A Dose Titration Study of CPC-201 in Patients With Dementia of Alzheimer's Type

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.

Inclusion criteria

• Signed an Institutional Review Board (IRB) approved informed consent document
• Aged 50 - 89 years inclusive.
• 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.
• Mild to severe severity (Mini-Mental Status Exam [MMSE] scores 7 - 24 inclusive).
• Rosen-Modified Hachinski Ischemia Score of ≤4.
• Have a suitable caregiver to supervise the at-home administration of study drugs and observe for AEs.
• Patients 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 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.
• Patients in generally good health as indicated by their medical history and physical examination, vital signs, electrocardiogram (ECG), and standard laboratory tests.

Exclusion criteria

• Women of child bearing potential.
• History or presence of a seizure disorder.
• Current unstable peptic ulcer disease, urinary or gastric retention; asthma or obstructive pulmonary disease.
• History or presence of bladder outflow obstruction, gastrointestinal obstructive disorder or reduced GI motility, or narrow-angle glaucoma.
• History or presence of gastrointestinal, hepatic, or renal disease, or other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs.
• 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)
• History or presence of myasthenia.
• History or family history of Prolonged QT Syndrome.
• History of unexplained syncope or family history of unexplained syncope or sudden death.
• Myocardial infarction or hospitalization for congestive heart failure within 6 months.
• 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
• Known hypersensitivity to donepezil, solifenacin or related drugs.
• History of drug significant allergy.
• History of substance abuse, known drug addiction, or positive test for drugs of abuse or alcohol.
• 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.

• Patients considered unlikely to co-operate in the study, and/or poor compliance anticipated by the investigator.
• Patients hospitalized within 4 weeks of screening.
• 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.
• Patients who have participated in another clinical trial with an investigational drug within previous 30 days.