/32 
0.97 
78/85 
0.92 
 
 
Week 5 
31/32 
0.97 
78/83 
0.94 
 
 
Weeks 2-5 
126/131 
0.96 
307/338 
0.91 
 
 
[1] In Study P-15086, whole-patch adhesion was measured every 12 hours on a 5-point scale (0=100% adhered; 5=0% adhered). 
A score <2 at all assessment time points indicated that a patch was >75% adhered throughout the wear period.  Subjects had  5 
mg/day patches (50 cm2 active drug area) applied during Week 1 and 10 mg/day patches (105 cm2active drug area) applied 
weekly during Weeks 2-5. 
[2] In Studies P-16010 and P-16012, whole-patch adhesion was measured every 12 hours on an 11-point scale (0=100% adhered; 
11=0% adhered). A score <3 at all assessment time points indicated that a patch was >80% adhered throughout the wear period.  
In study P-16010, subjects had  5 mg/day patches (53.5 cm2 active drug area) applied during Week 1 and 10 mg/day patches (107 
cm2active drug area) applied weekly during Weeks 2-5.  In Study P-16012, patches applied to the back (10 mg/day patches; 107 
cm2 active drug area) during a one-week treatment period are included. 
Source: Table 14.3.9.3.1 (Study P-15086); Table 14.3.9.1.1 (Study P-16010); Table 14.3.9.1.1 (Study P-16012)  
 
Study CL-P-20004 will enroll approximately 60 subjects, with around 48 subjects expected to 
complete the 109-day in-clinic study.  Prior single-dose crossover studies conducted by the 
Sponsor indicate that most dropouts occur during the first one to two treatment periods.  As a 
result, approximately 55 subjects are expected to have TDS included in the Adhesion Population 
for TDS A (5 mg/day TDS), and approximately 50 subjects are expected to have TDS included 
in the Adhesion Population for TDS B (10 mg/day TDS).  The number of 5 mg/day TDS (TDS 
A) in the Adhesion Population will be approximately 270, and the number of 10 mg/day TDS 
(TDS B) in the Adhesion Population will be approximately 245. 
Based on the three previous studies (Table 1), the point estimate for p is expected to be 0.90 – 
0.95 (i.e., fewer than 13 and 11 TDS are expected to have < 75% adherence at one or more 
adhesion assessment time points during the wear period for TDS A and TDS B, respectively).   
In the range for p that is expected in the current study, the Jeffreys lower confidence limit should 
provide good coverage probability (Cai 2005; Newcombe 2011).   
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As a sensitivity analysis, the Clopper Pearson method of constructing the 95% lower confidence 
limit also will be implemented for each treatment.  The Jeffreys prior confidence interval can be 
regarded as a continuity-corrected version of the Clopper–Pearson confidence interval and is 
always contained within the Clopper-Pearson confidence interval (Brown et al. 2001).  This one-
sided 95% Clopper-Pearson CI method is very conservative and has coverage probability ≥95% 
for all p between 0.0 and 1.0. 
As a second sensitivity analysis, a one-sided 95% confidence interval that takes into account 
clustering of adhesion failures (i.e., TDS with <75% adhered during the wear period) within 
subject will be presented.   
A generalized linear mixed model (GLMM) analysis of the probability that a patch is at least 
75% adhered during the entire wear period will be used.  The GLMM will model variation at 
both the individual and patch level.  The GLMM will assume that each subject has an 
underlying, unobservable probability that governs the tendency for a patch to remain at least 
75% adhered during the wear period. This probability is assumed to vary from subject to subject. 
Let 𝜋𝑖 denote the probability that a patch applied to the ith subject will remain at least 75% 
adhered during the wear period.  Let yij be the response variable for the jth patch applied to the ith 
subject: 
yij = {1 if the TDS is at least 75% adhered throughout the wear period    
0 if the TDS is less than 75% at some point during the wear period 
The number of patches applied to the ith subject with “favorable” adhesion (i.e., yij = 1), has a 
binomial distribution conditional on the random effect of subject: 
yi | si  ~ Binomial(ni, πi) 
where ni is the number of patches applied to the ith subject. In the current study, ni is usually 5 
but can range from 1 to 5).  
Since the log likelihood function of a binomial random variable with n Bernoulli trials and 
favorable outcome probability π is linear in the logit, log(𝜋(1 −𝜋)
⁄
), a linear model will be fit to 
the logit. 
Using the logit link function, a conditional GLMM for the adhesion analysis is as follows: 
ηi = log[
𝜋𝑖
(1−𝜋𝑖)] = η + si 
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where η is the intercept and si is the effect of the ith subject assumed to be independent, 
identically distributed N(0,𝜎𝑠
2). 
Here si is a latent variable centered at 0 that quantifies an individual subject’s tendency (i.e., 
probability) for having an applied TDS remain at least 75% adhered during the 7-day wear 
period in relationship to other subjects.  Variation in si,  𝜎𝑠
2, represents variation in this 
propensity among subjects.  
The inverse link function for this logistic model will be used to estimate π (Stroup et al 2018). 
From the link function, we have: 
𝜋̂ = 1
(1 + 𝑒−𝜂̂)
⁄
 
with standard error estimate 
SE[𝜋̂] = [𝜋̂(1 − 𝜋̂) ∗ 𝑆𝐸(𝜂̂) 
and a 90% two-sided confidence interval obtained by applying the inverse of the link function to 
the upper and lower confidence bounds of the logistic-scale 90% two-sided confidence interval. 
 
