Clinical trial NCT02549196
Conditions: Dementia of Alzheimer's Type
Sponsor: Chase Pharmaceuticals Corporation, an affiliate of Allergan plc
Start date: 2015-10-07; Completion date: 2017-09-28
Enrollment: 28 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase II, ascending dose study of CPC-201 in patients with dementia of Alzheimer's type to determine the optimal dose titration schedule.

Detailed description:
This is a Phase II, ascending dose study of CPC-201 in patients with dementia of Alzheimer's type to determine the optimal dose titration schedule. The study involves a step wise cohort design in two different patient populations: Group 1 will comprise of patients who have been treated with low dose of CPC-201(5 or 10 mg/day) (given once daily) for at least 4 weeks just prior to Day1. Group 2 will consist of patients who have never been treated with CPC-201 before or who have not received any other AChEI for the past 6 months.

In this study, CPC-201 dose will be increased at weekly intervals, in accordance with the schedules given below, to its first intolerable dose (FID) or maximum allowed dose (MAD) of 60 mg/day (40mg/day for Cohort 3c) together with solifenacin 15 mg/day.

Cohort 1 1st week: 20mg 2nd week: 30mg 3rd week: 40mg 4th week: 50mg 5th week: 60mg Cohort 2\* 1st week: 20mg 2nd week: 40mg 3rd week: 60mg Cohort 1b 1st - 2nd week: 10mg 3rd week: 20mg 4th week: 30mg 5th week: 40mg 6th week: 50mg 7th week: 60mg Cohort 3c\* 1st week: 10mg 2nd week: 15mg 3rd week: 20mg 4th week: 25mg 5th week: 30mg 6th week: 35mg 7th week: 40mg

\*: The dose titration schedule of Cohort 2 and 3 may be altered based on Cohort 1 result.

Patients will be enrolled in Cohort 2 only when patients enrolled in Cohort 1 have safely completed titration. Similary, patients will be enrolled in Cohort 3, only when patients enrolled in Cohort 2 have safely completed titration.

Patients reaching their FID or having completed one week treatment with donepezil 40mg/day, have two options.

Option 1: Patient will be allowed to immediately enter a long term extension at their Maximum tolerated dose (MTD) or MAD.

Option 2: Patients may choose not to enter the long term extension, in which case the Investigator will decide whether the patient should discontinue high dose of donepezil without down-titration, or whether donepezil should be downtitrated to their own standard of donepezil dose.

Arms: arm 1: Donepezil 20mg/day upward dose titration of 10mg at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) of 60mg/day with solifenacin 15 or 20mg/day. arm 2: Donepezil 20mg/day upward dose titration of 20mg at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) of 60mg/day with solifenacin 15 or 20mg/day. arm 3: Donepezil 10mg/day upward dose titration of 10mg at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) of 60mg/day with solifenacin 15 or 20mg/day. arm 4: Donepezil 10mg/day upward dose titration of 5mg at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) of 40mg/day with solifenacin 15mg/day.
Interventions: intervention 1: Donepezil intervention 2: Solifenacin
Intervention descriptions: intervention 1: Donepezil dose increased at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) together with solifenacin. intervention 2: Donepezil dose increased at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) together with solifenacin.

Protocol documents:
Prot_001.pdf: 
NCT02549196 
 
Study ID: CPC‐001‐12 
 
Title:  A phase II, dose titration study of CPC‐201 in Patients with Dementia of Alzheimer’s Type 
 
Protocol Amendment 3 Date: 22 July 2016 


Chase Pharmaceuticals Corporation 
Protocol CPC-001-12 
Version date: 07/22/2016 
Page 1 of 53 
 
 
 
Investigational Product:  
CPC-201 (donepezil plus solifenacin)  
Indication:  
 
 
Treatment of Dementia of Alzheimer Type  
Clinical phase:  
 
Phase II, Dose Titration Study  
Study code: 
 
 
CPC-001-12 
 
 
 
Dose titration study 
 
 
A PHASE II, DOSE TITRATION STUDY OF CPC-201 IN PATIENTS 
WITH DEMENTIA OF ALZHEIMER’S TYPE 
 
 
Version 3, date: July 22, 2016 
 
 
 
Sponsor: 
 
 
Chase Pharmaceuticals Corporation 
 
 
 
 
1825 K Street, NW, Suite 510 
 
 
 
 
Washington, DC 20006 
 
 
 
 
 
 
 
 
Confidential Information 
This material is the property of Chase Pharmaceuticals Corporation. 
It may not be used, divulged, published or otherwise disclosed without prior written consent. 
GCP compliance 
The study will be performed in compliance with Good Clinical Practices (GCP)  
and in accordance with the Declaration of Helsinki 
 
 
 


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Signature page for the Sponsor 
 
Investigational Product: 
 
CPC-201 (Donepezil plus solifenacin) 
Indication: 
 
 
 
Treatment of Dementia of Alzheimer Type 
Clinical Phase: 
 
 
Phase II, Dose Titration Study 
Study Code:  
 
 
CPC-001-12 
Protocol Version Date: 
 
Version 3 (July 22, 2016) 
 
 
Reviewed and approved by:  
…………………………………….. 
 
 
 
 
 
Date: ………………………………. 
 
 
 
 
 
 
 
 
 


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Signature page for the Investigator  
This Clinical Trial will be conducted in accordance with the study protocol, the 
International Conference on Harmonization (ICH), Good Clinical Practices (GCP), the 
ethical principles outlined in the current valid version of the Declaration of Helsinki and 
the European as well as other local regulations. 
 
As the Investigator for the Trial, I have read this protocol dated July 22, 2016 and agree 
to follow this protocol in accordance with all the above-mentioned regulations. 
…………………………………….. 
 
Date: ……………………….... 
 
 
 
 
 
 
 


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Table of contents  
 
LIST OF TABLES ................................................................................................................................................ 8 
PROTOCOL SUMMARY ................................................................................................................................... 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
OBJECTIVES ........................................................................................................................................... 23 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................... 23 
2.2 
SECONDARY OBJECTIVE .......................................................................................................................... 23 
3 
INVESTIGATIONAL PLAN ................................................................................................................... 23 
3.1 
OVERALL STUDY DESIGN ........................................................................................................................ 23 
3.2 
DOSE ESCALATION AND STOPPING RULES ............................................................................................... 25 
3.3 
TRIAL PROCEDURES ................................................................................................................................ 25 
 
3.3.2  Study Procedure............................................................................................................................... 29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.5 
DISCONTINUATION CRITERIA .................................................................................................................. 33 
3.5.1  Discontinuation of donepezil dose escalation in individual subjects ............................................... 33 
3.5.2  Discontinuation of individual subjects from the entire study .......................................................... 33 
4 
SELECTION OF SUBJECTS .................................................................................................................. 33 
4.1 
INCLUSION CRITERIA ............................................................................................................................... 33 
4.2 
EXCLUSION CRITERIA .............................................................................................................................. 34 
5 
STUDY DRUG .......................................................................................................................................... 36 
5.1 
BLINDING ................................................................................................................................................ 36 
 
 
5.3 
DESCRIPTION OF STUDY DRUG ............................................................................................................... 36 
 
5.3.2  Study drug manufacturing and labeling ........................................................................................... 37 
5.3.3  Study drug storage, handling and disposal ...................................................................................... 37 
5.4 
CONCOMITANT MEDICATION ................................................................................................................... 38 
5.4.1  Allowed Mediations ........................................................................................................................ 38 
5.4.2  Prohibited Mediations ..................................................................................................................... 38 
6 
ASSESSMENT OF PHARMACOKINETICS ....................................................................................... 38 
6.1 
PK BLOOD SAMPLING SCHEDULE AND SAMPLE ANALYSIS .................................................................... 38 
 
 
 
 
7 
SAFETY ASSESSMENTS ....................................................................................................................... 39 


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7.1 
ADVERSE EVENTS ................................................................................................................................... 39 
7.2 
SERIOUS ADVERSE EVENTS (SAE) ......................................................................................................... 40 
7.3 
ASSESSMENT OF TOLERABILITY .............................................................................................................. 40 
7.4 
SAFETY LABORATORY TEST ................................................................................................................... 40 
7.5 
URINALYSIS ............................................................................................................................................ 41 
7.6 
VITAL SIGNS AND BODY WEIGHT ............................................................................................................. 41 
7.7 
12-LEAD ECGS ....................................................................................................................................... 41 
7.8 
MMSE .................................................................................................................................................... 41 
7.9 
ADAS-COG ............................................................................................................................................ 41 
7.10  MODIFIED C-SSRS ................................................................................................................................. 41 
8 
PROCEDURES FOR REPORTING TEAES AND SERIOUS ADVERSE EVENTS ........................ 42 
8.1 
REPORTING TEAES ................................................................................................................................. 42 
8.2 
REPORTING SERIOUS ADVERSE EVENTS ................................................................................................. 42 
9 
STATISTICS ............................................................................................................................................. 43 
9.1 
ASSESSMENT OF SAFETY AND TOLERABILITY AND ................................................................................. 43 
9.1.1  Assessment of MTD ........................................................................................................................ 43 
9.1.2  Adverse Events ................................................................................................................................ 43 
9.1.3  Laboratory Tests (Safety laboratory test and urinalysis) ................................................................. 43 
9.1.4  ECGs ............................................................................................................................................... 43 
9.1.5  Vital Signs and weight ..................................................................................................................... 43 
9.2 
PHARMACOKINETICS ............................................................................................................................... 43 
9.3 
PATIENT DISPOSITION ............................................................................................................................. 44 
9.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................................................................... 44 
9.5 
PROTOCOL DEVIATIONS .......................................................................................................................... 44 
9.6 
COMPLIANCE .......................................................................................................................................... 44 
10 
ACCESS TO SOURCE DATA/DOCUMENTS ..................................................................................... 44 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 44 
11.1  STUDY MONITORING ............................................................................................................................... 44 
11.2  AUDITS AND INSPECTIONS ...................................................................................................................... 45 
11.3  DATA QUALITY ASSURANCE .................................................................................................................. 45 
12 
ETHICS AND ADMINISTRATIVE ISSUES ........................................................................................ 45 
12.1  ETHICAL CONDUCT OF THE TRIAL ........................................................................................................... 45 
12.2  INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) AND REGULATORY 
AUTHORITY ...................................................................................................................................................... 46 
12.3  SUBJECT INFORMED CONSENT ................................................................................................................. 46 
12.4  SUBJECT DATA PROTECTION ................................................................................................................... 46 
12.5  DATA MONITORING COMMITTEE ............................................................................................................ 46 
12.6  FINANCIAL DISCLOSURE ......................................................................................................................... 46 
12.7  INVESTIGATOR OBLIGATIONS ................................................................................................................. 46 
12.8  CHANGES TO THE PROTOCOL .................................................................................................................. 47 
12.9  CONFIDENTIALITY/PUBLICATION OF THE STUDY .................................................................................... 47 
12.10 DISCONTINUATION OF ENTIRE STUDY ..................................................................................................... 47 
13 
DATA HANDLING AND RECORD KEEPING ................................................................................... 48 
13.1  INSPECTION OF RECORDS ........................................................................................................................ 48 
13.2  RETENTION OF RECORDS ........................................................................................................................ 48 
14 
REFERENCES .......................................................................................................................................... 49 
 


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LIST OF ABBREVIATIONS  
 
ACh ......................... Acetylcholine 
AChEI ..................... Acetylcholinesterase Inhibitor 
AD ........................... Alzheimer’s disease 
ADAS-cog...............Alzheimer’s disease Assessment Scale-cognition 
ADR.........................Adverse Drug Reaction 
AE ........................... Adverse Event 
AV...........................Atrioventricular 
CFS...................... ... Cerebrospinal Fluid 
CNS ......................... Central Nervous System 
CRF ......................... Case Report Form  
CRO ........................ Contract Research Organization 
C-SSRS. .................. Columbia-Suicide Severity Rating Scale 
DSM. ....................... Diagnostic and Statistical Manual of Mental Disorders 
E2020. ..................... Donepezil  
ECG ......................... Electrocardiogram 
FDA ......................... Food and Drug Administration 
FID .......................... First Intolerable Dose 
GCP ......................... Good Clinical Practice 
GI ............................ Gastrointestinal 
HR. .......................... Heart Rate 
ICD. ......................... Implantable Cardiac Defibrillator 
ICH .......................... International Conference On Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IEC .......................... Independent Ethics Committee 
IRB .......................... Institutional Review Board 
KG. .......................... Kilogram 
MAD………………Maximum Allowed Dose 
MEDDRA. .............. Medical Dictionary for Regulatory Activities 
MG. ......................... Milligram 
ML. .......................... Milliliter 
MMSE. .................... Mini Mental Status Examination 
MSEC. ..................... Millisecond 
MTD ........................ Maximum Tolerated Dose 
NDA. ....................... New Drug Application 
NG/ML. ................... Nanogram/Milliliter 
NIA-ADA. .............. National Institute on Aging – Alzheimer’s Disease Association 
OAB. ....................... Overactive Bladder Disorder 
OTC. ........................ Over-the-Counter 
QTC. ........................ Corrected QT interval 
QTCF. ..................... Corrected QT intervals by Fridericia's formula 
PR Interval. ............. On ECG, time from onset of P wave to start of QRS Complex 
QRS complex. ......... On ECG, central part of tracing, Q,R and S waves 


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QT interval. ............. On ECG, interval between start of Q wave and end of the T 
wave 
SOC ......................... System Organ Class 
SOP ......................... Standard Operating Procedures 
SAE ......................... Serious Adverse Event 
SEM. ....................... Standard Error of Mean 
TEAE ...................... Treatment Emergent Adverse Event 
UNL. ....................... Upper Normal Limit 
US ........................... United States 
WHO ....................... World Health Organization 


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LIST OF TABLES 
 
 
 
 
 
Table 5: Combination of tablets for each dosage .................................................................................. 36 
 


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PROTOCOL SUMMARY 
Name of Sponsor/Company: 
Chase Pharmaceuticals Corporation 
Name of Investigational Product: 
CPC-201: Donepezil plus solifenacin 
Name of Active Ingredient: 
Donepezil, solifenacin 
Title of Study: 
A phase II, dose titration study of CPC-201 in Patients with Dementia of Alzheimer’s Type 
Number of clinical centers: 
Multicenter 
Objectives:  
Primary: 
 
To determine the optimal initial dose and subsequent dose titration schedule (rate and 
increment) for CPC-201. 
Secondary: 
 
To evaluate the safety and tolerability of CPC-201 as a function of dose and initial rate of dose 
titration. 
Methodology:  
This is a Phase II, ascending dose study of CPC-201 in patients with dementia of Alzheimer’s type to 
determine the optimal dose titration schedule. The study involves a step wise cohort design in two 
different patient populations: Group 1 will consist of patients who have been treated with donepezil 5 or 
10 mg/day (given once daily) for at least 4 weeks just prior to Day1. Group 2 will consist of patients who 
have never been treated with donepezil before (donepezil naïve) or who have not received any other 
AChEI for the past 6 months. 
 
In this study, donepezil dose will be increased at weekly intervals, in accordance with the schedules 
given below, to its first intolerable dose (FID) or maximum allowed dose (MAD) of 60mg/day (40 
mg/day for Cohort 3c) together with solifenacin 15 mg/day. If a patient does not tolerate a donepezil 
dose higher than 40mg/day with solifenacin 15 mg/day, the solifenacin dose can be increased to 
20mg/day per the Investigator’s decision. 
 
Cohort 1 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 30mg donepezil + 15mg solifenacin 
3rd week: 40mg donepezil + 15mg solifenacin 
4th week: 50mg donepezil + 15mg (or 20mg) solifenacin 
5th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 40mg donepezil + 15mg solifenacin 
3rd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*: The dose titration schedule of Cohorts 2 and 3 may be altered based on Cohort 1 result. 
Per this amendment, patients currently treated with donepezil (Group 1) will receive solifenacin 15 


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mg/day during a two week run in period; donepezil treatment will continue at 10mg/day. Once on 15 
mg/day of solifenacin for two weeks (based upon the investigator judgment), the donepezil dose will be 
increased at weekly or bi-weekly intervals, in accordance with the schedules given below, to its first 
intolerable dose (FID) or maximum allowed dose (MAD) of 60mg/day.  
 
Cohort 1b 
1st-2nd week: 10mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th  week: 30mg donepezil + 15mg solifenacin 
5th  week: 40mg donepezil + 15mg solifenacin 
6th  week: 50mg donepezil + 15mg (or 20mg) solifenacin 
7th  week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2b 
1st – 2nd week: 10mg donepezil + 15mg solifenacin 
3rd  week: 20mg donepezil + 15mg solifenacin 
4th  week: 40mg donepezil + 15mg solifenacin 
5th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3b 
1st – 2nd week: 10mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*: The dose titration schedule of Cohorts 2 and 3 may be altered based on Cohort 1 result. 
 
Per this amendment, all patients not treated with an AchEI for at least 6 months (Group 2) will receive 
15mg solifenacin and 10mg donepezil for 2 weeks before starting donepezil titration.  
 
Each cohort will include approximately 6 patients donepezil-treated (Group 1) and approximately 6 
patients not treated with an AchEI for at least 6 months (Group 2). Within each cohort, Group 2 patients 
will be enrolled only when at least 3 Group 1 patients have completed dose titration per protocol.  
Patients will be enrolled in Cohort 2 only when patients enrolled in Cohort 1 have safely completed 
titration. Similary, patients will be enrolled in Cohort 3 only when patients enrolled in Cohort 2 have 
safely completed titration. 
 
Cohorts 1 and 2 were completed prior to this amendment. This amendment is to change the dosing 
regimen of cohort 3. All subjects entering the study in cohort 3c will start with a dose regimen of 10mg 
donepezil + 15mg solifenacin and will continue to increase the donepezil dose by 5mg increments every 
7 days (or up to 14 days per PI discretion) up to 40mg or the MTD. 
Cohort 3c 
1st week: 10mg donepezil + 15mg solifenacin 
2nd week: 15mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th week: 25mg donepezil + 15mg solifenacin 
5th week: 30mg donepezil + 15mg solifenacin 
6th week: 35mg donepezil + 15mg solifenacin 
7th week: 40mg donepezil + 15mg solifenacin 
 
Patients reaching their FID or having completed one week treatment with donepezil 40mg/day, have two 
options.  
 
Option 1: Patient will be allowed to immediately enter a long term extension at their maximum tolerated 


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dose (MTD) or MAD. 
 
Option 2: Patients may choose not to enter the long term extension, in which case the Investigator will 
decide whether the patient should discontinue high dose of donepezil without down-titration, or whether 
donepezil should be downtitrated to their own standard of donepezil dose. Whatever the decision, the 
patient will be treated at least an additional 7 days with solifenacin 15 mg/day. 
 
Number of patients planned:  
To ensure a suitable number of subjects to evaluate the optimal dose titration schedule, approximately 6 
patients per population group per cohort will be enrolled. 
Diagnosis and main criteria for inclusion: 
 
Males and females suffering from AD  
 
Inclusion Criteria: 
1) Signed an Institutional Review Board (IRB) approved informed consent document indicating 
that they understand the purpose of and procedures required by the study and are willing to 
participate in the study and comply with all study procedures and restrictions. Informed consent 
must be obtained from the patient and/or a designated representative prior to initiating screening 
procedures to evaluate eligibility for the study. 
2) Aged 50 – 89 years inclusive. 
3) Meeting the diagnosis of probable AD consistent with: 
 
Revised National Institute on Aging-Alzheimer’s Disease Association (NIA-ADA) criteria 
and  
 
Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria.  
4) Mild to severe severity (Mini-Mental Status Exam [MMSE] scores 7 – 24 inclusive). 
5) Rosen-Modified Hachinski Ischemia Score of ≤4. 
6) Have a suitable caregiver to supervise the at-home administration of study drugs and observe 
for AEs. 
7) Patients will be required to have been treated with donepezil 5 or 10 mg/day (given once daily) 
for at least 4 weeks just prior to Day1 for Population (group) 1 or; 
Patients have never been treated with donepezil before (donepezil naïve) or who have not 
received any other AChEI for the past 6 months for Population (group) 2. 
8) Patients must be in generally good health as indicated by their medical history and physical 
examination, vital signs, electrocardiogram (ECG), and standard laboratory tests. 
Key exclusion criteria: 
The criteria for exclusion of a subject from enrollment in the study are as follows: 
1) Women of child bearing potential.  
2) History or presence of a seizure disorder. 
3) Current unstable peptic ulcer disease, urinary or gastric retention; asthma or obstructive 
pulmonary disease. 
4) History or presence of bladder outflow obstruction, gastrointestinal obstructive disorder or 
reduced GI motility, or narrow-angle glaucoma. 
5) History or presence of gastrointestinal, hepatic, or renal disease, or other condition known to 
interfere with the absorption, distribution, metabolism or excretion of drugs. 
6) Renal and hepatic dysfunction with: 
 
Total Bilirubin: >1.5 x UNL 


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 
AST: >2.5 x UNL 
 
ALT: >2.5 x UNL 
 
Serum Creatinine: >1.5 x UNL 
 
Creatinine Clearance: <30 mL/min (calculated by Cockcroft and Gault equation) 
7) History or presence of myasthenia. 
8) History or family history of Prolonged QT Syndrome. 
9) History of unexplained syncope or family history of unexplained syncope or sudden death. 
10) Myocardial infarction or hospitalization for congestive heart failure within 6 months. 
11) ECG findings of: 
 
Complete Left Bundle Branch Block; 
 
Ventricular pacing; 
 
2nd degree or 3rd degree AV block; 
 
Atrial fibrillation or atrial flutter; 
 
HR <45 or >100; 
 
PR >220 msec; or 
 
QTcF >450 msec in male, >470 msec in female 
12) Known hypersensitivity to donepezil, solifenacin or related drugs. 
13) History of drug significant allergy. 
14) History of substance abuse, known drug addiction, or positive test for drugs of abuse or alcohol.
15) Patients treated with the following medications within 8 weeks of screening 
 
Peripherally acting anticholinergics (such as drugs for the treatment of overactive bladder 
disorder), 
 
Psychoactive medications (including antipsychotics, antidepressants, anxiolytics or 
sedative hypnotics) having significant anticholinergic effects and/or believed to affect 
cognitive function.  
Other medications are acceptable, at the investigators discretion, if dosage is held stable for at 
least 4 weeks prior to screening and throughout the study. 
16) Patients considered unlikely to co-operate in the study, and/or poor compliance anticipated by 
the investigator. 
17) Patients hospitalized within 4 weeks of screening. 
18) Any other clinically relevant acute or chronic diseases which could interfere with patients’ 
safety during the trial, or expose them to undue risk, or which could interfere with study 
objectives. 
19) Patients who have participated in another clinical trial with an investigational drug within 
previous 30 days. 


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Investigational product (IP) 
Donepezil (Aricept® or generic equivalent): 5 mg, 10 mg tablet  
Solifenacin (Vesicare®): 5 mg, 10 mg tablets 
Placebo (Similar in size to donepezil 10 mg or solifenacin 5 mg/10 mg tablets 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duration of treatment:  
Screening: 4 weeks 
Dosing: up to 7 weeks 
Reference therapy, dosage and mode of administration:  
None 
Statistical Analysis: 
Since the objective of this study is to determine the optimal initial dose and subsequent dose titration 
schedule, the data will be analyzed only by means of descriptive statistics to reveal possible trends that 
will help guide the design of future, more definitive, clinical trials. 
Sample size calculations: 
No formal sample size calculation has been made. Based on experience from previous similar studies, a 
total 4-6 evaluable subjects per group per cohort is considered sufficient. 


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2 OBJECTIVES 
2.1 
Primary objective 
To determine the optimal initial dose and subsequent dose titration schedule (rate and 
increment) for CPC-201. 
2.2 
Secondary objective 
To evaluate the safety and tolerability of CPC-201 as a function of dose and initial rate of 
dose titration. 
 
3 INVESTIGATIONAL PLAN 
3.1 
Overall Study design 
This is a Phase II, ascending dose study of CPC-201 in patients with dementia of 
Alzheimer’s type to determine the optimal dose titration schedule. The study involves a 
step wise cohort design in two different patient populations: Group 1 will consist of 
patients who have been treated with donepezil 5 or 10 mg/day (given once daily) for at 
least 4 weeks just prior to Day1. Group 2 will consist of patients who have never been 
treated with donepezil before (donepezil naïve) or who have not received any other 
AChEI for the past 6 months. 
 
In this study, donepezil dose will be increased at weekly intervals, in accordance with the 
schedules given below, to its first intolerable dose (FID) or maximum allowed dose 
(MAD) 60 mg/day (40 mg/day for Cohort 3c) together with solifenacin 15 mg/day. If a 
patient does not tolerate a donepezil dose higher than 40mg/day with solifenacin 15 
mg/day, the solifenacin dose can be increased to 20mg/day per the Investigator’s decision. 
 
Cohort 1 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 30mg donepezil + 15mg solifenacin 
3rd week: 40mg donepezil + 15mg solifenacin 
4th week: 50mg donepezil + 15mg (or 20mg) solifenacin 
5th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 40mg donepezil + 15mg solifenacin 
3rd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*: The dose titration schedule of Cohort 2 and 3 may be altered based on Cohort 1 result. 
 
