CPC-12: A Dose Titration Study of CPC-201 in Patients With Dementia of Alzheimer's Type

• Sponsor: Chase Pharmaceuticals Corporation, an affiliate of Allergan plc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02549196
• Collaborator: (none)
• Enrollment: 28
• Locations: 4
• Arms: 4
• Actual Duration (Months): 23.7
• Patients Per Site: 7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Dementia of Alzheimer's Type	Drug: Donepezil; Drug: Solifenacin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: A Phase II, Dose Titration Study of CPC-201 in Patients With Dementia of Alzheimer's Type
• Actual Study Start Date: Oct 7, 2015
• Actual Primary Completion Date: Sep 28, 2017
• Actual Study Completion Date: Sep 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 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.	Drug: Donepezil; Donepezil dose increased at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) together with solifenacin.; Drug: Solifenacin; Donepezil dose increased at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) together with solifenacin.
Experimental: Cohort 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.	Drug: Donepezil; Donepezil dose increased at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) together with solifenacin.; Drug: Solifenacin; Donepezil dose increased at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) together with solifenacin.
Experimental: Cohort 1b 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.	Drug: Donepezil; Donepezil dose increased at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) together with solifenacin.; Drug: Solifenacin; Donepezil dose increased at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) together with solifenacin.
Experimental: Cohort 3c 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.	Drug: Donepezil; Donepezil dose increased at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) together with solifenacin.; Drug: Solifenacin; Donepezil dose increased at weekly intervals up to first intolerable dose (FID) or to maximum allowed dose (MAD) together with solifenacin.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Reached the Maximum Allowed Dose (MAD) in Their Respective Cohort [1-7 weeks]

   Of the four cohorts with different dosing schedules for CPC-201, the cohort with the greatest proportion of participants to reach the donepezil MAD was determined to be the optimal administration regimen.

Secondary Outcome Measures

1. Number of Participants With TEAEs Leading to Study Drug Discontinuation [1-7 weeks]

   Number of subjects who experienced any treatment-emergent adverse events (TEAEs) leading to study drug discontinuation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 89 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. Mild to severe severity (Mini-Mental Status Exam [MMSE] scores 7 - 24 inclusive).

2. Rosen-Modified Hachinski Ischemia Score of ≤4.

3. Have a suitable caregiver to supervise the at-home administration of study drugs and observe for AEs.

4. 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;

5. 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.

6. 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)

1. History or presence of myasthenia.

2. History or family history of Prolonged QT Syndrome.

3. History of unexplained syncope or family history of unexplained syncope or sudden death.

4. Myocardial infarction or hospitalization for congestive heart failure within 6 months.

5. 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

1. Known hypersensitivity to donepezil, solifenacin or related drugs.

2. History of drug significant allergy.

3. History of substance abuse, known drug addiction, or positive test for drugs of abuse or alcohol.

4. 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.

1. Patients considered unlikely to co-operate in the study, and/or poor compliance anticipated by the investigator.

2. Patients hospitalized within 4 weeks of screening.

3. 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.

4. Patients who have participated in another clinical trial with an investigational drug within previous 30 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Quantum Laboratories	Deerfield Beach	Florida	United States	33064
2	Miami Jewish Health Systems	Miami	Florida	United States	33137
3	Premiere Research Institute	West Palm Beach	Florida	United States	33407
4	PMG Research	Winston-Salem	North Carolina	United States	27103

Sponsors and Collaborators

• Chase Pharmaceuticals Corporation, an affiliate of Allergan plc

Investigators

• Study Chair: Lynn James, Allergan

Study Documents (Full-Text)

• Statistical Analysis Plan - Aug 2, 2017
• Study Protocol - Jul 22, 2016

More Information

Publications

None provided.

• Responsible Party: Chase Pharmaceuticals Corporation, an affiliate of Allergan plc
• ClinicalTrials.gov Identifier: NCT02549196
• Other Study ID Numbers: CPC-001-12
• First Posted: Sep 15, 2015
• Last Update Posted: Mar 5, 2019
• Last Verified: Feb 1, 2019

• Additional relevant MeSH terms: Dementia; Alzheimer Disease; Donepezil; Solifenacin Succinate

Study Results

Participant Flow

Pre-assignment Detail	A total of 28 subjects between the chronological ages of 50 and 89 years with dementia of Alzheimer's type were enrolled in the study.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 1b	Cohort 3c
Arm/Group Description	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.	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.	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.	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.
Period Title: Overall Study
STARTED	8	1	6	13
COMPLETED	7	1	5	12
NOT COMPLETED	1	0	1	1

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Cohort 1b	Cohort 3c	Total
Arm/Group Description	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	8	1	6	13	28
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	72 (10.6)	74	75.5 (6.9)	73 (8.4)	73.3 (8.8)
Sex: Female, Male (Count of Participants)
Female	6 75%	0 0%	3 50%	5 38.5%	14 50%
Male	2 25%	1 100%	3 50%	8 61.5%	14 50%
Race/Ethnicity, Customized (Count of Participants)
White	8 100%	1 100%	5 83.3%	11 84.6%	25 89.3%
Black or African- American	0 0%	0 0%	1 16.7%	2 15.4%	3 10.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Reached the Maximum Allowed Dose (MAD) in Their Respective Cohort
Description	Of the four cohorts with different dosing schedules for CPC-201, the cohort with the greatest proportion of participants to reach the donepezil MAD was determined to be the optimal administration regimen.
Time Frame	1-7 weeks

Outcome Measure Data

Analysis Population Description

The MTD evaluable population was defined as all patients who completed the donepezil dose titration.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 1b	Cohort 3c
Arm/Group Description	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.	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.	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.	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.
Measure Participants	7	1	5	12
Count of Participants [Participants]	2 25%	0 0%	1 16.7%	6 46.2%

2. Secondary Outcome

Title	Number of Participants With TEAEs Leading to Study Drug Discontinuation
Description	Number of subjects who experienced any treatment-emergent adverse events (TEAEs) leading to study drug discontinuation
Time Frame	1-7 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2	Cohort 1b	Cohort 3c
Arm/Group Description	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.	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.	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.	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.
Measure Participants	8	1	6	13
Count of Participants [Participants]	2 25%	0 0%	1 16.7%	4 30.8%

Adverse Events

Time Frame	Adverse events were collected until week 7.
Adverse Event Reporting Description	All subjects who received at least one dose of any study drug.
Arm/Group Title	Cohort 1		Cohort 2		Cohort 1b		Cohort 3c
Arm/Group Description	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.		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.		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.		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.
All Cause Mortality
	Cohort 1		Cohort 2		Cohort 1b		Cohort 3c
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Serious Adverse Events
	Cohort 1		Cohort 2		Cohort 1b		Cohort 3c
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Cardiac disorders
Cardio-respiratory arrest	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Gastrointestinal disorders
Duodenal ulcer haemorrhage	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Nervous system disorders
Syncope	1/8 (12.5%)		0/1 (0%)		0/6 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1		Cohort 2		Cohort 1b		Cohort 3c
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/8 (75%)		1/1 (100%)		6/6 (100%)		12/13 (92.3%)
Eye disorders
Blepharospasm	1/8 (12.5%)		0/1 (0%)		0/6 (0%)		0/13 (0%)
Gastrointestinal disorders
Abdominal pain upper	2/8 (25%)		0/1 (0%)		0/6 (0%)		0/13 (0%)
Constipation	1/8 (12.5%)		0/1 (0%)		0/6 (0%)		3/13 (23.1%)
Nausea	4/8 (50%)		1/1 (100%)		2/6 (33.3%)		2/13 (15.4%)
Vomiting	4/8 (50%)		0/1 (0%)		1/6 (16.7%)		2/13 (15.4%)
Dry mouth	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Dyspepsia	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Dysphagia	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Eructation	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
General disorders
Fatigue	1/8 (12.5%)		0/1 (0%)		0/6 (0%)		2/13 (15.4%)
Asthenia	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Chills	0/8 (0%)		0/1 (0%)		1/6 (16.7%)		0/13 (0%)
Crying	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Feeling jittery	0/8 (0%)		0/1 (0%)		1/6 (16.7%)		0/13 (0%)
Pyrexia	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Infections and infestations
Upper respiratory tract infection	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Urinary tract infection	1/8 (12.5%)		0/1 (0%)		0/6 (0%)		0/13 (0%)
Injury, poisoning and procedural complications
Eye injury	0/8 (0%)		0/1 (0%)		1/6 (16.7%)		0/13 (0%)
Fall	0/8 (0%)		0/1 (0%)		1/6 (16.7%)		0/13 (0%)
Investigations
Blood pressure systolic increased	0/8 (0%)		0/1 (0%)		0/6 (0%)		3/13 (23.1%)
Blood glucose increased	0/8 (0%)		0/1 (0%)		1/6 (16.7%)		0/13 (0%)
Blood pressure increased	0/8 (0%)		0/1 (0%)		1/6 (16.7%)		0/13 (0%)
Heart rate decreased	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Weight decreased	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Metabolism and nutrition disorders
Decreased appetite	0/8 (0%)		0/1 (0%)		1/6 (16.7%)		3/13 (23.1%)
Musculoskeletal and connective tissue disorders
Back pain	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Nervous system disorders
Dizziness	2/8 (25%)		0/1 (0%)		2/6 (33.3%)		1/13 (7.7%)
Headache	2/8 (25%)		0/1 (0%)		0/6 (0%)		0/13 (0%)
Tremor	1/8 (12.5%)		0/1 (0%)		1/6 (16.7%)		1/13 (7.7%)
Drooling	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Somnolence	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Psychiatric disorders
Anxiety	0/8 (0%)		0/1 (0%)		1/6 (16.7%)		1/13 (7.7%)
Confusional state	0/8 (0%)		0/1 (0%)		1/6 (16.7%)		1/13 (7.7%)
Depression	0/8 (0%)		0/1 (0%)		0/6 (0%)		2/13 (15.4%)
Abnormal dreams	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Hallucination	0/8 (0%)		0/1 (0%)		1/6 (16.7%)		0/13 (0%)
Renal and urinary disorders
Pollakiuria	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Cough	0/8 (0%)		0/1 (0%)		0/6 (0%)		2/13 (15.4%)
Dry throat	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)
Surgical and medical procedures
Cancer surgery	0/8 (0%)		0/1 (0%)		0/6 (0%)		1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.