 
  
  
  
 
 
  
 
 
 
 
 
 
 
 
 
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6.13 
Duration of Patch Wear and Patch Detachment     
Duration of patch wear will be summarized by treatment for the Adhesion Population. Total 
duration will be calculated as follows: 
𝑇𝑜𝑡𝑎𝑙 𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 = (𝑟𝑒𝑚𝑜𝑣𝑎𝑙 𝑑𝑎𝑡𝑒/𝑡𝑖𝑚𝑒) −(𝑎𝑝𝑝𝑙𝑖𝑐𝑎𝑡𝑖𝑜𝑛 𝑑𝑎𝑡𝑒/𝑡𝑖𝑚𝑒)  
Total duration will be reported in days to two decimal places.  
All TDS detachment data will be listed including: 
• Descriptions of circumstances related to detachment, including full detachment 
• Date and time of application 
• Date and time of removal/full detachment 
7 CHANGES TO PLANNED PROTOCOL ANALYSIS 
No changes to the planned protocol analysis have been identified.  
 
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8 REFERENCES 
1. Phoenix™ WinNonlin® (Version 8.1 or higher, Certara L.P.) 
2. SAS Institute Inc. (Version 9.4 or higher), Cary, NC, 27513, USA 
3. Brown LD, Cai TT, DasGupta A. Interval estimation for a binomial proportion. Stat 
Science. 2001; 16(2):101-133. 
4. Cai T.T., 2005. One-sided confidence intervals in discrete distributions. Journal of 
Statistical Planning and Inference 131 (2005) 63 – 88 
5. Chow S-C, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. 
3rd ed. Boca Raton: CRC Press; 2009, pp 55 – 57 
6. Newcombe RG Measures of location for confidence intervals for proportion. 
Communications in Stat – Theory and Methods. 2011;40:1743-1767.   
7. Stroup WW, Milliken GA, Classen EA, Wolfinger RD. SAS for Mixed Models: 
Introduction and Basic Applications. Cary, NC: SAS Institute Inc. 2018. 
 
 
 
 
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9 LIST OF TABLES, FIGURES AND LISTINGS 
The following table includes details of the tables, figures and listings to be included within each 
section of the eCTD. The eCTD section is shown in bold. The following validation methods 
maybe used  
• Independent programming of numbers and manual review of format (IP) 
• Independent programming by statistician of numbers and manual review of format (Stat 
IP) 
• Manual review (MR) 
• Code review (CR) 
Table Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
Items in bold are not table titles but references to the section headings within 
eCTD. 
 
14.1  
Demographics Data 
 
 
14.1.1  
Disposition 
 
 
14.1.1.1 
Subject Level Disposition, Analysis Populations 
– Randomized Population 
IP 
 
14.1.1.2 
Patch Level Disposition and Analysis 
Populations – Randomized Population   
IP 
 
14.1.2  
Demographics 
 
 
14.1.2.1 
Demographics by Treatment – Safety Analysis 
Population 
IP 
 
14.1.2.2 
Demographics by Treatment Sequence – 
Randomized Population 
IP 
 
14.1.3 
Baseline Characteristics 
 
 
14.1.3.1 
Baseline Characteristics at Screening – Safety 
Analysis Population  
IP 
 
14.1.3.2 
Baseline Characteristics at Screening – PK 
Population 
IP 
14.1.3.1 
14.2  
Efficacy Data 
 
 
 
Not Applicable 
 
 
14.3  
Safety Data 
 
 
14.3.1  
Displays Of Adverse Events 
 
 
14.3.1.1 
Overall Summary of Treatment-Emergent 
Adverse Events (TEAEs) – Safety Analysis 
Population 
IP 
 
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Table Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
14.3.1.2 
Number (%) of Subjects with TEAEs by System 
Organ Class and Preferred Term – Safety 
Analysis Population 
IP 
 
14.3.1.3 
Number (%) of Subjects with Serious TEAEs by 
System Organ Class and Preferred Term – 
Safety Analysis Population 
IP 
14.3.1.2 
14.3.1.4 
Number (%) of Subjects with Treatment Related 
TEAEs by System Organ Class and Preferred 
Term – Safety Analysis Population 
IP 
14.3.1.2 
14.3.1.5 
Number (%) of Subjects with TEAEs by System 
Organ Class, Preferred Term and Maximum 
Severity – Safety Analysis Population 
IP 
 
14.3.1.6 
Number (%) of Subjects with TEAEs by System 
Organ Class, Preferred Term, and Relationship 
to Study Treatment – Safety Analysis Population 
IP 
 
14.3.1.7 
Number (%) of Subjects with TEAEs Leading to 
Early Termination by System Organ Class and 
Preferred Term – Safety Analysis Population 
IP 
14.3.1.2 
14.3.1.8 
Number (%) of Subjects with TEAEs associated 
with the TDS Application Sites Within the 
General Disorders and Administration Site 
Conditions by System Organ Class by Preferred 
Term - Safety Analysis Population 
IP 
 
14.3.2  
Listings of Deaths, Other Serious and 
Significant Adverse Events 
 
 
14.3.2.1 
Listing of Serious TEAEs – Safety Analysis 
Population 
IP 
 
14.3.2.2 
Listing of Deaths – Safety Analysis Population 
IP 
 
14.3.3  
Narratives of Deaths, Other Serious and 
Certain Other Significant Adverse Events 
 
 
14.3.4  
Abnormal Laboratory Values 
 
 
14.3.5  
Extent of Exposure, Dosage Information, and 
Compliance 
 
 
14.3.5.1 
Extent of Exposure – Safety Analysis Population  
IP 
 
14.3.5.2 
Protocol Deviations – Safety Analysis 
Population 
IP 
 
14.3.6  
Vital Signs And Physical Examination 
 
 
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Table Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
14.3.6.1 
Vital Signs, Descriptive Statistics by Visit and 
Change from Baseline by Visit – Safety 
Analysis Population 
IP 
 
14.3.7  
Other Safety 
 
 
14.3.7.1 
Hematology Data, Descriptive Statistics by Visit 
and Change from Baseline to Post-Dose 
Assessments – Safety Analysis Population 
IP 
 
14.3.7.2 
Hematology Data, Normal Range Shifts – Safety 
Analysis Population 
IP 
 
14.3.7.3 
Serum Chemistry Data, Descriptive Statistics by 
Visit and Change from Baseline to Post-Dose 
Assessments – Safety Analysis Population 
IP 
14.3.7.1 
14.3.7.4 
Serum Chemistry Data, Normal Range Shifts – 
Safety Analysis Population 
IP 
14.3.7.2 
14.3.7.5 
Coagulation Data, Descriptive Statistics b Visit 
and Change from Baseline to Post-Dose 
Assessments – Safety Analysis Population 
IP 
14.3.7.1 
14.3.7.6 
Coagulation Data, Normal Range Shifts – Safety 
Analysis Population 
IP 
14.3.7.2 
14.3.7.7 
Urinalysis Data, Descriptive Statistics by Visit 
and Change from Baseline to Post-Dose 
Assessments – Safety Analysis Population 
IP 
14.3.7.1 
14.3.7.8 
Urinalysis Data, Normal Range Shifts – Safety 
Analysis Population 
IP 
14.3.7.2 
14.3.7.9 
12-Lead ECG, Descriptive Statistics by Visit 
and Change from Baseline to End of Treatment / 
Early Termination – Safety Analysis Population 
IP 
 
14.3.7.10 
12-Lead ECG, Overall Interpretation, Shift from 
Baseline to End of Treatment / Early 
Termination – Safety Analysis Population 
IP 
 
14.3.7.11 
Skin Tolerability Assessments, Dermal 
Response Scores – Skin Irritation Population 
IP 
 
14.3.7.12 
Skin Tolerability Assessments, Other Effects 
Scores – Skin Irritation Population 
IP 
 
14.3.7.13 
Skin Tolerability Assessments, Combined Skin 
Irritation Scores – Skin Irritation Population 
IP 
 
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Table Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
14.3.7.14 
Skin Tolerability Assessments, Skin Irritation 
Summary – Skin Irritation Population 
IP 
 
14.3.7.15 
Observed Percent Adhered Distribution by Time 
Point Post TDS Application – Adhesion 
Population 
IP 
 
14.3.7.16 
Average Observed Percent Adhered at each 
Post-TDS Application Assessment Time Point – 
Adhesion Population 
IP 
 
14.3.7.17 
Adhesion Assessments, Patch Adhesion 
Summary Data – Adhesion Population 
IP 
14.3.7.15 
14.3.7.18 
Modified Percent Adhered Distribution by Time 
Point Post TDS – Adhesion Population 
IP 
14.3.7.16 
14.3.7.19 
Adhesion Assessments, Patch Adhesion 
Summary Data  - Adhesion Population 
IP 
 
14.3.7.20 
Summary of the Point Estimate and 95% Lower 
Confidence Limits of the Probability that a TDS 
maintains at least 75% Adhesion during the 
Entire Wear Period 
IP 
 
14.3.7.21 
Summary of the Point Estimate and 95% Lower 
Confidence Limits of the Probability that a TDS 
maintains at least 75% Adhesion during the 
Entire Wear Period Using A Generalized Linear 
Mixed Model (GLMM) 
IP 
 
14.3.8  
Concomitant Medication 
 
 
14.3.8.1 
Concomitant Medications – Safety Analysis 
Population 
IP 
 
14.4  
PK Tables 
 
 
14.4.1 
Descriptive Statistics for Donepezil and 6-O-
Desmethyl Donepezil Concentration-Time Data 
in Plasma after 5 mg/day TDS and 10 mg/day 
TDS Application on Week 1 (Days 1-7 
Following TDS Application) - PK Population 
IP 
 
14.4.2 
Descriptive Statistics for Donepezil and 6-O-
Desmethyl Donepezil Concentration-Time Data 
in Plasma after 5 mg/day TDS and 10 mg/day 
TDS Application on Week 2 (Days 8-14 
Following TDS Application)- PK Population 
IP 
 
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Table Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
14.4.3 
Descriptive Statistics for Donepezil and 6-O-
Desmethyl Donepezil Concentration-Time Data 
in Plasma after 5 mg/day TDS and 10 mg/day 
TDS Application on Week 5 (Days 29-36 
Following TDS Application)- PK Population 
IP 
 
14.4.4 
Descriptive Statistics for Donepezil and 6-O-
Desmethyl Donepezil Trough Concentration-
Time Data (Ctau) in Plasma after 5 mg/day TDS 
and 10 mg/day TDS Application on Days 1, 8, 
15, 22, 29, and 35- PK Population 
IP 
 
14.4.5 
Descriptive Statistics for Donepezil and 6-O-
Desmethyl Donepezil Concentration-Time Data 
in Plasma after QD Administration of 10 mg 
Aricept for Week 5 (Days 35-36 Following First 
Dose)- PK Population 
IP 
 
14.4.6 
Descriptive Statistics for Donepezil and 6-O-
Desmethyl Donepezil Trough Concentration-
Time Data in Plasma after QD Administration of 
10 mg Aricept on Days 1, 8, 15, 22, 29, and 36- 
PK Population 
IP 
 
14.4.7 
Descriptive Statistics for Dose-Normalized 
Donepezil and 6-O-Desmethyl Donepezil 
Concentration-Time Data in Plasma after 5 
mg/day TDS Application on Week 1 (Days 1-7 
Following TDS Application) - PK Population  
IP 
 
14.4.8 
Descriptive Statistics for Dose-Normalized 
Donepezil and 6-O-Desmethyl Donepezil 
Concentration-Time Data in Plasma after 5 
mg/day TDS Application on Week 2 (Days 8-14 
Following TDS Application) - PK Population 
IP 
 
14.4.9 
Descriptive Statistics for Dose-Normalized 
Donepezil and 6-O-Desmethyl Donepezil 
Concentration-Time Data in Plasma after 5 
mg/day TDS Application on Week 5 (Days 29-
36 Following TDS Application) - PK Population 
IP 
 
14.4.10 
Descriptive Statistics for Dose-Normalized 
Donepezil and 6-O-Desmethyl Donepezil 
IP 
 
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Table Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
Trough Concentration-Time Data (Ctau) in 
Plasma after 5 mg/day TDS Application on Days 
1, 8, 15, 22, 29, and 35- PK Population 
14.4.11 
Plasma Donepezil and 6-O-Desmethyl 
Donepezil PK Parameters after 5 mg/day and 10 
mg/day TDS Application on Week 1- PK 
Population 
IP 
 
14.4.12 
Plasma Donepezil and 6-O-Desmethyl 
Donepezil PK Parameters after 5 mg/day and 10 
mg/day TDS Application on Week 5- PK 
Population 
IP 
 
14.4.13 
Plasma Donepezil and 6-O-Desmethyl 
Donepezil Daily AUC0-24,ss after 5 mg/day and 
10 mg/day TDS Application on Week 5- PK 
Population 
IP 
 
14.4.14 
Plasma Donepezil and 6-O-Desmethyl 
Donepezil PK Parameters after QD 
Administration of 10 mg Aricept During Week 
5- PK Population 
IP 
 
14.4.15 
Dose-Normalized Plasma Donepezil and 6-O-
Desmethyl Donepezil PK Parameters after 5 
mg/day TDS Application on Week 1- PK 
Population 
IP 
 
14.4.16 
Dose-Normalized Plasma Donepezil and 6-O-
Desmethyl Donepezil PK Parameters after 5 
mg/day TDS Application on Week 5- PK 
Population 
IP 
 
14.4.17 
Dose-Normalized Plasma Donepezil and 6-O-
Desmethyl Donepezil Daily AUC0-24,ss after 5 
mg/day TDS Application on Week 5- PK 
Population 
IP 
 
14.4.18 
Mean Squared Error, Coefficient of Variation 
Estimates, and Intraclass Correlation for 
Donepezil Pharmacokinetic Parameters from 
ANOVA Relative Bioavailability Population 
IP 
 
14.4.19 
Mean Squared Error, Coefficient of Variation 
Estimates, and Intraclass Correlation for 6-O-
IP 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 114
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Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 51 of 61 
 
 
Confidential 
 
Table Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
Desmethyl Donepezil Pharmacokinetic 
Parameters from ANOVA Relative 
Bioavailability Population 
14.4.20 
Mean Squared Error, Coefficient of Variation 
Estimates, and Intraclass Correlation for 
Donepezil Pharmacokinetic Parameters from 
ANOVA Relative Bioavailability Population 
IP 
 
14.4.21 
Mean Squared Error, Coefficient of Variation 
Estimates, and Intraclass Correlation for 6-O-
Desmethyl Donepezil Pharmacokinetic 
Parameters from ANOVA Relative 
Bioavailability Population 
IP 
 
14.4.22 
Statistical Assessment of Relative 
Bioavailability of the Natural Log Transformed 
Systemic Exposure of Donepezil Comparing 
10 mg/day TDS to 10 mg Aricept QD – Relative 
Bioavailability Population 
IP 
 
14.4.23 
Statistical Assessment of Relative 
Bioavailability of the Natural Log Transformed 
Systemic Exposure of 6-O-Desmethyl 
Donepezil Comparing 10 mg/day TDS to 10 mg 
Aricept QD – Relative Bioavailability 
Population 
IP 
 
14.4.24 
Statistical Assessment of Relative 
Bioavailability of the Natural Log Transformed 
Systemic Exposure of Donepezil Comparing 5 
mg/day TDS to 10 mg Aricept QD – Relative 
Bioavailability Population 
IP 
 
14.4.25 
Statistical Assessment of Relative 
Bioavailability of the Natural Log Transformed 
Systemic Exposure of 6-O-Desmethyl 
Donepezil Comparing 5 mg/day TDS to 10 mg 
Aricept QD – Relative Bioavailability 
Population 
IP 
 
14.4.26 
Attainment of Steady State for Trough 
Donepezil by Period - PK Population 
IP 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 115
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Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 52 of 61 
 
 
Confidential 
 
Table Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
14.4.27 
Attainment of Steady State for Trough 
Donepezil (Combined Periods) - PK Population 
 
 
14.4.28 
Subgroup Analysis: Comparison of Males and 
Females within Treatment for Donepezil 
Pharmacokinetic Parameters at Steady State -
Relative Bioavailability Population 
IP 
 
14.4.29 
Subgroup Analysis: Comparison of Ethnic 
Subgroups within Treatment for Donepezil 
Pharmacokinetic Parameters at Steady State -
Relative Bioavailability Population 
IP 
 
14.4.30 
Subgroup Analysis: Relationship of Age to 
Natural Log Transformed Donepezil 
Pharmacokinetic Parameters at Steady State - 
Relative Bioavailability Population 
IP 
 
14.5  
PD Tables 
 
 
14.6  
Other Data 
 
 
 
 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 116
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Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 53 of 61 
 
 
Confidential 
 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.4.1 
Mean Plasma Donepezil Concentration-Time Data in 
Plasma (Week 5) after 5 mg/day and 10 mg/day TDS 
Application on Week 5 (Days 29-36 Following TDS 
Application) and after QD Administration of 10 mg 
Aricept for Week 5 (Days 35-36 Following First 
Dose) on Linear Scale - PK Population 
IP 
 
14.4.2 
Mean Plasma 6-O-Desmethyl Donepezil 
Concentration-Time Data in Plasma (Week 5) after 5 
mg/day and 10 mg/day TDS Application on Week 5 
(Days 29-36 Following TDS Application) and after 
QD Administration of 10 mg Aricept for Week 5 
(Days 35-36 Following First Dose) on Linear Scale - 
PK Population 
IP 
 
14.4.3 
Mean Plasma 6-O-Desmethyl Donepezil to Donepezil 
Concentration Ratios after 5 mg/day TDS Application 
on Week 5 (Days 29-36 Following TDS Application) 
on Linear Scale - PK Population 
IP 
 
14.4.4 
Mean Plasma 6-O-Desmethyl Donepezil to Donepezil 
Concentration Ratios after 10 mg/day TDS 
Application on Week 5 (Days 29-36 Following TDS 
Application) on Linear Scale - PK Population 
IP 
 
14.4.5 
Mean Plasma 6-O-Desmethyl Donepezil to Donepezil 
Concentration Ratios after QD Administration of 10 
mg Aricept for Week 5 (Days 35-36 Following First 
Dose) on Linear Scale - PK Population 
IP 
 
14.4.6 
Mean Steady-State Plasma Donepezil Concentration-
Time Data in Plasma (Week 5) after 5 mg/day and 10 
mg/day TDS Application on Week 5 (Days 29-36 
Following TDS Application) and after QD 
Administration of 10 mg Aricept for Week 5 (Days 
35-36 Following First Dose) on Linear Scale - PK 
Population 
IP 
 
14.4.7 
Mean Steady-State Plasma 6-O-Desmethyl Donepezil 
Concentration-Time Data in Plasma (Week 5) after 
5 mg/day and 10 mg/day TDS Application on Week 5 
IP 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 117
Confidential


 
 
Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 54 of 61 
 
 
Confidential 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
(Days 29-36 Following TDS Application) and after 
QD Administration of 10 mg Aricept for Week 5 
(Days 35-36 Following First Dose) on Linear Scale - 
PK Population 
14.4.8 
Mean Plasma Donepezil Concentration-Time Data in 
Plasma (Week 5) after 5 mg/day and 10 mg/day TDS 
Application on Weeks 1 through  5 (Days 1-36 
Following TDS Application) and after QD 
Administration of 10 mg Aricept on Weeks 1 through 
5 (Days 1-36 Following First Dose) on Linear Scale - 
PK Population 
IP 
 
14.4.9 
Mean Plasma Donepezil Concentration-Time Data in 
Plasma (Week 5) after 5 mg/day (Dose-Normalized)[1] 
and 10 mg/day TDS Application on Week 5 (Days 29-
36 Following TDS Application) and after QD 
Administration of 10 mg Aricept for Week 5 (Days 
35-36 Following First Dose) on Linear Scale - PK 
Population 
IP 
 
14.4.10 
Mean Plasma 6-O-Desmethyl Donepezil 
Concentration-Time Data in Plasma (Week 5) after 5 
mg/day (Dose-Normalized)[1] and 10 mg/day TDS 
Application on Week 5 (Days 29-36 Following TDS 
Application) and after QD Administration of 10 mg 
Aricept for Week 5 (Days 35-36 Following First 
Dose) on Linear Scale - PK Population 
IP 
 
14.4.11 
Plasma Donepezil Concentration-Time Data after 5 
mg/day TDS Application on Week 5 (Days 29-36 
Following TDS Application) for All Subjects on 
Linear Scale - PK Population 
IP 
 
14.4.12 
Plasma Donepezil Concentration-Time Data after 10 
mg/day TDS Application on Week 5 (Days 29-36 
Following TDS Application) for All Subjects on 
Linear Scale - PK Population 
IP 
 
14.4.13 
Plasma Donepezil Concentration-Time Data after QD 
Administration of 10 mg Aricept for Week 5 (Days 
IP 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 118
Confidential


 
 
Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 55 of 61 
 
 
Confidential 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
35-36 Following First Dose) for All Subjects on 
Linear Scale - PK Population 
14.4.14 
Plasma 6-O-Desmethyl Donepezil Concentration-
Time Data after 5 mg/day TDS Application on Week 
5 (Days 29-36 Following TDS Application) for All 
Subjects on Linear Scale - PK Population 
IP 
 
14.4.15 
Plasma 6-O-Desmethyl Donepezil Concentration-
Time Data after 10 mg/day TDS Application on Week 
5 (Days 29-36 Following TDS Application) for All 
Subjects on Linear Scale - PK Population 
IP 
 
14.4.16 
Plasma 6-O-Desmethyl Donepezil Concentration-
Time Data after QD Administration of 10 mg Aricept 
for Week 5 (Days 35-36 Following First Dose) for All 
Subjects on Linear Scale - PK Population 
IP 
 
14.4.17 
Plasma Donepezil Concentration-Time Data in 
Plasma after 5 mg/day TDS Application on Weeks 1 
through  5 (Days 1-36 Following TDS Application) 
for All Subjects on Linear Scale - PK Population 
IP 
 
14.4.18 
Plasma Donepezil Concentration-Time Data in 
Plasma after 10 mg/day TDS Application on Weeks 1 
through 5 (Days 1-36 Following TDS Application) for 
All Subjects on Linear Scale - PK Population 
IP 
 
14.4.19 
Plasma Donepezil Concentration-Time Data in Plasm 
after  QD Administration of 10 mg Aricept for Weeks 
1 through  5 (Days 1-36 Following First Dose) for All 
Subjects on Linear Scale - PK Population 
IP 
 
14.4.20 
Plasma Donepezil Concentration-Time Data in 
Plasma (Week 5) after 5 mg/day and 10 mg/day TDS 
Application on Week 5 (Days 29-36 Following TDS 
Application) and after QD Administration of 10 mg 
Aricept for Week 5 (Days 35-36 Following First 
Dose) for Individual Subjects on Linear Scale - PK 
Population 
IP 
 
14.4.21 
Plasma 6-O-Desmethyl Donepezil Concentration-
Time Data in Plasma (Week 5) after 5 mg/day and 10 
mg/day TDS Application on Week 5 (Days 29-36 
IP 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 119
Confidential


 
 
Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 56 of 61 
 
 
Confidential 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
Following TDS Application) and after QD 
Administration of 10 mg Aricept for Week 5 (Days 
35-36 Following First Dose) for Individual Subjects 
on Linear Scale - PK Population 
14.4.22 
Plasma 6-O-Desmethyl Donepezil to Donepezil 
Concentration Ratios after 5 mg/day TDS Application 
on Week 5 (Days 29-36 Following TDS Application) 
for Individual Subjects on Linear Scale - PK 
Population 
IP 
 
