Transmural Collaborative Care Model for Cardiovascular Risk Management (CVRM) and Medication Review for Patients Using Antipsychotics: a Cluster Randomised Stepped Wedge Trial
Phase: NA
Conditions: Mental Disorders, Severe
Sponsor: Radboud University Medical Center

ZonMw GGG Complexe interventie studies Project ID 10140021910502 
TACTIC 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH PROTOCOL 
 
 
Transmural collaborative care model for cardiovascular risk 
management and medication review for patients using 
antipsychotics (TACTIC): a cluster randomised stepped wedge trial 
 
 

ZonMw GGG Complexe interventie studies Project ID 10140021910502 
TACTIC 
 
 
 
PROTOCOL TITLE ‘Transmural collaborative care model for cardiovascular risk 
management and medication review for patients using antipsychotics: a cluster randomised 
stepped wedge trial’ 
 
Protocol ID 
10140021910502 
Short title 
TACTIC trial 
EudraCT number  
n.a. 
Version 
1 
Date 
28-07-2022 
Coordinating 
investigator/project leader 
 
K.J. van den Brule-Barnhoorn, MSc MD 
Department of Primary and Community Care 
Radboud university medical centre 
P.O. Box 9101, Internal Code 117 
6500 HB Nijmegen 
The Netherlands 
Tel.: +31 24 36 13 237 
E-mail: karlijn.vandenbrule-
barnhoorn@radboudumc.nl 
Principal investigator (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
 
Dr. E. Bischoff, MD PhD 
Department of Primary and Community Care 
Radboud university medical centre 
P.O. Box 9101, Internal Code 117 
6500 HB Nijmegen 
The Netherlands 
Tel.: +31 24 36 13 237 
E-mail: erik.bischoff@radboudumc.nl 
 
 
Junior researcher 
Drs KM Jakobs 
Department of Primary and Community Care 
Radboud university medical centre 
P.O. Box 9101, Internal Code 117, 
6500 HB Nijmegen 

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The Netherlands 
Tel.: 00 31 24 36 13 237 
Email: Kirsti.Jakobs@radboudumc.nl 
kjakobs@onzehuisartsen.nl 
Research team member from the 
department of Primary and 
Community Care 
Dr MCJ Biermans 
Department of Primary and Community Care 
Radboud university medical centre 
P.O. Box 9101, Internal Code 117, 
6500 HB Nijmegen 
The Netherlands 
Tel.: 00 31 24 36 13 237 
Email: Marion.Biermans@radboudumc.nl 
Research team member from the 
department of IQ healthcare 
Dr J van Lieshout 
Department of IQ healthcare 
Radboud university medical centre 
Email: Jan.vanLieshout@radboudumc.nl 
Psychiatrist-researcher/advisor 
from the department of 
Psychiatry 
Dr J Janzing 
Department of Psychiatry 
Radboud university medical centre 
Postbus 9108, 
6500 HB Nijmegen 
The Netherlands 
Tel.: 00 31 24 36 66 495 
Email: Joost.Janzing@radboudumc.nl 
Pscyhiatrist-researcher/advisor 
form the department of 
Psychiatry University Medical 
Centre Utrecht 
Prof. dr. W. Cahn 
Department of Psychiatry 
Heidelberglaan 100 
3584 CX Utrecht 
The Netherlands 
Tel. 00 31 88 755 5555 
Email: w.cahn@umcutrecht.nl 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Radboudumc 
 

ZonMw GGG Complexe interventie studies Project ID 10140021910502 
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Subsidising party 
ZonMw (Goed Gebruik Geneesmiddelen open ronde 
9) 
Independent expert 
Mark van der Wel 
Wijkgezondheidscentrum Lindenholt 
Horstacker 1644  
6546 EX Nijmegen  
Tel:  024 - 378 18 18 / 06 22 63 96 05 
 
Email: Mark.vanderWel@radboudumc.nl 
 
 
Laboratory sites 
n.a. 
 
 
Pharmacy 
n.a. 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
 
Head of Department: 
Prof. Dr. Aura Timen 
Department of Primary and Community 
Care  
 
 
 
Principal Investigator: 
Dr. Erik Bischoff 
Department of Primary and Community 
Care 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
OBJECTIVES ................................................................................................................15 
2. 
STUDY DESIGN ...........................................................................................................15 
3. 
STUDY POPULATION ..................................................................................................16 
3.1 
Setting and population ............................................................................................16 
3.2 
Inclusion criteria .....................................................................................................17 
3.3 
Exclusion criteria ....................................................................................................17 
3.4 
Sample size calculation ..........................................................................................17 
4. 
TREATMENT OF SUBJECTS .......................................................................................18 
Investigational treatment ...................................................................................................18 
5. 
METHODS ....................................................................................................................19 
5.1 
Study parameters/endpoints ...................................................................................19 
5.1.1 
Main study parameters ....................................................................................19 
5.1.2 
Secondary study parameters ...........................................................................20 
5.2 
Randomisation, blinding and treatment allocation ..................................................21 
5.3 
Study procedures ...................................................................................................21 
5.4 
Withdrawal of individual subjects ............................................................................23 
5.5 
Replacement of individual subjects after withdrawal ...............................................23 
5.6 
Follow-up of subjects withdrawn from treatment .....................................................24 
5.7 
Premature termination of the study .........................................................................24 
6. 
SAFETY REPORTING ..................................................................................................24 
6.1 
Temporary halt for reasons of subject safety ..........................................................24 
6.2 
AEs and SAEs ........................................................................................................24 
6.2.1 
Adverse events (AEs) ......................................................................................24 
6.2.2 
Serious adverse events (SAEs) .......................................................................24 
6.3 
Follow-up of adverse events ...................................................................................25 
6.4 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ..................................25 
7. 
STATISTICAL ANALYSIS .............................................................................................25 
7.1 
Primary study parameters ......................................................................................25 
7.2 
Secondary study parameter(s) ...............................................................................27 
7.3 
Other study parameters ..........................................................................................28 
8. 
ETHICAL CONSIDERATIONS ......................................................................................28 
8.1 
Regulation statement .............................................................................................28 
8.2 
Recruitment and consent........................................................................................28 
8.3 
Objection by minors or incapacitated subjects (if applicable) ..................................29 
8.4 
Benefits and risks assessment, group relatedness .................................................29 
8.5 
Compensation for injury ................................... Fout! Bladwijzer niet gedefinieerd. 
9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .............................30 
9.1 
Handling and storage of data and documents ........................................................30 
9.2 
Amendments ..........................................................................................................31 
9.3 
Temporary halt and (prematurely) end of study report ............................................31 
9.4 
Public disclosure and publication policy ..................................................................31 

