Clinical trial NCT02187276: The Predictive Factors of Good Clinical Response to Cholinesterase Inhibitors in Alzheimer Disease and Mixed Dementia
Official title: The Predictive Factors of Good Clinical Response to Cholinesterase Inhibitors in Mild and Moderate Alzheimer Disease and Mixed Dementia: a Naturalistic Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Alzheimer Disease, Late Onset
Keywords: Predictive factors of response
mild and moderate
Alzheimer disease
mixed dementia
APOE
polymorphisms of CYP 2D6
Lead sponsor: Federal University of Minas Gerais
Sponsor class: OTHER
First posted: 2014-07-11
Enrollment: 129
Sex: ALL
Minimum age (years): 59
Maximum age (years): 92
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Eligible patients were those who spontaneously went to the outpatient units to be diagnosed and presented cognitive, functional, and in many cases, behavioral symptoms.

Brief summary: Background and objectives: The aims of this naturalistic study were: to analyze factors which could be predictive of good response to cholinesterase inhibitors (ChEI), such as: age, sex, schooling, mild (CDR 1) or moderate Alzheimer's disease (AD),(CDR 2), Apoliprotein epsilon 4 (APOE Ɛ4), among others, in their cognitive and clinical response. We also classified patients according to their response to Mini mental State of Examination (MMSE). Finally we saw the polymorphisms of APO E and cytochrome P450 2D6 (CYP2D6) and tried to correlate the response with different allelic forms of Apo E and among others with wild type homozygotes (wt/wt) and their polymorphisms (CYP2D6\*3,\*4, \*5, \*6 and 10) of CYP 2D6.

Patients and Methods: 129 patients were diagnosed as AD or AD+cerebrovascular disease (CVD) mild or moderate. After 12 month-treatment, 97 patients completed the study. They were assessed (four) times. In the first visit, without taking ChEI, after 3, 6 and 12 month-treatment, they were taking donepezil or rivastigmine or galantamine. We also extracted 5 mL of blood sample to genotype the DNA. In each visit, we applied cognitive, functional, mood and behavior scales. Good responders were defined as those who scored \> 2 in MMSE.

Results and Conclusion: In longitudinal analysis, patients with mild AD and good responders at 3 months were considered good responders at 12 months. We obtained a higher rate of good responders comparing with other researches (27.8%). There was no correlation between dose, APOE and CYP 2D6 polymorphisms, although we already obtained clinical results with the dose dosage of 5mg.

Detailed description: Genomic DNA for genotyping was extracted from total blood samples collected in ethylenediaminetetraacetic acid (EDTA) (Wizard Genomic DNA Purification Kit: Promega®, USA) and kept frozen at seventy degrees Celsius negative (-70ºC) until analysis. For APOE genotyping (alleles Ɛ2, Ɛ3 and Ɛ4), DNA samples were amplified by polymerase chain reaction (PCR), followed by digestion with Haemophilus haemolyticus restriction endonuclease I (HhaI) and restriction fragment length polymorphism (RFLP) analysis, as previously described by Hixson and Vernier.

The CYP2D6\*3, CYP2D6\*4 and CYP2D6\*6 alleles were investigated by tetra-primer PCR and the CYP2D6\*5 allele, which presents the entire CYP2D6 gene deletion, was identified by long PCR reaction, according to the method described by Hersberger et al. The CYP2D6\*10 allele was amplified by PCR following Baclig et al. and the RFLP analysis was performed with Type II restriction enzyme (HphI). For all analysis a positive and negative controls were included.

Subjects carrying Epsilon 3, Epsilon 3 (Ɛ3Ɛ3), CYP2D6\*3/4/5/6/10-nor specific mutations are classified as wild-type and functional allele carriers. The subjects carrying two defective alleles were classified as poor metabolizers (PM) and those heterozygous were classified as extensive metabolizers (EM).

Eligibility criteria: Inclusion Criteria:

- AD diagnosis or AD with CVD according the criteria of National Institute on Aging and the Alzheimer's Association workgroup and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA)

Exclusion Criteria:

* Patients with mild cognitive impairment;
* Other types of dementia, such as pure vascular dementia, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration;
* Severe dementia (CDR 3)
* Those who were already taking ChEI,
* If there have not been agreement between the first researcher and the treating physician.

Primary outcomes:
measure: Cognitive results
timeFrame: Patients were evaluated from 06/2009 to 03/2013 for four times - first visit ( without taking medication), after three, six and 12 months of treatment with cholinesterase inhibitors (up to 12 months)
Secondary outcomes:
measure: Genetic and biochemical analyzes
timeFrame: To correlate allelic forms of APOE and CYP 2D6 polymorphisms with the response (up to 12 months)
Other outcomes:
measure: Determination of the concentration of donepezil
timeFrame: After 12 months-treatment the concentration of donepezil was measured
Locations:
Study officials:
affiliation: Federal University of Minas Gerais
name: Paulo Caramelli, Profesor
role: STUDY_CHAIR
References: