Monitoring Anti-Dementia Drugs by Serum Levels

NCT ID: NCT04117178

Last Updated: 2025-02-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 132 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-04
• Study Completion Date: 2023-02-16

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).

Conditions

Dementia; Dementia With Lewy Bodies; Dementia in Parkinsons Disease; Dementia Alzheimers; Alzheimer Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Standard of care

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.

Group Type: ACTIVE_COMPARATOR

Measurement of serum level of anti-dementia drug

Intervention Type: DIAGNOSTIC_TEST

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.

Intervention arm

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.

Group Type: EXPERIMENTAL

Donepezil

Intervention Type: DRUG

Adjustment of treatment with donepezil according to serum level.

Memantine

Intervention Type: DRUG

Adjustment of treatment with memantine according to serum level.

Measurement of serum level of anti-dementia drug

Intervention Type: DIAGNOSTIC_TEST

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.

Interventions

Donepezil

Adjustment of treatment with donepezil according to serum level.

Intervention Type: DRUG

Memantine

Adjustment of treatment with memantine according to serum level.

Intervention Type: DRUG

Measurement of serum level of anti-dementia drug

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.

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Filadelfia Epilepsy Hospital

OTHER

Sponsor Role: collaborator

Zealand University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter Høgh, MD, ph.d.

Role: PRINCIPAL_INVESTIGATOR

Regionalt Videnscenter for Demens

Michael Fischer, MD

Role: STUDY_DIRECTOR

Regionalt Videnscenter for Demens

Locations

Regionalt Videnscenter for Demens

Roskilde, Region Sjælland, Denmark

Countries

Denmark

References

Fischer MHF, Zibrandtsen IC, Johannsen P, Siersma V, Rasmussen JB, Larsen JB, Hogh P. Therapeutic drug monitoring for dose optimization in Alzheimer's disease and in dementia with Lewy bodies: A randomized single-blinded clinical trial. J Alzheimers Dis Rep. 2024 Nov 24;8(1):1516-1528. doi: 10.1177/25424823241289373. eCollection 2024.

Reference Type: DERIVED

PMID: 40034344 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

2017-002707-10

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

REG-007-2018

Identifier Type: -

Identifier Source: org_study_id