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10. 
REFERENCES ..........................................................................................................32 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application 
form that is required for submission to the accredited Ethics Committee; 
in Dutch: Algemeen Beoordelings- en Registratieformulier (ABR-
formulier) 
AE 
Adverse Event 
AP 
Antipsychotic (medication) 
AR 
Adverse Reaction 
BMI 
Body Mass Index 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CRSWT 
Cluster randomised stepped wedge trial 
CV 
Curriculum Vitae 
CVD 
Cardiovascular disease 
CVR(M) 
Cardiovascular risk (management) 
DSMB 
Data Safety Monitoring Board 
EMR 
Electronic medical record 
EQ-5D-5L EuroQol 5 Dimensions 5 Levels questionnaire for quality of life 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
GP 
General practitioner/practice 
IC 
MDM 
Informed Consent 
Multidisciplinary meeting 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
MHI-5 
Mental Health Inventory 
QRISK3 
Predicted 10-year cardiovascular risk score  
(S)AE 
(Serious) Adverse Event  
SF-36 
36-item Short Form health survey for quality of life 
SMI 
Severe mental illness 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 

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company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it, is 
not regarded as the sponsor, but referred to as a subsidising party. 
TACTIC 
Transmural collaborative care model for cardiovascular risk 
management and medication review for patients using antipsychotics 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; 
in Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
Rationale: The use of antipsychotic medication is increasing worldwide (1-3). It is well 
established that patients with a severe mental illness and patients treated with atypical 
antipsychotics have excess metabolic dysfunction (4) and are at an increased risk of 
cardiovascular disease (4, 5). Currently, monitoring of usage and effects of antipsychotic 
treatment (5-7), as well as cardiovascular risk screening in patients with severe mental 
illness or antipsychotic treatment (6) is not sufficient. General practitioners experience 
barriers regarding knowledge, collaboration with psychiatrists, and patient compliance (6). To 
overcome these barriers, the primary care cooperative Onze Huisartsen Arnhem BV 
developed in close collaboration with Radboudumc a transmural collaborative care model for 
cardiovascular risk management and medication review for patients using atypical 
antipsychotics in general practice (TACTIC). We have recently explored the feasibility of 
TACTIC in a pilot study (CMO 2020-7240) and used our findings to optimize the intervention 
for assessment of its effectiveness. 
 
Objective: To assess the effectiveness of TACTIC regarding predicted cardiovascular risk 
and mental quality of life. The secondary objective is to assess its cost-effectiveness. 
 
Study design: Incomplete cluster randomised stepped wedge trial. 
 
Study population: Adult patients (>25yrs) from general practices, using atypical 
antipsychotics prescribed by their general practitioner. 
 
Intervention: TACTIC is a one-time transmural intervention comprising three steps: 1) online 
information video to inform patients about the cardiovascular risks of antipsychotic use and 
about the procedures of the multidisciplinary meeting, 2) a multidisciplinary meeting with the 
patient to review his or her antipsychotic use and cardiovascular risk and to provide tailored 
treatment advice, and 3) a follow-up contact with the general practitioner to translate the 
treatment advice into an individualised action plan through shared decision making. TACTIC 
complements the current regular cardiovascular risk management programme for primary 
prevention of cardiovascular diseases of the primary care cooperative Onze Huisartsen BV 
that has been based on the specific guidelines of Dutch College of General Practitioners 
(NHG) and has been used in the Arnhem region since several years 
 
Main study parameters/endpoints: Change in cardiovascular risk, as measured with the 
QRISK3 score, and change in mental quality of life, as measured with the MHI5 
questionnaire. 

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Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
 
Burden and risk associated with the intervention: 
Patients who are eligible and who want to participate in the study will be included in the 
regular cardiovascular risk management programme of the Arnhem primary care 
cooperative. This programme includes, according to current Dutch guidelines, 1 to 5 
consultations with the GP and/or the practice nurse in which physical examination, i.e. 
measuring blood pressure and body weight, and blood and urine sample collection will take 
place. The frequency depends on the severity of the cardiovascular risk and the 
corresponding follow-up period. On top of the regular cardiovascular care patients who 
participate in the study will also receive the three-step TACTIC intervention. This is a one-
time intervention. Patients who are eligible but who do not want to participate in the study will 
be included in the regular cardiovascular risk management programme, but will not receive 
the TACTIC intervention.  
 
There is a potential risk associated with participation, as patients whose antipsychotic 
medication is altered during participation may destabilize mentally. However, this risk is 
expected to be low. Changes in medication will only take place after this advice has been 
given in Step 2 (i.e. multidisciplinary meeting including the patient’s GP, a psychiatrist, and 
the patient self) and has been followed in Step 3 (i.e. shared decision making between the 
patient and his/her GP). The advice to change medication will only be given in Step 2 as the 
psychiatrist, the GP, and the patient consider this option to be safe. Besides, the advice will 
only be followed in Step 3 if both patient and GP feel safe with it. In addition, TACTIC 
contains precautionary measures to prevent destabilisation, i.e. any change in antipsychotic 
medication is accompanied with the advice of follow up consultations with the general 
practitioner or mental health nurse, and all patients who alter their antipsychotic medication 
will have a crisis prevention plan to ensure safety. 
 
The potential benefit of participation is high, as changes in antipsychotic medication and 
appropriate cardiovascular risk screening and management will result in decreased 
cardiovascular risk. 
 
Burden and risk associated with outcomes measurements: 
Patients fill in questionnaires at baseline and every 5 months during follow-up. Based on our 
experiences in the pilot study, we expect that it will take approximately 20 minutes to fill in 

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the questionnaire. For the assessment of the primary outcome QRISK3 score routinely 
collected data from the cardiovascular risk management programme, i.e. blood pressure, 
body weight, smoking behaviour, and blood cholesterol and glucose levels. 

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INTRODUCTION AND RATIONALE 
Antipsychotic medication is effective for a variety of psychiatric disorders, such as 
schizophrenia, bipolar disorder, schizoaffective disorder, or major depressive disorder. 
Remarkably, however, a large proportion of patients on antipsychotics do not have a 
diagnosis of a severe mental illness (6). Jakobs et al. found that, among patients in general 
practices who use antipsychotic medication, up to 68% did not have a registered diagnosis of 
a severe mental illness. These patients are using antipsychotics off-label. Reasons for off-
label prescription can be anxiety, dementia, or sleep- and personality disorders. 
 
The use of antipsychotic medication is increasing worldwide (1-3), but this is not without risk. 
It is well established that patients with a severe mental illness and patients treated with 
antipsychotics have excess metabolic dysfunction (4) and are at an increased risk of 
cardiovascular disease (4, 5). The increased risk of cardiovascular disease is multifactorial. 
Patients with a severe mental illness or on antipsychotic medication tend to have a high 
incidence of lifestyle risk factors, such as poor diet, lack of exercise, stress and smoking, 
besides possible genetic susceptibility (8, 9). Furthermore, there is evidence that people with 
severe mental illness are less likely to receive standard levels of care (5). 
Moreover, antipsychotics can cause weight gain, hypertension, glucose intolerance and 
dyslipidaemia, and can cause cardiac toxicity (10).  
 
Although these factors may contribute as independent risk factors for cardiometabolic 
dysfunction and cardiovascular disease, having a severe mental illness itself is also an 
important independent risk factor (5), as well as antipsychotic treatment, particularly for 
certain drugs and for vulnerable patients (9). In a large prospective open cohort study in 
England, severe mental illness was associated with a 14% increased risk for women and a 
13% increased risk for men (11). This was independent of the risk associated with atypical 
antipsychotics. Atypical antipsychotics were associated with an increased cardiovascular risk 
of 29% in women and 15% in men. In addition, antipsychotics cause a dose-related 
increased risk of sudden cardiac death (12). All in all, this results in a 8-20 years reduction in 
life expectancy (11). 
 
In the Netherlands, it is common that psychiatrists initiate treatment with antipsychotic 
medication, but when patients reach a stable state, care is shifted to the general practice. 
This includes monitoring of treatment effects, adherence and side effects, as well as 
management of cardiovascular risk. However, monitoring of usage and effects of 
antipsychotic treatment as well as cardiovascular risk screening in patients with severe 
mental illness or on antipsychotic treatment is currently not sufficient (5-7). Lifestyle factors 

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are relatively easy to measure, but are barely considered for screening. Baseline testing of 
important physical parameters, prior to starting antipsychotic medication, is insufficiently 
performed (5). This is a serious aspect that needs to be addressed, even more since the 
adverse effects of antipsychotic medication may also impair the patient’s adherence to 
treatment (13). 
 
The increased cardiovascular risk in patients taking antipsychotic medications can be treated 
in a primary care setting, with lifestyle counselling as well as pharmacological interventions, 
in the same way as managing cardiovascular risk in other patient groups. The advantage of 
cardiovascular risk management in primary care is that general practices are very 
experienced in providing such care and are able to reach a broad population and detect the 
patients at risk. This also includes patients with mental disorders using antipsychotics who 
are in a stable phase and, as a consequence, are not under regular specialist care. 
However, general practitioners are generally not as familiar with the (long-term) side effects 
of antipsychotic use as psychiatrists, which may lead to a lack of follow-up. They often renew 
prescriptions that were initiated by the psychiatrist, without thorough check up. Furthermore, 
general practitioners and psychiatrists often do not collaborate in reducing cardiovascular 
risk in patients using antipsychotics. All healthcare professionals must learn to recognize the 
factors indicating antipsychotic-related cardiometabolic problems to prevent progression to 
type II diabetes, cardiovascular events and premature death (9). 
 
To address both problems of potential overtreatment with antipsychotic medication and 
undertreatment of cardiovascular risk, we have developed a one-time transmural 
collaborative care model for structured antipsychotic medication review and cardiovascular 
risk management for patients in general practices (TACTIC). During TACTIC, the general 
practitioner closely collaborates with the patient, a carer (optional), a patient coach with lived 
experience, and a psychiatrist in a structured multidisciplinary meeting. This review results in 
tailored advice on antipsychotic treatment (continuation, lowering the dosage, switching to 
other medication, or discontinuation) and management of cardiovascular risk (e.g. losing 
weight, treatment of hypertension, regulation of cholesterol). Subsequently, the advice is 
converted to an individualised action plan through shared-decision making by GP and 
patient.  
 
We have recently conducted a pilot study in which we assessed the feasibility of TACTIC 
(CMO 2020-7240). We followed three general practices who provided the TACTIC 
intervention to 28 patients in total. The feasibility appeared to be high. Based on the positive 
experiences and after the necessary adjustments in the procedures of the 3-step TACTIC 

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approach, the primary care cooperative decided to continue with TACTIC in an 
implementation process including a cluster randomised controlled trial. The pilot study was 
not powered nor designed to detect a statistically significant and clinically relevant difference, 
but did show a trend towards a positive health benefit regarding cardiovascular risk, 
particularly in patients with a moderate to high baseline QRISK3 score, i.e. score ≥ 5%. Pre-
post analyses showed a decrease in predicted 10-year cardiovascular risk of 1.9% (SD 3.4) 
(unpublished data). Qualitative analysis, including individual interviews with patients and 
carers, and focus groups with healthcare professionals, gave us input to optimize the 
TACTIC procedures prior to assessing its effectiveness in the upcoming cluster RCT 
(unpublished data). 
 
To our knowledge, TACTIC is the first intervention focussing on both medication review and 
primary prevention of cardiovascular disease in patients on atypical antipsychotic medication 
in general practice. With this study, we aim to contribute to better healthcare for this 
particular population, which is at a significantly higher risk of developing cardiovascular 
disease, but up until now seems to be forgotten in Dutch primary care. 
 
1. OBJECTIVES 
Primary objective: to assess the effectiveness of TACTIC in patients using atypical 
antipsychotics in general practice on cardiovascular risk and mental quality of life. 
Secondary objectives: to assess cost effectiveness of the intervention TACTIC and its 
effectiveness regarding individual risk factors for cardiovascular disease.  
 
2. STUDY DESIGN 
We will conduct an incomplete cluster randomised stepped wedge trial including 32 general 
practices. Clusters (units of a general practitioner and his/her practice nurse) will be 
randomly allocated to four sequential steps over a 22-month period to implement TACTIC 
(Figure 1). Clusters will be randomised to time points at which they will receive the 
intervention. To minimize patient burden, data collection is not continuous, but undertaken on 
a selective number of occasions, which causes an “incomplete” stepped wedge design (14). 
Recruitment of clusters will start in September 2022, follow-up of the first step will start in 
March 2023. Follow-up of the last step will end in December 2024.  
 

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Fig. 1. Incomplete stepped wedge study design; rows are steps to which clusters will be randomised; 
columns are time periods of each 5 months. 
 
3. STUDY POPULATION 
3.1 Setting and population 
This study will be conducted in the primary care cooperative ‘Onze Huisartsen BV 
Arnhem’. This primary care cooperative serves around general practices with > 360,00 
registered patients of whom approximately 4,000 patients use antipsychotics. Based on 
our pilot study we know that around 80 practices are sufficiently equipped to participate in 
our trial, i.e. they use the General Practice Information Systems Medicom or Promedico 
ASP and VIPlive, which are necessary for requesting digital consultations with the 
psychiatrist. A cluster is defined as a duo (or unit) of a general practitioner with his of her 
practice nurse. As a result, large general practices may provide multiple clusters when 
consisting of multiple duos.  
 
 

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3.2 Inclusion criteria 
In order to be eligible to participate in this study, a patient must meet all of the following 
criteria: 1) aged between 25 and 84 years, 2) using atypical antipsychotic medication for 
at least 3 months at baseline, 3) the atypical antipsychotic medication is prescribed by the 
general practitioner, and 4) a 10-year cardiovascular risk of at least 5% at baseline 
(moderate to severe risk). 
 
3.3 Exclusion criteria 
A potential patient who meets any of the following criteria will be excluded from 
participation in this study: 1) diagnosis of dementia or organic psychosis, 2) diagnosis of 
cardiovascular disease (acute myocardial infarction, acute coronary syndrome, heart 
failure, ischemic stroke, transient ischemic attack, peripheral artery disease, aortic 
aneurysm or a revascularization procedure, i.e. percutaneous coronary intervention or 
coronary artery bypass grafting). 
 
3.4 Sample size calculation 
The sample size calculation is based on the following findings and expectations. Our pilot 
showed a reduction of the mean QRISK3 score of 1.9 points. This was after a follow-up 
period of 3 months, and under suboptimal intervention conditions, e.g. unclear expectation 
management, modified information meeting due to the corona pandemic. The standard 
deviation of the difference of QRISK3 score was 3.4 and the standard deviation of a single 
measurement was 12. This means there is a high reliability on patient level. 
 
𝒓𝒔= 𝟏−(𝑺𝑫𝒅𝒊𝒇𝒇/𝑺𝑫)
𝟐
𝟐
≈𝟎. 𝟗𝟓 
 
We expect that in the trial, after optimalisation of the TACTIC procedures, we will be able 
to detect a reduction of a clinically relevant mean QRISK3 score of 2.5 points in the 
intervention group, compared to the control condition. Given an SD of 12, an intracluster 
correlation (ICC) of 0.10, and an α of 0.05, 500 simulated trials indicate that 32 general 
practices with each 12 patients are needed to provide a power of at least 80%. Given 
drop-out rates of 20% observed in our pilot study and less than 10% in a UK primary care 
study evaluating a comparable intervention (15), we include 15 patients per cluster. The 
required total number of participants will be 480 patients in 32 (or more) clusters. 

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This calculated sample size has also enough power to detect a clinically relevant 
improvement of 5 points on de mental health inventory, the mental domain of the SF36, 
which will be our second primary outcome. 
 
4.  TREATMENT OF SUBJECTS 
Investigational treatment 
A transmural taskforce in the region of Arnhem has previously developed the TACTIC 
intervention. This taskforce consists of all relevant stakeholders: patients with lived 
experience from the patient organization ‘Vitale Verbindingen’, general practitioners from 
the primary care group ‘Onze Huisartsen’, psychiatrists from ‘Pro Persona’ and ‘GGNet’, 
mental health nurses from primary and secondary care (including addiction care), 
pharmacists, life style coaches and members of the municipal social welfare team. The 
TACTIC intervention has been tested in a recent pilot study which provided valuable input 
for improving the feasibility and effectiveness of the intervention. We followed the Medical 
Research Council framework for developing and evaluating complex interventions (16). 
 
TACTIC is a one-time intervention that takes place in the general practice setting. It 
entails three consecutive steps in addition to usual care, i.e. regular cardiovascular risk 
management programmes:  
Step 1: All participating patients are invited to watch an information video in which they 
are informed about the multidisciplinary meeting. This information video aims to motivate 
and prepare patients (and their carers) to participate in the multidisciplinary meeting. The 
healthcare professionals who take part in the multidisciplinary meeting will introduce 
themselves and tell about their expertise. After the information video, patients are able to 
contact their healthcare professional for questions. The information video will take 
approximately 20 minutes. If desired, patients can meet their pharmacist or the experience 
expert in advance of the multidisciplinary meeting.  
Step 2: A 15-minute multidisciplinary meeting per patient will be held. The general 
practitioner will open a digital consultation for each patient at least one week before the 
meeting, enabling the psychiatrist to prepare. When a consultation is initiated digitally, the 
psychiatrist has access to a part of the electronic medical record of the general 
practitioner, including diagnosis, medication use, blood pressure, Body Mass Index, and 
laboratory results. The most recent letter from the psychiatrist will be enclosed (if 
applicable), together with the results of the Liverpool University Neuroleptic Side Effect 
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on antipsychotic use, and the QRISK3 score at baseline (see Methods 6.1.2. Secondary 
study parameters). 
During the multidisciplinary meeting, the participating patient (and carer), the general 
practitioner, a psychiatrist, the primary care nurse, and if desired an experience expert 
(patient coach who lived the experience) will review the patient’s antipsychotic use and all 
other relevant medication (if applicable). Also, possible cardiovascular risk factors will be 
addressed, such as smoking status, blood pressure, Body Mass Index, blood glucose and 
cholesterol levels. The multidisciplinary meeting will result in a set of individualised 
treatment suggestions, including advice on antipsychotic use (e.g. continuation, 
deprescribing, or switching) and reducing cardiovascular risk. 
Step 3: A week after the multidisciplinary meeting, the patient has a consultation with the 
general practitioner during which the set of individualised treatment suggestions will be 
translated into an action plan through shared-decision making. This shared-decision 
making process will benefit the adherence and outcome of the plan. The plan will also 
define the tasks and responsibilities of the various healthcare providers. Potential actions 
are altering antipsychotic use, initiating antihypertensive medication or statins, referral to 
the chronic care nurse (in Dutch: POH-S) for example for smoking cessation, referral to 
the primary care mental health nurse (in Dutch: POH-GGZ), the dietician, the physical 
therapist, or a life style coach. 
 
The effects of TACTIC in addition to usual care will be compared to usual care alone, in 
which patients will be their own comparator, prior to treatment initiation. 
 
5. METHODS 
5.1 Study parameters/endpoints 
5.1.1 Main study parameters 
- Our first primary outcome measure is the QRISK3 score (11). The QRISK3 
algorithm (www.qrisk.org/three) calculates a person's risk of developing a 
cardiovascular event (e.g. a heart attack or stroke) over the next 10 years. The 
score presents the average risk of people with the same risk factors as those 
entered for that person. The QRISK3 is the preferred algorithm for assessing 
cardiovascular risk according to the NICE guideline Cardiovascular Disease (18). It 
includes severe mental illness and use of atypical antipsychotics as predictors for 
cardiovascular disease, which makes it suitable for use in our study. 
The QRISK3 score is calculated based on age, gender, ethnicity, Townsend 
deprivation score, smoking status, diabetes status, having chronic kidney disease, 