Per this amendment, patients currently treated with donepezil (Group 1) will receive 
solifenacin 15 mg/day during a two week run in period; donepezil treatment will continue 
at 10mg/day. Once on 15 mg/day of solifenacin for two weeks (based upon the 
investigator judgment), the donepezil dose will be increased at weekly or bi-weekly 


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intervals, in accordance with the schedules given below, to its first intolerable dose (FID) 
or maximum allowed dose (MAD) of 60mg/day  
 
Cohort 1b 
1st-2nd week: 10mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th week: 30mg donepezil + 15mg solifenacin 
5th week: 40mg donepezil + 15mg solifenacin 
6th week: 50mg donepezil + 15mg (or 20mg) solifenacin 
7th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2b 
1st – 2nd week: 10mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th week: 40mg donepezil + 15mg solifenacin 
5th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3b 
1st – 2nd week: 10mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*: The dose titration schedule of Cohorts 2 and 3 may be altered based on Cohort 1 result. 
 
Per this amendment, all patients not treated with an AchEI for at least 6 months (Group 2) 
will receive 15mg solifenacin for 2 weeks before starting donepezil. 
 
Each cohort will include approximately 6 patients donepezil-treated (Group 1) and 
approximately 6 patients not treated with an AchEI for at least 6 months (Group 2). 
Within each cohort, Group 2 patients will be enrolled only when at least 3 Group 1 
patients have completed dose titration per protocol.  
 
Patients will be enrolled in Cohort 2 only when patients enrolled in Cohort 1 have safely 
completed titration. Similary, patients will be enrolled in Cohort 3, only when patients 
enrolled in Cohort 2 have safely completed titration. 
 
Cohorts 1 and 2 were completed prior to this amendment. This amendment is to change 
the dosing regimen of cohort 3. All subjects entering the study in cohort 3 will start with 
a dose regimen of 10mg donepezil + 15mg solifenacin and will continue to increase the 
donepezil dose by 5mg increments every 7 days (or up to 14 days per PI discretion) up to 
40mg or the MTD. 
 
Cohort 3c 
1st  week: 10mg donepezil + 15mg solifenacin 
2nd week: 15mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th week: 25mg donepezil + 15mg solifenacin 
5th week: 30mg donepezil + 15mg solifenacin 
6th week: 35mg donepezil + 15mg solifenacin 
7th week: 40mg donepezil + 15mg solifenacin 
 
Patients reaching their FID or having completed one week treatment with donepezil 
60mg/day (40 mg/day for Cohort 3c), have two options.  


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Option 1: Patient will be allowed to immediately enter a long term extension at their 
maximum tolerated dose (MTD) or MAD. 
 
Option 2: Patients may choose not to enter the long term extension, in which case the 
Investigator will decide whether the patient should discontinue high dose of 
donepezil without down-titration, or whether donepezil should be 
downtitrated to their own standard of donepezil dose. Whatever the decision, 
the patient will be treated at least an additional 7 days with solifenacin 15 
mg/day. 
3.2 
Dose Escalation and Stopping rules 
For all patients, donepezil dose escalation will be discontinued if they manifest over a 24 
hour period after study drug administration the following symptoms judged by the 
investigator as possibly or probably study-drug related: 
 
 One (1) episode of vomiting, or 
 Two (2) episodes of severe retching (separated by more than one hour on the 
same day), or 
 One (1) episode of severe nausea (Grade 3; defined as nausea interfering with 
activities of daily living or inadequate oral caloric or fluid intake; tube feeding, 
total parenteral nutrition or hospitalization indicated) and/or severe abdominal 
discomfort (Grade 3; defined as severely interfering with activities of daily living), 
or 
 Three (3) episodes of moderate nausea (Grade 2; defined as subjectively 
symptomatic, but not interfering with activities of daily living)  and/or moderate 
abdominal discomfort (Grade 2; defined as interfering with function, but not 
interfering with activities of daily living) each on the same day, or  
 One (1) episode of moderate diarrhea (Grade 2; defined as 4 to 6 stools more than 
at baseline). 
 Any other circumstance that merits an adjustment in study drug dosage in the 
opinion of the investigator 
 
All those meeting one or more of the foregoing stopping rules will be withdrawn from 
dose titration and proceed in accordance with either of the two options given above. 
3.3 
Trial procedures 
3.3.1 
Schedule of Assessments 
The schedule of assessments for the study is provided in Table 1, Table 2 and Table 3. 


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3.3.2 
Study Procedure 
For each visit, procedures and assessments are listed in the order in which they should be 
performed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.5 
Discontinuation criteria 
3.5.1 
Discontinuation of donepezil dose escalation in individual subjects 
For all patients, donepezil dose escalation will be discontinued if they manifest over a 24 
hour period after study drug administration the following symptoms judged by the 
investigator as possibly or probably study-drug related: 
 
 One (1) episode of vomiting, or 
 Two (2) episodes of severe retching (separated by more than one hour on the 
same day), or 
 One (1) episode of severe nausea (Grade 3; defined as nausea interfering with 
activities of daily living or inadequate oral caloric or fluid intake; tube feeding, 
total parenteral nutrition or hospitalization indicated) and/or severe abdominal 
discomfort (Grade 3; defined as severely interfering with activities of daily living), 
or 
 Three (3) episodes of moderate nausea (Grade 2; defined as subjectively 
symptomatic, but not interfering with activities of daily living)  and/or moderate 
abdominal discomfort (Grade 2; defined as interfering with function, but not 
interfering with activities of daily living) each on the same day, or  
 One (1) episode of moderate diarrhea (Grade 2; defined as 4 to 6 stools more than 
at baseline). 
 Any other circumstance that merits an adjustment in study drug dosage in the 
opinion of the investigator 
3.5.2 
Discontinuation of individual subjects from the entire study 
During the study, the investigator or the sponsor may decide to discontinue a subject’s 
participation in the study in the following cases: 
 A protocol violation occurs; 
 A serious or intolerable (other than those listed in the discontinuation of 
rivastigmine escalation criteria) AE occurs; 
 The Sponsor or Investigator terminates the study. 
 The subject requests to be discontinued from the study. 
 The subject is non-compliant to any part of the study. 
 The Investigator feels it is not in the best interest of the subject to continue in the 
study. 
 
4 SELECTION OF SUBJECTS 
4.1 
Inclusion criteria 
The criteria for inclusion that each subject must meet to be enrolled in the study are as 
follows: 


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1. Signed an Institutional Review Board (IRB) approved informed consent document 
indicating that they understand the purpose of and procedures required by the 
study and are willing to participate in the study and comply with all study 
procedures and restrictions. Informed consent must be obtained from the patient 
and/or a designated representative prior to initiating screening procedures to 
evaluate eligibility of the study. 
2. Aged 50 – 89 years inclusive. 
3. Meeting the diagnosis of probable AD consistent with: 
- 
Revised National Institute on Aging-Alzheimer’s Association (NIA-ADA) 
criteria and  
- 
Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria.  
4. Of mild to severe severity (Mini-Mental Status Exam [MMSE] scores 7 – 24 
inclusive). 
5. Rosen-Modified Hachinski Ischemia Score of ≤4. 
6. Have a suitable caregiver to supervise the at-home administration of study drugs 
and observe for AEs. 
7. Patients will be required to have been treated with donepezil 5 or 10 mg/day 
(given once daily) for at least 4 weeks just prior to Day1 for Population (group) 1 
or; 
8. Patients have never been treated with donepezil before (donepezil naïve) or who 
have not received any other AChEI for the past 6 months for Population (group) 2. 
9. Patients must be in generally good health as indicated by their medical history and 
physical examination, vital signs, electrocardiogram (ECG), and standard 
laboratory tests. 
4.2 
Exclusion criteria 
The criteria for exclusion of a subject from enrollment in the study are as follows: 
1. Women of child bearing potential.  
2. History or presence of a seizure disorder. 
3. Current unstable peptic ulcer disease, urinary or gastric retention; asthma or 
obstructive pulmonary disease. 
4. History or presence of bladder outflow obstruction, gastrointestinal obstructive 
disorder or reduced GI motility, or narrow-angle glaucoma. 
5. History or presence of gastrointestinal, hepatic, or renal disease, or other 
condition known to interfere with the absorption, distribution, metabolism or 
excretion of drugs. 
6. Renal and hepatic dysfunction with: 
- 
Total Bilirubin: >1.5 x UNL 
- 
AST: >2.5 x UNL 


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- 
ALT: >2.5 x UNL 
- 
Serum Creatinine: >1.5 x UNL 
- 
Creatinine Clearance: <30 mL/min  
7. History or presence of myasthenia. 
8. History or family history of Prolonged QT Syndrome. 
9. History of unexplained syncope or family history of unexplained syncope or 
sudden death. 
10. Myocardial infarction or hospitalization for congestive heart failure within 6 
months. 
11. ECG findings of: 
- 
Complete Left Bundle Branch Block; 
- 
Ventricular pacing; 
- 
2nd degree or 3rd degree AV block; 
- 
Atrial fibrillation or atrial flutter; 
- 
HR <45 or >100; 
- 
PR >220 msec; or 
- 
QTcF >450 msec in male, >470 msec in female 
12. Known hypersensitivity to donepezil, solifenacin or related drugs. 
13. History of drug significant allergy. 
14. History of substance abuse, known drug addiction, or positive test for drugs of 
abuse or alcohol. 
15. Patients treated with the following medications within 8 weeks of screening 
- 
AChEIs (other than donepezil),  
- 
Peripherally acting anticholinergics (such as drugs for the treatment of 
overactive bladder disorder), 
- 
Psychoactive medications (including antipsychotics, antidepressants, 
anxiolytics or sedative hypnotics) having significant anticholinergic effects 
and/or believed to affect cognitive function.  
Other medications are acceptable, at the investigators discretion, if dosage is held 
stable for at least 4 weeks prior to screening and throughout the study. 
16. Patients considered unlikely to co-operate in the study, and/or poor compliance 
anticipated by the investigator. 
17. Patients hospitalized within 4 weeks of screening. 
18. Any other clinically relevant acute or chronic diseases which could interfere with 
patients’ safety during the trial, or expose them to undue risk, or which could 
interfere with study objectives. 
19. Patients who have participated in another clinical trial with an investigational drug 
within previous 30 days. 


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5 STUDY DRUG 
5.1 
Blinding 
This is a single-blind study. The subject, caregiver, and site personnel who assess MMSE 
and ADAS-Cog are blinded. 
 
5.3 
Description of Study Drug 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 


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Placebo tablet 
Placebo tablet is similar in size to donepezil 10 mg or solifenacin 5 mg/10 mg tablets. 
5.3.2 
Study drug manufacturing and labeling 
Donepezil and solifenacin will be purchased by 
 from a licensed supplier of 
these pharmaceuticals.  
 
The placebo tablet will be manufactured, packaged in bottle, labeled by 
 
 Label will include the following information: protocol 
number, quantity of tablets, required storage conditions, lot number, name and address of 
the manufacturer and the following cautionary statement: New Drug – Limited by 
Federal law to investigational use. 
5.3.3 
Study drug storage, handling and disposal 
At the site, all study drugs should be stored at room temperature 
 in a 
secure area accessible only to the designated qualified site personnel. All study drugs 
must be stored, inventoried and the inventories carefully and accurately documented 
according to applicable state, federal and local regulations, International Conference on 
Harmonisation (ICH) Guidelines, Good Clinical Practice (GCP) and study procedures. 
The study drug is to be prescribed only by the Investigator or his/her named sub-
investigator(s), and is to be used only in accordance with the protocol. The study drug 
must be distributed only to patients properly enrolled in the study. 
 
The Investigator must keep an accurate accounting of the study drug received from the 
Sponsor, including the temperature of the storage area, the amount of study drug 
dispensed to patients, amount of study drug returned to the Investigator by the patients, 
and the amount returned to the Sponsor upon completion of the study. A detailed 
inventory must be completed for the study drug.  
 
Unused study drug must be kept in a secure location for accountability and reconciliation 
by the study monitor. Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials. 
 
Unused study drug may be destroyed on site, per the site’s standard operating procedures 
(SOPs), but only after the Sponsor has granted approval for drug destruction. The monitor 
must account for all study drugs in a formal reconciliation process prior to study drug 
destruction. All study drug destroyed on site must be documented. Documentation must 
be provided to the Sponsor and retained in the Investigator’s study files. If a site is unable 
to destroy study drug appropriately, the site can return unused study drug to the Sponsor 
or designee upon request. The return of study drug or study drug materials must be 
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5.4 
Concomitant medication 
5.4.1 
Allowed Mediations 
Dosage of allowed concomitant medication should be stabilized for at least 4 weeks prior 
to screening and should remain constant during the course of the study. Patients on 
concomitant memantine should be on a stable dose for at least 3 months. With the 
exception of medications listed in the exclusion criteria (Section 4.2) and in Section 5.4.2 
below, concomitant medications will be allowed at the Investigator's discretion.  
 
All concomitant medications and therapies (prescription and OTC) should be recorded in 
the CRF, with generic name (if known, otherwise brand name), indication, dose, route, 
frequency, and date(s) of administration. Any change in any of these parameters during 
the study should be documented. 
5.4.2 
Prohibited Mediations 
Concomitant use of the following drugs is not allowed (such medications must have been 
discontinued at least 8 weeks prior to screening): 
 peripherally acting anticholinergics (such as drugs for the treatment of overactive 
bladder disorder), 
 psychoactive medications (including antipsychotics, antidepressants, anxiolytics 
or sedative hypnotics) having significant anticholinergic effects and/or believed to 
affect cognitive function 
 
In addition, the following drugs are prohibited during the study: 
 Strong CYP3A4 inhibitors  
 Strong CYP3A4 inducers  
 Strong CYP2D6 inhibitors 
  
Patients who use prohibited medications during the study listed above may be 
discontinued from study drug. Medications prescribed after patients have discontinued 
the study drug will not be considered as prohibited medications. 
Note: The discontinuation of a patient due to use of a prohibited medication is dependent 
upon the Sponsor's decision. The Investigator should contact the Sponsor prior to 
discontinuing a patient for disallowed medications. 
 
6 ASSESSMENT OF PHARMACOKINETICS 
6.1 
PK Blood Sampling Schedule and Sample Analysis 
The blood samplings will be performed at approximately 15 minutes before and 4 hours 
(± 15 min) after study drug administration at each visits. 


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7 SAFETY ASSESSMENTS 
7.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical-investigation subject 
administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. A TEAE is defined as any AE that occurs after 
administration of the first dose of study drug. An AE can therefore be an unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. The failure of the anticipated 
pharmaceutical action of an investigational drug does not constitute a related AE. 
AE rating 
The condition of the subjects will be closely monitored throughout the study. The 
investigator will collect the AEs reported spontaneously, observed, or elicited in response 
to a non-leading question (for example, "How have you been feeling since we last asked 
you?"). The investigator will record all AEs in the source records and the CRF. 
 
The intensity/severity of an AE will be rated as follows: 
Mild 
: Awareness of signs or symptoms, but no disruption of usual activity. 
Moderate 
: Event sufficient to affect usual activity (disturbing). 
Severe 
: Inability to work or perform usual activities (unacceptable). 
 
The causal relationship of an AE to the study drugs will be rated as follows: 
Not related 
: Temporal relationship of the onset of the event, relative to the 
administration of the product, is not reasonable or another cause can 
by itself explain the occurrence of the event 
Unlikely 
: Is general, this category can be considered applicable to those AEs 


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related 
which after careful medical consideration at the time they are 
evaluated, are judged to be unrelated to the study drug 
Related 
: AEs incontrovertibly related to the administration of the product. 
Of the above definitions, AEs related to study drug are considered adverse reactions, 
while “unlikely” and “not related” do not represent a causal relationship. 
 
The action taken with the study drug for an AE will be rated as product withdrawn, 
not changed, not applicable. AEs requiring therapy will be treated with recognised 
standards of medical care to protect the health and the well-being of the subject. 
 
The outcome of an AE will be rated as recovered, recovering, not recovered, 
recovered with sequellae or fatal. The investigator will follow up any AE until it is 
resolved or until the medical condition of the subject is stable. All relevant follow-up 
information will be collected. For AEs that are ongoing at the last visit, the 
investigator will make thorough efforts to document the outcome. 
7.2 
Serious Adverse Events (SAE) 
An SAE is any untoward medical occurrence that results in death, is life threatening, 
requires in-patient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. In 
addition, important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
An AE is life-threatening if the subject is at immediate risk of death from the event as it 
occurs, i.e. it does not include a reaction that, if it had occurred in a more serious form, 
might have caused death. For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not have been considered life-threatening, even though 
drug-induced hepatitis can be fatal. 
 
An AE is incapacitating or disabling if the experience resulted in a substantial and/or 
permanent disruption of the subject’s ability to carry out normal life functions. 
7.3 
Assessment of tolerability 
The FID of each patient will be recorded. 
7.4 
Safety Laboratory Test 
Blood samples will be collected as indicated in Table 1-4 for the following clinical 
laboratory tests: 
 
Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils) and platelet 
count. 
 


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Serum chemistry: calcium, sodium, chloride, potassium, blood urea nitrogen, glucose, 
total bilirubin, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, 
alanine aminotransferase, creatinine, calculated creatinine clearance,  uric acid, 
phosphorous, total protein, albumin, and globulin. 
 
 
 
7.5 
Urinalysis 
Urine samples will be collected as indicated in Table 1-4 for the following tests: glucose, 
bilirubin, ketones, specific gravity, blood, pH, protein, urobilinogen, nitrites, and 
leukocytes and, if necessary, microscopic examination. 
7.6 
Vital signs and body weight 
Vital signs, including blood pressure, heart rate, respiratory rate, and temperature, will be 
measured after the patient rests in the supine position for at least 5 minutes.  
 
Body weight will be measured as indicated in Table 1-4.  
7.7 
12-Lead ECGs 
A standard 12-lead ECG will be recorded as indicated in Table 1-4. The Investigator will 
evaluate the ECG results as normal, abnormal, not clinically significant, or abnormal, 
clinically significant. 
 
If QTcF on an on treatment ECG is ≥500 msec then hold treatment and perform 3 repeat 
ECGs over 20-60 min; if the mean QTcF of the three ECGs is ≥500 msec, withhold 
treatment and perform a repeat ECG the following day; if the QTcF has returned to 
baseline, dosing may resume..  
7.8 
MMSE 
MMSE will be assessed by blinded rater at visits indicated in Table 1-4. 
7.9 
ADAS-Cog 
ADAS-Cog will be assessed by blinded rater at visits indicated in Table 1-4. 
7.10 Modified C-SSRS 
Modified C-SSRS will be assessed by a qualified and experienced clinician who does not 
perform psychometric at visits indicated in Table 1-4. 
 


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8 PROCEDURES FOR REPORTING TEAES AND SERIOUS 
ADVERSE EVENTS 
8.1 
Reporting TEAEs 
All TEAEs, regardless of seriousness, severity or presumed relationship to study therapy, 
must be recorded using medical terminology in the source document and transcribed into 
the CRF. Whenever possible, the diagnosis should be given when signs and symptoms 
are due to a common etiology (e.g. cough, runny nose, sneezing, sore throat, and head 
congestion should be reported as “upper respiratory infection” instead of identifying and 
listing the individual signs and symptoms). The Investigator must record, in the source 
document and transcribe into the AE page of the CRF, his or her medical assessment of 
the severity of the event and the relationship of the AE to study drug. 
 
All TEAEs must be followed until they have resolved or until a stable clinical endpoint is 
reached. All measures required for managing the TEAE and the ultimate outcome of the 
TEAE must be recorded in the source document and reported in the CRF. 
8.2 
Reporting Serious Adverse Events 
When the Investigator or designee becomes aware that an SAE has occurred, the Sponsor 
representative must be notified by both telephone and fax, regardless of the relationship 
(or lack thereof) of the SAE to study drug within 24 hours of the event. All SAEs must be 
submitted to the Sponsor as a written report, as well as reported verbally. A follow-up 
report must be submitted to the Sponsor as requested when pertinent information 
becomes available and if additional information is requested. 
 
The Investigator is responsible for ensuring that the IRB is informed of this information 
within appropriate IRB established timelines. 
 
ANY SAE OR ADR, INCLUDING ANY OUTCOME OF DEATH DUE TO ANY 
CAUSE THAT OCCURS DURING THIS STUDY MUST BE REPORTED 
IMMEDIATELY TO THE SPONSOR REPRESENTATIVE. 
This verbal and faxed report must be followed no later than 3 working days by a written 
report signed by the Investigator. The Sponsor is responsible for submitting the report 
to all applicable regulatory authorities. 
 
 
 
 
 
 
 
 


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9 STATISTICS 
Since the objective of this study is to determine the optimal initial dose and subsequent 
dose titration schedule, the statistics are not applicable. 
The data will be analyzed only by means of descriptive statistics to reveal possible trends 
that will help guide the design of future, more definitive, clinical trials. 
9.1 
Assessment of Safety and Tolerability and  
Safety and tolerability parameters will be analyzed as a function of dose and dose 
titration schedule. 
9.1.1 
Assessment of MTD  
Descriptive statistics will be presented for the MTD and the FID for each patient in each 
dose titration schedule. 
9.1.2 
Adverse Events 
Data Listings will present the verbatim-reported event along with the preferred term and 
SOC, onset and stop dates, severity, relatedness, SAE status, action taken and outcome. 
For summaries by severity, the most severe event episode will be counted if a subject has 
more than one event within the same coded term. For summaries of treatment-associated 
events, the subject will be counted as “associated” for that term if a subject has more than 
one event within the same coded term or if one event is considered “not associated” and 
the other “associated”. 
 
Unless otherwise indicated, AE summary tables will be presented by study period, 
treatment group, SOC, and preferred term for each study period. 
9.1.3 
Laboratory Tests (Safety laboratory test and urinalysis) 
For the continuous laboratory parameters, descriptive statistics will be presented. 
Additionally, parameters will be categorized as low, normal or high according to 
laboratory range specifications. The number and percentage of subjects will be presented 
by dosing cohort and treatment arm.  
9.1.4 
ECGs 
The overall interpretation of the ECG results will be presented as normal, abnormal (not 
clinically significant) and abnormal (clinically significant) by time point and study period.  
9.1.5 
Vital Signs and weight 
Descriptive statistics will be presented for each vital sign measurement recorded at each 
time point during each study period.  
9.2 
Pharmacokinetics 
Blood concentration results of donepezil and solifenacin for each subject will be 
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9.3 
Patient Disposition  
Disposition of all subjects will be summarized descriptively. 
9.4 
Demographics and Baseline Characteristics 
Individual subject demographic and baseline characteristics data will be presented in 
subject data listings. Concomitant medications (all recorded medications) will be listed 
for enrolled subjects. The listing will be sorted by start date of medication within the 
standard sort order. The listing will include all collected information. 
9.5 
Protocol Deviations 
All protocol deviations will be listed by subject number. 
9.6 
Compliance  
Dosing information collected on the CRF will be listed for each subject. Compliance will 
be summarized by presenting the numbers and percentages of subjects receiving each 
dose of study drug. 
 
10 ACCESS TO SOURCE DATA/DOCUMENTS 
Checking of case report forms (CRF’s) for completeness and clarity and cross-checking 
with source documents will be required to monitor the progress of the study. The 
Monitors are entitled to compare CRF entries with source data and to inform the 
investigator about errors and omissions. The monitor will request correction / 
clarification from the investigator using electronic data clarifications that should be 
answered and closed as quickly as possible. The Investigator will provide direct access to 
source data/documents for the Sponsor’s designated representatives (monitors and 
auditors) as well as IRB/IEC members and regulatory inspections. 
 
Regulatory authorities and/or the Sponsor’s clinical quality assurance personnel may also 
carry out source data checks and/or on-site audit inspections. These will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator 
is to give the Sponsor whatever support is necessary. 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Study Monitoring 
The study will be initiated by the Sponsor during an on-site visit after all required study 
documents have been sent to the Sponsor and approved. A monitor will perform 
subsequent on-site monitoring visits as frequently as deemed necessary. At these visits, 
the monitor will compare the data entered onto the CRFs with the hospital or clinic 
records (source documents) and check for protocol compliance, including a review of 
records of informed consent, all subject visit dates, all AEs, all concomitant medications, 


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and key efficacy observations. In addition, drug accountability records will be reviewed 
and findings from this review will be discussed with the Investigator. 
 
The Sponsor expects that during monitoring visits, the study coordinator, Investigator, 
CRFs and source documentation will be available and a suitable environment will be 
provided for review of study-related documents. 
11.2 Audits and Inspections 
Trial sites, facilities, laboratories and all data (including sources) and documentation must 
be available for GCP audit by the Sponsor or inspection by competent authorities.  Any 
aspect of the trial may be subject to audit by the Sponsor and/or inspection by regulatory 
authorities or the IRB.  Such audits/inspections may take place at the Sponsor’s site(s) or 
at the trial site including laboratories, pharmacies etc. In case of audit, the monitor will 
announce this in advance to the Investigator (or representative) and be present at the 
particular trial site during the audit. 
 
The site staff should assist in all aspects of audit/inspection. 
11.3 Data Quality Assurance 
The Sponsor and their designated Contract Research Organization (CRO) will implement 
a system of quality assurance, including all elements described in this protocol.  Within 
this system the CRO SOPs will be implemented to ensure that the clinical trial is 
conducted in compliance with regulatory requirements and GCP.  Quality control is 
applied to each stage of data handling to ensure that data are accurate, reliable and 
processed correctly. 
 
