Clinical trial NCT04117178: Monitoring Anti-Dementia Drugs by Serum Levels
Official title: Monitoring Anti-Dementia Drugs by Serum Levels: Importance of Serum Levels, Drug-monitoring, Side-effects, Clinical Efficacy and Compliance (Translation of Official Danish Title)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Dementia
Dementia With Lewy Bodies
Dementia in Parkinsons Disease
Dementia Alzheimers
Alzheimer Disease
Keywords: Therapeutic Drug Monitoring
TDM
Adverse effects
Dementia
Alzheimer's disease
Lead sponsor: Zealand University Hospital
Sponsor class: OTHER
Collaborators: name: Filadelfia Epilepsy Hospital
First posted: 2019-10-07
Enrollment: 132
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: Change of Mini Mental State Examination (MMSE) Test Result
timeFrame: 1 year (enrollment in study and at 1-year follow-up)
measure: Change of Adenbrooke's Cognitive Examination (ACE) Test Result
timeFrame: 1 year (enrollment in study and at 1-year follow-up)
measure: Percentage of Participants With a Serum Concentration Within the Therapeutic Reference Range (TRR) at 12 Month Follow-up Visit.
timeFrame: Counted at the 12 month visit
measure: Level of Compliance to Treatment
timeFrame: Level of compliance will be scored at the one year follow-up by both questioning the participant and the primary relative.
Secondary outcomes:
measure: Change of Clinical Global Impression (CGI) Score Result
timeFrame: 1 year (enrollment in study and at 1-year follow-up)
measure: Change in Geriatric Depression Scale (GDS) Symptoms Score
timeFrame: The GDS is administered to all participants at the both the baseline and 12-month follow-up visit.
measure: Change of Disability Assessment for Dementia (DAD) Score Result
timeFrame: 1 year (enrollment in study and at 1-year follow-up)
measure: Change of Neuropsychiatric Inventory Questionnaire (NPI-Q) Score Result
timeFrame: 1 year (enrollment in study and at 1-year follow-up)
measure: C2D6 Phenotype
timeFrame: 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.
measure: Genetic Test for BcHE K Variant
timeFrame: 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.
Other outcomes:
measure: Genetic Test for APOe4 Allele Status.
timeFrame: For participants who complete the trial APOe4 allele status is assessed at the 1 year visit.
Locations:
city: Roskilde
country: Denmark
facility: Regionalt Videnscenter for Demens
state: Region Sjælland
Study officials:
affiliation: Regionalt Videnscenter for Demens
name: Peter Høgh, MD, ph.d.
role: PRINCIPAL_INVESTIGATOR
affiliation: Regionalt Videnscenter for Demens
name: Michael Fischer, MD
role: STUDY_DIRECTOR
References: