Alzheimer Disease, Late OnsetNCT02187276
The Predictive Factors of Good Clinical Response to Cholinesterase Inhibitors in Alzheimer Disease and Mixed Dementia
An observational study of Alzheimer Disease, Late Onset, run by Federal University of Minas Gerais.
Trial 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… Read more about this study
- Who is it for?
- Ages 59 to 92 years
- Conditions the study is for
- Alzheimer Disease, Late Onset
- What is being tested?
- cholinesterase inhibitors
- How many people
- 129 participants
- Where
- No sites listed yet
- Study dates
- Jun 2009to Mar 2013
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 59 to 92 years
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Who may be able to join
- 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)
Who cannot join
- 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.
About this study
Official title: The Predictive Factors of Good Clinical Response to Cholinesterase Inhibitors in Mild and Moderate Alzheimer Disease and Mixed Dementia: a Naturalistic Study
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.
Read the 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).
- Conditions
- Alzheimer Disease, Late Onset
- Being tested
- cholinesterase inhibitors
- Keywords
- Predictive factors of response, mild and moderate, Alzheimer disease, mixed dementia, APOE, polymorphisms of CYP 2D6
- Medical subject headings
- Alzheimer Disease, Lymphoma, Follicular, Mixed Dementias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
cholinesterase inhibitorsDrug
Also called No applicable
The first group received donepezil (5 or 10 mg) the second group received galantamine (16 or 24 mg) The third group received rivastigmine (3 or 4,5 or 6 mg BID) according to the treating physician.
| Study group | Role | What they receive |
|---|---|---|
| Alzheimer disease or mixed dementia | Patients were evaluated four times. In the first consultation, without taking cholinesterase inhibitors (ChEI), after three, six and 12 months taking ChEI. Receives: Drug: cholinesterase inhibitors |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cognitive results
Clinical assessment: The clinical domains examined and the respective evaluation tools were: global cognition - MMSE, clock drawing test score and Mattis Dementia Rating Scale - DRS). Patients were seen between 06/2009 to 03/2013. Good clinical responders were those who scored ≥ 2 on the MMSE after 12 month-treatment, the neutrals had the scores between -1 and +1, and bad responders scored ≤ -2 at the same period. A subgroup who scored > 2 on the MMSE were defined as very good responders. Patients were seen for four times: at the first consultation (n=129), at three (n=114), six (n=105) and twelve months of treatment (n=97).
Measured: 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 (1)
Genetic and biochemical analyzes
Genomic DNA for genotyping was extracted from total blood samples collected in EDTA (Wizard Genomic DNA Purification Kit: Promega®, USA) and kept frozen at -70ºC until analysis. For APOE genotyping (alleles Ɛ2, Ɛ3 and Ɛ4), DNA samples were amplified by polymerase chain reaction (PCR), followed by digestion with HhaI and restriction fragment length polymorphism (RFLP) analysis, as previously described by Subjects carrying Ɛ3Ɛ3, CYP2D6*3/4/5/6/10-nor specific mutations are classified as wild-type and functional allele carriers.Patients were seen four times (see Primary outcome).
Measured: To correlate allelic forms of APOE and CYP 2D6 polymorphisms with the response (up to 12 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jul 2014 (estimated)
- Study startJun 2009
- Primary completionMar 2013
- Study completionMar 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Alzheimer Disease, Late OnsetStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 129 participants (actual)
Sponsor and investigators
- Lead sponsor
- Federal University of Minas Gerais
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Luís Felipe José Ravic de Miranda, Federal University of Minas Gerais
- Investigators
- Paulo Caramelli, Profesor, Study chair, Federal University of Minas Gerais
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02187276
- Sponsor's protocol ID
- 0172/2010
- Status last verified
- Sep 2014
- First submitted
- 5 Jul 2014
- Last updated
- 12 Sep 2014
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 12 Sep 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Predictive Factors of Good Clinical Response to Cholinesterase Inhibitors in Mild and Moderate Alzheimer Disease and Mixed Dementia: a Naturalistic Study
- ClinicalTrials.gov ID
- NCT02187276
- Acronym / sponsor ID
- 0172/2010
- Conditions
- Alzheimer Disease, Late Onset
- Keywords
- Predictive factors of response, mild and moderate, Alzheimer disease, mixed dementia, APOE, polymorphisms of CYP 2D6
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 129 participants (actual)
- Lead sponsor
- Federal University of Minas GeraisUniversity, hospital or other
- Study start
- Jun 2009
- Primary completion
- Mar 2013 (actual)
- Study completion
- Mar 2013 (actual)
- First posted
- 11 Jul 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Alzheimer disease or mixed dementia | – | Drug: cholinesterase inhibitorsPatients were evaluated four times. In the first consultation, without taking cholinesterase inhibitors (ChEI), after three, six and 12 months taking ChEI. |
Who may qualify
- Ages
- 59 to 92 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (1 listed)
- 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)
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| cholinesterase inhibitorsAlso: No applicableThe first group received donepezil (5 or 10 mg) the second group received galantamine (16 or 24 mg) The third group received rivastigmine (3 or 4,5 or 6 mg BID) according to the treating physician. | Drug | Alzheimer disease or mixed dementia |
Primary outcome
Cognitive results
Time frame: 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)
Clinical assessment: The clinical domains examined and the respective evaluation tools were: global cognition - MMSE, clock drawing test score and Mattis Dementia Rating Scale - DRS). Patients were seen between 06/2009 to 03/2013. Good clinical responders were those who scored ≥ 2 on the MMSE after 12 month-treatment, the neutrals had the scores between -1 and +1, and bad responders scored ≤ -2 at the same period. A subgroup who scored > 2 on the MMSE were defined as very good responders. Patients were seen for four times: at the first consultation (n=129), at three (n=114), six (n=105) and twelve months of treatment (n=97).
1 secondary outcome
Genetic and biochemical analyzes
Time frame: To correlate allelic forms of APOE and CYP 2D6 polymorphisms with the response (up to 12 months)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Sep 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paulo Caramelli, Profesor study chair
Federal University of Minas Gerais
Questions about this trial
What is this clinical trial studying?
An observational study of Alzheimer Disease, Late Onset, run by Federal University of Minas Gerais.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Sep 2014. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cognitive results (time frame: 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)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Sep 2014.