14.4.23 
Plasma 6-O-Desmethyl Donepezil to Donepezil 
Concentration Ratios after 10 mg/day TDS 
Application on Week 5 (Days 29-36 Following TDS 
Application) for Individual Subjects on Linear Scale - 
PK Population 
IP 
 
14.4.24 
Plasma 6-O-Desmethyl Donepezil to Donepezil 
Concentration Ratios after QD Administration of 10 
mg Aricept for Week 5 (Days 35-36 Following First 
Dose) for Individual Subjects on Linear Scale - PK 
Population 
IP 
 
14.4.25 
Steady-State Plasma Donepezil Concentration-Time 
Data in Plasma (Week 5) after 5 mg/day and 10 
mg/day TDS Application on Week 5 (Days 29-36 
Following TDS Application) and after QD 
Administration of 10 mg Aricept for Week 5 (Days 
35-36 Following First Dose) for Individual Subjects 
on Linear Scale - PK Population 
IP 
 
14.4.26 
Steady-State Plasma 6-O-Desmethyl Donepezil 
Concentration-Time Data in Plasma (Week 5) after 
5 mg/day and 10 mg/day TDS Application on Week 5 
(Days 29-36 Following TDS Application) and after 
QD Administration of 10 mg Aricept for Week 5 
(Days 35-36 Following First Dose) for Individual 
Subjects on Linear Scale - PK Population 
IP 
 
14.4.27 
Plasma Donepezil Concentration-Time Data in 
Plasma after 5 mg/day and 10 mg/day TDS 
Application on Weeks 1 through  5 (Days 1-36 
IP 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 120
Confidential


 
 
Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 57 of 61 
 
 
Confidential 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
Following TDS Application) and after QD 
Administration of 10 mg Aricept on Weeks 1 through 
5 (Days 1-36 Following First Dose) for Individual 
Subjects on Linear Scale - PK Population 
14.4.28 
Plasma Donepezil Concentration-Time Data in 
Plasma after 5 mg/day (Dose-Normalized)[1] and 10 
mg/day TDS Application on Week 5 (Days 29-36 
Following TDS Application) and after QD 
Administration of 10 mg Aricept for Week 5 (Days 
35-36 Following First Dose) for Individual Subjects 
on Linear Scale - PK Population 
IP 
 
14.4.29 
Plasma 6-O-Desmethyl Donepezil Concentration-
Time Data in Plasma (Week 5) after 5 mg/day (Dose-
Normalized)[1] and 10 mg/day TDS Application on 
Week 5 (Days 29-36 Following TDS Application) and 
after QD Administration of 10 mg Aricept for Week 5 
(Days 35-36 Following First Dose) for Individual 
Subjects on Linear Scale - PK Population 
IP 
 
14.4.30 
Forest Plot of Donepezil Exposure Comparing 10 
mg/day TDS Application on Week 5 (Days 29-36 
Following TDS Application) and after QD 
Administration of 10 mg Aricept for Week 5 (Days 
35-36 Following First Dose) – Relative 
Bioavailability Population 
IP 
 
14.4.31 
Forest Plot of Donepezil Exposure Comparing 5 
mg/day TDS Application (Dose-Normalized[1]) on 
Week 5 (Days 29-36 Following TDS Application) and 
after QD Administration of 10 mg Aricept for Week 5 
(Days 35-36 Following First Dose) – Relative 
Bioavailability Population 
IP 
 
14.4.32 
Forest Plot of 6-O-Desmethyl Donepezil Exposure 
Comparing 10 mg/day TDS Application on Week 5 
(Days 29-36 Following TDS Application) and after 
QD Administration of 10 mg Aricept for Week 5 
(Days 35-36 Following First Dose) – Relative 
Bioavailability Population 
IP 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 121
Confidential


 
 
Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 58 of 61 
 
 
Confidential 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.4.33 
Forest Plot of 6-O-Desmethyl Donepezil Exposure 
Comparing 5 mg/day TDS Application (Dose-
Normalized[1]) on Week 5 (Days 29-36 Following 
TDS Application) and after QD Administration of 
10 mg Aricept for Week 5 (Days 35-36 Following 
First Dose) – Relative Bioavailability Population 
IP 
 
14.4.34 
Subgroup Analysis: Box-Plot of Donepezil Cmax,ss 
and AUC0-168,ss at Steady State (Week 5) by Gender 
and Treatment – Relative Bioavailability Population 
IP 
 
14.4.35 
Subgroup Analysis: Box-Plot of Donepezil Cmax,ss 
and AUC0-168,ss at Steady State (Week 5) by Ethnicity 
and Treatment – Relative Bioavailability Population 
IP 
 
14.4.36 
Subgroup Analysis: Estimated Regression Lines with 
Least Squares Means for Cmax,ss at Steady State (Week 
5) versus Age by Treatment- Relative Bioavailability 
Population 
IP 
 
14.4.37 
Subgroup Analysis: Estimated Regression Lines with 
Least Squares Means for AUC0-168,ss at Steady State 
(Week 5) versus Age by Treatment- Relative 
Bioavailability Population 
IP 
 
