Monitoring Anti-Dementia Drugs by Serum Levels: Importance of Serum Levels, Drug-monitoring, Side-effects, Clinical Efficacy and Compliance (Translation of Official Danish Title)
Phase: PHASE4
Conditions: Dementia, Dementia With Lewy Bodies, Dementia in Parkinsons Disease, Dementia Alzheimers, Alzheimer Disease
Sponsor: Zealand University Hospital

MONANTI 
Study protocol version 1.9 
April 19, 2022  
 
 
(Date of translation March 28, 2023) 
MONitoring of ANTI-dementia drugs by determining serum 
concentrations, importance of monitoring for the incidence 
of side effects, clinical effect and compliance (“MONANTI”) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document type: Study Protocol with Statistical Analysis Plan 
Document date: March 28, 2023 
NCT number: NCT04117178  
EudraCT: 2017-002707-10 
Protocol version: 1.9 (April 19, 2022) 
Translation: Danish to English (March 28, 2023) 
 
 

MONANTI 
Study protocol version 1.9 
April 19, 2022  
 
 
(Date of translation March 28, 2023) 
 
Introduction 
 
MONANTI is a prospective clinical study consecutively enrolling patients treated 
with anti-dementia drugs after diagnostic evaluation in the interdisciplinary 
memory clinic at the Regional Knowledge Center for Dementia (RVD), Roskilde, 
Denmark. Eligible participants include all patients who during the trial period are 
A): 
diagnosed with either Alzheimer's Dementia (AD), Dementia with 
Lewy-Bodies (DLB) or Parkinson's disease dementia (PDD) 
and 
B): 
who begin medical treatment with anti-dementia drugs (either 
Donepezil or Memantine)  
and  
C): 
give informed consent to participation.  
Participants are randomized into 2 groups:  
1) The control group, which follows the normal procedure for 
treatment titration and follow-up. The control group will also have 
serum determined after 12 months of treatment and will be offered 
one extra control visit in connection with this (6 months after last 
rutine follow-up visit at the clinic).  
2) The intervention group, which is offered serum determination and 
dose adjustment for early side effects as well as serum 
determination, dose adjustment and additional follow-up after 6 and 
12 months. 
The follow-up phase for participants will be a maximum of 6 months longer than 
a the rutine follow-up time at the clinic. In connection with study visits to the 
clinic, data on clinical tests of the participant i cognition (MMSE, ACE),and data 
on interviews of relatives on ADL function (DAD) and neuropsychiatric 
symptoms (NPI-Q), are collected. In addition the researcher assesses the 
overall participant performance using the Clinical Global Impression score (CGI). 

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Systematic observations are carried out regarding treatment compliance in both 
control and intervention groups. In addition, an electroencephalography (EEG) 
examination is carried out at the baseline visit and after 12 months in 30 
participants. After the 12-month visit, a qualitative study is conducted. This study 
will collect data by interviewing spouses of participants.  After the end of the 
study, the utility of serum determinations of anti-dementia drugs in relation to 
side effects and clinical efficacy is assessed by comparing the scores of 
participants in the control and intervention groups for the aforementioned clinical 
scales.  
Project initiator, sponsor, responsible physician and contact person:  
Peter Høgh, senior physician, MD, PhD  
Department of Neurology Zealand University Hospital (SUH) Vestermarksvej 11 
DK-4000 Roskilde Denmark  
 
 

MONANTI 
Study protocol version 1.9 
April 19, 2022  
 
 
(Date of translation March 28, 2023) 
Aims of the study 
  
• Investigate whether determination of serum concentration, and regulation of 
the dose on the basis hereof, improve the clinical treatment response – including 
whether insufficient clinical effect could be due to too low a serum concentration  
• Investigate whether early development of side effects during treatment with 
anti-dementia drugs is due to too high a serum concentration (ie. serum 
concentrations above the therapeutic reference range).   
• Characterize the proportion of participants who reach a serum concentration 
within the recommended therapeutic reference range when treated with 
standard dosages of anti-dementia drugs.  
• Study whether the recommended therapeutic reference ranges are valid in 
relation to clinical efficacy  
• Investigate the relationship between serum concentrations and clinical efficacy 
in different stages of the dementia disease  
• Investigate whether measurements of serum concentrations improve treatment 
compliance, both in relation to side effects and in relation to clinical efficacy 
 • Investigate whether sex differences impact serum concentrations, which 
potentially may have an impact on optimal drug dosing.   
• Investigate whether genetic variation of the metabolism of anti-dementia drugs, 
impact serum concentration and thus potentially may be important for optimal 
dosing. With regards to this, analysis of the APOE genotype and analysis of the 
BchE-K/K variant will be carried out.  
• Describe aspects of treatment compliance in in a Danish memory clinic  
• Describe the perspectives of participant relatives on treatment with anti-
dementia medication in a Danish memory clinic  
• Investigate change in qEEG coherence after initiation of treatment with anti-
dementia drugs in participants with Alzheimer's disease.   
• Investigate whether other qEEG measures are affected in patients with 
Alzheimer's disease after initiating anti-dementia medication 
 
 

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Background  
 
Alzheimer's disease (AD) is the most common cause of dementia in all 
developed countries, and thus accounts for over half of all cases of dementia. 
The disease is extremely common among the elderly, with a prevalence of 5% 
among those over 65, rising to 85% among those over 85. Currently, there is no 
curative treatment for AD. AD is a very resource-demanding disease, not only 
for the patient and their relatives, but to a large extent also for the health care 
system and society. In Denmark, the annual costs for diagnostic assessment, 
treatment, care and care of dementia are estimated to amount to around 24 
billion DKK annually. The annual costs are predicted to increase two-fold by 
2040 according to recognized forecasts, unless significantly better methods for 
diagnostic assessment and treatment are invented. From the early 1980s, 
symptomatic treatment of the disease has been available and in recent years an 
increasing number of studies have been carried out on potentially disease-
modifying treatments (especially immunization therapy, anti-inflammatory drugs 
and secretase inhibitors). In Denmark, the marketed drugs for symptomatic 
treatment AD in the mild to moderate phase are also registered for the treatment 
of DLB and PDD. There is general agreement that future potentially disease-
modifying treatments must be introduced very early in the course of the diseases 
to be effective, whilst treatments introduced later in the course of disease, ie. 
when the patient has reached a state of actual dementia are unlikely to be 
clinically effective. Until now [translators note: April 20th 2022), none of these 
studies have resulted in the marketing of new forms of treatment, and a 
fundamental problem is that there are no methods to make a safe early AD 
diagnosis in vivo. The prevalence of AD is increasing in all developed and many 
non-developed countries due to increased average life expectancy, with 
increasing age being the main known risk factor for AD. The diagnosis of AD is 
based on a number of diagnostic tests, which together can make the diagnosis 
probable. But no single test or examination can unequivocally determine 
whether the underlying disease is in fact AD. In 2011, leading experts worldwide 
in the field of dementia published proposals for new diagnostic criteria for AD 
(Guy M. McKhann et al. "The diagnosis of dementia due to Alzheimer's disease: 
Recommendations from the National Institute on Aging – Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease." 
Alzheimer's & Dementia: The Journal of the Alzheimer's Association 
2011;7(3):263 – 269 (1)). According to Guy M. McKhann et al. (2011), the 
diagnosis of AD can be made if the patient has an insidious onset, gradually 
progressive and objectifiable impact on at least 2 cognitive domains, which 