12 ETHICS AND ADMINISTRATIVE ISSUES 
12.1 Ethical conduct of the trial 
This protocol was designed and will be conducted, recorded and reported in compliance 
with the principles of Good Clinical Practice (GCP) regulations and in accordance with 
the principles outlined in the Declaration of Helsinki. These requirements are stated in 
federal regulations as well as ICH of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, “E6 Guideline for Good Clinical Practice”. The Sponsor 
representative will review these obligations with the Investigator prior to the initiation 
and throughout the course of the study. The Investigator or any of his or her staff should 
contact the Sponsor representative for any questions or issues regarding compliance with 
GCP/ICH guidelines. 
 
This study will be conducted in compliance with IRB guidelines and in accordance with 
applicable regulations regarding clinical safety data management. In addition this study 
will adhere to all local regulatory requirements and requirements for data protection. 
The Investigator should refer to 21 CFR Part 312, Subpart D, ICH Guidelines E6 for 
clarification of the Investigator’s responsibilities for fulfillment of GCP Guidelines for 
Investigator’s qualifications and agreements, adequate resources, medical care of study 


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subjects, communication with IRB, compliance with the protocol, responsibility for 
investigational products, randomization procedures, informed consent, records and 
reporting, premature termination or suspension of a study and final reports. 
 
Before initiating the study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject recruitment procedures (e.g. 
advertisements), and any written information to be provided to subjects, and a statement 
from the IRB that they comply with GCP requirements. The IRB approval must identify 
the protocol version as well as the documents reviewed. 
12.2 Institutional review board/independent ethics committee (IRB/IEC) and 
Regulatory Authority 
All protocols and protocol amendments must be signed and dated by the Investigator and 
approved by the IRB prior to implementation. The Investigator must provide an annual 
report to the IRB on the progress of the study in compliance with 21 CFR Part 56 and the 
IRB’s policies and procedures. The Investigator must provide notification to the IRB of 
the completion, termination or discontinuation the study. It is required that a yearly 
review of the protocol by the IRB be documented in a letter from the IRB. 
12.3 Subject informed consent 
Executed informed consent, and other locally required documents such as those related to 
Protected Health Information, are required. The consent form must be executed prior to 
performing any study-related activities that are not part of the subject’s routine care. The 
consent form that is used must be approved by both the reviewing IRB and by the 
Sponsor representative. 
12.4 Subject Data Protection 
Each subject must provide written informed consent as well as any authorizations 
required by local law (e.g. authorizations related to Protected Health Information). The 
Investigator agrees not to use or disclose Protected Health Information other than as 
permitted or required by the subject authorization or as required by law.  
12.5 Data Monitoring Committee 
Not applicable. 
12.6 Financial Disclosure 
Study personnel on the Form FDA 1572 will complete a financial disclosure form at the 
beginning of the study. New study personnel added to Form FDA 1572 must also meet 
these requirements. 
12.7 Investigator Obligations 
The Investigator should refer to 21 CFR Part 312, Subpart D, ICH Guidelines E6 for 
clarification of the Investigator’s responsibilities to fulfill GCP Guidelines for 
Investigator’s qualifications and agreements, adequate resources, medical care of study 


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subjects, communication with IRB, compliance with the protocol, responsibility for 
investigational products, randomization procedures, informed consent, records and 
reporting, premature termination or suspension of a study and final reports. 
 
The Investigator agrees when signing the protocol to adhere to the instructions and 
procedures described in it, and thereby, to adhere to the principles of GCP that it 
conforms to. 
12.8 Changes to the Protocol 
All protocols and protocol amendments must be signed and dated by the Investigator and 
approved by the IRB prior to implementation. 
12.9 Confidentiality/Publication of the Study 
All information supplied to the Investigator by a Sponsor representative and not 
previously published is considered confidential and remains the sole property of the 
Sponsor. The Investigator must agree to use this information only to accomplish this 
study, and must not use it for other purposes without the Sponsor’s written consent. 
The information developed in this study will be used by the Sponsor in connection with 
the continued development of this product and thus may be disclosed as required to other 
clinical Investigators or government regulatory agencies. To permit the information 
derived from the clinical studies to be used, the Investigator is obligated to provide the 
Sponsor with all data obtained in the study. 
 
No publication of any study data, results, other deliverables or records is permitted by the 
Investigator.  
12.10 Discontinuation of entire study 
The Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study either at a single site or at all sites at any time for reasons including, but not limited 
to, safety or ethical issues or severe non-compliance.  
 
In particular cases, the study may be terminated at a single investigational site, if the 
Sponsor has relevant reasons, e.g., suspicion of a deceit or conduct of the study which is 
not in accordance to the guidelines for GCP. 
 
If the Sponsor determines such action is needed, the Sponsor will discuss this with the 
Investigator (including the reasons for taking such action) at that time. When feasible, the 
Sponsor will provide advance notification to the Investigator of the impending action 
prior to it taking effect. 
 
The Sponsor will promptly inform all other Investigators and/or institutions conducting 
the study if the study is suspended or terminated for safety reasons, and will also inform 
the regulatory authorities of the suspension or termination of the study and the reason(s) 
for the action. If required by applicable regulations, the investigator must inform the 
Ethics Committee promptly and provide the reason for the suspension or termination. 
 


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13 DATA HANDLING AND RECORD KEEPING 
13.1 Inspection of Records 
Local regulatory agencies may request access to all study records, including source 
documents, for inspection and copying, in keeping with U.S. regulations. The 
Investigator should immediately notify the Sponsor of any upcoming regulatory agency 
inspections. The Sponsor may also perform an audit of the data if deemed necessary. 
The Investigator will be responsible for the accuracy of the data entered in the CRFs. The 
Investigator will permit designated Sponsor representatives and regulatory bodies to have 
direct access to the source documents to verify data represented in the CRFs. 
13.2 Retention of Records 
All source documents (e.g. informed consent forms, laboratory reports, progress notes, 
medical histories, physical and diagnostic findings, diagnosis and pharmacy records, and 
study drug dispensing/disposition records) that support data in the CRFs of each study 
subject must be retained in the files of the Investigator for at least two years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region; or at least two years have elapsed 
since the formal discontinuation of clinical development of the investigational drug. 
These documents should be retained for a longer period, however, if required by 
applicable regulatory requirements. 
 
If the Investigator retires, relocates, or for any other reason withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. Prior to transfer, the Sponsor representative must be 
notified in writing of the name and address of the new custodian. 


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14 REFERENCES 
Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti BJ, Koeppe RA, Meltzer CC, 
Constantine G, Davis JG, Mathis CA, Dekosky ST, Moore RY. Degree of inhibition of 
cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in 
Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2005;76(3):315-9. 
 
Bontempi B, Whelan KT, Risbrough VB, Lloyd GK, Menzaghi F. Cognitive enhancing 
properties and tolerability of cholinergic agents in mice: a comparative study of nicotine, 
donepezil, and SIB-1553A, a subtype-selective ligand for nicotinic acetylcholine 
receptors. Neuropsychopharmacology. 2003;28(7):1235-46.  
 
Brvar M, Mozina M, Bunc M. Poisoing with rivastigmine.  Clin Toxicol (Phila). 2005; 
43(7): 891-2. 
 
Cheng DH, Tang XC. Comparative studies of huperzine A, E2020, and tacrine on 
behavior and cholinesterase activities. Pharmacol Biochem Behav. 1998;60(2):377-86. 
 
Doody R, Corey-Bloom J, Zhang R, Honglan L, Ieni J, Schindler R. Safety and  
tolerability of donepezil at doses up to 20 mg/day – Results froma p ilot study in patients 
with Alzheimer’s Disease. Drugs, Aging. 2008; 25(2): 163-174. 
 
Exelon® Capsules and Oral Solution Prescribing Information.  Revised:  October 2013.  
Novartis Pharmaceuticals Corporation. 
 
Faber RA, Negro PJ. Enhancing the tolerability of tacrine with propantheline.  Am J. 
Psychiatry. 1999; Jan: 156. 
 
Farlow MR, Salloway S, Tariot PN, Yardley J, Moline ML, Wang Q, Brand-Schieber E, 
Zou H, Hsu T, Satlin A. Effectiveness and tolerability of high-dose (23 mg/d) versus 
standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, 
randomized, double-blind study. Clin Ther. 2010b;32(7):1234-51. 


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FDA Approval Package for NDA 20-690: Aricept® (donepezil hydrochloride) 5 and 10 
mg tablets.  Obtained under the Freedom of Information Act.  Approval date:  November 
25, 1996.   
 
Giacobini E, Spiegel R, Enz A, Veroff AE, Cutler NR. Inhibition of acetyl- and butyryl-
cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by 
rivastigmine: correlation with cognitive benefit. J Neural Transm. 2002;109(7-8):1053-65. 
 
Greene Y, Noviasky J, Tariot P. Donepezil overdose. J Clin Psychiatry 1999; Jan. 60:1. 
 
Hoffman RS, Manini AF, Russell-Haders AL, Felberbaum M, Mercurio-Zappala M. Use 
of oralidoxime without atropine in rivastigmine (carbamate) toxicity. Hum Exp Toxicol. 
2009;28(9):599-602. 
 
Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of 
cholinesterase inhibitors. Clin Pharmacokinet. 2002;41(10):719-39. 
 
Kaasinen V, Någren K, Järvenpää T, Roivainen A, Yu M, Oikonen V, Kurki T, Rinne JO. 
Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in 
Alzheimer's disease. J Clin Psychopharmacol. 2002;22(6):615-20. 
 
Kosasa T, Kuriya Y, Yamanishi Y. Effect of donepezil hydrochloride (E2020) on 
extracellular acetylcholine concentration in the cerebral cortex of rats. Jpn J Pharmacol. 
1999;81(2):216-22. 
 
Kosasa T, Kuriya Y, Matsui K, Yamanishi Y. Inhibitory effect of orally administered 
donepezil hydrochloride (E2020), a novel treatment for Alzheimer's disease, on 
cholinesterase activity in rats. Eur J Pharmacol. 2000;389(2-3):173-9. 
 
Kuhl DE, Minoshima S, Frey KA, Foster NL, Kilbourn MR, Koeppe RA. Limited 
donepezil inhibition of acetylcholinesterase measured with positron emission tomography 
in living Alzheimer cerebral cortex. Ann Neurol. 2000; 48(3):391-5. 


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Lai M, Moen M, Ewald MB. Pesticide-like poisoning from a prescription drug. N Engl J 
Med.  2005; 353:327-318. 
 
Perara P, Shahmy S, Gawarammana I, Dawson A. Comparison of two commonly 
practiced atropinisation regimens in acute organophosphorus and carbamate poisoning, 
doubing doses vs ‘ad hoc’ – a prospective ovservational study. Hum Exp Toxicol. 2008; 
June: 27(6): 513-518. 
 
Politis AM, Theleritis C, Passa M, Maillis A, Papadimitriou GN. Improvement of 
cognitive dysfunction with high-dose rivastigmine. Psychosomatics. 2010;51(1):89-90. 
 
Rogers SL, Friedhoff LT, Donepezil Study Group. The efficacy and safety of donepezil 
in patients with Alzheimer's disease: results of a US Multicentre, Randomized, Double-
Blind, Placebo-Controlled Trial. Dementia. 1996;7(6):293-303. 
 
Rogers SL, Cooper NM, Sukovaty R, Pederson JE, Lee JN, Friedhoff LT. 
Pharmacokinetic and pharmacodynamic profile of donepezil HCl following multiple oral 
doses. Br J Clin Pharmacol. 1998a;46 Suppl 1:7-12. 
 
Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and 
global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. 
Donepezil Study Group. Arch Intern Med. 1998b;158(9):1021-31. 
 
Rupniak NM, Tye SJ, Field MJ. Enhanced performance of spatial and visual recognition 
memory tasks by the selective acetylcholinesterase inhibitor E2020 in rhesus monkeys. 
Psychopharmacology (Berl). 1997;131(4):406-10. 
 
Sener S and Ozsarac M. Case of the month: rivastigmine (Exelon) toxicity with evidence 
of respiratory depression.  Emerg Med J. 2006 Jan; 23(1): 62-5. 
 
Shepherd G, Klein-Schwartz W, Edwards R. Donepezil overdose: a tenfold dosing error. 
Ann Phaarmacother, 1999; Jul-Aug: 33(7-8): 812-5. 


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Shinotoh H, Fukushi K, Nagatsuka S, Irie T. Acetylcholinesterase imaging: its use in 
therapy evaluation and drug design. Curr Pharm Des. 2004;10(13):1505-17. 
 
Smith RD, Kistler MK, Cohen-Williams M, Coffin VL. Cholinergic improvement of a 
naturally-occurring memory deficit in the young rat. Brain Res. 1996;707(1):13-21.  
 
Sugimoto H, Ogura H, Arai Y, Limura Y, Yamanishi Y. Research and development of 
donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn J Pharmacol. 
2002;89(1):7-20. 
 
Suh GH, Yeon Jung H, Uk Lee C, Hoon Oh B, Nam Bae J, Jung HY, Ju YS, Kil Yeon B, 
Park J, Hong I, Choi S, Ho Lee J; Korean Galantamine Study Group. A prospective, 
double-blind, community-controlled comparison of three doses of galantamine in the 
treatment of mild to moderate Alzheimer's disease in a Korean population. Clin Ther. 
2004;26(10):1608-18. 
 
Tiseo PJ, Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamic profile of 
donepezil HCl following evening administration. Br J Clin Pharmacol. 1998a;46 Suppl 
1:13-8.  
 
Tokita K, Yamazaki S, Yamazaki M, Matsuoka N, Mutoh S. Combination of a novel 
antidementia drug FK960 with donepezil synergistically improves memory deficits in rats. 
Pharmacol Biochem Behav. 2002;73(3):511-9. 
 
Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, Zechner S, 
Nagel J, Lane R. A six-month double-blind, randomized, placebo-controlled study of a 
transdermal patch in Alzheimer's disease--rivastigmine patch versus capsule. Int J Geriatr 
Psychiatry. 2007;22(5):456-67. 
 
Yano H, Fukuhara Y, Wada K, Kowa H, Nakashima K. A case of acute choinergic 
adverse effects induced by donepezil overdose: a follow-up of clinical course and plasma 
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Zhang WW, Xu ZP, Cui YY, Wang H, Song MK, Li J, Shao BY, Xia Z, Chen HZ.  
Peripheral cholinoceptor antagonist anisodamine counteracts cholinergic adverse effects 
and facilitates cognitive amelioration of rivastigmine. J Neural Transm. 2009 Dec; 
116(12): 1643-9. 


NCT02549196 
 
Study ID: CPC‐001‐12 
 
Title:  A phase II, dose titration study of CPC‐201 in Patients with Dementia of Alzheimer’s Type 
 
Protocol Amendment 2 Date: 04 Jan 2016 


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Investigational Product:  
CPC-201 (donepezil plus solifenacin)  
Indication:  
 
 
Treatment of Dementia of Alzheimer Type  
Clinical phase:  
 
Phase II, Dose Titration Study  
Study code: 
 
 
CPC-001-12 
 
 
 
Dose titration study 
 
 
A PHASE II, DOSE TITRATION STUDY OF CPC-201 IN PATIENTS 
WITH DEMENTIA OF ALZHEIMER’S TYPE 
 
 
Version 2, date: January 4, 2016 
 
 
 
Sponsor: 
 
 
Chase Pharmaceuticals Corporation 
 
 
 
 
1825 K Street, NW, Suite 520 
 
 
 
 
Washington, DC 20006 
 
 
 
 
 
 
 
 
Confidential Information 
This material is the property of Chase Pharmaceuticals Corporation. 
It may not be used, divulged, published or otherwise disclosed without prior written consent. 
GCP compliance 
The study will be performed in compliance with Good Clinical Practices (GCP)  
and in accordance with the Declaration of Helsinki 
 
 
 




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Signature page for the Investigator  
This Clinical Trial will be conducted in accordance with the study protocol, the 
International Conference on Harmonization (ICH), Good Clinical Practices (GCP), the 
ethical principles outlined in the current valid version of the Declaration of Helsinki and 
the European as well as other local regulations. 
 
As the Investigator for the Trial, I have read this protocol dated January 4, 2016 and 
agree to follow this protocol in accordance with all the above-mentioned regulations. 
…………………………………….. 
 
Date: ……………………….... 
 
 
 
 
 
 
 


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Table of contents  
 
LIST OF TABLES ................................................................................................................................................ 8 
PROTOCOL SUMMARY ................................................................................................................................... 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
OBJECTIVES ........................................................................................................................................... 23 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................... 23 
2.2 
SECONDARY OBJECTIVE .......................................................................................................................... 23 
3 
INVESTIGATIONAL PLAN ................................................................................................................... 23 
3.1 
OVERALL STUDY DESIGN ........................................................................................................................ 23 
3.2 
DOSE ESCALATION AND STOPPING RULES ............................................................................................... 25 
3.3 
TRIAL PROCEDURES ................................................................................................................................ 25 
3.3.1 Schedule of Assessments ..................................................................................................................25 
3.3.2 Study Procedure................................................................................................................................29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.5 
DISCONTINUATION CRITERIA .................................................................................................................. 33 
3.5.1 Discontinuation of donepezil dose escalation in individual subjects ................................................33 
3.5.2 Discontinuation of individual subjects from the entire study ...........................................................33 
4 
SELECTION OF SUBJECTS .................................................................................................................. 33 
4.1 
INCLUSION CRITERIA ............................................................................................................................... 33 
4.2 
EXCLUSION CRITERIA .............................................................................................................................. 34 
5 
STUDY DRUG .......................................................................................................................................... 36 
5.1 
BLINDING ................................................................................................................................................ 36 
5.2 
STUDY DRUG ADMINISTRATION ............................................................................................................. 36 
5.3 
DESCRIPTION OF STUDY DRUG ............................................................................................................... 36 
 
5.3.2 Study drug manufacturing and labeling ............................................................................................37 
5.3.3 Study drug storage, handling and disposal .......................................................................................37 
5.4 
CONCOMITANT MEDICATION ................................................................................................................... 38 
5.4.1 Allowed Mediations .........................................................................................................................38 
5.4.2 Prohibited Mediations ......................................................................................................................38 
6 
ASSESSMENT OF PHARMACOKINETICS ....................................................................................... 38 
6.1 
PK BLOOD SAMPLING SCHEDULE AND SAMPLE ANALYSIS .................................................................... 38 
 
 
 
 
7 
SAFETY ASSESSMENTS ....................................................................................................................... 39 


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7.1 
ADVERSE EVENTS ................................................................................................................................... 39 
7.2 
SERIOUS ADVERSE EVENTS (SAE).......................................................................................................... 40 
7.3 
ASSESSMENT OF TOLERABILITY .............................................................................................................. 40 
7.4 
SAFETY LABORATORY TEST ................................................................................................................... 40 
7.5 
URINALYSIS ............................................................................................................................................ 41 
7.6 
VITAL SIGNS AND BODY WEIGHT ............................................................................................................. 41 
7.7 
12-LEAD ECGS ....................................................................................................................................... 41 
7.8 
MMSE .................................................................................................................................................... 41 
7.9 
ADAS-COG ............................................................................................................................................ 41 
7.10 MODIFIED C-SSRS ................................................................................................................................. 41 
8 
PROCEDURES FOR REPORTING TEAES AND SERIOUS ADVERSE EVENTS ........................ 42 
8.1 
REPORTING TEAES................................................................................................................................. 42 
8.2 
REPORTING SERIOUS ADVERSE EVENTS ................................................................................................. 42 
9 
STATISTICS ............................................................................................................................................. 43 
9.1 
ASSESSMENT OF SAFETY AND TOLERABILITY AND ................................................................................. 43 
9.1.1 Assessment of MTD .........................................................................................................................43 
9.1.2 Adverse Events .................................................................................................................................43 
9.1.3 Laboratory Tests (Safety laboratory test and urinalysis) ..................................................................43 
9.1.4 ECGs ................................................................................................................................................43 
9.1.5 Vital Signs and weight ......................................................................................................................43 
9.2 
PHARMACOKINETICS ............................................................................................................................... 44 
9.3 
PATIENT DISPOSITION ............................................................................................................................. 44 
9.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................................................................... 44 
9.5 
PROTOCOL DEVIATIONS .......................................................................................................................... 44 
9.6 
COMPLIANCE .......................................................................................................................................... 44 
10 
ACCESS TO SOURCE DATA/DOCUMENTS ..................................................................................... 44 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 44 
11.1 STUDY MONITORING ............................................................................................................................... 44 
11.2 AUDITS AND INSPECTIONS ...................................................................................................................... 45 
11.3 DATA QUALITY ASSURANCE .................................................................................................................. 45 
12 
ETHICS AND ADMINISTRATIVE ISSUES ........................................................................................ 45 
12.1 ETHICAL CONDUCT OF THE TRIAL ........................................................................................................... 45 
12.2 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) AND REGULATORY 
AUTHORITY ...................................................................................................................................................... 46 
12.3 SUBJECT INFORMED CONSENT ................................................................................................................. 46 
12.4 SUBJECT DATA PROTECTION ................................................................................................................... 46 
12.5 DATA MONITORING COMMITTEE ............................................................................................................ 46 
12.6 FINANCIAL DISCLOSURE ......................................................................................................................... 47 
12.7 INVESTIGATOR OBLIGATIONS ................................................................................................................. 47 
12.8 CHANGES TO THE PROTOCOL .................................................................................................................. 47 
12.9 CONFIDENTIALITY/PUBLICATION OF THE STUDY .................................................................................... 47 
12.10 DISCONTINUATION OF ENTIRE STUDY ..................................................................................................... 47 
13 
DATA HANDLING AND RECORD KEEPING ................................................................................... 48 
13.1 INSPECTION OF RECORDS ........................................................................................................................ 48 
13.2 RETENTION OF RECORDS ........................................................................................................................ 48 
14 
REFERENCES .......................................................................................................................................... 49 
 


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LIST OF ABBREVIATIONS  
 
ACh ......................... Acetylcholine 
AChEI ..................... Acetylcholinesterase Inhibitor 
AD ........................... Alzheimer’s disease 
ADAS-cog...............Alzheimer’s disease Assessment Scale-cognition 
ADR.........................Adverse Drug Reaction 
AE ........................... Adverse Event 
AV...........................Atrioventricular 
CFS...................... ... Cerebrospinal Fluid 
CNS ......................... Central Nervous System 
CRF ......................... Case Report Form  
CRO ........................ Contract Research Organization 
C-SSRS. .................. Columbia-Suicide Severity Rating Scale 
DSM. ....................... Diagnostic and Statistical Manual of Mental Disorders 
E2020. ..................... Donepezil  
ECG ......................... Electrocardiogram 
FDA ......................... Food and Drug Administration 
FID .......................... First Intolerable Dose 
GCP ......................... Good Clinical Practice 
GI ............................ Gastrointestinal 
HR. .......................... Heart Rate 
ICD. ......................... Implantable Cardiac Defibrillator 
ICH .......................... International Conference On Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IEC .......................... Independent Ethics Committee 
IRB .......................... Institutional Review Board 
KG. .......................... Kilogram 
MAD………………Maximum Allowed Dose 
MEDDRA. .............. Medical Dictionary for Regulatory Activities 
MG. ......................... Milligram 
ML. .......................... Milliliter 
MMSE. .................... Mini Mental Status Examination 
MSEC. ..................... Millisecond 
MTD ........................ Maximum Tolerated Dose 
NDA. ....................... New Drug Application 
NG/ML. ................... Nanogram/Milliliter 
NIA-ADA. .............. National Institute on Aging – Alzheimer’s Disease Association 
OAB. ....................... Overactive Bladder Disorder 
OTC. ........................ Over-the-Counter 
QTC. ........................ Corrected QT interval 
QTCF. ..................... Corrected QT intervals by Fridericia's formula 
PR Interval. ............. On ECG, time from onset of P wave to start of QRS Complex 
QRS complex. ......... On ECG, central part of tracing, Q,R and S waves 


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QT interval. ............. On ECG, interval between start of Q wave and end of the T 
wave 
SOC ......................... System Organ Class 
SOP ......................... Standard Operating Procedures 
SAE ......................... Serious Adverse Event 
SEM. ....................... Standard Error of Mean 
TEAE ...................... Treatment Emergent Adverse Event 
UNL. ....................... Upper Normal Limit 
US ........................... United States 
WHO ....................... World Health Organization 


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LIST OF TABLES 
 
 
 
 
 
Table 5: Combination of tablets for each dosage .................................................................................. 36 
 


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PROTOCOL SUMMARY 
Name of Sponsor/Company: 
Chase Pharmaceuticals Corporation 
Name of Investigational Product: 
CPC-201: Donepezil plus solifenacin 
Name of Active Ingredient: 
Donepezil, solifenacin 
Title of Study: 
A phase II, dose titration study of CPC-201 in Patients with Dementia of Alzheimer’s Type 
Number of clinical centers: 
Multicenter 
Objectives:  
Primary: 
• 
To determine the optimal initial dose and subsequent dose titration schedule (rate and 
increment) for CPC-201. 
Secondary: 
• 
To evaluate the safety and tolerability of CPC-201 as a function of dose and initial rate of dose 
titration. 
Methodology:  
This is a Phase II, ascending dose study of CPC-201 in patients with dementia of Alzheimer’s type to 
determine the optimal dose titration schedule. The study involves a step wise cohort design in two 
different patient populations: Group 1 will consist of patients who have been treated with donepezil 5 or 
10 mg/day (given once daily) for at least 4 weeks just prior to Day1. Group 2 will consist of patients who 
have never been treated with donepezil before (donepezil naïve) or who have not received any other 
AChEI for the past 6 months. 
 
In this study, donepezil dose will be increased at weekly intervals, in accordance with the schedules 
given below, to its first intolerable dose (FID) or maximum allowed dose (MAD) of 60mg/day together 
with solifenacin 15 mg/day. If a patient does not tolerate a donepezil dose higher than 40mg/day with 
solifenacin 15 mg/day, the solifenacin dose can be increased to 20mg/day per the Investigator’s decision. 
 
Cohort 1 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 30mg donepezil + 15mg solifenacin 
3rd week: 40mg donepezil + 15mg solifenacin 
4th week: 50mg donepezil + 15mg (or 20mg) solifenacin 
5th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 40mg donepezil + 15mg solifenacin 
3rd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*: The dose titration schedule of Cohorts 2 and 3 may be altered based on Cohort 1 result. 
Per this amendment, patients currently treated with donepezil (Group 1) will receive solifenacin 15 
mg/day during a two week run in period; donepezil treatment will continue at 10mg/day. Once on 15 


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mg/day of solifenacin for two weeks (based upon the investigator judgment), the donepezil dose will be 
increased at weekly or bi-weekly intervals, in accordance with the schedules given below, to its first 
intolerable dose (FID) or maximum allowed dose (MAD) of 60mg/day.  
 
Cohort 1b 
1st-2nd week: 10mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th  week: 30mg donepezil + 15mg solifenacin 
5th  week: 40mg donepezil + 15mg solifenacin 
6th  week: 50mg donepezil + 15mg (or 20mg) solifenacin 
7th  week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2b 
1st – 2nd week: 10mg donepezil + 15mg solifenacin 
3rd  week: 20mg donepezil + 15mg solifenacin 
4th  week: 40mg donepezil + 15mg solifenacin 
5th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3b 
1st – 2nd week: 10mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*: The dose titration schedule of Cohorts 2 and 3 may be altered based on Cohort 1 result. 
 
Per this amendment, all patients not treated with an AchEI for at least 6 months (Group 2) will receive 
15mg solifenacin and 10mg donepezil for 2 weeks before starting donepezil titration.  
 
Each cohort will include approximately 6 patients donepezil-treated (Group 1) and approximately 6 
patients not treated with an AchEI for at least 6 months (Group 2). Within each cohort, Group 2 patients 
will be enrolled only when at least 3 Group 1 patients have completed dose titration per protocol.  
 
Patients will be enrolled in Cohort 2 only when patients enrolled in Cohort 1 have safely completed 
titration. Similary, patients will be enrolled in Cohort 3 only when patients enrolled in Cohort 2 have 
safely completed titration. 
 
Patients reaching their FID or having completed one week treatment with donepezil 60mg/day, have two 
options.  
 
Option 1: Patient will be allowed to immediately enter a long term extension at their maximum tolerated 
dose (MTD) or MAD. 
 
Option 2: Patients may choose not to enter the long term extension, in which case the Investigator will 
decide whether the patient should discontinue high dose of donepezil without down-titration, or whether 
donepezil should be downtitrated to their own standard of donepezil dose. Whatever the decision, the 
patient will be treated at least an additional 7 days with solifenacin 15 mg/day. 
 
Number of patients planned:  
To ensure a suitable number of subjects to evaluate the optimal dose titration schedule, approximately 6 
patients per population group per cohort will be enrolled. 
Diagnosis and main criteria for inclusion: 
 


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Males and females suffering from AD  
 
Inclusion Criteria: 
1) Signed an Institutional Review Board (IRB) approved informed consent document indicating 
that they understand the purpose of and procedures required by the study and are willing to 
participate in the study and comply with all study procedures and restrictions. Informed consent 
must be obtained from the patient and/or a designated representative prior to initiating screening 
procedures to evaluate eligibility for the study. 
2) Aged 50 – 89 years inclusive. 
3) Meeting the diagnosis of probable AD consistent with: 
• 
Revised National Institute on Aging-Alzheimer’s Disease Association (NIA-ADA) criteria 
and  
• 
Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria.  
4) Mild to severe severity (Mini-Mental Status Exam [MMSE] scores 7 – 24 inclusive). 
5) Rosen-Modified Hachinski Ischemia Score of ≤4. 
6) Have a suitable caregiver to supervise the at-home administration of study drugs and observe 
for AEs. 
7) Patients will be required to have been treated with donepezil 5 or 10 mg/day (given once daily) 
for at least 4 weeks just prior to Day1 for Population (group) 1 or; 
Patients have never been treated with donepezil before (donepezil naïve) or who have not 
received any other AChEI for the past 6 months for Population (group) 2. 
8) Patients must be in generally good health as indicated by their medical history and physical 
examination, vital signs, electrocardiogram (ECG), and standard laboratory tests. 
Key exclusion criteria: 
The criteria for exclusion of a subject from enrollment in the study are as follows: 
1) Women of child bearing potential.  
2) History or presence of a seizure disorder. 
3) Current unstable peptic ulcer disease, urinary or gastric retention; asthma or obstructive 
pulmonary disease. 
4) History or presence of bladder outflow obstruction, gastrointestinal obstructive disorder or 
reduced GI motility, or narrow-angle glaucoma. 
5) History or presence of gastrointestinal, hepatic, or renal disease, or other condition known to 
interfere with the absorption, distribution, metabolism or excretion of drugs. 
6) Renal and hepatic dysfunction with: 
• 
Total Bilirubin: >1.5 x UNL 
• 
AST: >2.5 x UNL 
• 
ALT: >2.5 x UNL 
• 
Serum Creatinine: >1.5 x UNL 
• 
Creatinine Clearance: <30 mL/min (calculated by Cockcroft and Gault equation) 
7) History or presence of myasthenia. 
8) History or family history of Prolonged QT Syndrome. 
9) History of unexplained syncope or family history of unexplained syncope or sudden death. 
10) Myocardial infarction or hospitalization for congestive heart failure within 6 months. 
11) ECG findings of: 
• 
Complete Left Bundle Branch Block; 
• 
Ventricular pacing; 


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• 
2nd degree or 3rd degree AV block; 
• 
Atrial fibrillation or atrial flutter; 
• 
HR <45 or >100; 
• 
PR >220 msec; or 
• 
QTcF >450 msec in male, >470 msec in female 
12) Known hypersensitivity to donepezil, solifenacin or related drugs. 
13) History of drug significant allergy. 
14) History of substance abuse, known drug addiction, or positive test for drugs of abuse or alcohol. 
15) Patients treated with the following medications within 8 weeks of screening 
• 
Peripherally acting anticholinergics (such as drugs for the treatment of overactive bladder 
disorder), 
• 
Psychoactive medications (including antipsychotics, antidepressants, anxiolytics or 
sedative hypnotics) having significant anticholinergic effects and/or believed to affect 
cognitive function.  
Other medications are acceptable, at the investigators discretion, if dosage is held stable for at 
least 4 weeks prior to screening and throughout the study. 
16) Patients considered unlikely to co-operate in the study, and/or poor compliance anticipated by 
the investigator. 
17) Patients hospitalized within 4 weeks of screening. 
18) Any other clinically relevant acute or chronic diseases which could interfere with patients’ 
safety during the trial, or expose them to undue risk, or which could interfere with study 
objectives. 
19) Patients who have participated in another clinical trial with an investigational drug within 
previous 30 days. 
Investigational product (IP) 
Donepezil (Aricept®): 10 mg tablet (or generic equivalent) 
Solifenacin (Vesicare®): 5 mg, 10 mg tablets 
Placebo (Similar in size to donepezil 10 mg or solifenacin 5 mg/10 mg tablets 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Duration of treatment:  
Screening: 4 weeks 
Dosing: up to 7 weeks 
Reference therapy, dosage and mode of administration:  
None 
Statistical Analysis: 
Since the objective of this study is to determine the optimal initial dose and subsequent dose titration 
schedule, the data will be analyzed only by means of descriptive statistics to reveal possible trends that 
will help guide the design of future, more definitive, clinical trials. 
Sample size calculations: 
No formal sample size calculation has been made. Based on experience from previous similar studies, a 
total 4-6 evaluable subjects per group per cohort is considered sufficient. 


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2 OBJECTIVES 
2.1 
Primary objective 
To determine the optimal initial dose and subsequent dose titration schedule (rate and 
increment) for CPC-201. 
2.2 
Secondary objective 
To evaluate the safety and tolerability of CPC-201 as a function of dose and initial rate of 
dose titration. 
 
3 INVESTIGATIONAL PLAN 
3.1 
Overall Study design 
This is a Phase II, ascending dose study of CPC-201 in patients with dementia of 
Alzheimer’s type to determine the optimal dose titration schedule. The study involves a 
step wise cohort design in two different patient populations: Group 1 will consist of 
patients who have been treated with donepezil 5 or 10 mg/day (given once daily) for at 
least 4 weeks just prior to Day1. Group 2 will consist of patients who have never been 
treated with donepezil before (donepezil naïve) or who have not received any other 
AChEI for the past 6 months. 
 
In this study, donepezil dose will be increased at weekly intervals, in accordance with the 
schedules given below, to its first intolerable dose (FID) or maximum allowed dose 
(MAD) 60 mg/day together with solifenacin 15 mg/day. If a patient does not tolerate a 
donepezil dose higher than 40mg/day with solifenacin 15 mg/day, the solifenacin dose 
can be increased to 20mg/day per the Investigator’s decision. 
 
Cohort 1 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 30mg donepezil + 15mg solifenacin 
3rd week: 40mg donepezil + 15mg solifenacin 
4th week: 50mg donepezil + 15mg (or 20mg) solifenacin 
5th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 40mg donepezil + 15mg solifenacin 
3rd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*: The dose titration schedule of Cohort 2 and 3 may be altered based on Cohort 1 result. 
 
Per this amendment, patients currently treated with donepezil (Group 1) will receive 
solifenacin 15 mg/day during a two week run in period; donepezil treatment will continue 
at 10mg/day. Once on 15 mg/day of solifenacin for two weeks (based upon the 
investigator judgment), the donepezil dose will be increased at weekly or bi-weekly 


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intervals, in accordance with the schedules given below, to its first intolerable dose (FID) 
or maximum allowed dose (MAD) of 60mg/day  
 
Cohort 1b 
1st-2nd week: 10mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th  week: 30mg donepezil + 15mg solifenacin 
5th  week: 40mg donepezil + 15mg solifenacin 
6th  week: 50mg donepezil + 15mg (or 20mg) solifenacin 
7th  week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2b 
1st – 2nd week: 10mg donepezil + 15mg solifenacin 
3rd  week: 20mg donepezil + 15mg solifenacin 
4th  week: 40mg donepezil + 15mg solifenacin 
5th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3b 
1st – 2nd week: 10mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*: The dose titration schedule of Cohorts 2 and 3 may be altered based on Cohort 1 result. 
 
Per this amendment, all patients not treated with an AchEI for at least 6 months (Group 2) 
will receive 15mg solifenacin for 2 weeks before starting donepezil. 
 
Each cohort will include approximately 6 patients donepezil-treated (Group 1) and 
approximately 6 patients not treated with an AchEI for at least 6 months (Group 2). 
Within each cohort, Group 2 patients will be enrolled only when at least 3 Group 1 
patients have completed dose titration per protocol.  
 
Patients will be enrolled in Cohort 2 only when patients enrolled in Cohort 1 have safely 
completed titration. Similary, patients will be enrolled in Cohort 3, only when patients 
enrolled in Cohort 2 have safely completed titration. 
 
Patients reaching their FID or having completed one week treatment with donepezil 
60mg/day, have two options.  
 
Option 1: Patient will be allowed to immediately enter a long term extension at their 
maximum tolerated dose (MTD) or MAD. 
 
Option 2: Patients may choose not to enter the long term extension, in which case the 
Investigator will decide whether the patient should discontinue high dose of 
donepezil without down-titration, or whether donepezil should be 
downtitrated to their own standard of donepezil dose. Whatever the decision, 
the patient will be treated at least an addtional 7 days with solifenacin 15 
mg/day. 


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3.2 
Dose Escalation and Stopping rules 
For all patients, donepezil dose escalation will be discontinued if they manifest over a 24 
hour period after study drug administration the following symptoms judged by the 
investigator as possibly or probably study-drug related: 
 
• One (1) episode of vomiting, or 
• Two (2) episodes of severe retching (separated by more than one hour on the 
same day), or 
• One (1) episode of severe nausea (Grade 3; defined as nausea interfering with 
activities of daily living or inadequate oral caloric or fluid intake; tube feeding, 
total parenteral nutrition or hospitalization indicated) and/or severe abdominal 
discomfort (Grade 3; defined as severely interfering with activities of daily living), 
or 
• Three (3) episodes of moderate nausea (Grade 2; defined as subjectively 
symptomatic, but not interfering with activities of daily living)  and/or moderate 
abdominal discomfort (Grade 2; defined as interfering with function, but not 
interfering with activities of daily living) each on the same day, or  
• One (1) episode of moderate diarrhea (Grade 2; defined as 4 to 6 stools more than 
at baseline). 
• Any other circumstance that merits an adjustment in study drug dosage in the 
opinion of the investigator 
 
All those meeting one or more of the foregoing stopping rules will be withdrawn from 
dose titration and proceed in accordance with either of the two options given above. 
3.3 
Trial procedures 
3.3.1 
Schedule of Assessments 
The schedule of assessments for the study is provided in Table 1, Table 2 and Table 3. 
 


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3.3.2 
Study Procedure 
For each visit, procedures and assessments are listed in the order in which they should be 
performed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.5 
Discontinuation criteria 
3.5.1 
Discontinuation of donepezil dose escalation in individual subjects 
For all patients, donepezil dose escalation will be discontinued if they manifest over a 24 
hour period after study drug administration the following symptoms judged by the 
investigator as possibly or probably study-drug related: 
 
• One (1) episode of vomiting, or 
• Two (2) episodes of severe retching (separated by more than one hour on the 
same day), or 
• One (1) episode of severe nausea (Grade 3; defined as nausea interfering with 
activities of daily living or inadequate oral caloric or fluid intake; tube feeding, 
total parenteral nutrition or hospitalization indicated) and/or severe abdominal 
discomfort (Grade 3; defined as severely interfering with activities of daily living), 
or 
• Three (3) episodes of moderate nausea (Grade 2; defined as subjectively 
symptomatic, but not interfering with activities of daily living)  and/or moderate 
abdominal discomfort (Grade 2; defined as interfering with function, but not 
interfering with activities of daily living) each on the same day, or  
• One (1) episode of moderate diarrhea (Grade 2; defined as 4 to 6 stools more than 
at baseline). 
• Any other circumstance that merits an adjustment in study drug dosage in the 
opinion of the investigator 
3.5.2 
Discontinuation of individual subjects from the entire study 
During the study, the investigator or the sponsor may decide to discontinue a subject’s 
participation in the study in the following cases: 
• A protocol violation occurs; 
• A serious or intolerable (other than those listed in the discontinuation of 
rivastigmine escalation criteria) AE occurs; 
• The Sponsor or Investigator terminates the study. 
• The subject requests to be discontinued from the study. 
• The subject is non-compliant to any part of the study. 
• The Investigator feels it is not in the best interest of the subject to continue in the 
study. 
 
4 SELECTION OF SUBJECTS 
4.1 
Inclusion criteria 
The criteria for inclusion that each subject must meet to be enrolled in the study are as 
follows: 


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1. Signed an Institutional Review Board (IRB) approved informed consent document 
indicating that they understand the purpose of and procedures required by the 
study and are willing to participate in the study and comply with all study 
procedures and restrictions. Informed consent must be obtained from the patient 
and/or a designated representative prior to initiating screening procedures to 
evaluate eligibility of the study. 
2. Aged 50 – 89 years inclusive. 
3. Meeting the diagnosis of probable AD consistent with: 
- 
Revised National Institute on Aging-Alzheimer’s Association (NIA-ADA) 
criteria and  
- 
Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria.  
4. Of mild to severe severity (Mini-Mental Status Exam [MMSE] scores 7 – 24 
inclusive). 
5. Rosen-Modified Hachinski Ischemia Score of ≤4. 
6. Have a suitable caregiver to supervise the at-home administration of study drugs 
and observe for AEs. 
7. Patients will be required to have been treated with donepezil 5 or 10 mg/day 
(given once daily) for at least 4 weeks just prior to Day1 for Population (group) 1 
or; 
8. Patients have never been treated with donepezil before (donepezil naïve) or who 
have not received any other AChEI for the past 6 months for Population (group) 
2. 
9. Patients must be in generally good health as indicated by their medical history and 
physical examination, vital signs, electrocardiogram (ECG), and standard 
laboratory tests. 
4.2 
Exclusion criteria 
The criteria for exclusion of a subject from enrollment in the study are as follows: 
1. Women of child bearing potential.  
2. History or presence of a seizure disorder. 
3. Current unstable peptic ulcer disease, urinary or gastric retention; asthma or 
obstructive pulmonary disease. 
4. History or presence of bladder outflow obstruction, gastrointestinal obstructive 
disorder or reduced GI motility, or narrow-angle glaucoma. 
5. History or presence of gastrointestinal, hepatic, or renal disease, or other 
condition known to interfere with the absorption, distribution, metabolism or 
excretion of drugs. 
6. Renal and hepatic dysfunction with: 
- 
Total Bilirubin: >1.5 x UNL 


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- 
AST: >2.5 x UNL 
- 
ALT: >2.5 x UNL 
- 
Serum Creatinine: >1.5 x UNL 
- 
Creatinine Clearance: <30 mL/min  
7. History or presence of myasthenia. 
8. History or family history of Prolonged QT Syndrome. 
9. History of unexplained syncope or family history of unexplained syncope or 
sudden death. 
10. Myocardial infarction or hospitalization for congestive heart failure within 6 
months. 
11. ECG findings of: 
- 
Complete Left Bundle Branch Block; 
- 
Ventricular pacing; 
- 
2nd degree or 3rd degree AV block; 
- 
Atrial fibrillation or atrial flutter; 
- 
HR <45 or >100; 
- 
PR >220 msec; or 
- 
QTcF >450 msec in male, >470 msec in female 
12. Known hypersensitivity to donepezil, solifenacin or related drugs. 
13. History of drug significant allergy. 
14. History of substance abuse, known drug addiction, or positive test for drugs of 
abuse or alcohol. 
15. Patients treated with the following medications within 8 weeks of screening 
- 
AChEIs (other than donepezil),  
- 
Peripherally acting anticholinergics (such as drugs for the treatment of 
overactive bladder disorder), 
- 
Psychoactive medications (including antipsychotics, antidepressants, 
anxiolytics or sedative hypnotics) having significant anticholinergic effects 
and/or believed to affect cognitive function.  
Other medications are acceptable, at the investigators discretion, if dosage is held 
stable for at least 4 weeks prior to screening and throughout the study. 
16. Patients considered unlikely to co-operate in the study, and/or poor compliance 
anticipated by the investigator. 
17. Patients hospitalized within 4 weeks of screening. 
18. Any other clinically relevant acute or chronic diseases which could interfere with 
patients’ safety during the trial, or expose them to undue risk, or which could 
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19. Patients who have participated in another clinical trial with an investigational drug 
within previous 30 days. 
 
5 STUDY DRUG 
5.1 
Blinding 
This is a single-blind study. The subject, caregiver, and site personnel who assess MMSE 
and ADAS-Cog are blinded.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3 
Description of Study Drug 
 
 
 
 
 
 
 
 
 


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Placebo tablet 
Placebo tablet is similar in size to donepezil 10 mg or solifenacin 5 mg/10 mg tablets. 
5.3.2 
Study drug manufacturing and labeling 
Donepezil and solifenacin will be purchased by
 from a licensed supplier of 
these pharmaceuticals.  
 
The placebo tablet will be manufactured, packaged in bottle, labeled by 
 
. Label will include the following information: protocol 
number, quantity of tablets, required storage conditions, lot number, name and address of 
the manufacturer and the following cautionary statement: New Drug – Limited by 
Federal law to investigational use. 
5.3.3 
Study drug storage, handling and disposal 
At the site, all study drugs should be stored at room temperature 
 in a 
secure area accessible only to the designated qualified site personnel. All study drugs 
must be stored, inventoried and the inventories carefully and accurately documented 
according to applicable state, federal and local regulations, International Conference on 
Harmonisation (ICH) Guidelines, Good Clinical Practice (GCP) and study procedures. 
The study drug is to be prescribed only by the Investigator or his/her named sub-
investigator(s), and is to be used only in accordance with the protocol. The study drug 
must be distributed only to patients properly enrolled in the study. 
 
The Investigator must keep an accurate accounting of the study drug received from the 
Sponsor, including the temperature of the storage area, the amount of study drug 
dispensed to patients, amount of study drug returned to the Investigator by the patients, 
and the amount returned to the Sponsor upon completion of the study. A detailed 
inventory must be completed for the study drug.  
 
Unused study drug must be kept in a secure location for accountability and reconciliation 
by the study monitor. Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials. 
 
Unused study drug may be destroyed on site, per the site’s standard operating procedures 
(SOPs), but only after the Sponsor has granted approval for drug destruction. The monitor 
must account for all study drugs in a formal reconciliation process prior to study drug 
destruction. All study drug destroyed on site must be documented. Documentation must 
be provided to the Sponsor and retained in the Investigator’s study files. If a site is unable 
to destroy study drug appropriately, the site can return unused study drug to the Sponsor 
or designee upon request. The return of study drug or study drug materials must be 
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5.4 
Concomitant medication 
5.4.1 
Allowed Mediations 
Dosage of allowed concomitant medication should be stabilized for at least 4 weeks prior 
to screening and should remain constant during the course of the study. Patients on 
concomitant memantine should be on a stable dose for at least 3 months. With the 
exception of medications listed in the exclusion criteria (Section 4.2) and in Section 5.4.2 
below, concomitant medications will be allowed at the Investigator's discretion.  
 
All concomitant medications and therapies (prescription and OTC) should be recorded in 
the CRF, with generic name (if known, otherwise brand name), indication, dose, route, 
frequency, and date(s) of administration. Any change in any of these parameters during 
the study should be documented. 
5.4.2 
Prohibited Mediations 
Concomitant use of the following drugs is not allowed (such medications must have been 
discontinued at least 8 weeks prior to screening): 
• peripherally acting anticholinergics (such as drugs for the treatment of overactive 
bladder disorder), 
• psychoactive medications (including antipsychotics, antidepressants, anxiolytics 
or sedative hypnotics) having significant anticholinergic effects and/or believed to 
affect cognitive function 
 
In addition, the following drugs are prohibited during the study: 
• Strong CYP3A4 inhibitors  
• Strong CYP3A4 inducers  
• Strong CYP2D6 inhibitors 
  
Patients who use prohibited medications during the study listed above may be 
discontinued from study drug. Medications prescribed after patients have discontinued 
the study drug will not be considered as prohibited medications. 
Note: The discontinuation of a patient due to use of a prohibited medication is dependent 
upon the Sponsor's decision. The Investigator should contact the Sponsor prior to 
discontinuing a patient for disallowed medications. 
 
6 ASSESSMENT OF PHARMACOKINETICS 
6.1 
PK Blood Sampling Schedule and Sample Analysis 
The blood samplings will be performed at approximately 15 minutes before and 4 hours 
(± 15 min) after study drug administration at each visits. 


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7 SAFETY ASSESSMENTS 
7.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical-investigation subject 
administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. A TEAE is defined as any AE that occurs after 
administration of the first dose of study drug. An AE can therefore be an unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. The failure of the anticipated 
pharmaceutical action of an investigational drug does not constitute a related AE. 
AE rating 
The condition of the subjects will be closely monitored throughout the study. The 
investigator will collect the AEs reported spontaneously, observed, or elicited in response 
to a non-leading question (for example, "How have you been feeling since we last asked 
you?"). The investigator will record all AEs in the source records and the CRF. 
• 
The intensity/severity of an AE will be rated as follows: 
Mild 
: Awareness of signs or symptoms, but no disruption of usual activity. 
Moderate 
: Event sufficient to affect usual activity (disturbing). 
Severe 
: Inability to work or perform usual activities (unacceptable). 
• 
The causal relationship of an AE to the study drugs will be rated as follows: 
Not related 
: Temporal relationship of the onset of the event, relative to the 
administration of the product, is not reasonable or another cause can 
by itself explain the occurrence of the event 
Unlikely 
: Is general, this category can be considered applicable to those AEs 


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related 
which after careful medical consideration at the time they are 
evaluated, are judged to be unrelated to the study drug 
Related 
: AEs incontrovertibly related to the administration of the product. 
Of the above definitions, AEs related to study drug are considered adverse reactions, 
while “unlikely” and “not related” do not represent a causal relationship. 
• 
The action taken with the study drug for an AE will be rated as product withdrawn, 
not changed, not applicable. AEs requiring therapy will be treated with recognised 
standards of medical care to protect the health and the well-being of the subject. 
• 
The outcome of an AE will be rated as recovered, recovering, not recovered, 
recovered with sequellae or fatal. The investigator will follow up any AE until it is 
resolved or until the medical condition of the subject is stable. All relevant follow-up 
information will be collected. For AEs that are ongoing at the last visit, the 
investigator will make thorough efforts to document the outcome. 
7.2 
Serious Adverse Events (SAE) 
An SAE is any untoward medical occurrence that results in death, is life threatening, 
requires in-patient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. In 
addition, important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
An AE is life-threatening if the subject is at immediate risk of death from the event as it 
occurs, i.e. it does not include a reaction that, if it had occurred in a more serious form, 
might have caused death. For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not have been considered life-threatening, even though 
drug-induced hepatitis can be fatal. 
 