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atrial fibrillation, migraines, rheumatoid arthritis, systemic lupus erythematosus, 
severe mental illness or a family history of premature coronary heart disease in a 
first degree relative, being on blood pressure treatment, on regular steroid tablets, or 
on atypical antipsychotic medication, having a diagnosis of or treatment for erectile 
disfunction, levels of cholesterol/HDL ratio, systolic blood pressure, standard 
deviation of blood pressure, and Body Mass Index. As the Townsend deprivation 
score is not applicable to the Dutch population, we will set this to 0, meaning neither 
deprived nor affluent, as is advised by the authors. The QRISK3 score can range 
from 0 to 100%. We consider a decrease of 2.5%-points as clinically relevant. 
- Our other primary outcome measure is the Mental Health Inventory, five-item 
version (MHI-5), which is a measure for the mental quality of life (19). The MHI-5 is 
a derivative of the 36-item short form health survey, the SF36, and assesses 
symptoms of depression and anxiety, loss of behavioural or emotional control, and 
psychological well-being in the prior four weeks. The MHI-5 ranges from 0 to 100, 
where a score of 100 equals perfect mental health. A score of 60 or higher is seen 
as good mental health, whereas a score below 60 is seen as poor mental health. 
We will consider an increase of 5 points as clinically relevant. 
5.1.2 Secondary study parameters 
- Health-related quality of life will be measured with the EuroQol-5D-5L (EQ-5D). 
This instrument is available in a validated Dutch translation. The EQ-5D comprises 
five domains: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. The EQ-5D index is obtained by applying predetermined 
weights to the five domains, and ranges from 0 to 1, where a score of 1 equals 
perfect health. 
- We will measure change in side effects using the Liverpool University Neuroleptic 
Side Effect Rating Scale (LUNSERS) (17). 
- We will use the 8-item Client Satisfaction Questionnaire (CSQ-8) to measure 
participants’ satisfaction with care. This questionnaire is recommended for use in 
psychiatric patients (20),(21) and has a Dutch validated version (22). 
- Number of groups meetings (Step 1), multidisciplinary meetings (Step 2), and GP 
contacts (Step 3);  
- Number and content of individualized treatment plans;  
- Percentage of patients who attend group meeting (Step 1);  
- Percentage of patients who attend multidisciplinary meeting (Step 2);  
- Percentage of patients who contact GP to discuss individualized treatment plan 
(Step 3);  

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- Reasons for drop-out. 
- Numbers and type of (serious) adverse events. 
- Numbers and type of advice given in Step 3 of the intervention, and numbers and 
type of advice followed up or executed. 
- Healthcare utilization as measured with the Dutch version of the Treatment 
Inventory of Costs in Patients with psychiatric disorders (TIC-P) questionnaire; 
- Costs related to health care, such as medication, visits to the general practice, 
visits to relevant medical specialists. 
- Patient costs, such as travel costs, time costs and over the counter medication 
- Costs in other sectors, such as health promotion costs within budget of 
municipalities 
 
5.2 Randomisation, blinding and treatment allocation 
 
Clusters will be randomised to either of the four steps, or cluster groups, as described in  
 
figure 1. The randomisation program we will use, will be custom made by an investigator 
 
with no clinical involvement in the trial. Blinding and treatment allocation are not  
     applicable, as it is not possible to blind clusters. 
 
5.3 Study procedures 
After enrolment of the general practice, a list with all eligible patients will be generated in 
VIPlive. A computerized programme will randomly select 30 eligible patients per general 
practice, who will receive a letter from their general practitioner, informing the patient 
about the upcoming trial. Patients will be invited to contact the general practice when they 
are interested in participation. An appointment for a regular cardiovascular risk 
management consultation at the general practice will then be made. Patients who did not 
reply to the letter, will be contacted by phone. In the context of the existing regional 
cardiovascular risk management programme patients will undergo physical examination 
(for measuring length, weight and blood pressure), venapunction and urinalysis (for 
measuring risk factors, i.e. HbA1c, blood glucose, lipid spectrum and kidney function), and 
will be asked about their ethnicity, smoking status and family history of coronary heart 
disease. All other information will be derived from their medical file, e.g. having atrial 
fibrillation, migraines, or rheumatoid arthritis. In addition to the usual SCORE calculation, 
the QRISK score will also be calculated specifically for this study. When the QRISK3 
score is below 5%, the patient does not meet the inclusion criteria and will be followed by 
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programme. Patients with a QRISK3 ≥5% will be invited to sign informed consent for 
participation in the TACTIC intervention study. 
  
After signed informed consent and inclusion, baseline measurement will take place and 
patients will fill in a digital questionnaire using Castor EDC, containing MHI-5, EQ-5D-5L, 
TIC-P and LUNSERS. As part of the preparation for the multidisciplinary meeting, patients 
will be asked to fill in a custom-made questionnaire on antipsychotic use. This 
questionnaire will help healthcare professionals prepare for the meeting and will give the 
patient insight in possible topics that can be addressed during the meeting. In case 
patients do not have an email address, we will send the questionnaires by mail. 
Patients will then watch the information video at home, attend the multidisciplinary 
meeting, and attend a consultation with their general practitioner, as described in section 
5. At five months follow-up, patients will be invited for follow-up (monitoring) 
measurements at the general practice as part of the regular regional cardiovascular risk 
management programme (usual care|), to undergo physical examination (measuring 
weight and blood pressure), venapunction and urinalysis (for measuring risk factors, i.e. 
HbA1c, blood glucose, lipid spectrum and kidney function). As part of the evaluation. 
patients will also fill in questionnaires, containing MHI-5, EQ-5D-5L, LUNSERS, TIC-P and 
general questions about smoking status and family history of coronary heart disease.  
Depending on which step the cluster has started, patients will undergo one to four follow-
up measurements, every five months. This is in line with the routine check-ups patients 
will have in the regular cardiovascular risk management programme. During the last 
follow-up measurement, they are also asked to fill in the CSQ-8. Table 1 presents the 
schedule of assessments.  
 
No diagnostic procedures or treatment will be postponed.  
 
 
Visit general 
practice 
Digital 
information 
Physical 
examination 
Laboratory 
tests 
Question-
naires 
Week 1 
Routine screening and 
inclusion after informed 
consent 
X 
 
X 
X 
 
Week 2 
Baseline measurement 
 
 
 
 
X 
Week 3 
Information video 
 
X 
 
 
 
Week 4/5 
X 
 
 
 
 

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Multidisciplinary meeting 
Week 5/6 
Consultation with GP 
X 
 
 
 
 
Month 5 
Routine consultation as 
part of usual care. 
Follow-up measurement 1  
Start Step 2 at Week 1 
X 
 
X 
X 
X 
Month 10 
Routine consultation as 
part of usual care. 
Follow-up measurement 2 
Start Step 3 at Week 1 
X 
 
X 
X 
X 
Month 15 Routine 
consultation as part of 
usual care. 
Follow-up measurement 3 
Start Step 4 at Week 1 
X 
 
X 
X 
X 
Month 20 
Routine consultation as 
part of usual care. 
Follow-up measurement 4 
Finish Follow-up all 
clusters 
X 
 
X 
X 
X 
 
Table 1. Schedule of assessments. 
 
5.4 Withdrawal of individual subjects 
Patients can leave the study at any time for any reason if they wish to do so, without any 
consequences. If a patient moves to a different general practice during the study, the 
patient will be excluded from analysis from the moment of changing practice. 
The investigator can decide to withdraw a patient from the study for urgent medical 
reasons. If a patient withdraws from the study, they will continue to receive care as usual. 
 
5.5 Replacement of individual subjects after withdrawal 
 
Patients can be replaced in case of withdrawal of another patient, provided that coming 
 
measurements are under the same conditions as they would be for the withdrawing  

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patient, i.e. when a patient is in the intervention condition at the time of withdrawal, this 
patient can only be replaced by a patient who is also in the intervention condition.  
 
5.6 Follow-up of subjects withdrawn from treatment 
In case of withdrawal from treatment, we will strive to collect all necessary data for 
analysis, unless, of course, informed consent is also withdrawn. This is according to the 
intention-to-treat principle. 
 
5.7 Premature termination of the study 
The study will be terminated in its current design as recruitment of the necessary     
number of cluster fails.  
In case the study will be terminated prematurely, we will fill in the form “Melden 
beëindiging studie” on www.ccmo.nl and notify the medical research ethics committee 
within 15 days.  
 
 
6. SAFETY REPORTING 
6.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise patient 
health or safety. The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all patients are kept informed.  
 
6.2 AEs and SAEs 
6.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a patient 
during the study, whether or not considered related to the trial procedure or the 
experimental intervention. All adverse events reported spontaneously by the patient 
or observed by the general practitioner, his staff, or the investigator will be recorded. 
6.2.2 Serious adverse events (SAEs) 
During the control period, patients receive care as usual, so no AE and SAE are 
expected, and if they do, they are part of the usual care process and cannot be 
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We will instruct all general practitioners to warn the investigator about every SAE 
occurring during the study, i.e. psychosis, (attempted) suicide, requirement of the 
crisis intervention team, and death. We will examine every case to see whether 
the trial procedure or the intervention caused the SAE. The investigator will report 
all SAEs to the sponsor without undue delay after obtaining knowledge of the events. 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening, followed by a period of maximum 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
 
6.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general practitioner or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol.  
 
6.4 [Data Safety Monitoring Board (DSMB) / Safety Committee] 
Given the low-risk character of the study, no Data Safety Monitoring Board is installed or 
interim analyses are planned. 
 
7. STATISTICAL ANALYSIS 
All measured data will be assembled in a computer database and analysed using SPSS 
25. 
7.1 Primary study parameters 
As mentioned in chapter 6.1.1, the QRISK3 score is calculated based on several 
parameters that are collected during regular cardiovascular risk management 
consultations as part of usual care. For age, we will use age at baseline (T0) at all 
measurement points. Since the QRISK3 score cannot be calculated when individual items 
are missing, we will use the following values: 
• 
In case ethnicity is missing, we will use “white or not stated”.  

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• 
In case smoking status is missing, we will use “non-smoker”.  
• 
In case the patient is a smoker, but the amount of cigarettes is not stated, we will use 
“moderate (10-19)”.  
• 
In case cholesterol/HDL ratio is missing, we will use 4.4 for men and 3.7 for women 
(11). In case systolic blood pressure is missing, we will use the latest measurement of 
this value, or, if no measurements are available, we will use 129mmHg for men and 
123mmHg for women (11).  
• 
In case standard deviation of systolic blood pressure is missing, we will use “0”.  
• 
In case either weight or both length and weight are missing, we will use the latest 
measurement of the Body Mass Index, or, if no BMI is available, we will use Body 
Mass Index values as mentioned in table 2.  
• 
In case only length is missing at all measurement points, we will use values as 
mentioned in appendix … for calculating Body Mass Index.  
• 
In case calculated Body Mass Index is <20kg/m2, the value is set to 20kg/m2, as the 
algorithm is not validated for values of Body Mass Index lower than 20kg/m2. 
 
Age (years) 
Men 
Women 
25-39 
25.2 
24.4 
40-49 
26.2 
24.7 
50-59 
26.5 
25.7 
60-84 
26.8 
26.4 
Table 2. Mean Body Mass Index (kg/m2) by age and gender, based on RIVM 2012. 
 
• 
In case family history of premature coronary heart disease in a first degree relative is 
“yes” at any measurement point, all measurement points will be set to “yes”, as this 
factor might not be manifest at the start of enrolment, but does contribute to the 
patient’s cardiovascular risk, regardless to the moment this factor becomes manifest. 
This also applies for the factors migraines, rheumatoid arthritis, systemic lupus 
erythematosus, and erectile dysfunction. 
• 
In case a patient starts blood pressure treatment due to the intervention, all prior 
measurement points will be set to “yes”, as the indication for blood pressure treatment 
would have been present provided the patient was on appropriate usual care.  
 
The MHI-5 consists of five questions with each six answer categories: continuously-
mostly-often-sometimes-rarely-never. The answers of the positively formulated questions 
(questions 3 and 5) will be assigned the values 5, 4, 3, 2, 1, and 0, respectively. The 

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answers of the negatively formulated questions (questions 1, 2, and 4) will be assigned 
the values 0, 1, 2, 3, 4, and 5, respectively. Subsequently, a sum score will be calculated, 
multiplied by 4, resulting in an MHI-5 score ranging from 0 to 100, where a score of 100 
equals perfect mental health. 
 
Data analysis will be performed according to the intention-to-treat principle. Data from 
patients who discontinued follow-up will be included in the analysis up to the point of 
dropout. Descriptive analyses will be performed to describe the patient characteristics. 
Mean and standard deviation (std) or median and interquartile range for continuous 
characteristics and number and percentages for categorical characteristics will be 
determined. The relationship between treatment and outcome measures measured at 5, 
10, 15, and 20 month follow up will be analysed with mixed three level linear or logistic 
regression, taking into account that the times of measurement are clustered within 
patients, and patients within general practices. We will perform a model with a random 
intercept and all other variables fixed. To test the effect of the intervention a model with 
time, group (intervention or control) and the interaction between time and group will be 
performed. A value of p<0.05 will be considered statistically significant for all analyses, 
based on two-sided testing. Analyses will be performed using the Statistical Package for 
Social Sciences (SPSS, IBM Corp., Armonk, NY) version 25. 
 
We will present QRISK3 scores and MHI-5 scores as means (SDs) for every 
measurement point, with notification of the number of patients included in the calculation. 
 
