Response to Donepezil, Drug Plasma Concentration and the... | NCT03349320

Studies
Response to Donepezil, Drug Plasma Concentration and the CYP2D6 and APOE Genetic Polymorphisms

NCT03349320

Sponsor

Federal University of Minas Gerais

Status

Completed

Last Update Posted

Dec 18, 2017Actual

Enrollment

37Actual

Phase

Not provided

Conditions

Late Onset Alzheimer Disease

Interventions

Not provided

Countries

Not provided

Protocol Section

Identification Module Status Module Sponsor/Collaborators Module Oversight Module Description Module Conditions Module Design Module Arms/Interventions Module Outcomes Module Eligibility Module Contacts/Locations Module References Module IPD Sharing Statement Module

Results Section

Participant Flow Module Baseline Characteristics Module Outcome Measures Module Adverse Events Module More Info Module

Annotation Section

Annotation Module

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module Condition Browse Module Intervention Browse Module

Protocol Section

Identification Module

NCT ID

Results Section

No data available

No data is available for this block.

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Version Holder

Status Module

Record Verification Date

Dec 2017

Overall Recruitment Status or Expanded Access Status

Completed

Last Known Status

Not provided

Delayed Posting

Not provided

Why Stopped

Not provided

Expanded Access Info

Start Date

Jun 2009Actual

Primary Completion Date

Mar 2013Actual

Completion Date

Mar 2013Actual

First Submitted Date

Jun 21, 2017

First Submission Date that Met QC Criteria

Nov 19, 2017

First Posted Date

Nov 21, 2017Actual

Results Waived

Not provided

Results First Submitted Date

Not provided

Results First Submitted that Met QC Criteria

Not provided

Results First Posted Date

Not provided

Certification/Extension (aka Delayed Results) First Submitted Date

Not provided

Certification/Extension First Submitted that Passed QC Review

Not provided

Certification/Extension First Posted Date

Not provided

Last Update Submitted Date

Dec 14, 2017

Last Update Posted Date

Dec 18, 2017Actual

Oversight Module

Has Data Monitoring Committee (DMC)

Is FDA Regulated Drug

Is FDA Regulated Device

Is Unapproved Device

Not provided

Pediatric Postmarket Surveillance of a Device Product

Not provided

Product Exported from US

Not provided

FDAAA801 Violation

Not provided

Description Module

Brief Summary

Pharmacological treatment of AD is currently based on cholinesterase inhibitors (ChEI) and memantine, which have been shown to lead to modest, although effective, clinical benefits. Donepezil is a ChEI metabolized through the cytochrome P (CYP) 450, primarily by the 3A4 and 2D6 isoforms. The CYP2D6 gene presents polymorphisms that can alter its expression. The plasma therapeutic level ranges from 30 to 75 ng/mL, and 50% of acetylcholinesterase inhibition is achieved when the concentration reaches 15.6 ng/mL. An optimal plasma level is greater than 50 ng/mL.

These polymorphisms may influence the individual's response to treatment with donepezil and the concentration of the drug in AD patients, without achieving the desired effect. However, most of the individuals are EM, i.e., the metabolism of the drug occurs according to the expected kinetics and is associated with the presence of one or two wild-type alleles.

Objective: investigate the pattern of clinical response to donepezil in a group of patients with AD and AD with cerebrovascular disease (CVD) in relation to the plasmatic concentration of donepezil and polymorphisms of the CYP2D6 and apolipoprotein E (APOE) genes.

Detailed Description

Patients taking donepezil were seen four times (from June 2009 to March 2013) and were submitted to the MMSE test, the Consortium to Establish a Registry for Alzheimer'sDisease battery (CERAD), and the Pfeffer Functional Activities Questionnaire. CERAD memory evaluation was further divided into five components: incidental recall (CERAD151 INC), immediate recall 1 and 2 (CERAD-RM1, CERAD-RM2, respectively) and delayed recall after five minutes (CERAD-R). Each aspect was analyzed individually and compared between groups at baseline and after 12 months of treatment with donepezil. All patients had blood samples (10mL) collected to obtain donepezil plasmatic concentration (DPC) measurements and for APOE and CYP2D6 genotyping.

Design Module

Study Type

Observational

Number of References to an Expanded Access Study

Not provided

Expanded Access Types

Not provided

Patient Registry

Target Follow-Up Duration

Not provided

Phases

Not provided

Interventional Study Design

Allocation

Not provided

Intervention Model

Biospecimen

Retention

Enrollment

37Actual

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Association among donepezil serum concentration after 3, 6, and 12 months of treatment onset and clinical response.	Evaluate the serum concentration of donepezil after 3, 6, and 12 months of treatment onset in patients considered good responders (i.e., those who had an increment >1 in MMSE in comparison to baseline assessment after 1 year of donepezil treatment) in contrast to those considered bad responders (i.e., who had a reduction, a stabilization or an increment of 1 in MMSE in comparison to baseline assessment after 1 year of donepezil treatment).	September, 2009 until March, 2013

Secondary Outcomes

Measure	Description	Time Frame
Evaluation of baseline cognitive performance	Assess the baseline cognitive performance among included patients (notedly, MMSE test, CERAD batteries, and in the Pfeffer Functional Activities Questionnaire).	June, 2009 until March, 2012
Evaluation of CYP2D6 and APOE polymorphisms

Other Outcomes

Not provided

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Patients fulfilling the National Institute on Aging and the Alzheimer's Association diagnostic criteria of probable AD dementia or the NINDS-AIREN (National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences) diagnostic criteria of AD with cerebrovascular disease (AD + CVD)
Patients presenting mild or moderate dementia according to the Clinical Dementia Rating (CDR), i.e., CDR 1 or 2, respectively

Exclusion Criteria:

Patients treated with ChEI or memantine before study entry
Patients diagnosed with frontotemporal dementia, dementia with Lewy bodies or vascular dementia,
Patients classified as CDR 3 or with Mild Cognitive Impairment
Illiterate patients
Disagreement between the first investigator and the treating physician regarding the diagnosis

Accepts Healthy Volunteers

Yes

Sex

All

Sex/Gender Based

Not provided

Sex/Gender Description

Not provided

Minimum Age

Not provided

Maximum Age

Not provided

Standard Ages

ChildAdultOlder Adult

Study Population

A longitudinal, naturalist study, conducted at the Geriatric Outpatient Clinic of the Hospital das Clínicas at the Federal University of Minas Gerais (UFMG), in Belo Horizonte (MG), Brazil.

The sample comprised patients evaluated from June, 2009 until March, 2013

Sampling Method

Non-Probability Sample

Name	Affiliation	Role
Paulo Caramelli, MD, PhD	Federal University of Minas Gerais	Study Chair

ID	Term
D000544	Alzheimer Disease

ID	Term
D003704	Dementia
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases

Description

A blood sample was drawn from the patients on the first consultation for use in DNA extraction and Apolipoprotein E (APOE) genotyping. For the patients who were taking donepezil, after three, six and twelve months of treatment another blood sample were also drawn, separated in plasma and kept into the freezer at - 70 Celsius degree for further analysis of serum level of donepezil.