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constitutes a deterioration in relation to the patient's habitual level, has an 
impact on ordinary daily activities and cannot be explained by delirium or other 
psychiatric illness. A number of clinical subtypes are defined, of noted it is not 
mandatory that the cognitive domain of memory is affected as in previous 
definitions. A number of clinical and paraclinical [lab and scanning tests] findings 
may reduce the likelihood of AD, just as a number of findings may support a 
diagnosis of AD. Relevant supporting findings can be obtained from MRI scans 
or functional brain scans (PET) as well as cerebrospinal fluid (CSF) containing 
an abnormal level of biomarkers (a-beta, tau and phospho-tau). When 
investigating dementia, it is recommended that a structural brain scan is carried 
out, either in the form of a CT or MR scan. In Denmark, the routine scan is the 
CT due to scan is, due to restrictions on resource consumptions [fundings for in-
hospital diagnostic work-up] (2).  
The anti-dementia drugs currently on the market (acetylcholinesterase inhibitors 
(ChEI) and memantine) do not have any documented disease-modifying effect in 
relation to the pathophysiology of AD as such, but only a symptomatic effect. 
When ChEI were introduced, analyzes of the optimal dosage level were carried 
out both in relation to safety and side effects, but also in relation to clinical 
efficacy. It appears from the early studies of the drug Donepezil that it was 
estimated that 80% would achieve optimal therapeutic serum levels at the 
standard dosage of 10 mg per day (3,4,5). Correspondingly, a dose-response 
relationship was found for the other ChEIs (rivastigmine, galantamine) and the 
partial glutamate receptor antagonist memantine (Ebixa), which is reserved for 
patients with moderate to severe AD or LBD, and a recommended dosage was 
established with a view to optimal clinical response (6). The indicative serum 
ranges are 80-200 nmol/l and 500-840 nmol/l for donepezil and memantine 
respectively (7). There have been remarkably few following studies investigating 
whether serum concentrations in a clinical setting are actually within the 
therapeutic reference ranges of the current recommendations. A recently 
published study suggests that very few patients in fact do reach a serum 
concentration within the recommended theraupetic reference ranges on the 
standard dosage (8). At the same time, few researchers have previously taken 
an interest in whether the occurrence of early side effects, possibly on a low 
dosage, and/or clinical need for repeated adjustments in drug dosing or 
alternatively change of preparation, could be due to abnormally high serum 
concentrations of the drug. Possibly reason for this could be genetic variation, 
sex differences, co-morbidity, compliance problems or drug interactions (9,10). 
For the planned research study conducted according to this protocol, we will 
initially focus on the two most widely used anti-dementia drugs, Donepezil and 

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Memantine, because an estimated 80% of patients who are treated with anti-
dementia drugs are on one of these 2 drugs.  
A pilot study carried out in collaboration between RVD and [The Laboratory of] 
Filadelfia showed that out of 24 blood samples, all taken from patients treated 
with donepezil at steady-state, only 8 samples, i.e. corresponding to 1/3, were 
within in the recommended therapeutic reference range. Ten samples were 
below the lower recommended limit, while 6 samples were above.  
 
Figure 1. Pilot study Philadelphia 
 
 
 
A different aspect of this problem [of the optimal serum concentration of anti-
dementia medication] is that there are no tests that measure cholinergic activity 

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in the brain, which is why it can be difficult to assess whether the optimal dosage 
is prescribed. One possible method is quantitative electroencephalography 
(EEG) coherence, which measures the temporal correlations between two EEG 
signals. A reason for choosing of this method [for studying brain cholinergic 
activity] is that patients with Alzheimer's disease have a greatly reduced alpha 
coherence compared to healthy participants (24-33) and that alpha coherence 
has been associated with cholinergic dysfunction (24, 28). The [evidence in 
support of the] association between alpha coherence and cholinergic 
dysfunction is largely due to previous studies reporting reduced alpha coherence 
after administration of the anticholinergic substance scopolamine in healthy 
participants (34, 35). In addition, reduced alpha coherence has also been 
associated with the ApoE4 genetic risk factor (36), and recent studies have 
shown that cholinesterase inhibitors (Donepezil) lead to greater cognitive 
improvement in people with ApoE4 [37-40], which could indicate a connection 
between cholinergic dysfunction and alpha coherence. The change in alpha 
coherence in patients with AD has not previously been investigated in patients 
with Alzheimer's disease after initiation of treatment [with Donepezil] and 
changes in EEG after initiation Donepezil [treatment] have [to date] only been 
sparsely investigated [41]. It is therefore possible that alpha coherence could be 
used as a means to monitor treatment [with Donepezil]. 
 
Methods and materials 
 
Serum concentration measurements of anti-dementia drugs and genetic analysis 
(blood test)  
 
Quantitative determination of serum Donepezil and serum Memantine:  
The method is a UPLC-MS/MS method using an internal standard method with 
deuterium-labeled analogues used for both substances. The sample preparation 
is a protein precipitation with 20% zinc sulfate and methanol added as an 
internal standard. The subsequent analysis is performed on a Waters Acquity 
UPLC (BEH C18, 1.7 µm; 2.1x100 mm) column with gradient elution. A Waters 
TQD detector with positive electrospray ionization is used. The method has been 
validated to be used in the expected plasma concentrations with the following 
values for precision and correctness, CV <10% and bias <12%.  

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It has been shown that the metabolism of Donepezil is affected by the activity of 
the cytochrome oxidase enzyme 2D6. This enzyme is inhibited by Memantine, 
therefore in combination therapy [with the two drugs] metabolism of Donepezil 
may be affected. The Cyp2D6 gene, which codes for the enzyme, is highly 
polymorphic. Thus, it is estimated that around 20% of Caucasians have an 
abnormal conversion via this enzyme. Based on genetic testing (genotyping), an 
individual can be deemed to be a normal metabolizer, have partially reduced, or 
no Cyp2D6 activity. At the same time, such tests can also identify whether an 
individual is a fast metabolizer, a phenotype which is present when an individual 
via a specific mutation is the carrier of more than the normal 2 copies of the 
gene. In the study, participants will be offered a Cyp2D6 gene test, possibly 
supplemented with Cyp2C19. The Cyp2D6 test carried out at the Epilepsy 
Hospital's Laboratory covers the 8 most frequently occurring alleles, including 
variants that occur most often in Africans and East Asians, as well as rapid 
metabolizers. The results of the test will be used to determine the participants 
phenotype, and thereby efficiency of metabolism of Donepezil via Cyp2D6, and 
these data will be correlated with measured/expected plasma concentrations. In 
connection with the study, patients will also be offered a gene test for the BcHE 
K variant and for APOE4. BcHE K is determined based on a single mutation in 
the gene (rs1803274), while the analysis for the APOE4 genotype is based on 
the presence of two mutations in the APOE gene (respectively rs429358 and 
rs7412). The Epilepsy Hospital's laboratory in Dianalund will be responsible for 
carrying out both tests, which will use the 5'nuclease/Taqman principle. 
Commercial kits ordered from ThermoFischer Scientific will be used for the 
analysis. 
 
 
Mini Mental State Examination (MMSE) (11)  
A clinical test by which the patient's cognitive function is assessed on the basis 
of a 30-point scale, the higher the score the better the function. The test is by far 
the most used for clinical monitoring of patients with dementia, just as it is 
commonly used in clinical trials and other dementia research. The test can be 
completed by a trained professional in 10-15 minutes. Healthy people will 
generally score 26-30 points.  
 
Addenbrooke's Cognitive Examination (ACE) (12)  

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A clinical test which, compared to the MMSE, is not routinely used in all clinics, 
but especially in clinics with a special function, as well as in connection with 
research projects. The test is a 100-point scale, where points from the MMSE 
are included in the total score, the higher the score, the better the function. 
Compared to the MMSE, the test goes into all cognitive domains in more detail 
and is less language dependent. Healthy people will, depending on age and 
education, generally score above 85 points. The test can be completed by a 
trained professional in 10-15 minutes.  
 
Neuropsychiatric Inventory Questionnaire (NPI-Q) (13)  
A clinical scale to assess the presence and severity of neuropsychiatric 
symptoms in dementia. This results in an NPI score (0-36), which is based on an 
interview with the next of kin [relative]. The higher the score, the more 
pronounced neuropsychiatric symptoms.  
 
Disability Assessment for Dementia (DAD) (14)  
A scale for assessing ADL [Activities of Daily Living] functions (eating, personal 
hygiene, dressing, etc.), which is based on an interview with next of kin. With 
completely normal ADL functions, a score of 40 points is achieved, the higher 
the score, the better the function.  
 
Clinical Global Impression (CGI) (15) 
A "global" scale, which is commonly used in clinical trials. This is a 7-step scale 
by which the clinician grades his overall impression of treatment response. The 
scale was used in the previously mentioned recent study of plasma 
concentrations and clinical response. The scale will be weighted, rather than 
weighted on MMSE scores alone, when assessing treatment response.  
 
Geriatric Depression Scale (GDS)  
A scale for assessing severity of depressive symptoms in the elderly. Based on 
the total point score (0-15), the result is categorized as either "normal" (< 5 
points), "possible depression" (5-7 points), "probably mild to moderately severe 
depression" (8-10), "moderately severe" to severe depression” (11-12 points), 
“severe depression” (≥13 points). 

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Compliance Definition:  
Compliance means the patient's degree of compliance with the doctor's 
prescriptions. The term is used especially in drug treatment. Most often, the 
patient takes less medicine than prescribed. "Non-compliance" typically means 
that the patient takes < 80% of the prescribed doses. Low compliance can be 
intentional or unintentional (16). 
 
 
A possible explanation for the highly variable serum concentrations at the 
recommended maximum dose [of anti-dementia drug] is reduced patient 
compliance. A literature review from 2008 shows that reduced cognition and 
memory as well as impaired executive functions have a direct impact on the 
patient's compliance (17). Lack of acceptance of illnes [on part of the patient] 
together with changes in the personality can result in ethical dilemmas, in which 
considerations about how and when the patient needs of support for medication 
must be included in the care of the patient with dementia. The decision for 
others to take over the medication administration on behalf of the patient due to 
concerns of safety and comppliance must be weighted against the patient's 
capacity for self-determination and independence (17). Optimal compliance is 
usually achieved by agreement with the next of kin or the home nursing care. 
However, there may be a number of reasons why compliance is not optimal after 
all. Possible reasons could be: a) The patient does not want to take his 
medication and opposes suggestions by the close relative b) The patient has 
undisclosed side effects c) Insufficient focus on correct dosage as well as 
observation and reporting of side effects among those responsible for dosage, 
including a. The drug is taken in the wrong dose or at the wrong interval b. The 
drug is not taken regularly, as the patient or the relative experiences that "there 
is no effect" c. The patient informs about side effects, but the information is not 
passed on to RVD d) Patient and relatives perceive the medication as a "cure" 
and end the medication e) The patient's general practitioner adjusts the dose, 

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prescribes side effect medication (e.g. anti-nausea medication), prescribes 
inappropriate medication with interaction, or discontinues treatment without 
cooperating with RVD.  
 
Electroencephalography Electroencephalography (EEG) is a method in which 
electrodes are placed on the head and the electrical activity of the brain is 
measured. After recording, these measurements can be exported and cleaned 
up using different software, after which separate calculations can be made on 
the basis of the signals. In this case, we will calculate the connection between 
the signals using coherence. During the EEG recording, you will be stimulated 
with stroboscopic light for a few minutes (during the so-called 'photo-block'). In 
relation to clinical standard EEG, the photo-block is modified with regard to 
optimal study of quantitative EEG measures of relevance to the project. The 
photo block is composed as follows: 30 seconds with 1 Hz stimulation, 30 
seconds break with eyes open. Then respectively 8-10-12-14 Hz stimulation for 
10 sec. separated by short breaks of the same duration. After this 40 Hz 
stimulation for 10 sec. followed by a one-minute break. The photo-stimulation 
ends with 30-second stimulation of three rounds of 35, 45 and 55 Hz. each 
separated by a one-minute break. 
 
 
Study hypotheses  
 
• The clinical effect of anti-dementia drugs can be increased significantly through 
plasma concentration determinations and dose adjustment based on this. 
 • In clinical practice, patients treated with anti-dementia drugs generally do not 
achieve the recommended plasma concentration  
• Patients treated with anti-dementia drugs who experience early side effects are 
often patients who, on low or standard dosages, have plasma concentrations 
above the recommended level.  
• The cause of plasma concentration above or below the recommended level is 
often aberrant metabolism due to genetic variation  

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• There is a gender difference in relation to plasma concentration at 
recommended dosage  
• Treatment compliance can be improved significantly through plasma 
concentration determinations in the event of side effects and in the case of 
unsatisfactory clinical effect of anti-dementia drugs 
• EEG coherence in the alpha band will be higher after starting treatment with 
Donepezil 
 
 
 
Possible impacts of the project 
 
This project is, as far as we know, the first study to systematically examine the 
value of serum concentration determinations for anti-dementia drugs in 
Denmark. At the same time, there is also very limited knowledge about this 
internationally. The study will highlight conditions that will improve our 
knowledge of the conditions that influence an optimal treatment response when 
using the most commonly used anti-dementia drugs. The improvement of the 
treatment through serum concentration determinations and derivative dose 
monitoring or change of preparation could be important for a very large group of 
patients and relatives, which is also a group in sharp increase due to population 
development. Recruitment (see FLOWCHART) Patients with memory problems 
and possible dementia, who are referred to RVD, Zealand's University Hospital, 
will be asked at the information interview (general interview where they are 
informed about diagnosis and intended treatment) whether they want to 
participate in the study. Participation is voluntary. Furthermore, patients will 
always be accompanied by a close relative during the interview in RVD. Up to 
one week's reflection time is offered and written information material is provided. 
The patient is informed that any participation or non-participation in the project 
has no significance for future contacts with the healthcare system. The patients 
who show an interest in participating are contacted by telephone by the project 
manager within one week. If the patient wishes to participate, the patient and the 
next of kin are invited to an inclusion interview. The participants are informed 
here that they will be randomized into 2 groups, one group (control group) which 
will not have extra blood samples taken in connection with the regular follow-up, 
but rather a single extra blood sample after 1 year. This is used partly for genetic 

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tests, partly for serum concentration determination. They are also informed that 
they will receive at least 1 year of follow-up in RVD, against the usual ½ year. At 
the visit after 1 year, the same clinical tests and scales are carried out as during 
the patients' preliminary examination, and matters relating to compliance are 
queried. The other group (intervention group) will have an extra blood sample 
taken if they experience side effects from the treatment within the first 2 months. 
Everyone also has one extra blood test at each The ½- and 1-year check-ups. In 
addition, they will also be followed for at least 1 year against the normal ½ year. 
At the 1-year check-up, the same clinical tests and scales are carried out as in 
the pre-examination, and matters relating to compliance are queried. 
Subsequently, the respective compliance, distribution of serum concentrations, 
as well as the importance of serum concentration determination and derived 
dose regulation for the overall clinical response after 1 year (assessed on 
MMSE, ACE, NPI, DAD and CGI). A comparison is made of the occurrence, 
duration and outcome of side effects in the 2 groups, including the proportion of 
patients who had to change preparations or abandon medical treatment due to 
side effects. The project manager (alternatively the person performing the test) 
is blinded in relation to which group the patient is randomized to and to the result 
of serum values. The final statistical analysis of the clinical value of serum 
determinations and derivative monitoring is performed by an independent 
statistician. No participants will receive any form of remuneration for participation 
in the project. Any additional costs for transport are covered according to the 
appendix. Use of journal information Journal information is used to identify the 
target group, including clarifying inclusion and exclusion criteria (see these). 
During the project period of one year, the journal is used to document and 
monitor any side effects or unintended events, just as all possible side effects or 
unwanted events are entered into the patient's CRF. 
 
 
 

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FLOWCHART FOR PROJECT "MONANTI" 
 
 
 
 
 
Eligible patients for participation:  
Patient who after diagnostic 
assessment at RVD are scheduled for 
treatment initiation with an anti-
dementia drug (Donepezil or 
Memantine) 
The participant is enrolled after 
informed consent is obtained. 
Subsequently the participant is 
randomly allocated to either the 
control or the intervention group 
Control group: regular follow-up at RVD and in addition a 
1-year follow-up visit during which data on MMSE, ACE, 
NPI, DAD, CGI, GDS are collected. Data on comliance is 
registrered and if applicable new co-morbidities. A blood 
sample is collected for genetic analysis. After participation 
participants in the control gruop are offered dosage 
increase if serum concentration is below lower limit of 
therapeutic range regardless of clinical effect.  
Intervention group: Participants who experience side 
effects within weeks to months after treatment initiation 
are offered serum concentration measurements. In 
addition genetic tests are done. At the half-year study 
visit a blood sample is collected. Participants who have a 
serum concentration below therapeutic reference range 
are offered dosage increase regardless of clinical effect. 
Participants with low clinical effect but with serum 
concentration within the therapeutic reference range are 
offered change of treatment to a different anti-dementia 
drug [if on Donepezil treatment with Memantine is 
offered and vice versa]. The participant is offered to 
change treatment drug if he or she experiences side 
effects after dosage increase.  
At the 1-year follow-up visit during data on MMSE, ACE, 
NPI, DAD, CGI, GDS are collected. Data on comliance is 
registrered and if applicable new co-morbidities. A blood 
sample is collected for genetic analysis. 
End-of-study:  
Comparisions of serum concentrations, 
and clinical test scores betweens groups at 
baseline and 1 year follow-up. Assessment 
of the clinical efficacy of serum 
concentration measurements. What is the 
impact of serum concentration 
measurement on compliance?  
Qualitative study 
A qualitative study using focus groups of relatives is 
conducted after the 1 year follow-up visit.  

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Inclusion criteria for participants  
• All patients [evaluated at RVD] who after diagnostic assessment has been 
completed, meet the criteria for  
• Alzheimer's Dementia (AD), (NIA-AA, (1)), Dementia with Lewy-Bodies (DLB) 
(15) or Parkinson's Disease Dementia (PDD) (18), and  
• who are scheduled for treated with Donepezil or Memantine and  
• who give informed consent to participation.  
Both patients with mild-moderate dementia and patients with moderate to severe 
dementia are enrolled, because we want to explore whether the correlation 
between effect and serum concentration varies depending on the stage of 
dementia.  
 
Exclusion criteria for participants  
• Patients not accompanied by relatives to study visits.  
• Patients who live alone and do not have help with the medication 
administration  
• Inability to cooperate to testing, also severely impaired vision or hearing, 
amputation or other severe disabilities.  
• Inability to meaningfully give informed consent due to cognitive impairment.  
• Patients with known underlying psychiatric illnesses (schizophrenia, bipolar 
affective disorder, etc.). Depression is permitted if the patient has been on 
regular medical treatment for at least 3 months prior to inclusion.  
• Patients with known neurological conditions (MS, epilepsy, brain tumors etc.), 
which in themselves could be contributing to the patients cognitive symptoms.  
• Patients with medical conditions (kidney, liver, metabolic etc.) which in 
themselves could be contributing to the patients cognitive symptoms.  
• Patients who, currently or in the past 3 months before enrollment, have been 
treated with anti-psychotics or neuroleptics. Minimal doses of benzodiazepines 
or hypnotics are accepted.  
• Patients with previous heavy abuse of alcohol or illegal drugs, or any abuse 
within the last 3 months before inclusion.  

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• Patients with previous severe head trauma or neuroinfections, which in 
themselves could contribute to the patients cognitive symptoms.  
• Patients who have had ECT [Electro Convulsive Therapy] treatment within the 
last 3 months.  
• General anesthesia within the last 3 months.  
 
Withdrawal criteria for all  
• The participant or relative wishes to withdraw from the study.  
• Symptoms deemed unacceptable by the physician responsible for the trial in 
accordance with the above exclusion criteria. 
• Medical reasons, including if the treatment is changed to an anti-dementia drug 
for which serum concentrations are not measured in this study [galantamin or 
rivastigmine].   
  
 
Study execution and visits  
 
Inclusion interview/recruitment  
• At the weekly interdisciplinary diagnostic conference at RVD, all eligible 
patients are noted. An anonymized list is kept, which ensures that all patients 
who meet the criteria for participation are offered participation. An anonymized 
list of both included and non-included patients is maintained continuously 
[screening list].  
• Inclusion criteria are assessed.  
• Exclusion criteria are assessed.  
• If the patient meets the criteria, participation in the project is offered at the 
information visit [the visit during which the diagnosis is presented to the patient]. 
Written information is provided and time to reflec on the offer of study 
participation is provided.  
• Possible participants are contacted by telephone within one week, and those 
who wish to participate are immediately invited to an enrollment visit.  

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• Patient and accompanying relatives are informed both orally and in writing 
about the study’s purpose, background, execution and any side effects/possible 
harms of participation.  
• The patient is again offered time to reflect.  
• If the patient wishes to participate, a declaration of consent [must be] signed 
[by the patient].  
• Randomization is carried out to control or intervention group. The participant 
and the relative are informed via the project nurse about which group they have 
been allocated to. 
• The participant is registered in the Case Report Form (CRF).  
• The project nurse registers the participant's trial number [randomization 
number], which will be the only identification for the subsequent examinations 
(for reasons of blinding).  
• A blood sample for genetic analysis is taken from all participants.  
• Participants in the intervention group are offered an extra blood test if side 
effects develop within 2 weeks to 2 months after starting treatment. The dose is 
adjusted in relation to the serum concentration, if necessary the dosage and/or 
drug prescriped is changed. At the ½-year follow-up, one extra blood test is 
collected for all participants. The dosage is adjusted according to the serum 
concentration, if deemed appropriate an alternative [anti-dementia] drug is 
prescribed. 
• Participants belonging to the control group will not undergo any extra 
procedures, apart from a single blood test at the end of the project.  
• Approx. 30 patients will have a standard EEG with modified photo-block 
performed, if Donepezil treatment has not been started beforehand. These 
approx. 30 patients will have another standard EEG performed with the same 
modified photo-block approx. one year later in connection with the point below.  
• After one year, all participants are called for one additional visit. Here, a blood 
test is carried out on all participants, just as all participants are offered a dosage 
adjustment depending on the serum concentration, also if appropriate a change 
of preparation. The same clinical tests are carried out as during the preliminary 
examination [or enrollment visit]. All participants are asked about treatment 
compliance.  

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• If there a need for dose adjustment or possibly prescribtion change during the 
project, the decision will be made by the person in charge of the experiment 
[primary investigator] and not the project manager (PhD student). Practical 
handling is carried out in collaboration between the project manager and the 
project nurse.  
• A blinded calculation of the distribution of serum concentration, clinical scores, 
compliance and occurrence of side effects [is done by a statistician not affiliated 
with the study] 
 
Study visits 
• In connection with the information interview, as part of the general clinical 
course, the initial information about the project is provided and project 
information is provided.  
• Potential participants are contacted to participate in participate in one extra 
visit (inclusion interview with project manager) together with the relative.  
• If informed consent is obtained, one extra visit to the clinic 1 year after 
enrollment [“1 year follow-up visit”]. The visit ½ year after enrollment is part of 
the routine follow-up at RVD.  
 
End of study 
The study is ended on the date when the last participant (cf. power calculation) 
has been evaluated at the 1-year follow-up visit.  Subsequently, after registration 
and [external] monitoring [of data quality], data wil be transferred to blinded 
statistical analysis by a statistician. A need for future follow-up visits will be will 
be conducted at the GPs office.  
 
Study design  
Partly cross-sectional design, as the serum concentrations of anti-dementia 
drugs in the memory clinic population are correlated with clinical response. 
Partly prospective single-blind design (rater/rates of clinical function are blinded 
in relation to the patient's status in the control or intervention group, 
respectively), where participants have had administration of clinical tests [and 
questionaires to relatives] prior to enrollment, then followed clinically for one 
year with a follow-up data on the same scales. Blinding is upheld until data entry 

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is complete and has been processed. Data must be presented. Finally, a 
qualitative sub-study after the quantitative study has been completed with focus 
group interviews of relatives. In addition investigation of EEG coherence as a 
marker for cholinergic dysfunction in patients with Alzheimer's disease. 
Randomization  
All consecutive patients who meet the inclusion criteria and no exclusion criteria 
from the date the project initiation are offered participation. All patients who 
accepts and give consent, cf. the procedure described in the protocol, are 
assigned a project [allocation] number by lottery. In practical terms, this is done 
by inserting 150 project numbers (consecutive 1 to 110) into sealed envelopes 
before project initation. At the enrollment visit the participant chooses an 
envelope to open. The envelope contains a note with the project (allocation) 
number stipulation the allocation group of the participant.  
  
Blinding  
 
The project manager (PhD student) will be unaware of the result of 
randomization and serum concentrations until the study is completed and the 
results from the statistical analysis are returned. All study events that could 
potentially break blinding, including dose adjustment or extra blood tests, are not 
handled by the project manager. 
 
 
Methods and parameters  
 
The clinical tests and scales used in the study are all routinely included in the 
clinical assessment of patients with cognitive disorders. The only exception is 
the CGI, which is not an actual test, but simply a scale for semi-quantified rating 
of treatment response based on the existing knowledge of the patient. A regular 
blood test is carried out to determine serum concentrations and genetic analysis. 
The methods for serum concentration analysis and genetic analysis are 
described in the introduction to the protocol. Clinical symptoms and the results 
from the tests and scales used will be systematically recorded in the CRF, as will 

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information on co-morbidity, use of other medications, occurrence of side effects 
and treatment compliance.  
 
Focus group interviews with relatives 
 
When we assess the effect of a drug or the lack thereof, it is important not only 
to keep an eye on the purely biomedical causal relationships. In order to nuance 
the debate, it is relevant to analyze the experiences of the relatives in relation to 
the medication of the patient with Alzheimer's disease. This can lead to greater 
insights into what challenges might be present in relation to whether the drug is 
ingested as prescribed by the physician and whether it has the desired effect. 
Purpose: To describe relatives' perspective on treatment with anti-dementia 
medication in a Danish memory clinic. Method: a qualitative sub-study to gain 
insights and understanding of what challenges the relatives experience in 
connection with the patient's medication. The approach is phenomenological 
and hermeneutically inspired by Paul Ricour's philosophy of narratives (19), 
where openness to what the relative experiences (lifeworld) is essential.  
 
Participants: 15 relatives who are cohabiting spouses are included in the study. 
In qualitative research, 15 participants provide rich data (20). The participants 
are selected in collaboration with the Regional Knowledge Center for Dementia's 
team based on consideration of which relatives are able to reflect and express 
themselves on the subject. Qualitative research aims for the greatest possible 
variation in the sampling of informants (20), which is why the selection is made 
on the basis of differences in age, gender/relationship to the patient. 
 
Data collection for the qualitative study 
Data is produced and collected using focus group interviews. 3 focus group 
interviews are planned with 5 participants in each group. The size of the focus 
group can vary from 3-12 participants (21). A group of 5 participants will provide 
the opportunity to process the material in depth and uncover the relatives' 
attitudes and social negotiations during the interview. A group with more 
participants can be more difficult to moderate as an interviewer. During the 
interview, the interviewer must focus on being open, listening and appreciative, 
while at the same time being aware that all participants get the opportunity to 

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express themselves and be heard (21). The data collection is carried out using 
an interview guide (see appendix) with inspiration from Kvale and Brinkmann 
(22). The interview guide contains questions that can encourage the relatives to 
give rich descriptions of the problems and challenges. The interview guide is 
pilot tested before the 3 focus group interviews. Because of the interview guide, 
the interviews are structured by open questions related to the topic and thus not 
"free narration". The interviews are conducted in a conference room in the 
Neurological Outpatient Clinic in an undisturbed room.  
 
Data analysis:  
 
The relative interviews are transcribed, after which they are included in a 
Ricouer-inspired analysis and interpretation (19). The analysis is divided into 
three levels: the naive interpretation, the structural analysis and the critical 
interpretation. This takes place by first reading through the text material several 
times, where a comprehensive understanding is achieved. The text is then 
structured based on units of meaning, from which overarching themes are 
extracted. The structural analysis takes place in a dialectical process between 
explanation and understanding. Finally, the critical interpretation is carried out by 
comparing and discussing the themes found with existing relevant research 
literature.  
 
Monitoring treatment compliance  
Assessment of treatment compliance is carried out according to the memory 
clinic’s general clinical practice. This consists of participants and especially their 
relatives being interviewed by a physician and contact nurse at follow-up visits 
about whether the medication has been ingested regularly during the previous 
treatment period. If the medication is not ingested regularly as prescribed, this is 
included in the clinical assessment of effect and possibly side effects, and noted 
in the medical record. In the context of the study, this practice will be followed, 
i.e. the assessment is carried out at the control visits after ½ and 1 year of 
treatment. It will also be noted in the CRF whether the drug is ingested either 
"completely regularly", "regularly with less than 10 missed daily doses in 6 
months", "less regularly, with more than 30 missed daily doses in 6 months" or 
“irregularly with more than 60 missed daily doses in 6 months”.  

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Endpoints for the prospective study  
 
Primary endpoint  
When a participant has attended the 1-year follow-up visit the study participation 
is completed for that individual. When the last participant (as based on the powet 
calculation) has attended the 1-year follow-up visit quantitative data collection for 
the study will be complete.  
 
Quantitative outcome variables explored in the study  
• MMSE • ACE • DAD • CGI • NPI • serum concentrations [of eihter Donepezil or 
Memantine] • Genetic variants (liver enzymes, APOE, BchE-K/K) • Sex • co-
morbidity registration • compliance registration • EEG 
 
 
 
Statistics and power calculation  
Several studies and meta-analyses have shown that the clinical effect of anti-
dementia drugs can be detected for at least one year after initiation of treatment 
(23). The effect generally consists of a delay in the development of symptoms 
corresponding to 2 points on an MMSE scale after one year. We define 
optimized clinical effect as a decrease of less than 2 points on the MMSE scale 
in one year. This means that all participants whose score decreses 2 or more 
points in a year have a sub-optimal clinical effect, while participants whose score 
has a decrease of less than 2 points in a year has optimal clinical effect. It is 
emphasized that, as in general clinical practice, emphasis is not placed solely on 
the change in MMSE score when the effect is assessed. The assessment is 
based on an overall clinical assessment, where the CGI score is deemed 
suitable.  
Based on clinical database information, 15-20 newly referred patients eligible for 
study participation will likely be reffered to RVD per month. If it is assumed that 
approx. half will participate in the project, approx. 100 patients could be included 
in one year.  

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If it is assumed that <50% of the participants reach the recommended serum 
concentration and thus relevant clinical effect on standard dosing (cf. pilot 
study), and that this can be increased to 75% by dose adjustment after S 
concentration determination, the following calculation can be performed on the 
basis of the formula:  
N> (Z2α+Zβ)2 x (P1(1-P1) + P2(1-P2)) / (P1-P2)2 
 
where N is the number of necessary participants in each group, α is significance 
level 5%, β is the probability of type 2 error (strength is 1-β = 80%), P1 is dose 
optimization (optimized clinical effect) with regular dosing, P2 is dose 
optimization (optimized clinical effect) guided by S-level and possibly side 
effects.  
 
N > (1.96+0.84)2 x (0.5x0.5 + 0.75x0.25) / 0.252 = 7.84 x (0.25+0.1875) / 
0.0625 ~55  
 
In other words, 110 participants must be included in the project period in order to 
calculate the clinical utility of serum concentration measurements with the stated 
assumptions. Realistically this goal for participant recruitment can be reached 
withn a study period of one to two years.  
 
 
Risk assessment (risks and discomfort)  
 
Blood test  
For all participants in the study a single blood sample is collected for genetic 
analyses. For the intervention group, as stated, a single blood sample is also 
taken in case of side effects, and after ½ and 1 year. The blood sample is 
collected in a completely routine manner by a trained professional. The 
procedure is not associated with any other discomfort or inconvenience, apart 
from what is known for a routine blood test in a normal clinical context. For the 
control group, a blood sample is collected at the 1 year follow-up visit, when the 
CRF is closed for that participant.  

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MMSE, ACE, GDS, DAD, NPI  
These are simple and commonly used cognitive tests/scales, which are not 
associated with any kind of discomfort or discomfort for the subject (MMSE, 
ACE) or the relative (DAD, NPI). It can be slightly discomforting for a patient to 
be confronted with his or her cognitive deficits during a test, but the listed tests 
are all part of the clinical routine at RVD. In total, it will take a maximum of 30 
minutes to perform the MMSE and ACE, and roughly the same time to interview 
the relative for DAD and NPI. 
 
Side Effects and Adverse Events  
 
As by custom in ordinary clinical practice [in RVD], all patients and relatives are 
informed about potential side effects at the start of treatment and dose 
adjustments. Side effects are routinely reported to the contact nurse by 
telephone, in practice this happens on the same day or within a few days after 
side effects occur. In connection with the project, participants in the intervention 
group will receive the same information about side effects as in routine clinical 
practice, supplemented by corresponding information about the need to report 
by telephone to the contact nurse in the event of side effects. Furthermore, all 
participants are asked about side effects at the ½-year and 1-year follow-up 
visits. In each individual case, an assessment will be made by one of the clinic's 
specialists (senior physicians) as to whether side effects should lead to dose 
reduction or discontinuation. All reported side effects are entered into the 
participant's CRF. As by clinical routine, all participants and relatives will be 
encouraged to contact the contact nurse by telephone in case of any suspicion 
of side effects. If the reported side effects are deemed to be related to the 
medicine, common practice is to either switch to an alternative anti-dementia 
drug or reduce the dose. It depends on a medical assessment whether there is a 
basis for changing the preparation or reducing the dose. In all such cases, in 
connection with the project, a blood test will be offered to determine the serum 
concentration. Common side effects (in 1-10% of subjects): Less than 5% of 
patients who have a blood test will develop a minor hematoma at. the insertion 
site [of the needle]. This side effect is benign and will disappear without any 
treatment. Slight pain at the injection site itself and subsequent mild soreness 
may occur. It may occur that participants who are uptitrated in dose on the basis 
of low serum concentrations will develop side effects. These are mainly mild 
gastrointestinal side effects, and in rare cases cardiac side effects. Occurrence 

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of such potential side effects will be closely monitored and the clinic will 
immediately respond accordingly. Apart from the time consumption of the 
cognitive tests and interviews, there are no other known side effects of these 
studies. There are no side effects or significant risks when recording standard 
EEG with modified photo-block. The participants can at any time during the EEG 
recording refuse to complete this study, which must then be complied with by the 
person in charge of the experiment. In this context, an adverse event (AE) is 
defined as: any adverse event in a patient or subject in a clinical trial after 
treatment with a medicinal product, without necessarily having a connection 
between this treatment and the adverse event. 
 
 
Registration of unwanted events  
 
All of the following information is recorded by the physician in charge of the 
study for each adverse event:  
• Complete description of the unwanted event.  
• Date and time of onset.  
• Date and time of resolution.  
• The severity of the incident must be assessed by the physician responsible for 
the study [primary investigator] according to the definitions below. 
• Whether or not it is a serious incident.  
• Whether the incident was expected or not.  
• The relationship to the procedure, which must be assessed by the physician 
responsible for the study according to the definitions below.  
• Action taken (if applicable).  
• Result and information for all further follow-ups. Definitions of adverse event 
severity. 
 
The following are the only definitions used to describe the severity of adverse 
events:  

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• Mild – The adverse event does not interfere with the subject's daily routine. It 
causes slight discomfort.  
• Moderate – The adverse event interferes with some aspects of the subject's 
daily routine.  
• Severe – The adverse event causes an inability to perform the subject's daily 
routine. Only one definition of severity is used for each adverse event (eg a 
statement such as "mild/moderate" is not acceptable). Moderate or serious 
adverse events are considered very unlikely in the present project. 
 
 
Serious adverse events  
 
A serious adverse event (SAE) is understood in this context as all medical 
occurrences, such as:  
• results in death, 
• is life-threatening, 
• requires hospitalization or extension of an existing hospital stay, results in 
permanent or significant disability, or inability to work. 
Adverse events that meet all of the following criteria:  
• Unexpected (i.e. inconsistent with common knowledge about potential side 
effects)  
• There is at least a reasonable possibility that there is a causal connection 
between the incident and the procedure will be classified as Suspected 
Unexpected Serious Adverse Reactions (SUSAR).  
The assessment of the relationship between an adverse event and the 
procedure (probable, possible, unlikely, none, cannot be assessed) is a clinical 
decision based on all available information. Factors that should be considered in 
the relationship assessment include the temporal sequence from the time of the 
procedure, improvement upon cessation (withdrawal) of the procedure, 
underlying concurrent competing illnesses, concurrent medical procedures or 
treatment, known pattern of response to methods used, exposure to physical 
and/or psychological stress. The physician in charge of the study, senior doctor 
[consultant] Peter Høgh, is responsible for evaluating whether an adverse event 

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is serious or not and, in case of doubt, relevant information will be obtained and 
reported in detail. The product summaries for Donepezil and Memantine are 
used to assess whether a serious related side effect is expected. All adverse 
events in connection with the experiment will be registered and reported, cf. 
legislation, to the authorities. The sponsor is required to ensure that all 
information about SUSARs, which are fatal or life-threatening, is registered and 
reported to the Danish Medicines Agency as soon as possible and no later than 
7 days after the sponsor has become aware of such a suspected side effect. No 
later than 8 days after the report, the sponsor must notify the Danish Medicines 
Agency of all relevant information about the sponsor's and investigator's follow-
up to the report. All other SUSARs must be reported to the Danish Medicines 
Agency no later than 15 days after the sponsor has become aware of them.  
Monitoring subjects with adverse events  
 
All adverse events that occur during the study must be monitored and followed 
until they have either resolved, returned to normal or baseline values, reached 
clinical stability, or been shown to be unrelated to the project. 
 
 
Ethical considerations  
 
The Study will be conducted in accordance with the Helsinki Declaration of 
1984, modified at the 41st World Congress in Hong Kong 1989. The study has 
been approved by the local Scientific Ethics Committee (SJ-596) and the Danish 
Data Protection Agency. Participants will only be included after full written and 
verbal information and provision of informed written consent. Participants can 
withdraw from the study at any time without reason, and without this affecting 
any future treatment. Only participants who are deemed to be able to 
understand the information and independently consent to study participation are 
included. This also applies to patients with moderate to severe dementia. It may 
happen that, in connection with the blood sampling and dose regulation (up-
adjustment), inappropriate side effects appear temporarily, mainly in the form of 
gastro-intestinal discomfort (indigestion, abdominal pain, loose stools) and heart 
rhythm disturbances. Should this occur, the project manager will arrange for an 
immediate dose reduction and, if cardiac problems are suspected, for an 
emergency ECG to be taken. Depending on the nature and severity of the 

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discomfort, an appropriate medical response is given. It may also happen that a 
participant in the intervention group shows signs of unusual worsening of their 
dementia at the ½ or 1-year visit. Here, it is the responsibility of the project 
manager to screen the patient for co-morbidity (possibly in collaboration with his 
or her GP), and to ensure that the participant is offered combination treatment 
(AchE inhibitor + Memantine), especially if the S-value of the current treatment is 
at the recommended level . The participant continues regardless of this in the 
protocol (if it occurs at the ½-year visit), unless he or she express a wish to 
withdraw from the study. In addition to determining serum concentrations, the 
blood samples are used for genetic analysis of variants of liver enzymes 
[cyp2D6], APOE and BchE-K/K. Participants or relatives do not get specific 
feedback on the results of these analyses, which will only be used to assess the 
genetic variation in the population, as well as its significance in relation to the 
metabolism of anti-dementia drugs. It is our opinion that the expected 
disadvantages, discomfort and risks for study participants are small and do not 
outweigh the importance of the expected results. 
 
 
Approval and monitoring by external authorities  
In accordance with current regulations, the protocol was approval by the 
Regional Scientific Ethics Committee for Region Zealand and the Danish Data 
Protection Agency [Datatilsynet]. The project was approved by the Danish 
Medicines Agency and registered at www.clinicaltrials.gov. It will also be 
monitored externally by the GCP unit at Copenhagen University Hospital. 
 
Insurance  
All complaints during the study or possible damage to the test subjects will be 
handled in accordance with the Danish law on access to complaints and 
compensation within the healthcare system. The subjects are covered by the 
[Danish] Patient Insurance [Danish: ‘Patientforsikringen’].  
 
Time schedule  
 

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The first participant was recruited on 12 February 2020. The last participant was 
recruited on 24 February 2022. Completion of the last trial participant is 
expected to take place in early/mid March 2023. Apart from extended participant 
recruitment, the project is progressing at the time of writing (19 April 2022 ), 
according to plan without deviations from current protocol. 
 
Publication and storage of data and biological material.  
 
Blood samples used to measure the serum concentrations are destroyed by the 
laboratory immediately after the analyses. This applies to all blood samples 
taken - no biological material is stored or used in a biobank, the blood samples 
are destroyed immediately after the stated analyzes have been carried out. The 
Act on the processing of personal data will be complied with. All data will be 
handled confidentially and published in anonymized form. Raw data and 
randomization codes will be stored in anonymized form under secure conditions 
for 15 years after the end of the trial. Study results will be submitted to 
recognized international journals and both positive and negative results will be 
published.  
The attempt is expected to result in 4-5 publications with the following order of 
authors: Michael Fischer, Ivan Zibrandtsen, Peter Johannsen, Jan Borg 
Rasmussen, Jens Borggaard Larsen and Peter Høgh. Regarding the qualitative 
partial study, the following order of authors is expected: Susanne Kristiansen, 
Karen Christiansen, Peter Høgh, Malene Beck. Regarding measurement of 
compliance, the following order of authors is expected: Susanne Kristiansen, 
Michael Fischer, Ivan Zibrandtsen, Peter Johannsen, Jan Borg Rasmussen, 
Jens Borggaard Larsen and Peter Høgh. Related article describing correlations 
between quantitative and qualitative data for compliance: Susanne Kristiansen, 
Michael Fischer, Karen Christiansen, Malene Beck, Peter Høgh. Regarding 
articles that describe the connection between EEG coherence and cholinergic 
function, the following author order is expected: Christian Sandøe Musaeus, 
Michael Fischer, Ivan Zibrandtsen, Susanne, Kristiansen, Peter Johannsen, Jan 
Borg Rasmussen, Jens Borggaard Larsen, Troels Wesenberg Kjær/Peter Høgh 
Regarding articles that describe other possible connections between EEG and 
cholinergic function, the following author order is expected: Christian Sandøe 
Musaeus, Michael Fischer, Ivan Zibrandtsen, Susanne, Kristiansen, Peter 
Johannsen, Jan Borg Rasmussen, Jens Borggaard Larsen, Troels Wesenberg 
Kjær/Peter Høgh 

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Project economy  
 
Budget (expected number of participants 110):  
Salary project nurse: 1 hour per participants (110 in total) for screening and 
inclusion, data registration, practical aspects of transport, etc.) 110 study days of 
1 hour (conversation, registration, interviews) 100 hours for preparation, 
execution, analysis and article writing of a qualitative focus group interview study 
A total of 320 hours of DKK 260 (incl. holiday/pension) DKK 83,200  
Salary project secretary: 165 examinations of 1 hour (registration, transport, 
writing notes) A total of 165 hours of DKK 210 (incl. holiday/pension) DKK 
34,650  
Salary project manager: (3 years: 592,630/year, incl. holiday pay/pension) 110 
inclusion visits 110 1-year visits. Preparation of manuscripts + thesis 3-year PhD 
tax (50,000 x 3) DKK 1,927,890  
Analyzes of serum concentrations and genetic analyzes (100 genetic + 
estimated 200 S determinations) and EEG studies DKK 200,000  
Transport costs 110 patient transports of DKK 200/each: DKK 22,000  
Transport of samples to the laboratory DKK 20,000  
Travel and other expenses related to presentation of research results DKK 
150,000  
Assistance by statistician DKK 50,000  
Total of DKK 2,487,740  
 
Disadvantage compensation [Danish: ‘ulempegodtgørelse’]  
Disadvantage compensation is not paid to the participants, but the transport is 
paid (cheapest possible).  
 
Responsible department/Study site: 
 Department of Neurology Zealand University Hospital Vestermarksvej 11 DK-
4000 Roskilde Denmark.  

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Responsible professionals 
Michael Fischer Peter Hogh Ivan Zibrandtsen Peter Johannsen Jan Borg 
Rasmussen Susanne Kristiansen Malene Beck 
 
 
 
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Study protocol version 1.9 
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(Date of translation March 28, 2023) 
8. Hefner G, Brueckner A, Hiemke C, Fellgiebel A. Therapeutic drug 
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MONANTI 
Study protocol version 1.9 
April 19, 2022  
 
 
(Date of translation March 28, 2023) 
Lay summary  
MONitoring of ANTI-dementia drugs by determining serum concentrations, 
importance of monitoring for the incidence of side effects, clinical effect and 
compliance. (Measurement of the amount of drug in the blood for drugs against 
dementia with the aim of improving the effect and reducing side effects)  
Project initiator, sponsor, responsible physician and contact person: Peter Høgh, 
senior physician, PhD Department of Neurology Zealand University Hospital 
(SUH) Vestermarksvej 11 DK-4000 Roskilde Denmark  
Background  
Clinical experience shows that there is great variation in the occurrence of side 
effects and clinical effect when using anti-dementia drugs. Thus, some patients 
quickly experience side effects even at a small dose, while others have very 
limited or no detectable clinical effect. There may be several reasons for this, but 
one possible explanation may be that the great variety is due to differences in 
the concentration of the drugs in the blood. The recommended concentration 
range (the recommended amount in the blood) is relatively narrow. It can 
potentially be of great importance to monitor (manage) the treatment guided by 
blood concentration measurements because side effects (especially from the 
gastrointestinal tract) may occur with even minor excesses of the upper limit of 
the concentration range, and because a significant dose-effect correlation exists. 
There is very limited knowledge about how the blood concentration on standard 
dosage of anti-dementia drugs is distributed in a general clinical population, just 
as it is unknown whether monitoring the blood concentration can reduce the 
occurrence of side effects and perhaps also increase the clinical effect. The 
reasons for the observed variation can be attributed to several factors, such as 
diagnostic uncertainty, genetic variation, sex differences and variation in patient 
compliance.  
Purpose  
 
The aim of the study is to describe the variation in blood concentration of anti-
dementia drugs in a general memory clinic and to explore the extent to which a 
standard drug dosage results in blood drug concentration within the 
recommended interval. Furthermore the aim is to assess whether the incidence 
of side effects and clinical effect can be optimized through monitorering the 
blood concentration and to clarify causal mechanisms for the observed variation. 
It is the goal to provide a detailed description of patient compliance with the use 

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April 19, 2022  
 
 
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of anti-dementia drugs, reasons for varying compliance, and whether 
compliance can be improved by monitoring blood concentration. In addition, it 
will be investigated whether electroencephalography can be used to monitor the 
effect of anti-dementia drugs. 
The genetic studies  
As mentioned, all participants in the study will have a regular blood samples 
collected for genetic analyses. Individual differences in our genes may have a 
major impact on how the body reacts to drugs. In connection with the present 
study, we are particularly interested in genetic differences in relation to so-called 
liver enzymes, i.e. mechanisms in the liver which are important for how quickly 
the drugs are metabolized in and excreted from the body. In addition, we would 
like to analyze the gene for a protein (egg white) which has previously been 
shown to be important for the effect of drugs (apolipoprotein E). In the long term, 
the significance of this may be that, through genetic analyses, it becomes easier 
to adapt treatment and dose to the individual patient. As it is still uncertain what 
the genetic analyzes mean for the individual patient, participants will not be 
individually informed of the results of the genetic examinations.  
Hypothesis  
It is hypothesized that there is greater variation in the blood concentration on the 
standard [drug] dose in a general clinical population than [previously] assumed. 
Furthermore, it is hypothesized that monitoring the blood concentration is 
important both for the incidence of side effects, efficacy and compliance. Genetic 
variation has potentially great importance for the turnover and effect of the 
medicines, and genetic analyzes can have a role in relation to individualization 
and optimization of the treatment. In addition, our hypothesis is that 
electroencephalography can be used to monitor the effect of anti-dementia 
drugs.  
Importance  
Potentially, the results of this project can contribute to a far more rational use of 
the usual anti-dementia drugs, so that the occurrence of side effects is reduced, 
the clinical effect is improved, including that patient compliance is improved.  
Recruitment  
The participants are recruited from the population of patients referred to the 
Regional Knowledge Center for Dementia (RVD), Zealand's University Hospital. 
In order to obtain a [study] population as broad as possibl all patients who are 
eligible for participation during the study period are offered participation. 

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Study protocol version 1.9 
April 19, 2022  
 
 
(Date of translation March 28, 2023) 
Currently, approx. 300 patients are reffered to RVD annually, of whom more 
than half fall are eligible for participation. Based on a power calculation, it is 
deemed necessary to recruit approx. 100 participants. It is estimated that this 
can be achieved within a 1 year period.  
Design  
The study is intended to be conducted as a prospective single-blind randomized 
controlled study with a follow-up period of one year. This means that the 
professional who carries out tests and assessment of clinical effect as well as 
registration of the occurrence of side effects is unaware of whether the patient is 
in the control or intervention group. 
 
 
Side effects  
Common side effects (in 1-10% of the test subjects): A small proportion of the 
patients who have their dose increased on the basis of the blood concentration 
determination will be able to develop side effects, mainly from the 
gastrointestinal tract in the form of nausea, abdominal pain or loose stools. Mild 
headache and dizziness may also occur. The side effects are benign and will 
disappear after dose reduction without any treatment. Uncommon side effects 
(in 0.1-1% of participants): supposedly less thaan 1% may have transient 
cardiac side effects after increasing the dose based on the blood concentration 
measurement, typically problems associated with bradycardia (dizziness, 
fatigue, general malaise). These inconveniences are generally of a completely 
benign nature, and disappear quickly when the dose is reduced. Rare side 
effects (in 0.01-0.1% of participants) and very rare side effects (in less than 
0.01% of participants): Transient liver effects, muscle cramps, heart block and 
muscle stiffness are seen in rare cases. Likewise, these side effects are 
generally reversible upon dose reduction.  
Ethical considerations  
The study will follow the Helsinki declaration of 1984, which was modified at the 
41st World Congress in Hong Kong 1989. The study is approved by the 
Regional Scientific Ethics Committee for Region Zealand and the Data 
Protection Authority (we assess that the study is covered by Region Zealand's 
umbrella approval from the Data Protection Authority, and the study has been 
registered accordingly). Participants will only be included after full written and 
oral information and written informed consent. The participants can withdraw 

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from the study at any time without reason, and without it affecting current or 
possible future treatment. It is our opinion that the expected disadvantages, 
discomfort and risks for study participants are partly very limited and do not 
outweigh the importance of the expected results. We do not believe that there 
are any scientific ethical issues associated with participation in this trial other 
than the possible side effects. Eg. no information is obtained about the individual 
participant, which could be problematic for him or her. The study participants 
have no financial interest in [participation] in the study.  
Time schedule  
The first participant was recruited on February 12, 2020. The last participant was 
recruited February 24, 2022. The expected date of completion for the last 
participant is by mid-March 2023.  
 
No inconvenience allowance is paid to the subjects, but the subjects are paid 
transport costs related to the visit after one year.  
Publication  
All data will be handled confidentially and published in anonymized form. Raw 
data and randomization codes will be stored in anonymized form under secure 
conditions for 15 years after the end of the study. Study results will be submitted 
to recognized international [scientific] journals, and attempts are made to publish 
both positive and negative results. The study is expected to result in a minimum 
of 5-6 publications.