7.2 Secondary study parameter(s)  
We will convert the EQ-5D index into a utility score, using the Dutch algorithm. The utility 
score has a maximum of 1, indicating optimal health. A utility score of 0 equals death, but 
the score can also be negative, as some conditions are thought to be worse than death. 
By multiplying the utility score with the amount of time in which the score is applicable 
and then aggregating these scores over the relevant timeframe (trapezium method), we 
will compute quality-adjusted life years (QALYs) (22). 
 
The Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) is self-rating 
scale for measuring the side-effect of antipsychotic medications. LUNSERS was 
developed by researchers within the University of Liverpool to indicate the extent of side-
effects experienced by patients medicated with neuroleptic drugs. The scale consists of 
41 known side effects of neuroleptics. Each ‘side-effect’ listed is scored on a five point 

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rating scale of 0 – 4, i.e. 0 = ‘Not at all’ and 4 = Very much. A total score can be 
calculated by adding all item scores and then be graded into ‘very low’, ‘low’, ‘average’, 
‘high’, and ‘very high’, based on the percentiles (16). who have a clinically relevant 
improvement of at least the minimal clinically important difference (MCID), defined as 0.5 
x SD of the baseline mean 
 
7.3 Other study parameters 
We will perform a sub analysis on the QRISK3 score, determining the proportion of 
patients reaching 1) an absolute risk reduction of 2.5%, which we consider as clinically 
relevant, and 2) a proportional risk reduction of 20% of their optimal achievable reduction. 
To give an example: a patient has a 10-year cardiovascular risk of 20%, but after 
perfectly optimising all changeable risk factors, is able to reach a 10-year cardiovascular 
risk of 10%. When, after the intervention, the patient reaches a QRISK3 score of 17%, 
this means the patient reached a 3% absolute risk reduction (i.e. 20% - 17%), and a 30% 
proportional risk reduction (i.e. 3% / (20% - 10%)). 
As mentioned in chapter 6.1.1, the Townsend Deprivation Score is not applicable to the 
Dutch population. We do know, however, that deprivation has impact on cardiovascular 
risk. Therefore, we want to perform a secondary analysis on the QRISK3 score in which 
we use the Dutch equivalent of deprivation (“achterdstandsindex”). In the Netherlands, we 
use a deprivation index for patients with low social economic status, based on 
employment, income and percentage of non-western immigrants. This deprivation index 
is applicable for approximately 10% of the Dutch population. 
We decided to apply the Townsend Deprivation Score at p20 (below which are the 20% 
most deprived of the British population) for the 10% most deprived patients in our 
population. By choosing p20 instead of p10, we stay on the safe side and might 
underestimate the effect of deprivation, but we find this more important than 
overestimating its impact. 
 
8. ETHICAL CONSIDERATIONS 
8.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki of 
2013. 
 
8.2 Recruitment and consent 
Recruitment of patients has been described in section 6.3 Study procedures. After being 
found eligible for participation, the investigator will contact the patient for informed 

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consent. The patient has the opportunity to ask additional questions before giving 
consent. If desired, the patient can contact an independent physician, who knows about 
the study, but is not involved in execution of the study. 
The patient information letter and informed consent form can be found attached to this 
research protocol. Together with the patient information letter for adults, we provide an 
“easy reading” version for patients with low literacy, which is based on the patient 
information letter model for children under 16 years of age, provided by the CCMO. 
 
8.3 Objection by minors or incapacitated subjects (if applicable) 
Some eligible patients live in supervised communities (for instance RIBW) and are 
incapacitated. However, patients who are registered in a general practice are usually less 
incapacitated then those who are for example cared for by an intellectual disability 
physician. It is important that these patients have the opportunity to participate in this 
study because, both individually and as a group, they often are at risk of being 
overtreated with antipsychotic medication and undertreated for cardiovascular risk (24). It 
is important to study whether TACTIC is suitable for these patients as well. Caregivers 
and legal representatives will be involved in invitation, the informed consent procedure 
and during the entire study. 
 
8.4 Benefits and risks assessment, group relatedness 
Potential benefit of the intervention 
The potential benefit of participation is high, as changes in antipsychotic medication and 
appropriate cardiovascular risk screening and management will result in decreased 
cardiovascular risk. The intervention has been developed by the primary care cooperative 
Onze Huisartsen BV with the intention to implement it in the Arnhem region after 
demonstrating its feasibility and its (cost-)effectiveness. The intervention is in line with the 
current guideline of the European Society of Cardiology on cardiovascular disease 
prevention in clinical practice, which recognises the increased cardiovascular risk for patients 
with mental disorders (25). 
 
Burden and risk associated with the intervention: 
Patients who are eligible and who want to participate in the study will be included in the 
regular cardiovascular risk management programme of the Arnhem primary care 
cooperative. This programme includes, according to current Dutch guidelines, 1 to 5 
consultations with the GP and/or the practice nurse in which physical examination, i.e. 
measuring blood pressure and body weight, and blood and urine sample collection will take 

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place. The frequency depends on the severity of the cardiovascular risk and the 
corresponding follow-up period. On top of the regular cardiovascular care patients who 
participate in the study will also receive the three-step TACTIC intervention. This is a one-
time intervention. Patients who are eligible but who do not want to participate in the study will 
be included in the regular cardiovascular risk management programme, but will not receive 
the TACTIC intervention.  
 
There is a potential risk associated with participation, as patients whose antipsychotic 
medication is altered during participation may destabilize mentally. However, this risk is 
expected to be low. Changes in medication will only take place after this advice has been 
given in Step 2 (i.e. multidisciplinary meeting including the patient’s GP, a psychiatrist, and 
the patient self) and has been followed in Step 3 (i.e. shared decision making between the 
patient and his/her GP). The advice to change medication will only be given in Step 2 as the 
psychiatrist, the GP, and the patient consider this option to be safe. Besides, the advice will 
only be followed in Step 3 if both patient and GP feel safe with it. In addition, TACTIC 
contains precautionary measures to prevent destabilisation, i.e. any change in antipsychotic 
medication is accompanied with the advice of follow up consultations with the general 
practitioner or mental health nurse, and all patients who alter their antipsychotic medication 
will have a crisis prevention plan to ensure safety. 
 
Burden and risk associated with outcomes measurements: 
Patients fill in questionnaires at baseline and every 5 months during follow-up. Based on our 
experiences in the pilot study, we expect that it will take approximately 20 minutes to fill in 
the questionnaire. For the assessment of the primary outcome QRISK3 score routinely 
collected data from the cardiovascular risk management programme, i.e. blood pressure, 
body weight, smoking behaviour, and blood cholesterol and glucose levels. At the end of 
follow-up we will conduct focus-group interviews with a purposive sample of participants to  
explore experiences with the TACTIC intervention. 
 
9. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
9.1 Handling and storage of data and documents 
For the transfer of data, an agreement will be signed by the participating general 
practices and the Department of Primary and Community Care of the Radboud university 
medical centre, which states that the study will be performed according to the code of 
conduct for health research (in Dutch: Gedragscode Gezondheidsonderzoek); and the 

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Dutch Act on Implementation of the General Data Protection Regulation (in Dutch: 
Uitvoeringswet AVG). 
 
All study findings will be stored in a computer database at the Radboudumc and handled 
strictly confidentially. All personal data will be kept secret, with identification by research 
number only. The database will be accessible to the principal investigators and those 
employees actively involved in the study. The key to the identification code will be 
safeguarded by the two junior investigators. Coded data will be kept after closure of the 
study and can only be used for ancillary studies after strict approval of the principal 
investigators. 
 
All coded documents will be stored for 15 years after the study has ended. 
9.2 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
Non-substantial amendments will not be notified to the accredited METC, but will be 
recorded and filed by the sponsor.  
 
9.3 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC.  
 
9.4 Public disclosure and publication policy 
The study will be registered at www.clinicaltrials.gov before trial commencement.  
Within one year after the end of the study, the investigator will submit a final study report 
with the results of the study, including any publications/abstracts of the study, to the 
sponsor. 

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Results of the study will be published in peer reviewed journals. 
 
10. REFERENCES 
 
1. Hermann RC, Yang D, Ettner SL, Marcus SC, Yoon C, Abraham M. Prescription of 
Antipsychotic Drugs by Office-Based Physicians in the United States, 1989-1997. Psychiatric 
Services. 2002;53(4):425-30. 
2. Prah P, Petersen I, Nazareth I, Walters K, Osborn D. National changes in oral 
antipsychotic treatment for people with schizophrenia in primary care between 1998 and 
2007 in the United Kingdom. Pharmacoepidemiol Drug Saf. 2012;21(2):161-9. 
3. Morrens M, Destoop M, Cleymans S, S VDS, Dom G. Evolution of First-generation and 
Second-generation Antipsychotic Prescribing Patterns in Belgium Between 1997 and 2012: A 
Population-based Study. J Psychiatr Pract. 2015;21(4):248-58. 
4. Mackin P, Bishop D, Watkinson H, Gallagher P, Ferrier IN. Metabolic disease and 
cardiovascular risk in people treated with antipsychotics in the community. British Journal of 
Psychiatry. 2007;191:23-9. 
5. M DEH, Correll CU, Bobes J, Cetkovich-Bakmas M, Cohen D, Asai I, et al. Physical 
illness in patients with severe mental disorders. I. Prevalence, impact of medications and 
disparities in health care. World Psychiatry. 2011;10(1):52-77. 
6. Jakobs KM, Posthuma A, de Grauw WJC, Schalk BWM, Akkermans RP, Lucassen P, et 
al. Cardiovascular risk screening of patients with serious mental illness or use of 
antipsychotics in family practice. BMC Fam Pract. 2020;21(1):153. 
7. Morrato EH, Campagna EJ, Brewer SE, Dickinson LM, Thomas DS, Miller BF, et al. 
Metabolic Testing for Adults in a State Medicaid Program Receiving Antipsychotics: 
Remaining Barriers to Achieving Population Health Prevention Goals. JAMA Psychiatry. 
2016;73(7):721-30. 
8. Gough SCL, O'Donnovan MC. Clustering of metabolic comorbidity in schizophrenia: a 
genetic contribution? Journal of Psychopharmacology. 2005;19(6):47-55. 
9. Stahl SM, Mignon L, Meyer JM. Which comes first: atypical antipsychotic treatment or 
cardiometabolic risk? Acta Psychiatr Scand. 2009;119(3):171-9. 
10.  Correll CU. Prevalence, incidence and mortality from cardiovascular disease in patients 
with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 
patients and 113,383,368 controls. World Psychiatry. 2017;16:163-80. 
11.  Hippisley-Cox J, Coupland C, Brindle P. Development and validation of QRISK3 risk 
prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort 
study. BMJ. 2017;357:j2099. 

ZonMw GGG Complexe interventie studies Project ID 10140021910502 
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Version 28-07-2022 
 
33 of 33 
12.  Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the 
risk of sudden cardiac death. N Engl J Med. 2009;360(3):225-35. 
13.  Tschoner A, Engl J, Laimer M, Kaser S, Rettenbacher M, Fleischhacker WW, et al. 
Metabolic side effects of antipsychotic medication. Int J Clin Pract. 2007;61(8):1356-70. 
14.  Martin JT, Hemming K, Girling A. The impact of varying cluster size in cross-sectional 
stepped-wedge cluster randomised trials. BMC Med Res Methodol 19, 123 (2019). 
https://doi.org/10.1186/s12874-019-0760-6  
15.  Osborn D, Burton A, Hunter R, et al. Clinical and cost-effectiveness of an intervention for 
reducing cholesterol and cardiovascular risk for people with severe mental illness in English 
primary care: a cluster randomised controlled trial. Lancet Psychiatry. 2018 Feb;5(2):145-
154. doi: 10.1016/S2215-0366(18)30007-5. Epub 2018 Jan 22. 
16.  Craig P, Dieppe P, Macintyre S, Michie S, Nazareth I, Petticrew M, et al. Developing and 
evaluating complex interventions: the new Medical Research Council guidance. BMJ. 
2008;337:a1655. 
17.  Day JC, Wood G, Dewey M, Bentall RP. A self-rating scale for measuring neuroleptic 
side-effects. Validation in a group of schizophrenic patients. Br J Psychiatry. 
1995;166(5):650-3. 
18.  NICE. Cardiovascular disease: risk assessment and reduction, including lipid 
modification. 2014. 
19.  Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. 
Conceptual framework and item selection. Med Care. 1992;30(6):473-83. 
20.  Larsen DL, Attkisson CC, Hargreaves WA, Nguyen TD. Assessment of client/patient 
satisfaction: development of a general scale. Eval Program Plann. 1979;2(3):197-207. 
21.  Attkisson CC. The Client Satisfaction Queastionnaire - Psychometric properties and 
correlations with service utilization and psychotherapy outcome. 
22.  De Brey H. A cross-national validation of the Client Satisfaction Questionnaire: The 
Dutch experience. Evaluation and Program Planning. 1983;6(3):395-400. 
23.  Anderson P, Philips C. What is a QALY? 
24.  Neijmeijer L, Moerdijk L, Veneberg G, Muusse C. Licht verstandelijk gehandicapten in de 
GGZ, een verkennend onderzoek. Utrecht: Trimbos Instituut; 2010. 
25.  European Society of Cardiology. 2021 ESC Guidelines on cardiovascular disease 
prevention in clinical practice. Available from: https://www.escardio.org/Guidelines/Clinical-
Practice-Guidelines/2021-ESC-Guidelines-on-cardiovascular-disease-prevention-in-clinical-
practice.