tOwards a Patient Centred mulTIMorbidity Approach FOR Chronic Disease MAnagement in Primary Care (OPTIMA FORMA) PHASE 3: Cluster Randomized Controlled Evaluation Study
Phase: NA
Conditions: Chronic Condition, Chronic Conditions, Multiple
Sponsor: Radboud University Medical Center

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OPTIMA FORMA PHASE3 
 
 
 
 
 
 
 
tOwards a Patient centred mulTIMorbidity 
Approach FOR chronic disease MAnagement in 
primary care (OPTIMA FORMA) 
 PHASE 3:  
 
Cluster Randomized Controlled Evaluation 
Study 
(V1, July 2022) 
 
 
 
 
 

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OPTIMA FORMA PHASE3 
 
 
 
PROTOCOL TITLE ‘OPTIMA FORMA PHASE3: cluster randomized evaluation study’ 
 
Protocol ID 
R-004441 
Short title 
OPTIMA FORMA PHASE3 
EudraCT number  
N.A. 
Version 
1 
Date 
11-07-2022 
Coordinating investigator/project 
leader 
 
Erik Bischoff, Primary and Community Care, 
Radboudumc; 06-22221879; 
erik.bischoff@radboudumc.nl  
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder 
Erik Bischoff, Primary and Community Care, 
Radboudumc; 06-22221879; 
erik.bischoff@radboudumc.nl 
 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Radboudumc 
 
 
Subsidising party 
ZonMw 
Independent expert (s) 
N.A. 
 
 
 
 
Laboratory sites <if applicable> 
N.A. 
 
 
Pharmacy <if applicable> 
N.A. 
 
 
 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
 
Head of Department: 
Prof. Dr. Aura Timen 
 
 
 
Coordinating Investigator/Project 
leader/Principal Investigator]: 
Erik Bischoff MD PhD 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 9 
2. 
STUDY DESIGN ...........................................................................................................10 
2.1 
Population ..............................................................................................................10 
2.2 
Inclusion criteria .....................................................................................................11 
2.3 
Exclusion criteria ....................................................................................................11 
2.4 
Sample size calculation ..........................................................................................11 
3. 
TREATMENT OF SUBJECTS .......................................................................................13 
3.1 
OPTIMA FORMA intervention ................................................................................13 
3.2 
Usual care ..............................................................................................................14 
4. 
METHODS ....................................................................................................................14 
4.1 
Study parameters/endpoints ...................................................................................14 
4.1.1 
Main study parameter/endpoint .......................................................................14 
4.1.2 
Secondary study parameters/endpoints (if applicable) ....................................15 
4.2 
Randomisation, blinding and treatment allocation ..................................................16 
4.3 
Study procedures ...................................................................................................17 
4.4 
Withdrawal of individual subjects ............................................................................18 
4.5 
Replacement of individual subjects after withdrawal ...............................................18 
4.6 
Follow-up of subjects withdrawn from treatment .....................................................18 
4.7 
Premature termination of the study .........................................................................18 
5. 
SAFETY REPORTING ..................................................................................................18 
6. 
STATISTICAL ANALYSIS .............................................................................................18 
6.1 
Primary study parameter(s) ....................................................................................19 
6.2 
Secondary study parameter(s) ...............................................................................19 
6.3 
Cost analysis ..........................................................................................................19 
7. 
ETHICAL CONSIDERATIONS ......................................................................................20 
7.1 
Regulation statement .............................................................................................20 
7.2 
Recruitment and consent........................................................................................20 
7.3 
Benefits and risks assessment, group relatedness .................................................20 
7.4 
Handling and storage of data and documents ........................................................21 
7.4.1 
Qualitative data ...............................................................................................21 
7.4.2 
Quantitative data .............................................................................................21 
7.5 
Public disclosure and publication policy ..................................................................22 
8. 
REFERENCES ..............................................................................................................23 

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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) 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
COPD 
Chronic Obstructive Pulmonary Disease 
CVD 
Cardiovascular Diseases 
CV 
Curriculum Vitae 
DM2 
Diabetes Mellitus type 2 
EU 
European Union 
GCP 
Good Clinical Practice 
GDM 
Generic Disease Management 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IC 
NHG 
Informed Consent 
Dutch College of General Practitioners 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
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. 
P3CEQ 
Person Centred Coordinated Care Experiences Questionnaire 
PROMIS 
GLOBAL10 
Patient-Reported Outcomes Measurement Information System GLOBAL -
10 
SDM 
Single Disease Management 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Chronic diseases and multimorbidity are increasingly prevalent. However, over 
the last decades, attempts at improving primary care for chronic diseases have been 
focussed on the management of individual chronic diseases and single disease management 
(SDM) programs have been implemented in Dutch primary care. This causes multiple 
problems for patients with one or more chronic diseases, such as negative interaction 
between treatment of single diseases, high treatment burden, negative patient experiences, 
lack of attention for problems in other domains of life that may interact with the chronic 
disease, and difficulties in shared decision making by the use of strict protocols in SDM 
programs. A person-centred and holistic approach is widely recognized as the solution to the 
problems observed in chronic disease care. Therefore, we guided three large Dutch primary 
care cooperatives, who have been organizing SDM programmes on diabetes mellitus type 2 
(DM2), COPD, and cardiovascular diseases (CVD) in primary care for the last decades, with 
the development of a new generic disease management (GDM) programme including a 
person-centered and holistic approach (CMO 2019-5756). The three primary care 
cooperatives have recently conducted a pilot study in which we evaluated the feasibility of 
the programme (CMO 2021-8106) to further optimise its content and procedures. In the 
coming years, all three primary care cooperatives will gradually implement the optimised 
programme in all general practices in their regions. 
 
Objective: In the current study, our aim is to evaluate the effectiveness of the GDM 
programme on Quadruple Aim outcomes, i.e. patient experiences, population health, health 
care provider experiences, and cost effectiveness.  
 
Study design: we will conduct a cluster randomized controlled trial in the three primary care 
cooperatives with a follow-up of 12 months. Fifteen practices will be randomised to either 
care as usual according to the current SDM programmes, or to the GDM programme 
including a person-centered and holistic care approach. Approximately 40 patients per 
practice with DM2, COPD and/or CVD will be recruited. 
 
Study population: all patients with DM2, COPD and/or CVD who currently receive SDM 
according to the SDM programmes of the participating primary care cooperatives are eligible 
to participate.  
 

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Intervention: a GDM programme including person-centered and holistic care. This 
programme will replace the SDM programmes for DM2, COPD and CVD that are currently 
used in the participating primary care cooperatives. 
 
Main study parameters/endpoints: effectiveness will be evaluated by Quadruple Aim 
outcomes at baseline, at 6 months, and at 12 months follow-up by comparing changes in the 
intervention group with the comparator group. Patient experiences will be measured with the 
P3CEQ questionnaire. Population health will be measured with the PROMIS Global-10 
questionnaire. Self-management will be measured with the Patient Activation Measure 
(PAM) score. Healthcare professional experiences will be measured with the MASGZ and 
the COPILOT questionnaire. Data for calculating costs and conducting a cost-effectiveness 
analyses will be measured by the Medical Consumption questionnaire and the EQ-5D 
questionnaire and by process outcomes such as the number and type of consultations and 
referrals, and duration of consultations from the Electronical Medical Files. At 12 months, a 
purposive sample of patients and professionals will participate in focus group interviews to 
collect information on experiences and facilitators and barriers for further implementation. 
Also, the competences needed by the healthcare professionals to provide personalised and 
integrated chronic care will be explored.  
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
• 
The intervention has been developed by the three primary care cooperatives in close 
collaboration with their healthcare professionals and their patient panels and with the 
guidance of our research group. Also, input from the Dutch College of General 
Practitioners (NHG) and from InEen, the branch organisation for primary care 
cooperatives, has been obtained to ensure that the intervention will suit their vision 
and future plans for reorganising Dutch primary care chronic disease management. 
The intervention is also in line with current movements in healthcare, such as the 
Positive Health concept.  
• 
All three primary care cooperatives are intending to gradually implement the 
intervention throughout their regions in the upcoming years. Thus, the GDM 
programme will be implemented and will replace current SDM, even without the 
current cluster RCT as proposed in this study protocol. 
• 
The burden and risks associated with the intervention are negligible and comparable 
with the usual care, i.e. the current SDM programmes.  

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• 
Patients in the control group will continue with their care as usual, i.e. single chronic 
disease management according to the protocols of the SMD programmes that have 
been used in the participating cooperatives since the last decade.  
• 
The additional burden or risk associated with participation in this study is negligible. 
After written informed consent, patients in both groups will fill in a digital or paper 
questionnaire at baseline, 6 months, and 12 months. Estimated time to fill in the 
questionnaire is 20 minutes. A purposive sample of approximately 15 patients will 
participate in focus-groups interviews at the end of follow-up.  
 
 
 

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1. INTRODUCTION AND RATIONALE 
Multimorbidity is increasingly prevalent. In 2016, 52% of the Dutch population had at least 
one chronic disease; 37% of Dutch population had two or more chronic diseases.[1] This 
increasing prevalence results in several problems. Multimorbidity is associated with poorer 
quality of life, functional health status and physical functioning, and higher mortality 
compared to patients with zero or one chronic condition.[2, 3] In addition, patients with 
multimorbidity have higher health care utilization than patients with one or no chronic 
disease; multimorbid patients had more contacts with general practice, more medication 
prescriptions, and more referrals to specialized care.[4, 5] Because of the impact of chronic 
diseases and the increasing number of patients with multimorbidity, costs of primary health 
care in the Netherlands are quickly rising. For instance, over the course of 2013 to 2016, the 
costs of primary care increased from 2.7 to 3.1 billion euros. This can largely be attributed to 
the increase in cost of care for people with chronic conditions.[6] 
 
Over the last decade, attempts at improving primary care for chronic diseases have been 
focussed on the management of individual chronic diseases, with the implementation of 
single disease management (SDM) programs internationally. In the Netherlands, SDM 
programs have been widely implemented for diabetes mellitus type 2 (DM2), chronic 
obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). The disease 
specificity of these programs causes 3 distinct problems for people with multimorbidity. First, 
the treatment of one disease according to a disease-specific guideline can interact negatively 
with the treatment or natural course of a co-existing disease.[7] The second problem is that 
the combination of various disease-specific guidelines leads to polypharmacy and increased 
treatment burden.[8] Last, because of the disease-specific fragmentation of primary care, 
people with multimorbidity are more likely to experience problems with coordination of care 
and lower quality of care.[9]  
 
A patient centred and integrated care (PC-IC) approach is widely recognized as the solution 
to the problems in multimorbidity care.[7, 10, 11] Therefore, we guided three large Dutch 
primary care cooperatives, who have been organizing SDM programmes on DM2, COPD, 
and CVD in primary care for the last decades, with the development of a new generic 
disease management (GDM) programme including a person-centered, integrated, and 
holistic approach (CMO 2019-5756). The three primary care cooperatives have recently 
conducted a pilot study in which we evaluated the feasibility of the programme (CMO 2021-
8106) to further optimise its content and procedures. In the coming years, all three primary 
care cooperatives will gradually implement the optimised programme in all general practices 
in their regions. 

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OBJECTIVES 
In the current study, our aim is to evaluate the effectiveness of the GDM programme on 
Quadruple Aim outcomes, i.e. patient experiences, population health, health care provider 
experiences, and cost effectiveness. 
 
2. STUDY DESIGN 
We will perform a cluster randomized controlled trial with a follow-up time of 12 months.  
 
The three participating primary care cooperatives, i.e. Nijmegen, Arnhem, and Doetinchem, 
will recruit 15 general practices (clusters) who will be randomized using a 2:1 ratio in two 
study groups:  
1. The intervention group: the GDM programme including a person-centered, integrated, 
and holistic approach 
2. The control group: care as usual according the current SDM programmes 
 
All practices will receive instructions from the research team on the procedures of the 
evaluation study. Participating practices will then start recruiting patients from a random 
sample of eligible patients, i.e. patients with DM2, COPD, or CVD who are currently receiving 
SDM. After written informed consent, information will be collected through questionnaires at 
baseline, 6 months and 12 months, and by interviews and data collection from electronic 
medical records. Information will also be collected from the participating healthcare providers 
through questionnaires and interviews. 
 
In the two months prior to the start of the intervention, all practices in the intervention group 
will be trained in providing GDM by their own primary care cooperative. During follow-up two 
to three intervision meetings will take place including peer coaching and case study 
discussions. 
 
Practices who are allocated to the usual care group will not receive any training, but will 
continue with their SDM programmes. 
 
STUDY POPULATION 
2.1 Population 
All patients who are currently enrolled in any of the SDM programmes for DM2, COPD, 
asthma or CVD are eligible for participation. 

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2.2 Inclusion criteria 
- 
Currently enrolled in any of the SDM programmes for DM2, COPD, asthma or CVD. 
 
2.3 Exclusion criteria 
- 
Limited life expectancy (less than 3 months)  
- 
Unable to speak or read the Dutch language 
 
2.4 Sample size calculation 
Due to the complexity of our intervention we will use two primary outcomes, i.e. health-
related quality of life and patient experience of care. These outcomes are in line with the 2 
patient-related aims of the Quadruple Aims concept. Patient-reported health-related quality of 
life will be measured using the ‘PROMIS Global 10’ questionnaire and the patient experience 
of care will be measured using the ‘P3CEQ’. These questionnaires have been chosen after 
piloting several questionnaires in the preceding Phase2 of OPTIMA FORMA. Patients 
experienced these questionnaires as easy to complete and to understand.  
 
The ‘PROMIS global 10’ assesses a person’s health-related quality of life and consists of 10 
questions. Two dimensions representing physical and mental health underlie the global 
health items in PROMIS. These global health scales, Global Physical Health (GPH) and 
Global Mental Health (GMH), can be used to efficiently summarize physical and mental 
health in patient-reported outcome studies.[12] The 10 global health items include ratings of 
the five core PROMIS domains with a response scale ranging from 1 to 5.The PROMIS 
global 10 is publicly available and has been widely used as outcome measure for quality of 
life in studies on different diseases.  
 
The Person-Centred Coordinated Care Experience Questionnaire (P3CEQ) is a brief 
questionnaire that meets the requirements for a PREM that could assess the quality of care 
and guide quality improvement for people with (multiple) chronic conditions. It has been 
specifically designed to assess the experience of person-centred coordinated care, informed 
by a theoretical model that was developed to consider the relationship between care 
coordination, continuity and person-centred care. The P3CEQ was originally developed in 
the United Kingdom for persons with chronic conditions using primary care services.[13] 
Recently is has been translated and validated for the Dutch population.[14] It contains 14 
items and the response scale ranges from ‘never’ (0), ‘sometimes’ (1), ‘often’ (2) and ‘always’ 
(3). 

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Because we value each aim (population health and patient experience) as equally important, 
we are using a composite primary outcome, which consist of the percentage of patients 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, in either the PROMIS GMH score OR the 
PROMIS GPH score OR the P3CEQ-score AND who experience no decrease of at least the 
MCID in either the PROMIS GMH score OR the PROMIS GPH score OR the  P3CEQ-score. 
 
In our recent pilot study [unpublished] we followed 98 patients who received our intervention 
for six months. Of the 79 patients who completed all questionnaires, we found that in 30.4% 
of the patients the requirements for a positive score on the composite primary outcome were 
met. Loss to follow-up was 20%. Based on these results and the longer duration of 
intervention in the evaluation study (12 months vs 6 months), we hypothesised that in the 
evaluation study 35% of the intervention patients compared to 20% of the usual care patients 
will improve more than 0.5 x the expected SD of baseline mean on one of the scores at 12 
months, and show no decrease of the MCID on the other scores. We estimate that we need 
a total sample size of 680 patients (17 practices with an average of 40 patients per practice) 
to detect a difference of 15% between the control and intervention group, taken into account 
an alpha level of 5%, a power of 80%, an intra-class correlation coefficient (ICC) of 0.03 [15], 
and a loss to follow-up of 20%.  
 
 
 
 
 

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3. TREATMENT OF SUBJECTS 
3.1 OPTIMA FORMA intervention 
The core of GDM programme including person-centered and holistic approach is a cyclical 
process described in Figure 1. The practice nurse in the general practice will act as case 
manager. She/he can consult the general practitioner or other health providers when 
necessary. The first step in the intervention is assessing the integral health status of the 
patient (health across multiple domains, including physiological measurements and 
symptoms of disease), using a (preferably digital) questionnaire at home and physical 
measurements. The second step is an appointment in which the results are discussed with 
the patient in a semi-structured way. The case manager discusses if the results are 
recognizable, if there are other issues which haven’t come up, and the priorities of the 
patient. Personal goals are formulated in the third step, which can range from purely medical 
goals to social goals. In the fourth step, the healthcare professional and patient will choose 
through shared-decision making the most appropriate interventions and support to achieve 
these goals. The goals and interventions are documented in a personal healthcare plan, 
which is preferably digitally available for all relevant healthcare professionals and the patient. 
Next, referrals are made if necessary and the treatment is started. An evaluation is planned 
and carried out, if necessary multiple times. If a treatment goal is reached or another 
treatment goal is more urgent, the cycle can be repeated.  
 
 
Figure 1. Presentation of the cyclic process of the GDM programme 
 
In order to provide the OPTIMA FORMA intervention to participating patients all 
healthcare professionals involved will be trained by their primary care cooperative on the 
concept of Positive Health, communication skills, use of materials and ICT, and 
interprofessional collaboration prior to the start of the intervention. During follow-up, the 

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practices will receive additional support from the primary care cooperative through 
intervision meetings and case report discussions.  
 