An AE is incapacitating or disabling if the experience resulted in a substantial and/or 
permanent disruption of the subject’s ability to carry out normal life functions. 
7.3 
Assessment of tolerability 
The FID of each patient will be recorded. 
7.4 
Safety Laboratory Test 
Blood samples will be collected as indicated in Table 1-4 for the following clinical 
laboratory tests: 
 
Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils) and platelet 
count. 
 


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Serum chemistry: calcium, sodium, chloride, potassium, blood urea nitrogen, glucose, 
total bilirubin, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, 
alanine aminotransferase, creatinine, calculated creatinine clearance,  uric acid, 
phosphorous, total protein, albumin, and globulin. 
 
 
 
 
7.5 
Urinalysis 
Urine samples will be collected as indicated in Table 1-4 for the following tests: glucose, 
bilirubin, ketones, specific gravity, blood, pH, protein, urobilinogen, nitrites, and 
leukocytes and, if necessary, microscopic examination. 
7.6 
Vital signs and body weight 
Vital signs, including blood pressure, heart rate, respiratory rate, and temperature, will be 
measured after the patient rests in the supine position for at least 5 minutes.  
 
Body weight will be measured as indicated in Table 1-4.  
7.7 
12-Lead ECGs 
A standard 12-lead ECG will be recorded as indicated in Table 1-4. The Investigator will 
evaluate the ECG results as normal, abnormal, not clinically significant, or abnormal, 
clinically significant. 
 
If QTcF on an on treatment ECG is ≥500 msec then hold treatment and perform 3 repeat 
ECGs over 20-60 min; if the mean QTcF of the three ECGs is ≥500 msec, withhold 
treatment and perform a repeat ECG the following day; if the QTcF has returned to 
baseline, dosing may resume..  
7.8 
MMSE 
MMSE will be assessed by blinded rater at visits indicated in Table 1-4. 
7.9 
ADAS-Cog 
ADAS-Cog will be assessed by blinded rater at visits indicated in Table 1-4. 
7.10 Modified C-SSRS 
Modified C-SSRS will be assessed by a qualified and experienced clinician who does not 
perform psychometric at visits indicated in Table 1-4. 
 


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8 PROCEDURES FOR REPORTING TEAES AND SERIOUS 
ADVERSE EVENTS 
8.1 
Reporting TEAEs 
All TEAEs, regardless of seriousness, severity or presumed relationship to study therapy, 
must be recorded using medical terminology in the source document and transcribed into 
the CRF. Whenever possible, the diagnosis should be given when signs and symptoms 
are due to a common etiology (e.g. cough, runny nose, sneezing, sore throat, and head 
congestion should be reported as “upper respiratory infection” instead of identifying and 
listing the individual signs and symptoms). The Investigator must record, in the source 
document and transcribe into the AE page of the CRF, his or her medical assessment of 
the severity of the event and the relationship of the AE to study drug. 
 
All TEAEs must be followed until they have resolved or until a stable clinical endpoint is 
reached. All measures required for managing the TEAE and the ultimate outcome of the 
TEAE must be recorded in the source document and reported in the CRF. 
8.2 
Reporting Serious Adverse Events 
When the Investigator or designee becomes aware that an SAE has occurred, the Sponsor 
representative must be notified by both telephone and fax, regardless of the relationship 
(or lack thereof) of the SAE to study drug within 24 hours of the event. All SAEs must be 
submitted to the Sponsor as a written report, as well as reported verbally. A follow-up 
report must be submitted to the Sponsor as requested when pertinent information 
becomes available and if additional information is requested. 
 
The Investigator is responsible for ensuring that the IRB is informed of this information 
within appropriate IRB established timelines. 
 
ANY SAE OR ADR, INCLUDING ANY OUTCOME OF DEATH DUE TO ANY 
CAUSE THAT OCCURS DURING THIS STUDY MUST BE REPORTED 
IMMEDIATELY TO THE SPONSOR REPRESENTATIVE. 
This verbal and faxed report must be followed no later than 3 working days by a written 
report signed by the Investigator. The Sponsor is responsible for submitting the report 
to all applicable regulatory authorities. 
 
 
 
 
 
 
 
 


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9 STATISTICS 
Since the objective of this study is to determine the optimal initial dose and subsequent 
dose titration schedule, the statistics are not applicable. 
The data will be analyzed only by means of descriptive statistics to reveal possible trends 
that will help guide the design of future, more definitive, clinical trials. 
9.1 
Assessment of Safety and Tolerability and  
Safety and tolerability parameters will be analyzed as a function of dose and dose 
titration schedule. 
9.1.1 
Assessment of MTD  
Descriptive statistics will be presented for the MTD and the FID for each patient in each 
dose titration schedule. 
9.1.2 
Adverse Events 
Data Listings will present the verbatim-reported event along with the preferred term and 
SOC, onset and stop dates, severity, relatedness, SAE status, action taken and outcome. 
For summaries by severity, the most severe event episode will be counted if a subject has 
more than one event within the same coded term. For summaries of treatment-associated 
events, the subject will be counted as “associated” for that term if a subject has more than 
one event within the same coded term or if one event is considered “not associated” and 
the other “associated”. 
 
Unless otherwise indicated, AE summary tables will be presented by study period, 
treatment group, SOC, and preferred term for each study period. 
9.1.3 
Laboratory Tests (Safety laboratory test and urinalysis) 
For the continuous laboratory parameters, descriptive statistics will be presented. 
Additionally, parameters will be categorized as low, normal or high according to 
laboratory range specifications. The number and percentage of subjects will be presented 
by dosing cohort and treatment arm.  
9.1.4 
ECGs 
The overall interpretation of the ECG results will be presented as normal, abnormal (not 
clinically significant) and abnormal (clinically significant) by time point and study 
period.  
9.1.5 
Vital Signs and weight 
Descriptive statistics will be presented for each vital sign measurement recorded at each 
time point during each study period.  


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9.2 
Pharmacokinetics 
Blood concentration results of donepezil and solifenacin for each subject will be 
presented. 
9.3 
Patient Disposition  
Disposition of all subjects will be summarized descriptively. 
9.4 
Demographics and Baseline Characteristics 
Individual subject demographic and baseline characteristics data will be presented in 
subject data listings. Concomitant medications (all recorded medications) will be listed 
for enrolled subjects. The listing will be sorted by start date of medication within the 
standard sort order. The listing will include all collected information. 
9.5 
Protocol Deviations 
All protocol deviations will be listed by subject number. 
9.6 
Compliance  
Dosing information collected on the CRF will be listed for each subject. Compliance will 
be summarized by presenting the numbers and percentages of subjects receiving each 
dose of study drug. 
 
10 ACCESS TO SOURCE DATA/DOCUMENTS 
Checking of case report forms (CRF’s) for completeness and clarity and cross-checking 
with source documents will be required to monitor the progress of the study. The 
Monitors are entitled to compare CRF entries with source data and to inform the 
investigator about errors and omissions. The monitor will request correction / 
clarification from the investigator using electronic data clarifications that should be 
answered and closed as quickly as possible. The Investigator will provide direct access to 
source data/documents for the Sponsor’s designated representatives (monitors and 
auditors) as well as IRB/IEC members and regulatory inspections. 
 
Regulatory authorities and/or the Sponsor’s clinical quality assurance personnel may also 
carry out source data checks and/or on-site audit inspections. These will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator 
is to give the Sponsor whatever support is necessary. 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Study Monitoring 
The study will be initiated by the Sponsor during an on-site visit after all required study 
documents have been sent to the Sponsor and approved. A monitor will perform 


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subsequent on-site monitoring visits as frequently as deemed necessary. At these visits, 
the monitor will compare the data entered onto the CRFs with the hospital or clinic 
records (source documents) and check for protocol compliance, including a review of 
records of informed consent, all subject visit dates, all AEs, all concomitant medications, 
and key efficacy observations. In addition, drug accountability records will be reviewed 
and findings from this review will be discussed with the Investigator. 
 
The Sponsor expects that during monitoring visits, the study coordinator, Investigator, 
CRFs and source documentation will be available and a suitable environment will be 
provided for review of study-related documents. 
11.2 Audits and Inspections 
Trial sites, facilities, laboratories and all data (including sources) and documentation must 
be available for GCP audit by the Sponsor or inspection by competent authorities.  Any 
aspect of the trial may be subject to audit by the Sponsor and/or inspection by regulatory 
authorities or the IRB.  Such audits/inspections may take place at the Sponsor’s site(s) or 
at the trial site including laboratories, pharmacies etc. In case of audit, the monitor will 
announce this in advance to the Investigator (or representative) and be present at the 
particular trial site during the audit. 
 
The site staff should assist in all aspects of audit/inspection. 
11.3 Data Quality Assurance 
The Sponsor and their designated Contract Research Organization (CRO) will implement 
a system of quality assurance, including all elements described in this protocol.  Within 
this system the CRO SOPs will be implemented to ensure that the clinical trial is 
conducted in compliance with regulatory requirements and GCP.  Quality control is 
applied to each stage of data handling to ensure that data are accurate, reliable and 
processed correctly. 
 
12 ETHICS AND ADMINISTRATIVE ISSUES 
12.1 Ethical conduct of the trial 
This protocol was designed and will be conducted, recorded and reported in compliance 
with the principles of Good Clinical Practice (GCP) regulations and in accordance with 
the principles outlined in the Declaration of Helsinki. These requirements are stated in 
federal regulations as well as ICH of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, “E6 Guideline for Good Clinical Practice”. The Sponsor 
representative will review these obligations with the Investigator prior to the initiation 
and throughout the course of the study. The Investigator or any of his or her staff should 
contact the Sponsor representative for any questions or issues regarding compliance with 
GCP/ICH guidelines. 
 


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This study will be conducted in compliance with IRB guidelines and in accordance with 
applicable regulations regarding clinical safety data management. In addition this study 
will adhere to all local regulatory requirements and requirements for data protection. 
The Investigator should refer to 21 CFR Part 312, Subpart D, ICH Guidelines E6 for 
clarification of the Investigator’s responsibilities for fulfillment of GCP Guidelines for 
Investigator’s qualifications and agreements, adequate resources, medical care of study 
subjects, communication with IRB, compliance with the protocol, responsibility for 
investigational products, randomization procedures, informed consent, records and 
reporting, premature termination or suspension of a study and final reports. 
 
Before initiating the study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject recruitment procedures (e.g. 
advertisements), and any written information to be provided to subjects, and a statement 
from the IRB that they comply with GCP requirements. The IRB approval must identify 
the protocol version as well as the documents reviewed. 
12.2 Institutional review board/independent ethics committee (IRB/IEC) and 
Regulatory Authority 
All protocols and protocol amendments must be signed and dated by the Investigator and 
approved by the IRB prior to implementation. The Investigator must provide an annual 
report to the IRB on the progress of the study in compliance with 21 CFR Part 56 and the 
IRB’s policies and procedures. The Investigator must provide notification to the IRB of 
the completion, termination or discontinuation the study. It is required that a yearly 
review of the protocol by the IRB be documented in a letter from the IRB. 
12.3 Subject informed consent 
Executed informed consent, and other locally required documents such as those related to 
Protected Health Information, are required. The consent form must be executed prior to 
performing any study-related activities that are not part of the subject’s routine care. The 
consent form that is used must be approved by both the reviewing IRB and by the 
Sponsor representative. 
12.4 Subject Data Protection 
Each subject must provide written informed consent as well as any authorizations 
required by local law (e.g. authorizations related to Protected Health Information). The 
Investigator agrees not to use or disclose Protected Health Information other than as 
permitted or required by the subject authorization or as required by law.  
12.5 Data Monitoring Committee 
Not applicable. 


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12.6 Financial Disclosure 
Study personnel on the Form FDA 1572 will complete a financial disclosure form at the 
beginning of the study. New study personnel added to Form FDA 1572 must also meet 
these requirements. 
12.7 Investigator Obligations 
The Investigator should refer to 21 CFR Part 312, Subpart D, ICH Guidelines E6 for 
clarification of the Investigator’s responsibilities to fulfill GCP Guidelines for 
Investigator’s qualifications and agreements, adequate resources, medical care of study 
subjects, communication with IRB, compliance with the protocol, responsibility for 
investigational products, randomization procedures, informed consent, records and 
reporting, premature termination or suspension of a study and final reports. 
 
The Investigator agrees when signing the protocol to adhere to the instructions and 
procedures described in it, and thereby, to adhere to the principles of GCP that it 
conforms to. 
12.8 Changes to the Protocol 
All protocols and protocol amendments must be signed and dated by the Investigator and 
approved by the IRB prior to implementation. 
12.9 Confidentiality/Publication of the Study 
All information supplied to the Investigator by a Sponsor representative and not 
previously published is considered confidential and remains the sole property of the 
Sponsor. The Investigator must agree to use this information only to accomplish this 
study, and must not use it for other purposes without the Sponsor’s written consent. 
The information developed in this study will be used by the Sponsor in connection with 
the continued development of this product and thus may be disclosed as required to other 
clinical Investigators or government regulatory agencies. To permit the information 
derived from the clinical studies to be used, the Investigator is obligated to provide the 
Sponsor with all data obtained in the study. 
 
No publication of any study data, results, other deliverables or records is permitted by the 
Investigator.  
12.10 Discontinuation of entire study 
The Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study either at a single site or at all sites at any time for reasons including, but not limited 
to, safety or ethical issues or severe non-compliance.  
 
In particular cases, the study may be terminated at a single investigational site, if the 
Sponsor has relevant reasons, e.g., suspicion of a deceit or conduct of the study which is 
not in accordance to the guidelines for GCP. 
 


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If the Sponsor determines such action is needed, the Sponsor will discuss this with the 
Investigator (including the reasons for taking such action) at that time. When feasible, the 
Sponsor will provide advance notification to the Investigator of the impending action 
prior to it taking effect. 
 
The Sponsor will promptly inform all other Investigators and/or institutions conducting 
the study if the study is suspended or terminated for safety reasons, and will also inform 
the regulatory authorities of the suspension or termination of the study and the reason(s) 
for the action. If required by applicable regulations, the investigator must inform the 
Ethics Committee promptly and provide the reason for the suspension or termination. 
 
13 DATA HANDLING AND RECORD KEEPING 
13.1 Inspection of Records 
Local regulatory agencies may request access to all study records, including source 
documents, for inspection and copying, in keeping with U.S. regulations. The 
Investigator should immediately notify the Sponsor of any upcoming regulatory agency 
inspections. The Sponsor may also perform an audit of the data if deemed necessary. 
The Investigator will be responsible for the accuracy of the data entered in the CRFs. The 
Investigator will permit designated Sponsor representatives and regulatory bodies to have 
direct access to the source documents to verify data represented in the CRFs. 
13.2 Retention of Records 
All source documents (e.g. informed consent forms, laboratory reports, progress notes, 
medical histories, physical and diagnostic findings, diagnosis and pharmacy records, and 
study drug dispensing/disposition records) that support data in the CRFs of each study 
subject must be retained in the files of the Investigator for at least two years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region; or at least two years have elapsed 
since the formal discontinuation of clinical development of the investigational drug. 
These documents should be retained for a longer period, however, if required by 
applicable regulatory requirements. 
 
If the Investigator retires, relocates, or for any other reason withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. Prior to transfer, the Sponsor representative must be 
notified in writing of the name and address of the new custodian. 


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double-blind, community-controlled comparison of three doses of galantamine in the 
treatment of mild to moderate Alzheimer's disease in a Korean population. Clin Ther. 
2004;26(10):1608-18. 
 
Tiseo PJ, Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamic profile of 
donepezil HCl following evening administration. Br J Clin Pharmacol. 1998a;46 Suppl 
1:13-8.  
 
Tokita K, Yamazaki S, Yamazaki M, Matsuoka N, Mutoh S. Combination of a novel 
antidementia drug FK960 with donepezil synergistically improves memory deficits in rats. 
Pharmacol Biochem Behav. 2002;73(3):511-9. 
 
Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, Zechner S, 
Nagel J, Lane R. A six-month double-blind, randomized, placebo-controlled study of a 
transdermal patch in Alzheimer's disease--rivastigmine patch versus capsule. Int J Geriatr 
Psychiatry. 2007;22(5):456-67. 
 
Yano H, Fukuhara Y, Wada K, Kowa H, Nakashima K. A case of acute choinergic 
adverse effects induced by donepezil overdose: a follow-up of clinical course and plasma 
concentrtion of donepezil.  Rinsho Shinkeigaku. 2003;Aug; 43(8): 462-6. 


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Zhang WW, Xu ZP, Cui YY, Wang H, Song MK, Li J, Shao BY, Xia Z, Chen HZ.  
Peripheral cholinoceptor antagonist anisodamine counteracts cholinergic adverse effects 
and facilitates cognitive amelioration of rivastigmine. J Neural Transm. 2009 Dec; 
116(12): 1643-9. 


NCT02549196 
 
Study ID: CPC‐001‐12 
 
Title:  A phase II, dose titration study of CPC‐201 in Patients with Dementia of Alzheimer’s Type 
 
Protocol Date: 10 Sept 2015 


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Investigational Product:  
CPC-201 (donepezil plus solifenacin)  
Indication:  
 
 
Treatment of Dementia of Alzheimer Type  
Clinical phase:  
 
Phase II, Dose Titration Study  
Study code: 
 
 
CPC-001-12 
 
 
 
Dose titration study 
 
 
A PHASE II, DOSE TITRATION STUDY OF CPC-201 IN PATIENTS 
WITH DEMENTIA OF ALZHEIMER’S TYPE 
 
 
Version 1, date: September 10, 2015 
 
 
 
Sponsor: 
 
 
Chase Pharmaceuticals Corporation 
 
 
 
 
1825 K Street, NW, Suite 520 
 
 
 
 
Washington, DC 20006 
 
 
 
 
 
 
 
 
Confidential Information 
This material is the property of Chase Pharmaceuticals Corporation. 
It may not be used, divulged, published or otherwise disclosed without prior written consent. 
GCP compliance 
The study will be performed in compliance with Good Clinical Practices (GCP)  
and in accordance with the Declaration of Helsinki 
 
 
 




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Signature page for the Investigator  
This Clinical Trial will be conducted in accordance with the study protocol, the 
International Conference on Harmonization (ICH), Good Clinical Practices (GCP), the 
ethical principles outlined in the current valid version of the Declaration of Helsinki and 
the European as well as other local regulations. 
 
As the Investigator for the Trial, I have read this protocol dated August 26, 2015 and 
agree to follow this protocol in accordance with all the above-mentioned regulations. 
…………………………………….. 
 
Date: ……………………….... 
 
 
 
 
 
 
 


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Table of contents  
 
LIST OF TABLES ................................................................................................................................................ 8 
PROTOCOL SUMMARY ................................................................................................................................... 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
OBJECTIVES ........................................................................................................................................... 22 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................... 22 
2.2 
SECONDARY OBJECTIVE .......................................................................................................................... 22 
3 
INVESTIGATIONAL PLAN ................................................................................................................... 22 
3.1 
OVERALL STUDY DESIGN ........................................................................................................................ 22 
3.2 
DOSE ESCALATION AND STOPPING RULES ............................................................................................... 23 
3.3 
TRIAL PROCEDURES ................................................................................................................................ 24 
3.3.1 Schedule of Assessments ..................................................................................................................24 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.5.1 Discontinuation of donepezil dose escalation in individual subjects ................................................32 
3.5.2 Discontinuation of individual subjects from the entire study ...........................................................32 
4 
SELECTION OF SUBJECTS .................................................................................................................. 32 
4.1 
INCLUSION CRITERIA ............................................................................................................................... 32 
4.2 
EXCLUSION CRITERIA .............................................................................................................................. 33 
5 
STUDY DRUG .......................................................................................................................................... 35 
5.1 
BLINDING ................................................................................................................................................ 35 
5.2 
STUDY DRUG ADMINISTRATION ............................................................................................................. 35 
5.3 
DESCRIPTION OF STUDY DRUG ............................................................................................................... 35 
 
5.3.2 Study drug manufacturing and labeling ............................................................................................36 
5.3.3 Study drug storage, handling and disposal .......................................................................................36 
5.4 
CONCOMITANT MEDICATION ................................................................................................................... 37 
5.4.1 Allowed Mediations .........................................................................................................................37 
5.4.2 Prohibited Mediations ......................................................................................................................37 
6 
ASSESSMENT OF PHARMACOKINETICS ....................................................................................... 37 
6.1 
PK BLOOD SAMPLING SCHEDULE AND SAMPLE ANALYSIS .................................................................... 37 
 
 
 
 
7 
SAFETY ASSESSMENTS ....................................................................................................................... 38 


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7.1 
ADVERSE EVENTS ................................................................................................................................... 38 
7.2 
SERIOUS ADVERSE EVENTS (SAE).......................................................................................................... 39 
7.3 
ASSESSMENT OF TOLERABILITY .............................................................................................................. 39 
7.4 
SAFETY LABORATORY TEST ................................................................................................................... 39 
7.5 
URINALYSIS ............................................................................................................................................ 40 
7.6 
VITAL SIGNS AND BODY WEIGHT ............................................................................................................. 40 
7.7 
12-LEAD ECGS ....................................................................................................................................... 40 
7.8 
MMSE .................................................................................................................................................... 40 
7.9 
ADAS-COG ............................................................................................................................................ 40 
7.10 MODIFIED C-SSRS ................................................................................................................................. 40 
8 
PROCEDURES FOR REPORTING TEAES AND SERIOUS ADVERSE EVENTS ........................ 41 
8.1 
REPORTING TEAES................................................................................................................................. 41 
8.2 
REPORTING SERIOUS ADVERSE EVENTS ................................................................................................. 41 
9 
STATISTICS ............................................................................................................................................. 42 
9.1 
ASSESSMENT OF SAFETY AND TOLERABILITY AND ................................................................................. 42 
9.1.1 Assessment of MTD .........................................................................................................................42 
9.1.2 Adverse Events .................................................................................................................................42 
9.1.3 Laboratory Tests (Safety laboratory test and urinalysis) ..................................................................42 
9.1.4 ECGs ................................................................................................................................................42 
9.1.5 Vital Signs and weight ......................................................................................................................42 
9.2 
PHARMACOKINETICS ............................................................................................................................... 43 
9.3 
PATIENT DISPOSITION ............................................................................................................................. 43 
9.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................................................................... 43 
9.5 
PROTOCOL DEVIATIONS .......................................................................................................................... 43 
9.6 
COMPLIANCE .......................................................................................................................................... 43 
10 
ACCESS TO SOURCE DATA/DOCUMENTS ..................................................................................... 43 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 43 
11.1 STUDY MONITORING ............................................................................................................................... 43 
11.2 AUDITS AND INSPECTIONS ...................................................................................................................... 44 
11.3 DATA QUALITY ASSURANCE .................................................................................................................. 44 
12 
ETHICS AND ADMINISTRATIVE ISSUES ........................................................................................ 44 
12.1 ETHICAL CONDUCT OF THE TRIAL ........................................................................................................... 44 
12.2 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) AND REGULATORY 
AUTHORITY ...................................................................................................................................................... 45 
12.3 SUBJECT INFORMED CONSENT ................................................................................................................. 45 
12.4 SUBJECT DATA PROTECTION ................................................................................................................... 45 
12.5 DATA MONITORING COMMITTEE ............................................................................................................ 45 
12.6 FINANCIAL DISCLOSURE ......................................................................................................................... 46 
12.7 INVESTIGATOR OBLIGATIONS ................................................................................................................. 46 
12.8 CHANGES TO THE PROTOCOL .................................................................................................................. 46 
12.9 CONFIDENTIALITY/PUBLICATION OF THE STUDY .................................................................................... 46 
12.10 DISCONTINUATION OF ENTIRE STUDY ..................................................................................................... 46 
13 
DATA HANDLING AND RECORD KEEPING ................................................................................... 47 
13.1 INSPECTION OF RECORDS ........................................................................................................................ 47 
13.2 RETENTION OF RECORDS ........................................................................................................................ 47 
14 
REFERENCES .......................................................................................................................................... 48 
 


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LIST OF ABBREVIATIONS  
 
ACh ......................... Acetylcholine 
AChEI ..................... Acetylcholinesterase Inhibitor 
AD ........................... Alzheimer’s disease 
ADAS-cog...............Alzheimer’s disease Assessment Scale-cognition 
ADR.........................Adverse Drug Reaction 
AE ........................... Adverse Event 
AV...........................Atrioventricular 
CFS...................... ... Cerebrospinal Fluid 
CNS ......................... Central Nervous System 
CRF ......................... Case Report Form  
CRO ........................ Contract Research Organization 
C-SSRS. .................. Columbia-Suicide Severity Rating Scale 
DSM. ....................... Diagnostic and Statistical Manual of Mental Disorders 
E2020. ..................... Donepezil  
ECG ......................... Electrocardiogram 
FDA ......................... Food and Drug Administration 
FID .......................... First Intolerable Dose 
GCP ......................... Good Clinical Practice 
GI ............................ Gastrointestinal 
HR. .......................... Heart Rate 
ICD. ......................... Implantable Cardiac Defibrillator 
ICH .......................... International Conference On Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IEC .......................... Independent Ethics Committee 
IRB .......................... Institutional Review Board 
KG. .......................... Kilogram 
MAD………………Maximum Allowed Dose 
MEDDRA. .............. Medical Dictionary for Regulatory Activities 
MG. ......................... Milligram 
ML. .......................... Milliliter 
MMSE. .................... Mini Mental Status Examination 
MSEC. ..................... Millisecond 
MTD ........................ Maximum Tolerated Dose 
NDA. ....................... New Drug Application 
NG/ML. ................... Nanogram/Milliliter 
NIA-ADA. .............. National Institute on Aging – Alzheimer’s Disease Association 
OAB. ....................... Overactive Bladder Disorder 
OTC. ........................ Over-the-Counter 
QTC. ........................ Corrected QT interval 
QTCF. ..................... Corrected QT intervals by Fridericia's formula 
PR Interval. ............. On ECG, time from onset of P wave to start of QRS Complex 
QRS complex. ......... On ECG, central part of tracing, Q,R and S waves 


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QT interval. ............. On ECG, interval between start of Q wave and end of the T 
wave 
SOC ......................... System Organ Class 
SOP ......................... Standard Operating Procedures 
SAE ......................... Serious Adverse Event 
SEM. ....................... Standard Error of Mean 
TEAE ...................... Treatment Emergent Adverse Event 
UNL. ....................... Upper Normal Limit 
US ........................... United States 
WHO ....................... World Health Organization 


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LIST OF TABLES 
 
 
 
 
 
Table 5: Combination of tablets for each dosage .................................................................................. 35 
 


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PROTOCOL SUMMARY 
Name of Sponsor/Company: 
Chase Pharmaceuticals Corporation 
Name of Investigational Product: 
CPC-201: Donepezil plus solifenacin 
Name of Active Ingredient: 
Donepezil, solifenacin 
Title of Study: 
A phase II, dose titration study of CPC-201 in Patients with Dementia of Alzheimer’s Type 
Number of clinical centers: 
Multicenter 
Objectives:  
Primary: 
• 
To determine the optimal initial dose and subsequent dose titration schedule (rate and 
increment) for CPC-201. 
Secondary: 
• 
To evaluate the safety and tolerability of CPC-201 as a function of dose and initial rate of dose 
titration. 
Methodology:  
This is a Phase II, ascending dose study of CPC-201 in patients with dementia of Alzheimer’s type to 
determine the optimal dose titration schedule. The study involves a step wise cohort design in two 
different patient populations: Group 1 will consist  of patients who have been treated with donepezil 5 or 
10 mg/day (given once daily) for at least 4 weeks just prior to Day1. Group 2 will consist of patients who 
have never been treated with donepezil before (donepezil naïve) or who have not received any other 
AChEI for the past 6 months. 
 