 
 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 122
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Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 59 of 61 
 
 
Confidential 
 
Listing Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2  
Subject Data Listings 
 
 
16.2.1  
Discontinued Subjects 
 
 
16.2.1.1  
Subject Disposition – Randomized Population 
IP 
 
16.2.2 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations – Randomized Population 
IP 
 
16.2.2.2 
Informed Consent and Eligibility Criteria - 
Randomized Population 
 
 
16.2.3 
Subjects Excluded from the Efficacy Analyses 
 
 
16.2.3.1  
Analysis Populations  
IP 
 
16.2.4  
Demographic Data 
 
 
16.2.4.1  
Demographics – Randomized Population 
IP 
 
16.2.4.2 
Baseline Characteristics – Randomized 
Population 
IP 
 
16.2.4.3 
Medical History – Safety Analysis Population   
IP 
 
16.2.4.4 
Pregnancy – Safety Analysis Population  
IP 
 
16.2.4.5 
Non-Pharmacological Procedures – Safety 
Analysis Population 
IP 
 
16.2.4.6 
COVID-19 – Safety Analysis Population  
IP 
 
16.2.5  
Compliance and/or Drug Concentration Data 
 
 
16.2.5.1  
TDS Application/Removal and Treatment C (oral 
Aricept tablets)– Safety Analysis Population 
IP 
 
16.2.5.2 
PK Sampling Times – Safety Analysis 
Population 
IP 
 
16.2.5.3 
Prior and Concomitant Medications – Safety 
Analysis Population 
IP 
 
16.2.6  
Individual Efficacy Response Data   
 
 
16.2.6.1 
Plasma Donepezil Concentration-Time Data 
Listing by Subject – PK Population 
IP 
 
16.2.6.2 
Dose-Normalized Plasma Donepezil and 6-O-
Desmethyl Donepezil Concentration-Time Data 
Listing by Subject after 5 mg/day TDS 
Application– PK Population 
IP 
 
16.2.6.2 
Plasma Terminal Elimination Rate of Donepezil 
for Individual Subjects – PK Population 
IP 
 
16.2.6.3 
PK Output Text – PK Population 
IP 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 123
Confidential


 
 
Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 60 of 61 
 
 
Confidential 
 
Listing Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2.6.4 
SAS Output for Treatment Comparisons – 
Relative Bioavailability Population 
IP 
 
16.2.6.5 
SAS Output Text for Relative Bioavailability 
Assessment– Relative Bioavailability Population 
IP 
 
16.2.6.6 
SAS Output Text for Steady-State Assessment– 
PK Population 
IP 
 
16.2.6.7 
SAS Output Text for Subgroup Analysis: Gender 
Comparison – PK Population 
IP 
 
16.2.6.8 
SAS Output Text for Subgroup Analysis: 
Ethnicity Group Comparison – PK Population 
IP 
 
16.2.6.9 
SAS Output Text for Subgroup Analysis: Age 
Comparison – PK Population 
IP 
 
16.2.6.10 
Subjects Excluded from the Pharmacokinetic and 
Relative Bioavailability Populations 
IP 
 
16.2.7  
Adverse Event Listings 
 
 
16.2.7.1 
Adverse Events – Safety Analysis Population 
IP 
 
16.2.8  
Individual Laboratory Measurements and 
Other Safety 
 
 
16.2.8.1 
Hematology – Safety Analysis Population 
IP 
 
16.2.8.2 
Serum Chemistry – Safety Analysis Population 
IP 
 
16.2.8.3 
Coagulation – Safety Analysis Population 
IP 
 
16.2.8.4 
Abnormal Clinical Laboratory Values 
IP 
 
16.2.8.5 
Urinalysis – Safety Analysis Population 
IP 
 
16.2.8.6 
Drug and Alcohol Screen – Safety Analysis 
Population 
IP 
 
16.2.8.7 
Serology – Safety Analysis Population 
IP 
 
16.2.8.8 
Vital Signs – Safety Analysis Population 
IP 
 
16.2.8.9 
12-Lead ECG - – Safety Analysis Population 
IP 
 
16.2.8.10 
Physical Examination – Safety Analysis 
Population 
IP 
 
16.2.8.11 
C-SSRS (Part 1, 2, or 3 of 3)– Safety Analysis 
Population 
IP 
 
16.2.8.12 
Skin Photography – Safety Analysis Population 
IP 
 
16.2.9 
Adhesion and Skin Assessment 
 
 
16.2.9.1 
Skin Irritation Assessments – Skin Irritation 
Population 
IP 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
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Corium, Inc. 
 
CL-P-20003 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Issue Date 15-JUL-2021 
 
 
 
Page 61 of 61 
 
 
Confidential 
 
Listing Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2.9.2 
Adhesion Assessments – Adhesion Population 
IP 
 
 
Appendix 16.1.9 CL-P-20003
Corium, Inc.
Page 125
Confidential