Monitoring Anti-Dementia Drugs by Serum Levels

Phase 4

Completed

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

Interventions: Diagnostic Test: Measurement of serum level of anti-dementia drug
Drug: Donepezil
Drug: Memantine

Registration Number: NCT04117178

Lead Sponsor: Zealand University Hospital

Brief Summary: The main objective of the MONANTI study is twofold:

Firstly, to determine the serum concentration (SC) the anti-dementia drugs donepezil and memantine 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 based on measurements of the SC will benefit patients in terms of cognitive performance, activities of daily living (ADL), 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 SC outside the recommended therapeutic reference range (TRR).

Thus, MONANTI will investigate if this is indeed the case in a broadly comprised population of patients with dementia treated with donepezil or memantine. In addition, MONANTI will link SC to co-morbidity, level of compliance, medication interactions. It is hypothesized that the efficacy of anti-dementia drugs can be significantly improved by adjustment of treatment according to SC. Also, it is hypothesized that the burden of side effects can be reduced in patients in whom too high SC are detected, if dose 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 meet the enrollment criteria eligible participants must:

A) be newly diagnosed with either Alzheimer's disease dementia, dementia with Lewy-bodies or Parkinson's disease with dementia and B) be scheduled for treatment with either donepezil or memantine. C) not meet a list of (exclusion) criteria, which have been set up in order to avoid blur and biases of the results.

D) be able to give written informed consent to participation in presence of a close relative.

After enrollment the participants will be randomly assigned to one of two study groups. In the first of these, the control group, the participants receive standard treatment and follow-up at the outpatient clinic. In addition, all participants in the control group who complete the trial will have a blood sample collected at the final visit to measure the SC of the anti-dementia drug along with a genetic test for a few key genes thought to be relevant for the study (two liver enzymes (cyp2D6, cyp3A4/5, APOE-genotype, butyrylcholine-esterase K-variant).

In the other group, the intervention group, the participators will be closely monitored for side effects after prescription of anti-dementia drugs. All participants in the intervention group will be offered a measurement of the SC in case they experience drug side effects within 2 months of treatment initiation. All participants in the intervention group will have a measurement of the SC done at the 6 months visit. The measured SC will be compared to the TRR of the drug in question. This information, along with details from the clinical assessment at the 6 month visit will be used to guide the decision of whether or not to adjust treatment. All decisions on treatment adjustment during the trial are done by the PI according to details in the protocol.

All participants in the intervention group are evaluated again at a 12 month visit, identical to that of the control groups.

To assess the possible effects of SC guided treatment adjustment six clinical tests/rating scales will be used (MMSE, ACE, NPI-Q, DAD, CGI, GDS). The tests/rating scales will be administered both at the enrollement visit and one year later at the final 12 month follow-up visit.

To measure the effect of donepezil on brain cholinergic function approx. 30 participants will be recruited for electroencephalography (EEG). These participants will have an EEG done at enrollment and after 12 months.

In addition to the above mentioned quantitative study a qualitative study with relatives of enrolled participants is planned.

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 132

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
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard of care	Measurement of serum level of anti-dementia drug	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.
Intervention arm	Measurement of serum level of anti-dementia drug	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.
Intervention arm	Donepezil	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.
Intervention arm	Memantine	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.

Primary Outcome Measures

Name	Time	Method
Change of Mini Mental State Examination (MMSE) Test Result	1 year (enrollment in study and at 1-year follow-up)	Widely used clinical test for brief assesment of cognitive function. Total score ranging from 0 (worst) to 30 (best).
Change of Adenbrooke's Cognitive Examination (ACE) Test Result	1 year (enrollment in study and at 1-year follow-up)	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).
Percentage of Participants With a Serum Concentration Within the Therapeutic Reference Range (TRR) at 12 Month Follow-up Visit.	Counted at the 12 month visit	Percentage of participans in each group with serum concentrations of the study drugs within the therapeutic reference range (TRR) at the 12 month follow-up visit. According to the 2017 AGNP consensus guidelines the TRRs are "ranges of drug concentrations in blood that specify a lower limit below which a drug induced therapeutic response is relatively unlikely to occur and an upper limit above which tolerability decreases or above which it is relatively unlikely that therapeutic improvement may be still enhanced" (Pharmacopsychiatry . 2018 Jan;51(1-02):9-62. doi: 10.1055/s-0043-116492. Epub 2017 Sep 14). Donepezil has a serum TRR of 50-75 nanograms per milliliter (ng/mL) and memantine has a serum TRR of 90-150 ng/mL.
Level of Compliance to Treatment	Level of compliance will be scored at the one year follow-up by both questioning the participant and the primary relative.	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)

Secondary Outcome Measures

Name	Time	Method
Change in Geriatric Depression Scale (GDS) Symptoms Score	The GDS is administered to all participants at the both the baseline and 12-month follow-up visit.	The Geriatric Depression Scale (GDS) is a questionaire administered by the investigator to the participant. GDS is used to assess symptoms of depression in the elderly. A 15 item version of the GDS is used with a score from 0 (best) to 15 (worst).
Change of Clinical Global Impression (CGI) Score Result	1 year (enrollment in study and at 1-year follow-up)	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).
Genetic Test for BcHE K Variant	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.	BcHE butyryl cholinesterase (BChE), K variant.
Change of Disability Assessment for Dementia (DAD) Score Result	1 year (enrollment in study and at 1-year follow-up)	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)
Change of Neuropsychiatric Inventory Questionnaire (NPI-Q) Score Result	1 year (enrollment in study and at 1-year follow-up)	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).
C2D6 Phenotype	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.	Cyp2D6 is the gene which expresses the enzyme CYP2D6. Donepezil is metabolized by CYP2D6.