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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Signed an Institutional Review Board (IRB) approved informed consent document
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 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 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 in generally good health as indicated by their medical history and physical examination, vital signs, electrocardiogram (ECG), and standard laboratory tests.

Exclusion Criteria:

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

    * 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.