In this study, donepezil dose will be increased at weekly intervals, in accordance with the schedules 
given below, to its first intolerable dose (FID) or maximum allowed dose (MAD) of 60mg/day together 
with solifenacin 15 mg/day. If a patient does not tolerate a donepezil dose higher than 40mg/day with 
solifenacin 15 mg/day, the solifenacin dose can be increased to 20mg/day per the Investigator’s decision. 
 
Cohort 1 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 30mg donepezil + 15mg solifenacin 
3rd week: 40mg donepezil + 15mg solifenacin 
4th week: 50mg donepezil + 15mg (or 20mg) solifenacin 
5th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 40mg donepezil + 15mg solifenacin 
3rd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*: The dose titration schedule of Cohorts 2 and 3 may be altered based on Cohort 1 result. 
 
Each cohort will include approximately 6 patients donepezil-treated (Group 1) and approximately 6 


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patients not treated with an AchEI for at least 6 months (Group 2). Within each cohort, Group 2 patients 
will be enrolled only when at least 3 Group 1 patients have completed dose titration per protocol.  
 
Patients will be enrolled in Cohort 2 only when patients enrolled in Cohort 1 have safely completed 
titration. Similary, patients will be enrolled in Cohort 3 only when patients enrolled in Cohort 2 have 
safely completed titration. 
 
Patients reaching their FID or having completed one week treatment with donepezil 60mg/day, have two 
options.  
 
Option 1: Patient will be allowed to immediately enter a long term extension at their maximum tolerated 
dose (MTD) or MAD. 
 
Option 2: Patients may choose not to enter the long term extension, in which case the Investigator will 
decide whether the patient should discontinue high dose of donepezil without down-titration, or whether 
donepezil should be downtitrated to their own standard of donepezil dose. Whatever the decision, the 
patient will be treated at least an additional 7 days with solifenacin 15 mg/day. 
 
Number of patients planned:  
To ensure a suitable number of subjects to evaluate the optimal dose titration schedule, approximately 6 
patients per population group per cohort will be enrolled. 
Diagnosis and main criteria for inclusion: 
 
Males and females suffering from AD  
 
Inclusion Criteria: 
1) Signed an Institutional Review Board (IRB) approved informed consent document indicating 
that they understand the purpose of and procedures required by the study and are willing to 
participate in the study and comply with all study procedures and restrictions. Informed consent 
must be obtained from the patient and/or a designated representative prior to initiating screening 
procedures to evaluate eligibility for the study. 
2) Aged 50 – 89 years inclusive. 
3) Meeting the diagnosis of probable AD consistent with: 
• 
Revised National Institute on Aging-Alzheimer’s Disease Association (NIA-ADA) criteria 
and  
• 
Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria.  
4) Mild to severe severity (Mini-Mental Status Exam [MMSE] scores 7 – 24 inclusive). 
5) Rosen-Modified Hachinski Ischemia Score of ≤4. 
6) Have a suitable caregiver to supervise the at-home administration of study drugs and observe 
for AEs. 
7) Patients will be required to have been treated with donepezil 5 or 10 mg/day (given once daily) 
for at least 4 weeks just prior to Day1 for Population (group) 1 or; 
Patients have never been treated with donepezil before (donepezil naïve) or who have not 
received any other AChEI for the past 6 months for Population (group) 2. 
8) Patients must be in generally good health as indicated by their medical history and physical 
examination, vital signs, electrocardiogram (ECG), and standard laboratory tests. 


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Key exclusion criteria: 
The criteria for exclusion of a subject from enrollment in the study are as follows: 
1) Women of child bearing potential.  
2) History or presence of a seizure disorder. 
3) Current unstable peptic ulcer disease, urinary or gastric retention; asthma or obstructive 
pulmonary disease. 
4) History or presence of bladder outflow obstruction, gastrointestinal obstructive disorder or 
reduced GI motility, or narrow-angle glaucoma. 
5) History or presence of gastrointestinal, hepatic, or renal disease, or other condition known to 
interfere with the absorption, distribution, metabolism or excretion of drugs. 
6) Renal and hepatic dysfunction with: 
• 
Total Bilirubin: >1.5 x UNL 
• 
AST: >2.5 x UNL 
• 
ALT: >2.5 x UNL 
• 
Serum Creatinine: >1.5 x UNL 
• 
Creatinine Clearance: <30 mL/min (calculated by Cockcroft and Gault equation) 
7) History or presence of myasthenia. 
8) History or family history of Prolonged QT Syndrome. 
9) History of unexplained syncope or family history of unexplained syncope or sudden death. 
10) Myocardial infarction or hospitalization for congestive heart failure within 6 months. 
11) ECG findings of: 
• 
Complete Left Bundle Branch Block; 
• 
Ventricular pacing; 
• 
2nd degree or 3rd degree AV block; 
• 
Atrial fibrillation or atrial flutter; 
• 
HR <45 or >100; 
• 
PR >220 msec; or 
• 
QTcF >450 msec in male, >470 msec in female 
12) Known hypersensitivity to donepezil, solifenacin or related drugs. 
13) History of drug significant allergy. 
14) History of substance abuse, known drug addiction, or positive test for drugs of abuse or alcohol. 
15) Patients treated with the following medications within 8 weeks of screening 
• 
Peripherally acting anticholinergics (such as drugs for the treatment of overactive bladder 
disorder), 
• 
Psychoactive medications (including antipsychotics, antidepressants, anxiolytics or 
sedative hypnotics) having significant anticholinergic effects and/or believed to affect 
cognitive function.  
Other medications are acceptable, at the investigators discretion, if dosage is held stable for at 
least 4 weeks prior to screening and throughout the study. 
16) Patients considered unlikely to co-operate in the study, and/or poor compliance anticipated by 
the investigator. 
17) Patients hospitalized within 4 weeks of screening. 
18) Any other clinically relevant acute or chronic diseases which could interfere with patients’ 
safety during the trial, or expose them to undue risk, or which could interfere with study 
objectives. 
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previous 30 days. 
Investigational product (IP) 
Donepezil (Aricept®): 10 mg tablet (or generic equivalent) 
Solifenacin (Vesicare®): 5 mg, 10 mg tablets 
Placebo (Similar in size to donepezil 10 mg or solifenacin 5 mg/10 mg tablets 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duration of treatment:  
Screening: 4 weeks 
Dosing: up to 5 weeks 
Reference therapy, dosage and mode of administration:  
None 
Statistical Analysis: 
Since the objective of this study is to determine the optimal initial dose and subsequent dose titration 
schedule, the data will be analyzed only by means of descriptive statistics to reveal possible trends that 
will help guide the design of future, more definitive, clinical trials. 
Sample size calculations: 
No formal sample size calculation has been made. Based on experience from previous similar studies, a 
total 4-6 evaluable subjects per group per cohort is considered sufficient. 


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2 OBJECTIVES 
2.1 
Primary objective 
To determine the optimal initial dose and subsequent dose titration schedule (rate and 
increment) for CPC-201. 
2.2 
Secondary objective 
To evaluate the safety and tolerability of CPC-201 as a function of dose and initial rate of 
dose titration. 
 
3 INVESTIGATIONAL PLAN 
3.1 
Overall Study design 
This is a Phase II, ascending dose study of CPC-201 in patients with dementia of 
Alzheimer’s type to determine the optimal dose titration schedule. The study involves a 
step wise cohort design in two different patient populations: Group 1 will consist of 
patients who have been treated with donepezil 5 or 10 mg/day (given once daily) for at 
least 4 weeks just prior to Day1. Group 2 will consist of patients who have never been 
treated with donepezil before (donepezil naïve) or who have not received any other 
AChEI for the past 6 months. 
 
In this study, donepezil dose will be increased at weekly intervals, in accordance with the 
schedules given below, to its first intolerable dose (FID) or maximum allowed dose 
(MAD) 60 mg/day together with solifenacin 15 mg/day. If a patient does not tolerate a 
donepezil dose higher than 40mg/day with solifenacin 15 mg/day, the solifenacin dose 
can be increased to 20mg/day per the Investigator’s decision. 
 
Cohort 1 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 30mg donepezil + 15mg solifenacin 
3rd week: 40mg donepezil + 15mg solifenacin 
4th week: 50mg donepezil + 15mg (or 20mg) solifenacin 
5th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 40mg donepezil + 15mg solifenacin 
3rd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3* 
1st week: 20mg donepezil + 15mg solifenacin 
2nd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*: The dose titration schedule of Cohort 2 and 3 may be altered based on Cohort 1 result. 
 
Each cohort will include approximately 6 patients donepezil-treated (Group 1) and 
approximately 6 patients not treated with an AchEI for at least 6 months (Group 2). 
Within each cohort, Group 2 patients will be enrolled only when at least 3 Group 1 
patients have completed dose titration per protocol.  


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Patients will be enrolled in Cohort 2 only when patients enrolled in Cohort 1 have safely 
completed titration. Similary, patients will be enrolled in Cohort 3, only when patients 
enrolled in Cohort 2 have safely completed titration. 
 
Patients reaching their FID or having completed one week treatment with donepezil 
60mg/day, have two options.  
 
Option 1: Patient will be allowed to immediately enter a long term extension at their 
maximum tolerated dose (MTD) or MAD. 
 
Option 2: Patients may choose not to enter the long term extension, in which case the 
Investigator will decide whether the patient should discontinue high dose of 
donepezil without down-titration, or whether donepezil should be 
downtitrated to their own standard of donepezil dose. Whatever the decision, 
the patient will be treated at least an addtional 7 days with solifenacin 15 
mg/day. 
3.2 
Dose Escalation and Stopping rules 
For all patients, donepezil dose escalation will be discontinued if they manifest over a 24 
hour period after study drug administration the following symptoms judged by the 
investigator as possibly or probably study-drug related: 
 
• One (1) episode of vomiting, or 
• Two (2) episodes of severe retching (separated by more than one hour on the 
same day), or 
• One (1) episode of severe nausea (Grade 3; defined as nausea interfering with 
activities of daily living or inadequate oral caloric or fluid intake; tube feeding, 
total parenteral nutrition or hospitalization indicated) and/or severe abdominal 
discomfort (Grade 3; defined as severely interfering with activities of daily living), 
or 
• Three (3) episodes of moderate nausea (Grade 2; defined as subjectively 
symptomatic, but not interfering with activities of daily living)  and/or moderate 
abdominal discomfort (Grade 2; defined as interfering with function, but not 
interfering with activities of daily living) each on the same day, or  
• One (1) episode of moderate diarrhea (Grade 2; defined as 4 to 6 stools more than 
at baseline). 
• Any other circumstance that merits an adjustment in study drug dosage in the 
opinion of the investigator 
 
All those meeting one or more of the foregoing stopping rules will be withdrawn from 
dose titration and proceed in accordance with either of the two options given above. 


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3.3 
Trial procedures 
3.3.1 
Schedule of Assessments 
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3.3.2 
Study Procedure 
For each visit, procedures and assessments are listed in the order in which they should be 
performed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.5 
Discontinuation criteria 
3.5.1 
Discontinuation of donepezil dose escalation in individual subjects 
For all patients, donepezil dose escalation will be discontinued if they manifest over a 24 
hour period after study drug administration the following symptoms judged by the 
investigator as possibly or probably study-drug related: 
 
• One (1) episode of vomiting, or 
• Two (2) episodes of severe retching (separated by more than one hour on the 
same day), or 
• One (1) episode of severe nausea (Grade 3; defined as nausea interfering with 
activities of daily living or inadequate oral caloric or fluid intake; tube feeding, 
total parenteral nutrition or hospitalization indicated) and/or severe abdominal 
discomfort (Grade 3; defined as severely interfering with activities of daily living), 
or 
• Three (3) episodes of moderate nausea (Grade 2; defined as subjectively 
symptomatic, but not interfering with activities of daily living)  and/or moderate 
abdominal discomfort (Grade 2; defined as interfering with function, but not 
interfering with activities of daily living) each on the same day, or  
• One (1) episode of moderate diarrhea (Grade 2; defined as 4 to 6 stools more than 
at baseline). 
• Any other circumstance that merits an adjustment in study drug dosage in the 
opinion of the investigator 
3.5.2 
Discontinuation of individual subjects from the entire study 
During the study, the investigator or the sponsor may decide to discontinue a subject’s 
participation in the study in the following cases: 
• A protocol violation occurs; 
• A serious or intolerable (other than those listed in the discontinuation of 
rivastigmine escalation criteria) AE occurs; 
• The Sponsor or Investigator terminates the study. 
• The subject requests to be discontinued from the study. 
• The subject is non-compliant to any part of the study. 
• The Investigator feels it is not in the best interest of the subject to continue in the 
study. 
 
4 SELECTION OF SUBJECTS 
4.1 
Inclusion criteria 
The criteria for inclusion that each subject must meet to be enrolled in the study are as 
follows: 


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1. Signed an Institutional Review Board (IRB) approved informed consent document 
indicating that they understand the purpose of and procedures required by the 
study and are willing to participate in the study and comply with all study 
procedures and restrictions. Informed consent must be obtained from the patient 
and/or a designated representative prior to initiating screening procedures to 
evaluate eligibility of the study. 
2. Aged 50 – 89 years inclusive. 
3. Meeting the diagnosis of probable AD consistent with: 
- 
Revised National Institute on Aging-Alzheimer’s Association (NIA-ADA) 
criteria and  
- 
Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria.  
4. Of mild to severe severity (Mini-Mental Status Exam [MMSE] scores 7 – 24 
inclusive). 
5. Rosen-Modified Hachinski Ischemia Score of ≤4. 
6. Have a suitable caregiver to supervise the at-home administration of study drugs 
and observe for AEs. 
7. Patients will be required to have been treated with donepezil 5 or 10 mg/day 
(given once daily) for at least 4 weeks just prior to Day1 for Population (group) 1 
or; 
8. Patients have never been treated with donepezil before (donepezil naïve) or who 
have not received any other AChEI for the past 6 months for Population (group) 
2. 
9. Patients must be in generally good health as indicated by their medical history and 
physical examination, vital signs, electrocardiogram (ECG), and standard 
laboratory tests. 
4.2 
Exclusion criteria 
The criteria for exclusion of a subject from enrollment in the study are as follows: 
1. Women of child bearing potential.  
2. History or presence of a seizure disorder. 
3. Current unstable peptic ulcer disease, urinary or gastric retention; asthma or 
obstructive pulmonary disease. 
4. History or presence of bladder outflow obstruction, gastrointestinal obstructive 
disorder or reduced GI motility, or narrow-angle glaucoma. 
5. History or presence of gastrointestinal, hepatic, or renal disease, or other 
condition known to interfere with the absorption, distribution, metabolism or 
excretion of drugs. 
6. Renal and hepatic dysfunction with: 
- 
Total Bilirubin: >1.5 x UNL 


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- 
AST: >2.5 x UNL 
- 
ALT: >2.5 x UNL 
- 
Serum Creatinine: >1.5 x UNL 
- 
Creatinine Clearance: <30 mL/min  
7. History or presence of myasthenia. 
8. History or family history of Prolonged QT Syndrome. 
9. History of unexplained syncope or family history of unexplained syncope or 
sudden death. 
10. Myocardial infarction or hospitalization for congestive heart failure within 6 
months. 
11. ECG findings of: 
- 
Complete Left Bundle Branch Block; 
- 
Ventricular pacing; 
- 
2nd degree or 3rd degree AV block; 
- 
Atrial fibrillation or atrial flutter; 
- 
HR <45 or >100; 
- 
PR >220 msec; or 
- 
QTcF >450 msec in male, >470 msec in female 
12. Known hypersensitivity to donepezil, solifenacin or related drugs. 
13. History of drug significant allergy. 
14. History of substance abuse, known drug addiction, or positive test for drugs of 
abuse or alcohol. 
15. Patients treated with the following medications within 8 weeks of screening 
- 
AChEIs (other than donepezil),  
- 
Peripherally acting anticholinergics (such as drugs for the treatment of 
overactive bladder disorder), 
- 
Psychoactive medications (including antipsychotics, antidepressants, 
anxiolytics or sedative hypnotics) having significant anticholinergic effects 
and/or believed to affect cognitive function.  
Other medications are acceptable, at the investigators discretion, if dosage is held 
stable for at least 4 weeks prior to screening and throughout the study. 
16. Patients considered unlikely to co-operate in the study, and/or poor compliance 
anticipated by the investigator. 
17. Patients hospitalized within 4 weeks of screening. 
18. Any other clinically relevant acute or chronic diseases which could interfere with 
patients’ safety during the trial, or expose them to undue risk, or which could 
interfere with study objectives. 


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19. Patients who have participated in another clinical trial with an investigational drug 
within previous 30 days. 
 
5 STUDY DRUG 
5.1 
Blinding 
This is a single-blind study. The subject, caregiver, and site personnel who assess MMSE 
and ADAS-Cog are blinded.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3 
Description of Study Drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Placebo tablet 
Placebo tablet is similar in size to donepezil 10 mg or solifenacin 5 mg/10 mg tablets. 
5.3.2 
Study drug manufacturing and labeling 
Donepezil and solifenacin will be purchased by 
from a licensed supplier of 
these pharmaceuticals.  
 
The placebo tablet will be manufactured, packaged in bottle, labeled by 
 
 Label will include the following information: protocol 
number, quantity of tablets, required storage conditions, lot number, name and address of 
the manufacturer and the following cautionary statement: New Drug – Limited by 
Federal law to investigational use. 
5.3.3 
Study drug storage, handling and disposal 
At the site, all study drugs should be stored at room temperature
 in a 
secure area accessible only to the designated qualified site personnel. All study drugs 
must be stored, inventoried and the inventories carefully and accurately documented 
according to applicable state, federal and local regulations, International Conference on 
Harmonisation (ICH) Guidelines, Good Clinical Practice (GCP) and study procedures. 
The study drug is to be prescribed only by the Investigator or his/her named sub-
investigator(s), and is to be used only in accordance with the protocol. The study drug 
must be distributed only to patients properly enrolled in the study. 
 
The Investigator must keep an accurate accounting of the study drug received from the 
Sponsor, including the temperature of the storage area, the amount of study drug 
dispensed to patients, amount of study drug returned to the Investigator by the patients, 
and the amount returned to the Sponsor upon completion of the study. A detailed 
inventory must be completed for the study drug.  
 
Unused study drug must be kept in a secure location for accountability and reconciliation 
by the study monitor. Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials. 
 
Unused study drug may be destroyed on site, per the site’s standard operating procedures 
(SOPs), but only after the Sponsor has granted approval for drug destruction. The monitor 
must account for all study drugs in a formal reconciliation process prior to study drug 
destruction. All study drug destroyed on site must be documented. Documentation must 
be provided to the Sponsor and retained in the Investigator’s study files. If a site is unable 
to destroy study drug appropriately, the site can return unused study drug to the Sponsor 
or designee upon request. The return of study drug or study drug materials must be 
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5.4 
Concomitant medication 
5.4.1 
Allowed Mediations 
Dosage of allowed concomitant medication should be stabilized for at least 4 weeks prior 
to screening and should remain constant during the course of the study. Patients on 
concomitant memantine should be on a stable dose for at least 3 months. With the 
exception of medications listed in the exclusion criteria (Section 4.2) and in Section 5.4.2 
below, concomitant medications will be allowed at the Investigator's discretion.  
 
All concomitant medications and therapies (prescription and OTC) should be recorded in 
the CRF, with generic name (if known, otherwise brand name), indication, dose, route, 
frequency, and date(s) of administration. Any change in any of these parameters during 
the study should be documented. 
5.4.2 
Prohibited Mediations 
Concomitant use of the following drugs is not allowed (such medications must have been 
discontinued at least 8 weeks prior to screening): 
• peripherally acting anticholinergics (such as drugs for the treatment of overactive 
bladder disorder), 
• psychoactive medications (including antipsychotics, antidepressants, anxiolytics 
or sedative hypnotics) having significant anticholinergic effects and/or believed to 
affect cognitive function 
 
In addition, the following drugs are prohibited during the study: 
• Strong CYP3A4 inhibitors  
• Strong CYP3A4 inducers  
• Strong CYP2D6 inhibitors 
  
Patients who use prohibited medications during the study listed above may be 
discontinued from study drug. Medications prescribed after patients have discontinued 
the study drug will not be considered as prohibited medications. 
Note: The discontinuation of a patient due to use of a prohibited medication is dependent 
upon the Sponsor's decision. The Investigator should contact the Sponsor prior to 
discontinuing a patient for disallowed medications. 
 
6 ASSESSMENT OF PHARMACOKINETICS 
6.1 
PK Blood Sampling Schedule and Sample Analysis 
The blood samplings will be performed at approximately 15 minutes before and 4 hours 
(± 15 min) after study drug administration at each visits. 


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7 SAFETY ASSESSMENTS 
7.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical-investigation subject 
administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. A TEAE is defined as any AE that occurs after 
administration of the first dose of study drug. An AE can therefore be an unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. The failure of the anticipated 
pharmaceutical action of an investigational drug does not constitute a related AE. 
AE rating 
The condition of the subjects will be closely monitored throughout the study. The 
investigator will collect the AEs reported spontaneously, observed, or elicited in response 
to a non-leading question (for example, "How have you been feeling since we last asked 
you?"). The investigator will record all AEs in the source records and the CRF. 
• 
The intensity/severity of an AE will be rated as follows: 
Mild 
: Awareness of signs or symptoms, but no disruption of usual activity. 
Moderate 
: Event sufficient to affect usual activity (disturbing). 
Severe 
: Inability to work or perform usual activities (unacceptable). 
• 
The causal relationship of an AE to the study drugs will be rated as follows: 
Not related 
: Temporal relationship of the onset of the event, relative to the 
administration of the product, is not reasonable or another cause can 
by itself explain the occurrence of the event 
Unlikely 
: Is general, this category can be considered applicable to those AEs 


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related 
which after careful medical consideration at the time they are 
evaluated, are judged to be unrelated to the study drug 
Related 
: AEs incontrovertibly related to the administration of the product. 
Of the above definitions, AEs related to study drug are considered adverse reactions, 
while “unlikely” and “not related” do not represent a causal relationship. 
• 
The action taken with the study drug for an AE will be rated as product withdrawn, 
not changed, not applicable. AEs requiring therapy will be treated with recognised 
standards of medical care to protect the health and the well-being of the subject. 
• 
The outcome of an AE will be rated as recovered, recovering, not recovered, 
recovered with sequellae or fatal. The investigator will follow up any AE until it is 
resolved or until the medical condition of the subject is stable. All relevant follow-up 
information will be collected. For AEs that are ongoing at the last visit, the 
investigator will make thorough efforts to document the outcome. 
7.2 
Serious Adverse Events (SAE) 
An SAE is any untoward medical occurrence that results in death, is life threatening, 
requires in-patient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. In 
addition, important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
An AE is life-threatening if the subject is at immediate risk of death from the event as it 
occurs, i.e. it does not include a reaction that, if it had occurred in a more serious form, 
might have caused death. For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not have been considered life-threatening, even though 
drug-induced hepatitis can be fatal. 
 
An AE is incapacitating or disabling if the experience resulted in a substantial and/or 
permanent disruption of the subject’s ability to carry out normal life functions. 
7.3 
Assessment of tolerability 
The FID of each patient will be recorded. 
7.4 
Safety Laboratory Test 
Blood samples will be collected as indicated in Table 1-4 for the following clinical 
laboratory tests: 
 
Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils) and platelet 
count. 
 


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Serum chemistry: calcium, sodium, chloride, potassium, blood urea nitrogen, glucose, 
total bilirubin, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, 
alanine aminotransferase, creatinine, calculated creatinine clearance,  uric acid, 
phosphorous, total protein, albumin, and globulin. 
 
 
 
 
7.5 
Urinalysis 
Urine samples will be collected as indicated in Table 1-4 for the following tests: glucose, 
bilirubin, ketones, specific gravity, blood, pH, protein, urobilinogen, nitrites, and 
leukocytes and, if necessary, microscopic examination. 
7.6 
Vital signs and body weight 
Vital signs, including blood pressure, heart rate, respiratory rate, and temperature, will be 
measured after the patient rests in the supine position for at least 5 minutes.  
 
Body weight will be measured as indicated in Table 1-4.  
7.7 
12-Lead ECGs 
A standard 12-lead ECG will be recorded as indicated in Table 1-4. The Investigator will 
evaluate the ECG results as normal, abnormal, not clinically significant, or abnormal, 
clinically significant. 
 
If QTcF on an on treatment ECG is ≥500 msec then hold treatment and perform 3 repeat 
ECGs over 20-60 min; if the mean QTcF of the three ECGs is ≥500 msec, withhold 
treatment and perform a repeat ECG the following day; if the QTcF has returned to 
baseline, dosing may resume..  
7.8 
MMSE 
MMSE will be assessed by blinded rater at visits indicated in Table 1-4. 
7.9 
ADAS-Cog 
ADAS-Cog will be assessed by blinded rater at visits indicated in Table 1-4. 
7.10 Modified C-SSRS 
Modified C-SSRS will be assessed by a qualified and experienced clinician who does not 
perform psychometric at visits indicated in Table 1-4. 
 


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8 PROCEDURES FOR REPORTING TEAES AND SERIOUS 
ADVERSE EVENTS 
8.1 
Reporting TEAEs 
All TEAEs, regardless of seriousness, severity or presumed relationship to study therapy, 
must be recorded using medical terminology in the source document and transcribed into 
the CRF. Whenever possible, the diagnosis should be given when signs and symptoms 
are due to a common etiology (e.g. cough, runny nose, sneezing, sore throat, and head 
congestion should be reported as “upper respiratory infection” instead of identifying and 
listing the individual signs and symptoms). The Investigator must record, in the source 
document and transcribe into the AE page of the CRF, his or her medical assessment of 
the severity of the event and the relationship of the AE to study drug. 
 
All TEAEs must be followed until they have resolved or until a stable clinical endpoint is 
reached. All measures required for managing the TEAE and the ultimate outcome of the 
TEAE must be recorded in the source document and reported in the CRF. 
8.2 
Reporting Serious Adverse Events 
When the Investigator or designee becomes aware that an SAE has occurred, the Sponsor 
representative must be notified by both telephone and fax, regardless of the relationship 
(or lack thereof) of the SAE to study drug within 24 hours of the event. All SAEs must be 
submitted to the Sponsor as a written report, as well as reported verbally. A follow-up 
report must be submitted to the Sponsor as requested when pertinent information 
becomes available and if additional information is requested. 
 
The Investigator is responsible for ensuring that the IRB is informed of this information 
within appropriate IRB established timelines. 
 
ANY SAE OR ADR, INCLUDING ANY OUTCOME OF DEATH DUE TO ANY 
CAUSE THAT OCCURS DURING THIS STUDY MUST BE REPORTED 
IMMEDIATELY TO THE SPONSOR REPRESENTATIVE. 
This verbal and faxed report must be followed no later than 3 working days by a written 
report signed by the Investigator. The Sponsor is responsible for submitting the report 
to all applicable regulatory authorities. 
 
 
 
 
 
 
 
 


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9 STATISTICS 
Since the objective of this study is to determine the optimal initial dose and subsequent 
dose titration schedule, the statistics are not applicable. 
The data will be analyzed only by means of descriptive statistics to reveal possible trends 
that will help guide the design of future, more definitive, clinical trials. 
9.1 
Assessment of Safety and Tolerability and  
Safety and tolerability parameters will be analyzed as a function of dose and dose 
titration schedule. 
9.1.1 
Assessment of MTD  
Descriptive statistics will be presented for the MTD and the FID for each patient in each 
dose titration schedule. 
9.1.2 
Adverse Events 
Data Listings will present the verbatim-reported event along with the preferred term and 
SOC, onset and stop dates, severity, relatedness, SAE status, action taken and outcome. 
For summaries by severity, the most severe event episode will be counted if a subject has 
more than one event within the same coded term. For summaries of treatment-associated 
events, the subject will be counted as “associated” for that term if a subject has more than 
one event within the same coded term or if one event is considered “not associated” and 
the other “associated”. 
 
Unless otherwise indicated, AE summary tables will be presented by study period, 
treatment group, SOC, and preferred term for each study period. 
9.1.3 
Laboratory Tests (Safety laboratory test and urinalysis) 
For the continuous laboratory parameters, descriptive statistics will be presented. 
Additionally, parameters will be categorized as low, normal or high according to 
laboratory range specifications. The number and percentage of subjects will be presented 
by dosing cohort and treatment arm.  
9.1.4 
ECGs 
The overall interpretation of the ECG results will be presented as normal, abnormal (not 
clinically significant) and abnormal (clinically significant) by time point and study 
period.  
9.1.5 
Vital Signs and weight 
Descriptive statistics will be presented for each vital sign measurement recorded at each 
time point during each study period.  


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9.2 
Pharmacokinetics 
Blood concentration results of donepezil and solifenacin for each subject will be 
presented. 
9.3 
Patient Disposition  
Disposition of all subjects will be summarized descriptively. 
9.4 
Demographics and Baseline Characteristics 
Individual subject demographic and baseline characteristics data will be presented in 
subject data listings. Concomitant medications (all recorded medications) will be listed 
for enrolled subjects. The listing will be sorted by start date of medication within the 
standard sort order. The listing will include all collected information. 
9.5 
Protocol Deviations 
All protocol deviations will be listed by subject number. 
9.6 
Compliance  
Dosing information collected on the CRF will be listed for each subject. Compliance will 
be summarized by presenting the numbers and percentages of subjects receiving each 
dose of study drug. 
 
10 ACCESS TO SOURCE DATA/DOCUMENTS 
Checking of case report forms (CRF’s) for completeness and clarity and cross-checking 
with source documents will be required to monitor the progress of the study. The 
Monitors are entitled to compare CRF entries with source data and to inform the 
investigator about errors and omissions. The monitor will request correction / 
clarification from the investigator using electronic data clarifications that should be 
answered and closed as quickly as possible. The Investigator will provide direct access to 
source data/documents for the Sponsor’s designated representatives (monitors and 
auditors) as well as IRB/IEC members and regulatory inspections. 
 
Regulatory authorities and/or the Sponsor’s clinical quality assurance personnel may also 
carry out source data checks and/or on-site audit inspections. These will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator 
is to give the Sponsor whatever support is necessary. 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Study Monitoring 
The study will be initiated by the Sponsor during an on-site visit after all required study 
documents have been sent to the Sponsor and approved. A monitor will perform 


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subsequent on-site monitoring visits as frequently as deemed necessary. At these visits, 
the monitor will compare the data entered onto the CRFs with the hospital or clinic 
records (source documents) and check for protocol compliance, including a review of 
records of informed consent, all subject visit dates, all AEs, all concomitant medications, 
and key efficacy observations. In addition, drug accountability records will be reviewed 
and findings from this review will be discussed with the Investigator. 
 
The Sponsor expects that during monitoring visits, the study coordinator, Investigator, 
CRFs and source documentation will be available and a suitable environment will be 
provided for review of study-related documents. 
11.2 Audits and Inspections 
Trial sites, facilities, laboratories and all data (including sources) and documentation must 
be available for GCP audit by the Sponsor or inspection by competent authorities.  Any 
aspect of the trial may be subject to audit by the Sponsor and/or inspection by regulatory 
authorities or the IRB.  Such audits/inspections may take place at the Sponsor’s site(s) or 
at the trial site including laboratories, pharmacies etc. In case of audit, the monitor will 
announce this in advance to the Investigator (or representative) and be present at the 
particular trial site during the audit. 
 
The site staff should assist in all aspects of audit/inspection. 
11.3 Data Quality Assurance 
The Sponsor and their designated Contract Research Organization (CRO) will implement 
a system of quality assurance, including all elements described in this protocol.  Within 
this system the CRO SOPs will be implemented to ensure that the clinical trial is 
conducted in compliance with regulatory requirements and GCP.  Quality control is 
applied to each stage of data handling to ensure that data are accurate, reliable and 
processed correctly. 
 
12 ETHICS AND ADMINISTRATIVE ISSUES 
12.1 Ethical conduct of the trial 
This protocol was designed and will be conducted, recorded and reported in compliance 
with the principles of Good Clinical Practice (GCP) regulations and in accordance with 
the principles outlined in the Declaration of Helsinki. These requirements are stated in 
federal regulations as well as ICH of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, “E6 Guideline for Good Clinical Practice”. The Sponsor 
representative will review these obligations with the Investigator prior to the initiation 
and throughout the course of the study. The Investigator or any of his or her staff should 
contact the Sponsor representative for any questions or issues regarding compliance with 
GCP/ICH guidelines. 
 


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This study will be conducted in compliance with IRB guidelines and in accordance with 
applicable regulations regarding clinical safety data management. In addition this study 
will adhere to all local regulatory requirements and requirements for data protection. 
The Investigator should refer to 21 CFR Part 312, Subpart D, ICH Guidelines E6 for 
clarification of the Investigator’s responsibilities for fulfillment of GCP Guidelines for 
Investigator’s qualifications and agreements, adequate resources, medical care of study 
subjects, communication with IRB, compliance with the protocol, responsibility for 
investigational products, randomization procedures, informed consent, records and 
reporting, premature termination or suspension of a study and final reports. 
 
Before initiating the study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject recruitment procedures (e.g. 
advertisements), and any written information to be provided to subjects, and a statement 
from the IRB that they comply with GCP requirements. The IRB approval must identify 
the protocol version as well as the documents reviewed. 
12.2 Institutional review board/independent ethics committee (IRB/IEC) and 
Regulatory Authority 
All protocols and protocol amendments must be signed and dated by the Investigator and 
approved by the IRB prior to implementation. The Investigator must provide an annual 
report to the IRB on the progress of the study in compliance with 21 CFR Part 56 and the 
IRB’s policies and procedures. The Investigator must provide notification to the IRB of 
the completion, termination or discontinuation the study. It is required that a yearly 
review of the protocol by the IRB be documented in a letter from the IRB. 
12.3 Subject informed consent 
Executed informed consent, and other locally required documents such as those related to 
Protected Health Information, are required. The consent form must be executed prior to 
performing any study-related activities that are not part of the subject’s routine care. The 
consent form that is used must be approved by both the reviewing IRB and by the 
Sponsor representative. 
12.4 Subject Data Protection 
Each subject must provide written informed consent as well as any authorizations 
required by local law (e.g. authorizations related to Protected Health Information). The 
Investigator agrees not to use or disclose Protected Health Information other than as 
permitted or required by the subject authorization or as required by law.  
12.5 Data Monitoring Committee 
Not applicable. 


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12.6 Financial Disclosure 
Study personnel on the Form FDA 1572 will complete a financial disclosure form at the 
beginning of the study. New study personnel added to Form FDA 1572 must also meet 
these requirements. 
12.7 Investigator Obligations 
The Investigator should refer to 21 CFR Part 312, Subpart D, ICH Guidelines E6 for 
clarification of the Investigator’s responsibilities to fulfill GCP Guidelines for 
Investigator’s qualifications and agreements, adequate resources, medical care of study 
subjects, communication with IRB, compliance with the protocol, responsibility for 
investigational products, randomization procedures, informed consent, records and 
reporting, premature termination or suspension of a study and final reports. 
 
The Investigator agrees when signing the protocol to adhere to the instructions and 
procedures described in it, and thereby, to adhere to the principles of GCP that it 
conforms to. 
12.8 Changes to the Protocol 
All protocols and protocol amendments must be signed and dated by the Investigator and 
approved by the IRB prior to implementation. 
12.9 Confidentiality/Publication of the Study 
All information supplied to the Investigator by a Sponsor representative and not 
previously published is considered confidential and remains the sole property of the 
Sponsor. The Investigator must agree to use this information only to accomplish this 
study, and must not use it for other purposes without the Sponsor’s written consent. 
The information developed in this study will be used by the Sponsor in connection with 
the continued development of this product and thus may be disclosed as required to other 
clinical Investigators or government regulatory agencies. To permit the information 
derived from the clinical studies to be used, the Investigator is obligated to provide the 
Sponsor with all data obtained in the study. 
 
No publication of any study data, results, other deliverables or records is permitted by the 
Investigator.  
12.10 Discontinuation of entire study 
The Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study either at a single site or at all sites at any time for reasons including, but not limited 
to, safety or ethical issues or severe non-compliance.  
 
In particular cases, the study may be terminated at a single investigational site, if the 
Sponsor has relevant reasons, e.g., suspicion of a deceit or conduct of the study which is 
not in accordance to the guidelines for GCP. 
 


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If the Sponsor determines such action is needed, the Sponsor will discuss this with the 
Investigator (including the reasons for taking such action) at that time. When feasible, the 
Sponsor will provide advance notification to the Investigator of the impending action 
prior to it taking effect. 
 
The Sponsor will promptly inform all other Investigators and/or institutions conducting 
the study if the study is suspended or terminated for safety reasons, and will also inform 
the regulatory authorities of the suspension or termination of the study and the reason(s) 
for the action. If required by applicable regulations, the investigator must inform the 
Ethics Committee promptly and provide the reason for the suspension or termination. 
 
13 DATA HANDLING AND RECORD KEEPING 
13.1 Inspection of Records 
Local regulatory agencies may request access to all study records, including source 
documents, for inspection and copying, in keeping with U.S. regulations. The 
Investigator should immediately notify the Sponsor of any upcoming regulatory agency 
inspections. The Sponsor may also perform an audit of the data if deemed necessary. 
The Investigator will be responsible for the accuracy of the data entered in the CRFs. The 
Investigator will permit designated Sponsor representatives and regulatory bodies to have 
direct access to the source documents to verify data represented in the CRFs. 
13.2 Retention of Records 
All source documents (e.g. informed consent forms, laboratory reports, progress notes, 
medical histories, physical and diagnostic findings, diagnosis and pharmacy records, and 
study drug dispensing/disposition records) that support data in the CRFs of each study 
subject must be retained in the files of the Investigator for at least two years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region; or at least two years have elapsed 
since the formal discontinuation of clinical development of the investigational drug. 
These documents should be retained for a longer period, however, if required by 
applicable regulatory requirements. 
 
If the Investigator retires, relocates, or for any other reason withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. Prior to transfer, the Sponsor representative must be 
notified in writing of the name and address of the new custodian. 


Chase Pharmaceuticals Corporation 
Protocol CPC-001-12 
Version date: 08/26/2015 
Page 48 of 52 
 
 
 
14 REFERENCES 
Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti BJ, Koeppe RA, Meltzer CC, 
Constantine G, Davis JG, Mathis CA, Dekosky ST, Moore RY. Degree of inhibition of 
cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in 
Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2005;76(3):315-9. 
 
Bontempi B, Whelan KT, Risbrough VB, Lloyd GK, Menzaghi F. Cognitive enhancing 
properties and tolerability of cholinergic agents in mice: a comparative study of nicotine, 
donepezil, and SIB-1553A, a subtype-selective ligand for nicotinic acetylcholine 
receptors. Neuropsychopharmacology. 2003;28(7):1235-46.  
 
Brvar M, Mozina M, Bunc M. Poisoing with rivastigmine.  Clin Toxicol (Phila). 2005; 
43(7): 891-2. 
 
Cheng DH, Tang XC. Comparative studies of huperzine A, E2020, and tacrine on 
behavior and cholinesterase activities. Pharmacol Biochem Behav. 1998;60(2):377-86. 
 
Doody R, Corey-Bloom J, Zhang R, Honglan L, Ieni J, Schindler R. Safety and  
tolerability of donepezil at doses up to 20 mg/day – Results froma p ilot study in patients 
with Alzheimer’s Disease. Drugs, Aging. 2008; 25(2): 163-174. 
 
Exelon® Capsules and Oral Solution Prescribing Information.  Revised:  October 2013.  
Novartis Pharmaceuticals Corporation. 
 
Faber RA, Negro PJ. Enhancing the tolerability of tacrine with propantheline.  Am J. 
Psychiatry. 1999; Jan: 156. 
 
Farlow MR, Salloway S, Tariot PN, Yardley J, Moline ML, Wang Q, Brand-Schieber E, 
Zou H, Hsu T, Satlin A. Effectiveness and tolerability of high-dose (23 mg/d) versus 
standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, 
randomized, double-blind study. Clin Ther. 2010b;32(7):1234-51. 


Chase Pharmaceuticals Corporation 
Protocol CPC-001-12 
Version date: 08/26/2015 
Page 49 of 52 
 
 
 
FDA Approval Package for NDA 20-690: Aricept® (donepezil hydrochloride) 5 and 10 
mg tablets.  Obtained under the Freedom of Information Act.  Approval date:  November 
25, 1996.   
 
Giacobini E, Spiegel R, Enz A, Veroff AE, Cutler NR. Inhibition of acetyl- and butyryl-
cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by 
rivastigmine: correlation with cognitive benefit. J Neural Transm. 2002;109(7-8):1053-65. 
 
Greene Y, Noviasky J, Tariot P. Donepezil overdose. J Clin Psychiatry 1999; Jan. 60:1. 
 
Hoffman RS, Manini AF, Russell-Haders AL, Felberbaum M, Mercurio-Zappala M. Use 
of oralidoxime without atropine in rivastigmine (carbamate) toxicity. Hum Exp Toxicol. 
2009;28(9):599-602. 
 
Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of 
cholinesterase inhibitors. Clin Pharmacokinet. 2002;41(10):719-39. 
 
Kaasinen V, Någren K, Järvenpää T, Roivainen A, Yu M, Oikonen V, Kurki T, Rinne JO. 
Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in 
Alzheimer's disease. J Clin Psychopharmacol. 2002;22(6):615-20. 
 
Kosasa T, Kuriya Y, Yamanishi Y. Effect of donepezil hydrochloride (E2020) on 
extracellular acetylcholine concentration in the cerebral cortex of rats. Jpn J Pharmacol. 
1999;81(2):216-22. 
 
Kosasa T, Kuriya Y, Matsui K, Yamanishi Y. Inhibitory effect of orally administered 
donepezil hydrochloride (E2020), a novel treatment for Alzheimer's disease, on 
cholinesterase activity in rats. Eur J Pharmacol. 2000;389(2-3):173-9. 
 
Kuhl DE, Minoshima S, Frey KA, Foster NL, Kilbourn MR, Koeppe RA. Limited 
donepezil inhibition of acetylcholinesterase measured with positron emission tomography 
in living Alzheimer cerebral cortex. Ann Neurol. 2000; 48(3):391-5. 


Chase Pharmaceuticals Corporation 
Protocol CPC-001-12 
Version date: 08/26/2015 
Page 50 of 52 
 
 
 
Lai M, Moen M, Ewald MB. Pesticide-like poisoning from a prescription drug. N Engl J 
Med.  2005; 353:327-318. 
 
Perara P, Shahmy S, Gawarammana I, Dawson A. Comparison of two commonly 
practiced atropinisation regimens in acute organophosphorus and carbamate poisoning, 
doubing doses vs ‘ad hoc’ – a prospective ovservational study. Hum Exp Toxicol. 2008; 
June: 27(6): 513-518. 
 
Politis AM, Theleritis C, Passa M, Maillis A, Papadimitriou GN. Improvement of 
cognitive dysfunction with high-dose rivastigmine. Psychosomatics. 2010;51(1):89-90. 
 
Rogers SL, Friedhoff LT, Donepezil Study Group. The efficacy and safety of donepezil 
in patients with Alzheimer's disease: results of a US Multicentre, Randomized, Double-
Blind, Placebo-Controlled Trial. Dementia. 1996;7(6):293-303. 
 
Rogers SL, Cooper NM, Sukovaty R, Pederson JE, Lee JN, Friedhoff LT. 
Pharmacokinetic and pharmacodynamic profile of donepezil HCl following multiple oral 
doses. Br J Clin Pharmacol. 1998a;46 Suppl 1:7-12. 
 
Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and 
global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. 
Donepezil Study Group. Arch Intern Med. 1998b;158(9):1021-31. 
 
Rupniak NM, Tye SJ, Field MJ. Enhanced performance of spatial and visual recognition 
memory tasks by the selective acetylcholinesterase inhibitor E2020 in rhesus monkeys. 
Psychopharmacology (Berl). 1997;131(4):406-10. 
 
Sener S and Ozsarac M. Case of the month: rivastigmine (Exelon) toxicity with evidence 
of respiratory depression.  Emerg Med J. 2006 Jan; 23(1): 62-5. 
 
Shepherd G, Klein-Schwartz W, Edwards R. Donepezil overdose: a tenfold dosing error. 
Ann Phaarmacother, 1999; Jul-Aug: 33(7-8): 812-5. 


Chase Pharmaceuticals Corporation 
Protocol CPC-001-12 
Version date: 08/26/2015 
Page 51 of 52 
 
 
 
Shinotoh H, Fukushi K, Nagatsuka S, Irie T. Acetylcholinesterase imaging: its use in 
therapy evaluation and drug design. Curr Pharm Des. 2004;10(13):1505-17. 
 
Smith RD, Kistler MK, Cohen-Williams M, Coffin VL. Cholinergic improvement of a 
naturally-occurring memory deficit in the young rat. Brain Res. 1996;707(1):13-21.  
 
Sugimoto H, Ogura H, Arai Y, Limura Y, Yamanishi Y. Research and development of 
donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn J Pharmacol. 
2002;89(1):7-20. 
 
Suh GH, Yeon Jung H, Uk Lee C, Hoon Oh B, Nam Bae J, Jung HY, Ju YS, Kil Yeon B, 
Park J, Hong I, Choi S, Ho Lee J; Korean Galantamine Study Group. A prospective, 
double-blind, community-controlled comparison of three doses of galantamine in the 
treatment of mild to moderate Alzheimer's disease in a Korean population. Clin Ther. 
2004;26(10):1608-18. 
 
Tiseo PJ, Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamic profile of 
donepezil HCl following evening administration. Br J Clin Pharmacol. 1998a;46 Suppl 
1:13-8.  
 
Tokita K, Yamazaki S, Yamazaki M, Matsuoka N, Mutoh S. Combination of a novel 
antidementia drug FK960 with donepezil synergistically improves memory deficits in rats. 
Pharmacol Biochem Behav. 2002;73(3):511-9. 
 
Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, Zechner S, 
Nagel J, Lane R. A six-month double-blind, randomized, placebo-controlled study of a 
transdermal patch in Alzheimer's disease--rivastigmine patch versus capsule. Int J Geriatr 
Psychiatry. 2007;22(5):456-67. 
 
Yano H, Fukuhara Y, Wada K, Kowa H, Nakashima K. A case of acute choinergic 
adverse effects induced by donepezil overdose: a follow-up of clinical course and plasma 
concentrtion of donepezil.  Rinsho Shinkeigaku. 2003;Aug; 43(8): 462-6. 


Chase Pharmaceuticals Corporation 
Protocol CPC-001-12 
Version date: 08/26/2015 
Page 52 of 52 
 
 
 
Zhang WW, Xu ZP, Cui YY, Wang H, Song MK, Li J, Shao BY, Xia Z, Chen HZ.  
Peripheral cholinoceptor antagonist anisodamine counteracts cholinergic adverse effects 
and facilitates cognitive amelioration of rivastigmine. J Neural Transm. 2009 Dec; 
116(12): 1643-9. 

SAP_000.pdf: 
NCT02549196 
 
Study ID: CPC‐001‐12 
 
Title:  A phase II, dose titration study of CPC‐201 in Patients with Dementia of Alzheimer’s Type 
 
Statistical Analysis Plan Date: 02 Aug 2017 


Sponsor: 
STATISTICAL ANALYSIS PLAN 
FOR PROTOCOL CPC-001-12 
~11£1813 
Chase Pharmaceuticals 
Corporation 
a subsidiary of Allergan pie, 
2525 Dupont Drive, Irvine, 
California 92612, USA 
PHARMACEUTICALS 
Protocol Number: 
CPC-001-12 
Protocol Title: 
A Phase II, Dose Titration Study Of CPC-201 In Patients 
With Dementia Of Alzheimer's Type 
Protocol Date I Version: 
July 22, 2016/Version 3 
SAP Author: 
Plan Version: 
Plan Date: 
 
 
 
 
SAP - Final Version 1.0 
02 August 2017 
--- corifidential---
Telephone: 
 
 
Facsimile: 
 
02JUL2018 CSR CPC-001-12
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Protocol: CPC-001-12 
Chase Pharmaceuticals Corporation 
Protocol Number: 
Protocol Version: 
Protocol Name: 
Sponsor: 
Prepared by: 
SAP Version: 
SAP Date: 
CPC-001-12 
July 22, 2016Nersion 3 
Statistical Analysis Plan 
Page2 
A Phase II, Dose Titration Study OfCPC-201 In Patients 
With Dementia Of Alzheimer's Type 
Chase Pharmaceuticals Corporation 
a subsidiary of Allergan pie, 2525 Dupont Drive, Irvine, 
California 92612, USA 
 
 
 
SAP- Final Version LO 
02 August 2017 
I have read and approve the Statistical Analysis Plan specified above and agree on its 
content: 
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Protocol: CPC-001-12 
Statistical Analysis Plan 
Page 3 
Chase Pharmaceuticals Corporation 
TABLE OF CONTENTS 
Section 
Page 
ABBREVIATIONS, ACRONYMS, AND DEFINITIONS ................................................................. 5 
I. 
INTRODUCTION ............................................................................................................... 6 
2. 
PROTOCOL DESIGN ......................................................................................................... 6 
2.1 
Design Overview ...................................................................................................... 6 
2.2 
Clinical Trial Treatments ........................................................................................... 9 
2.2. l 
Dose Regimen and Administration ................................................................ 9 
2.2.2 
Randomization and Blinding ........................................................................ 9 
2.3 
Protocol Objective(s) ........ ...................................................................................... 10 
2.3.1 
Primary Objective ...................................................................................... 10 
2.3.2 
Secondary Objectives ................................................................................. 10 
2.4 
Study Outcome Measures ........................................................................................ 10 
2.4.1 
Primary Outcome Measure ......................................................................... 10 
2.4.2 
Secondary Outcome Measures .................................................................... 10 
 
 
3. 
SAMPLE SIZE DETERMINATION ................................................................................. 11 
4. 
INTERIM ANALYSIS/DSMB ........................................................................................... 11 
5. 
HYPOTHESIS TO BE TESTED ........................................................................................ 11 
6. 
ANALYSIS POPULATIONS ............................................................................................. 11 
6.1 
Safety Population ................................................................................................... 11 
6.2 
MTD (Maximum Tolerable Dose) Evaluable population ............................................ 11 
7. 
DAT A CONVENTION AND RELATED DEFINITIONS .................................................. 11 
7.1 
Baseline Definition ................................................................................................. 11 
7.2 
Duplicate Data ....................................................................................................... 11 
7.3 
Handling of Missing Data ........................................................................................ 12 
7.4 
Multicenter Clinical Trials ................................................................... .................... 12 
7.5 
Multiple Comparisons and Multiplicity .................................................................... 12 
7.6 
Covariates and Prognostic Factors ................................................... ......................... 12 
7. 7 
Stratification Factors ............................................................................................... 12 
7.8 
Standard Calculations ............................................................................................. 12 
7.8.l 
Age ................ ................. ......................................................................... 12 
7.8.2 
Body Mass Index (BMI) ............................................................................. 12 
7.8.3 
Change from Baseline ................................................................................ 12 
7.8.4 
QTcF ..................................... ................................................................... 12 
8. 
STATISTICAL METHODS ..................................•............................................................ 13 
8.1 
Summarizing and Tabulating the Collected Data ............. .. ........................................ 13 
8.1.1 
Subject Disposition and Withdrawals ....... ................................................... 13 
8.1.2 
Demographics and Other Baseline Characteristics ........................................ 13 
8.1.3 
Prior and Concomitant Medications ............................................................ 14 
8.1.4 
Study Drug Administration .............. ................................. .......................... 14 
8.2 
Analysis Primary Outcome Measure ........................................................................ 14 
8.3 
Analysis of Secondary Outcome Measures ................................................................ 14 
8.3.1 
Analysis of Safety and Tolerability Data .................................................. .... 14 
 
 
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Protocol: CPC-001-12 
Chase Pharmaceuticals Corporation 
Statistical Analysis Plan 
Page4 
 
 
 
 
9. 
APPENDIX 1 ..................................................................................................................... 18 
10. 
APPENDIX 2 ..................................................................................................................... 23 
I 0.1 
Planned By-Subject Listings .................................................................................... 23 
10.2 
Planned Summary Tables ........................................................................................ 24 
11. 
REFERENCES .................................................................................................................. 25 
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Protocol: CPC-001-12 
Statistical Analysis Plan 
Chase Pharmaceuticals Corporation 
Page 5 
ABBREV/A T/ONS, ACRONYMS, AND DEFINITIONS 
Abbreviation 
AD 
ADAS-Cog 
AE 
ASA 
CFR 
CNS 
CRF 
C-SSRS 
CTCAE 
DSMIV 
DSMB 
ECG 
FDA 
GCP 
HR 
ICF 
ICH 
IRB 
ITT 
MedDRA 
MMSE 
MTD 
NIA-ADA 
PK 
pp 
PT 
SAE 
SAP 
soc 
SOP 
WHO 
Definition 
Alzheimer's disease 
Alzheimer's Disease Assessment Scale - Cognitive subscale 
adverse event 
American Statistical Association 
Code of Federal Regulations 
central nervous system 
case report form 
Columbia Suicide Severity Rating Scale 
Common Terminology Criteria for Adverse Events 
Diagnostic and Statistical Manual of Mental Disorders (4th edition) 
data safety monitoring board 
electrocardiogram 
Food and Drug Administration 
Good Clinical Practice 
heart rate 
informed consent form 
International Conference on Harmonisation 
Institutional Review Board 
intent-to-treat 
Medical Dictionary for Regulatory Activities 
Mini-Mental Status Exam 
maximum tolerated dose 
National Institute on Aging-Alzheimer's Association 
pharmacokinetics 
per-protocol 
Preferred term 
serious adverse event 
statistical analysis plan 
System Organ Class 
standard operating procedure 
World Health Organization 
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Protocol: CPC-001-12 
Chase Pharmaceuticals Corporation 
1. 
INTRODUCTION 
Statistical Analysis Plan 
Page6 
This Statistical Analysis Plan (SAP) describes the planned analyses and reporting for the 
clinical trial protocol CPC-001-12, sponsored by Chase Pharmaceutical Corporation. The 
reader of this SAP is encouraged to review the complete protocol, as this plan contains 
only a limited overview of protocol information. The main objective of the plan is to 
provide details pertaining to statistical methodology, data conventions, and processes 
used for the analysis of data from this trial. 
The format and content of this SAP are structured to provide sufficient detail to meet the 
requirements specified by the International Conference on Harmonization (ICH) E9: 
Guidance on Statistical Principles in Clinical Trials. All analyses planned and presented 
in this SAP will follow the ethical guidelines published by the American Statistical 
Association (ASA). 
The following documents were reviewed in preparation of this Statistical Analysis Plan: 
• 
Version 3.0, protocol, July 22, 2016 
• 
Guidance for Industry Adaptive Design Clinical Trials for Drugs and Biologics 
(2010) 
• 
ASA Ethical Guidelines for Statistical Practice (2016) 
• 
The Royal Statistical Society: Code of Conduct (2014) 
• 
ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3, 1996) 
• 
ICH Guidance on the Statistical Principles for Clinical Trials (ICH E9, 1998) 
2. 
PROTOCOL DESIGN 
2.1 Design Overview 
This is a Phase II, ascending dose study of CPC-201 in patients with dementia of 
Alzheimer's type to determine the optimal dose titration schedule. The study involves a 
step wise cohort design in two different patient populations: Group I will consist of 
patients who have been treated with donepezil 5 or I 0 mg/day (given once daily) for at 
least 4 weeks just prior to Day I. Group 2 will consist of patients who have never been 
treated with donepezil before ( donepezil naive) or who have not received any other 
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Protocol: CPC-001-12 
Chase Pharmaceuticals Corporation 
AChEI for the past 6 months. 
Original Plan 
Statistical Analysis Plan 
Page7 
Donepezil dose will be increased at weekly intervals, in accordance with the schedules 
given below, to its first intolerable dose (FID) or maximum allowed dose (MAD) 60 
mg/day together with solifenacin 15 mg/day. If a patient does not tolerate a donepezil 
dose higher than 40mg/day with solifenacin 15 mg/day, the solifenacin dose can be 
increased to 20mg/day per the Investigator's decision. 
Cohort 1 
1 ''week: 20mg donepezil + 15mg solifenacin 
2"d week: 30mg donepezil + I 5mg solifenacin 
3rt!week: 40mgdonepezil + 15mgsolifenacin 
4•hweek: 50mg donepezil + I 5mg (or 20mg) solifenacin 
51hweek: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 2* 
I st week: 20mg donepezil + I 5mg solifenacin 
2"d week: 40mg donepezil + I 5mg solifenacin 
3rd week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Cohort 3* 
I'' week: 20mg donepezil + 15mg solifenacin 
2"d week: 60mg donepezil + 15mg (or 20mg) solifenacin 
*:The dose titration schedule of Cohort 2 and 3 may be altered based on Cohort 1 result. 
Patients reaching their FID or having completed one week treatment with MAD, have 
two options. 
Option 1: Patient will be allowed to immediately enter a long term extension at their 
maximum tolerated dose (MTD) or MAD. 
Option 2: Patients may choose not to enter the long term extension, in which case the 
Investigator will decide whether the patient should discontinue high dose of donepezil 
without down-titration, or whether donepezil should be downtitrated to their own 
standard of donepezil dose. Whatever the decision, the patient will be treated at least an 
additional 7 days with solifenacin 15 mg/day. 
First Amendment 
After 8 subjects in Cohort 1 and 1 subject in Cohort 2 were enrolled, the protocol was 
amended to add Cohort lb and to limit to enroll only Group 1. 
Patients currently treated with donepezil (Group l) will receive solifenacin 15 mg/day 
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Protocol: CPC-001-12 
Statistical Analysis Plan 
Chase Pharmaceuticals Corporation 
Page 8 
during a two week run in period; donepezil treatment will continue at lOmg/day. Once on 
15 mg/day of solifenacin for two weeks (based upon the investigator judgment), the 
donepezil dose will be increased at weekly or bi-weekly intervals, in accordance 
with the schedules given below, to its first intolerable dose (FID) or maximum allowed 
dose (MAD) of 60mg/day 
Cohort I b 
I st-2nd week: IOmg donepezil + I 5mg solifenacin 
3rd week: 20mg donepezil + l 5mg solifenacin 
4th week: 30mg donepezil + I 5mg solifenacin 
5th week: 40mg donepezil + 15mg solifenacin 
6th week: 50mg donepezil + 15mg (or 20mg) solifenacin 
7th week: 60mg donepezil + 15mg (or 20mg) solifenacin 
Second Amendment 
After 6 subjects were enrolled in Cohort 1 b, the protocol was amended to add Cohort 3c. 
All subjects entering the study in cohort 3 will start with a dose regimen of 1 Omg 
donepezil + 15mg solifenacin and will continue to increase the donepezil dose by 5mg 
increments every 7 days (or up to 14 days per PI discretion) up to 40mg or the MTD. 
Cohort 3c 
1st week: IOmg donepezil + 15mg solifenacin 
2nd week: 15mg donepezil + 15mg solifenacin 
3rd week: 20mg donepezil + 15mg solifenacin 
4th week: 25mg donepezil + I 5mg solifenacin 
5th week: 30mg donepezil + 15mg solifenacin 
6th week: 35mg donepezil + 15mg solifenacin 
7th week: 40mg donepezil + 15mg solifenacin 
All the schedule of assessments for this study are presented in the protocol and also in the 
Appendix l of this SAP. 
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Protocol: CPC-001-12 
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2.2 Clinical Trial Treatments 
Statistical Analysis Plan 
Page9 
2.2.2 Randomization and Blinding 
This is a single-blind dose escalating open label study. The subject, caregiver, and site personnel 
who assess MMSE and ADAS-Cog are blinded. 
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Protocol: CPC-001-12 
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2.3 Protocol Objective(s) 
2.3.1 Primary Objective 
Statistical Analysis Plan 
Page IO 
To determine the optimal initial dose and subsequent dose titration schedule (rate and increment) 
for CPC-201. 
2.3.2 Secondary Objectives 
To evaluate the safety and tolerability of CPC-201 as a function of dose and initial rate of dose 
titration. 
2.4 Study Outcome Measures 
2.4.1 Primary Outcome Measure 
The primary outcome for this study is optimal initial dose and subsequent dose titration schedule 
(rate and increment) for CPC-201. 
The FID of each patient 
The MTD of each patient 
2.4.2 Secondary Outcome Measures 
2.4.2. l Safety Assessments 
Safety will also be evaluated on: 
Dose limiting side effects 
AEs and SAEs (type, severity, and frequency), 
vital signs (systolic and diastolic blood pressure; radial artery pulse rate; body weight), 
12-lead ECG, 
Safety lab, 
Physical examination, and 
Suicidality modified C-SSRS. 
 
 
 
 
 
 
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Protocol: CPC-001-12 
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3. 
SAMPLE SIZE DETERMINATION 
Statistical Analysis Plan 
Page 11 
No formal sample size calculation has been made. Based on experience from previous similar 
studies, a total 4-6 evaluable subject per group per cohort is considered sufficient. 
4. INTERIM ANAL YSIS/DSMB 
No Interim Analysis (IA) was planned to be conducted. 
5. HYPOTHESIS TO BE TESTED 
There is no formal hypothesis testing for this study. The study is not powered to reliably yield 
statistically significant conclusions. 
6. ANALYSIS POPULATIONS 
6.1 Safety Population 
The Safety population is defined as all subjects those who received at least one dose of any study 
drug. This population will be used for analysis of safety parameters. 
6.2 MTD (Maximum Tolerable Dose) Evaluable population 
The MTD evaluable population is defined as all subjects who completed the donepezil dose 
titration. This population will be used for summary of the primary study outcome. 
7. DATA CONVENTION AND RELATED DEFINITIONS 
7.1 Baseline Definition 
For all parameters, baseline will be defined as the last available value before the first treatment. 
7.2 Duplicate Data 
For unplanned duplicate data within protocol-specified visit duration, the last measured value will 
be used for the analysis. If it is not possible to identify the "last measured value" the average of the 
duplicate values will be used. 
No data will be excluded. All collected data will be listed. 
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Protocol: CPC-001-12 
Chase Pharmaceuticals Corporation 
7 .3 Handling of Missing Data 
Statistical Analysis Plan 
Page 12 
All data will be used as observed, and no imputations will be made for any missing data point. All 
summaries will be based on observed data only. 
7.4 Multicenter Clinical Trials 
This is a multi-center clinical trial. 
7.5 Multiple Comparisons and Multiplicity 
Not applicable for this study. 
7.6 Covariates and Prognostic Factors 
Not applicable for this study. 
7.7 Stratification Factors 
Not applicable for this study. 
7.8 Standard Calculations 
7.8.1 Age 
Age will be calculated as the number of completed years between the date of informed consent and 
the subject's birth date. 
Age (years)= integer of[(date of informed consent- date ofbirth)/ 365.25+ 0.5] 
7.8.2 Body Mass Index (BM/) 
BMI will be calculated using height (in cm) and weight (in kg) according to the formula noted 
below. 
BMI (kg/m2) =weight (kg) I [[height (cm)/100]2] 
7.8.3 Change from Baseline 
Change will be calculated using according to the formula noted below. 
Change= Post Baseline Data - Baseline Data 
7.8.4 QTcF 
QTcF will be calculated using according to the formula noted below. 
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Protocol: CPC-001-12 
Chase Pharmaceuticals Corporation 
8. STATISTICAL METHODS 
QTcF= QT/RR113 
(RR=60NR) 
Statistical Analysis Plan 
Page 13 
All data from this clinical trial will be provided in data listings, study drug, clinical trial center, 
subject, and time point (if applicable). 
Data summary will be according to the variable type: 
• 
Continuous data summaries will include: 
o Number of observations, mean, standard deviation, median, and minimum and 
maximum values. 
• 
Categorical data summaries will include: 
o 
Frequency counts and percentages. 
8.1 Summarizing and Tabulating the Collected Data 
8.1.1 Subject Disposition and Withdrawals 
There will be a detailed accounting of all subjects who sign an informed consent to participate in 
this study. The following will be summarized: 
• 
The number of subjects who are enrolled 
• 
The number of subjects who completed the Dose Titration 
• 
The number of subjects who discontinued prior to completion of the dose titration 
o Reasons for discontinuation will also be summarized descriptively 
• 
The number of subjects who completed the long term extension (Optional) 
• 
The number of subjects who discontinued during the long term extension 
o 
Reasons for discontinuation will also be summarized descriptively 
In addition, there will also be a listing of all discontinued subjects, which will provide the specific 
reason for discontinuation. 
8.1.2 Demographics and Other Baseline Characteristics 
Individual subject demographic and baseline characteristics including baseline disease status based 
on MMSE data (i.e., Mild: 21-30, Moderate: 10-20 and Severe: <l 0) will be summarized and also 
presented in subject data listings. Medical history data will be listed for safety population subjects. 
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8.1.3 Prior and Concomitant Medications 
Statistical Analysis Plan 
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Prior and concomitant medications will be summarized for the Safety population. 
All prior and concomitant medications recorded in the case report form will be using the most 
recent version of WHO Drug dictionary. Descriptive summaries will be prepared using the coded 
term. All prior and concomitant medications recorded in the case report form will be listed. 
Medications entered as donepezil and memantine are captured in the Alzheimer's disease history 
and will not be included in the summary and listings of prior and concomitant medications. 
8.1.4 Study Drug Administration 
All available study drug administration data will be listed and/or summarized. 
8.2 Analysis Primary Outcome Measure 
The primary outcome measure for the study is the optimal initial dose and subsequent dose titration 
schedule of donepezil when given with solifenacin (15 mg/day or 20 mg/day). 
Time to reach FID (First Intolerable Dose) for each patient will be presented as a subject specific 
listing. The proportion of subjects at the different MTD levels and those who were able to tolerate 
the highest dose of donepezil (i.e., 40 mg/day) and the MTD will be summarized descriptively. In 
addition, descriptive summary (i.e., n, mean, SD) of the highest dose reached will be presented. 
The dose limiting side effect will be listed. 
8.3 Analysis of Secondary Outcome Measures 
8.3.J Analysis of Safety and Tolerability Data 
The Safety population will be used for all analyses of safety and tolerability. All Safety and 
tolerability parameters will be analyzed as a function of dose and dose titration schedule and be 
presented descriptively and as data listings. 
8.3.1.1 Adverse Events 
Adverse events will be classified by system organ class (SOC) and preferred term (PT) according to 
the most recent version ofMedDRA dictionary. 
TEAE are defined as events with an onset on or after administration of the first dose of study drug. 
TEAEs will be summarized, System Organ Class, and preferred term. The following TEAE 
summaries will be provided: 
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• 
Top line summary table including 
o all treatment emergent Adverse Events (TEAEs), treatment related TEAE and treatment 
unrelated TEAE, 
o Serious treatment emergent Adverse Events (STEAEs ), treatment related STEAE and 
treatment unrelated STEAE 
o Deaths 
• 
Overall (i.e., regardless of severity or relationship to treatment) 
• 
By cohort (i.e., 1, 2, 1 b, 3c) 
• 
By study phase (i.e., titration and long term extension) 
• 
By severity grade (mild, moderate, severe) 
• 
By relationship to study drug (definitely, probably, possibly, not related) 
Unless otherwise specified, at each level of subject summarization, a subject will be counted only 
once. If there is more than one occurrence of an event, the event of the worst severity or the worst-
case relationship category will be summarized. 
Serious Adverse Events (SAEs) will also be summarized by relationship. 
8.3.1.2 Laboratory Tests (Safety laboratory test and urinalysis) 
For the continuous laboratory parameters, descriptive statistics will be presented. Additionally, 
parameters will be categorized as low, normal or high according to laboratory range specifications. 
The number and percentage of subjects will be presented by dosing cohort. 
All available results of the clinical laboratory evaluations will be listed and summarized. 
Laboratory evaluations include hematology, serum chemistry and urinalysis. 
Summary statistics of raw data and change from baseline values for each laboratory parameter will 
be presented and time point. Data will be summarized as appropriate to the variable type. 
• 
For continuous data, summaries will include the number of observations, mean, standard 
deviation, median, and minimum and maximum values. 
• 
For categorical data, frequency counts and percentages will be used. 
For change from baseline summaries, subjects with an undefined change from baseline, because of 
missing data, will be excluded. 
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8.3.1.3 Vital Signs and weight 
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Summary statistics of raw data and change from baseline values will be presented by time point 
during each study period for each vital sign parameter (including Blood Pressure, Heart Rate, 
Respiration Rate, Temperature, and Body weight). 
Summaries will include the riumber of observations, mean, standard deviation, median, and 
minimum and maximum values. For change from baseline summaries, subjects with an undefined 
change from baseline, because of missing data, will be excluded. 
8.3.1.4 Electrocardiogram (ECGs) 
The ECG parameters include ventricular rate (beats per minute), PR interval (msec), QRS interval 
(msec), and QT interval (msec). All the evaluations from the site measurement will be presented. 
In addition ECG parameters RR and QTcF will be calculated per the formula in Section 7.8.4 and 
will be summarized. 
Descriptive statistics of raw data and change from baseline values for each ECG measurement will 
be presented. 
For change from baseline summaries, subjects with an undefined change from 
baseline, because of missing baseline data, will be excluded. 
8.3.1.4.1 Individual Subject Changes (Shift Tables) 
Individual subject changes will be identified through shift tables. Shift tables will be presented for 
the investigator ECG interpretation (i.e., Normal, Abnormal (not clinically significant) and 
Abnormal (clinically significant)) with counts and percentages of subjects for shift (change) from 
baseline, using the normal ranges. 
8.3.1.4.2 Clinically Significant Abnormalities 
A by-subject listing of treatment-emergent clinically significant ECGs will be prepared. 
8.3 .1.5 Physical Examination 
All physical examination findings will be listed. 
8.3.1.6 Assessment of Suicidality 
Suicidality will also be assessed using the modified Columbia Suicide Severity Rating Scale (C-
SSRS). All the results from this scale will be listed and summarized. 
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10. APPENDIX 2 
10.1 Planned By-Subject Listings 
DISPOSITION/WITHDRAWALS (LISTINGS 16.2.l.X) 
ELIGIBILITY AND PROTOCOL DEVIATIONS (LISTINGS I6.2.2.X) 
EXCLUDED SUBJECTS (LISTINGS 16.2.3.X) 
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DEMOGRAPHICS, POPULATION, AND BASELINE CHARACTERISTICS (LISTINGS 16.2.4.X) 
DRUG COMPLIANCE (LISTINGS I6.2.5.X) 
EFFICACY RESPONSE DATA (LISTINGS I6.2.6.X) 
ADVERSE EVENT DATA (LISTINGS 16.2.7.X) 
SAFETY DATA (LISTINGS 16.2.8.1.X) 
OTHER SAFETY DATA (LISTINGS 16.2.8.2.X) 
OTHER LISTINGS (LISTINGS 16.2.8.3.X) 
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10.2 Planned Summary Tables 
POPULATION DISPOSITION AND PROTOCOL DEVIATIONS 
POPULATION DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
CONCOMITANT MEDICATION USAGE 
SAFETY SUMMARIES 
ADVERSE EVENT SUMMARIES 
SERIOUS ADVERSE EVENTS 
LABORATORY 
VITAL SIGNS AND PE 
OTHER SAFETY 
EFFICACY SUMMARIES 
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11. 
REFERENCES 
Statistical Analysis Plan 
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1. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April, 2016. 
2. The Royal Statistical Society: Code of Conduct (2014). 
3. ES General Considerations for Clinical Trials, ICH Guidance, Federal Register, 1997. 
4. Guidance for Industry Adaptive Design Clinical Trials for Drugs and Biologics (2010). 
5. Guideline for Industry: Structure and Content of Clinical Study Reports (ICH E3), July 
1996. 
6. ICH Guidance on the Statistical Principles for Clinical Trials (ICH E9, 1998). 
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