Monitoring Anti-Dementia Drugs by Serum Levels

Study Overview
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Brief Summary
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The main objective of the MONANTI study is twofold: Firstly, to determine the amount of the anti-dementia drugs donepezil and memantine in the blood (henceforth mentioned as 'serum level) in a broadly defined clinical population of patients suffering from dementia treated with the two drugs in question. Secondly, to determine whether adjustment of treatment of anti-dementia medication according to serum levels will benefit patients in terms of cognitive performance, quality of life, frequency and severity of side effects. The reason for conduction of this study is that the relationship between serum-level of anti-dementia drugs, clinical efficacy, compliance and side effects has only been scarcely investigated. Both a previously published study and a preliminary (pilot)study conducted imply that roughly 50 % of patients on donepezil have serum-levels outside the recommended interval. Thus, MONANTI will investigate if this is indeed the case in a broadly comprised population of patients suffering from dementia treated with donepezil or memantine. In addition, MONANTI will link serum levels to co-morbidity, level of compliance, medication interactions. It is hypothesized that the efficacy of anti-dementia medication can be significantly improved by adjustment of treatment according to serum levels. Also, it is hypothesized that the burden of side effects can be reduced in patients in whom too high serum levels are detected, if dosage reduction or change of treatment drug is done. MONANTI is a randomized study, in which the assessor is blinded to avoid related biases to the extent possible. To fit the enrollment criteria a patient must be newly diagnosed with either Alzheimer's disease, dementia with Lewy-bodies or Parkinson's disease with dementia and be described treatment with either donepezil or memantine. Also, the patient must not meet a list of (exclusion) criteria, which have been set up in order to avoid blur and biases of the results. Patients can be selected as participators on account of the above, including an informed consent to participation. Next, the participators will randomized be assigned to one of two study arms. In the first of these, the control arm, the participators receive only standard treatment and follow-up at the outpatient clinic, except for measurement of serum level of the anti-dementia medication with which they are treated and a genetic test for a few key genes thought to be relevant for the study (two liver enzymes, two genes linked to Alzheimer's disease). In the other arm, the intervention arm, the participators will be closely monitored for side effects after prescription of anti-dementia drugs. All these participators will be offered a measurement of serum level in case they experience possible side effects within 2 months of treatment initiation. If, not a measurement of the serum level will be done after 6 months. All patients in the intervention arm, will be offered adjustment of their treatment with the anti-dementia drug based upon serum level. To assess the possible effects of treatment adjustment seven clinical scoring tests will be used (MMSE, ACE, clock-drawing test, NPI-Q, DAD, GCI, GDS). Assessment includes symptom severity and level of compliance according to close relatives. To measure the effect of donepezil on brain (cholinergic) function 30 participants will be recruited for electroencephalography (EEG). These participants will have an EEG done at enrollment and after 6 months. In addition to the quantitative part study a qualitative part study with relatives of enrolled patients will be conducted. All the needed approvals have been obtained according to Danish law (approval by the Danish Data Protection Agency, Scientific Ethics Committee for Region Sjaelland, The Danish Medical Agencies).

Official Title
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Monitoring Anti-Dementia Drugs by Serum Levels: Importance of Serum Levels, Drug-monitoring, Side-effects, Clinical Efficacy and Compliance (Translation of Official Danish Title)

Conditions
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Dementia, Dementia With Lewy Bodies, Dementia in Parkinsons Disease, Dementia Alzheimers, Alzheimer Disease

Intervention / Treatment
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* Drug: Donepezil
* Drug: Memantine
* Diagnostic Test: Measurement of serum level of anti-dementia drug


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The following 3 inclusion criteria (A+B+C) must be met: A. Participant must be newly diagnosed with one of the three conditions below Alzheimer's disease dementia with Lewy Bodies Dementia in Parkinson's disease B. Participant must be prescribed either donepezil or memantine at enrollment. C. Participant must be able to give informed consent to participation in the study. Exclusion Criteria: no accompanying relative at the enrollment and/or follow-up visits patients living alone who do not receive help to administer medication. lack of ability to cooperate, including severely reduced vision or impaired hearing and/or other severe disabilities. patients unable to give informed consent in a meaningful sense due to cognitive decline at enrollment. known psychiatric disease (schizophrenia, bipolar affective disorder etc.). However, patients suffering from depression are eligible if they have been in continuously medically treated for at least 3 months prior to enrollment. known neurologic disorder, which by it self could contribute to cognitive symptoms. other known medical condition (kidney-, liver-, metabolic disease etc.) which by itself could contribute to cognitive symptoms. treatment with anti-psychotic drugs within 3 months of possible enrollment. A minimal daily dosage of benzodiazepine is deemed permissable for enrollment. patients with a history of substantial previous abuse of alcohol or drugs. Also, any kind of substance abuse within last 3 months. any previous severe trauma to the head or neuroinfections which could contribute to cognitive symptoms. electro convulsive treatment within last 3 months. anesthesia within last 3 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single blinded, randomized study with two arms: 'standard of care' arm and 'intervention' arm. Participants in the intervention arm will have their treatment adjusted according to Serum levels of the anti-dementia drug prescribed.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of care<br>Participants allocated to this arm follow the usual routines of the out patient dementia clinic but are requested to have the serum level of the prescribed drug measured after 12 month. Also, CYP2D6, BcHE K and APOe4 status will be determined after 12 months. | Diagnostic Test: Measurement of serum level of anti-dementia drug<br>* Participants allocated to the intervention arm are requested to inform the sponsor of any side effects up to 2 months after prescription of the anti-dementia drug. If so, they will have their treatment adjusted according to the serum level. Participants in the intervention group not experiencing side effects will have their treatment adjusted after 6 months based upon serum levels of the drug in question. Participants allocated to the standard of care arm follow the usual routines of the dementia clinic but are requested to have the serum level of the prescribed drug and CYP2D6-genotype measured after 12 month.<br>|
| Experimental: Intervention arm<br>Participants allocated to this arm follow are requested to inform the sponsor of any side effects up to 2 months after prescription of the anti-dementia drug. If so, they will have their treatment adjusted according to the serum level. Participants in the intervention arm not experiencing side effects will have their treatment adjusted after 6 months based upon serum level of the drug in question. | Drug: Donepezil<br>* Adjustment of treatment with donepezil according to serum level.<br>Drug: Memantine<br>* Adjustment of treatment with memantine according to serum level.<br>Diagnostic Test: Measurement of serum level of anti-dementia drug<br>* Participants allocated to the intervention arm are requested to inform the sponsor of any side effects up to 2 months after prescription of the anti-dementia drug. If so, they will have their treatment adjusted according to the serum level. Participants in the intervention group not experiencing side effects will have their treatment adjusted after 6 months based upon serum levels of the drug in question. Participants allocated to the standard of care arm follow the usual routines of the dementia clinic but are requested to have the serum level of the prescribed drug and CYP2D6-genotype measured after 12 month.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Mini Mental State Examination (MMSE) test result | Widely used clinical test for brief assesment of cognitive function. Total score ranging from 0 (worst) to 30 (best). | 1 year (enrollment in study and at 1-year follow-up) | 
| Change of Adenbrooke's Cognitive Exam (ACE) test result | Widely used clinical test for assesment of cognitive function. The total score ranges from 0 (worst) 100 (best) and includes the score of the MMSE test (0-30). | 1 year (enrollment in study and at 1-year follow-up) | 
| Change of Neuropsychiatric Inventory Questionnaire (NPI-Q) score result | A questionaire filled in by the primary relative of the participant. NPI-Q measures the severity of neuropsychiatric symptoms of demented patients. The total score ranges between 0 (best) and (36 worst). | 1 year (enrollment in study and at 1-year follow-up) | 
| Change of Disability Assessment for Dementia (DAD) score result | A questionaire filled in by the primary relative of the participant. DAD measures the impact of dementia symptoms on activities of daily living (ADL), including eating, dressing, personal hygiene. Total score ranges from 0 (worst) to 40 (best) | 1 year (enrollment in study and at 1-year follow-up) | 
| Change of Clinical Global Impression (CGI) score result | The overall clinical impression of the clinical response to treatment as assessed by the investigator. Ranges from 1 (very much improved) to 7 (very much worse). | 1 year (enrollment in study and at 1-year follow-up) | 
| Serum level of donepezil | Level of the drug donepezil the (serum part of the) blood (nanomoles per liter). | For participants in the standard of care arm will this be measured 1 year after enrollment. For participants in the intervention arm serum level will be measured within 2 months if side effects are experienced, if not then after 6 months. | 
| Serum level of memantine | Level of the drug memantine in the (serum part of the) blood (nanomoles per liter). | For participants in the standard of care arm this will be measured 1 year after enrollment. For participants in the intervention group serum level will be measured within 2 months if side effects are experienced, if not then after 6 months. | 
| Level of compliance to treatment | The level to which the medication has been ingested as prescribed. Both the participant him/her self is questioned as is the primary relative. The level of compliance is rated as belonging to one of the four categories: 1) 'completely regular drug intake' (no missed daily doses within 6 months), 2 'regular drug intake' (less than 10 missed daily doses within 6 months), 3) 'less regular drug intake' (10 - 30 missed daily doses with 6 months), 4) 'irregular drug intake' (more than 30 missed daily doses within 6 months) | Level of compliance will be scored at the one year follow-up by both questioning the participant and the primary relative. | 
| Change in Geriatric Depression Scale (GDS) symptoms score | The Geriatric Depression Scale (GDS) is a self-report assessment tool used to identify symptoms of depression in the elderly. A 15 item version of the GDS will be used to detect and measure severity of depressive symptoms. | All participators will be requested to fill in the GDS questionaire at enrollment and at 12 months follow-up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in quantitative electroencephalogram (qEEG) | quantitative electroencephalogram used to detect changes in alpha-coherence after prescription of donepezil. Estimated 30 patients will be recruited to qEEG testing. | qEEG done within 2 weeks after enrollment and after 6 months | 
| Cyp2D6 gene test | Cyp2D6 is the gene which expresses the enzyme CYP2D6. Donepezil is metabolized by CYP2D6. | For participants in the standard of care arm CYP2D6 status will be determined 1 year after enrollment. For participants in the intervention arm Cyp2D6 will be tested within 2 months if side effects are experienced, if not then after 6 months. | 
| genetic test for BcHE K variant | BcHE butyryl cholinesterase (BChE), K variant. From a previous case-control study it is suspected that this enzyme influences the efficacy of donepezil. | For participants in the standard of care arm BcHE K variant status will be tested 1 year after enrollment. For participants in the intervention arm BcHE K variant status will be determined at the 6 month follow-up. | 
| genetic test for APOe4 allele status. | The APOe4 allele is linked to an increased risk of developing Alzheimer's disease. | For participants in the standard of care arm APOe4 allele status will be determined 1 year after enrollment. APOe4 allele status will be determined at the 6 month follow-up for participants in the intervention arm. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Therapeutic Drug Monitoring, TDM, Adverse effects, Dementia, Alzheimer's disease