3.2 Usual care 
Practices in the control group provide care as usual, which consists of the SDM programmes 
according to the national care standards and General Practice guidelines (NHG) for DM2, 
COPD and CVD. According to these protocolised programmes, patients with COPD, CVD or 
DM2 visit their general practice at a standard frequency per year (1 – 4 times) and standard 
monitoring measurements and topics are discussed.  
 
The practices that are randomised to the control group will not receive any additional training 
related to this study. 
 
4. METHODS 
4.1 Study parameters/endpoints 
Outcome measurement will be based on the quadruple aim framework.[16] To measure 
population health we will assess quality of life, self-management, and disease-specific 
physiological factors. Our composite primary outcome will be health-related quality of life and 
patient experience, measured with the PROMIS Global 10 and P3CEQ, as described in 
paragraph 2.4. Secondary outcomes will be: self-management, measured with the Dutch 
short version of the patient activation measure (PAM-13).[17]  Measurement of disease-
specific physiological factors will take place as part of routine care in both study groups and 
include blood pressure, body mass index (BMI), cholesterol, blood glucose levels and lung 
function parameters, if applicable. All outcomes will be measured at baseline, 6 months, and 
12 months follow-up. Physiological factors will be recorded in the electronic medical records 
as part of routine care and will be extracted from 3 months before baseline until 12 months 
follow-up. Also, healthcare utilisation and prescription data will be extracted from the 
electronic medical records at the end of follow-up. Health care provider experiences will be 
measured with an appropriate self-reported experience measure. 
4.1.1 Main study parameter/endpoint 
Our primary outcome will be patient-reported health-related quality of life and patient 
experience of care, in line with the 2 patient-related aims of the Quadruple Aims. Patient-
reported health-related quality of life will be measured using the PROMIS global 10 
questionnaire and the patient experience of care will be measured using the P3CEQ 
questionnaire. These questionnaires have been chosen after piloting several questionnaires 

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in the preceding phase. Patients experienced these questionnaires as easy to fill in and to 
understand and both questionnaires match well with the concepts we want to measure.  
 
The PROMIS global 10 assesses a person’s health-related quality of life. Two dimensions 
representing physical and mental health underlie the global health items in PROMIS. These 
global health scales can be used to efficiently summarize physical and mental health in 
patient-reported outcome studies, Global Physical Health (GPH; 4 items on overall physical 
health, physical function, pain, and fatigue) and Global Mental Health (GMH; 4 items on 
quality of life, mental health, satisfaction with social activities, and emotional problems).[12] 
The 10 global health items include ratings of the five core PROMIS domains with a response 
scale ranging from 1 to 5, the labels of those scores different per question, but a higher 
scoring is always indicating a better health-related quality of life. The PROMIS global 10 is 
publicly available and has been widely used as outcome measure for quality of life in studies 
on different diseases.  
 
The Person-Centred Coordinated Care Experience Questionnaire (P3CEQ) is a brief 
questionnaire that meets the requirements for a PREM that could assess the quality of care 
and guide quality improvement for people with (multiple) chronic conditions. It has been 
specifically designed to assess the experience of person-centred coordinated care, informed 
by a theoretical model that was developed to consider the relationship between care 
coordination, continuity and person-centred care. The P3CEQ was originally developed in 
the United Kingdom for persons with chronic conditions using primary care services.[13] 
Recently is has been translated and validated for the Dutch population.[14] It contains 14 
items and the response scale ranges from ‘never’ (0), ‘sometimes’ (1), ‘often’ (2) and ‘always’ 
(3). 
 
Because we value each aim (population health and patient experience) as equally important, 
we are using a composite primary outcome, which consist of the percentage of patients 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, in either the PROMIS GMH score OR the 
PROMIS GPH score OR the P3CEQ-score AND who experience no decrease of at least the 
MCID in either the PROMIS GMH score OR the PROMIS GPH score OR the  P3CEQ-score. 
4.1.2 Secondary study parameters/endpoints (if applicable) 
• 
PROMIS dimension GPH score 
• 
PROMIS dimension GPM score 
• 
P3CEQ-score 

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• 
Patient Activation Measure (PAM) 
• 
EQ-5D-5L 
• 
Health care use according to Medical Consumption Questionnaire 
• 
Health care use according to general practice data 
• 
Body weight, BMI, smoking status, HbA1c, glucose, cholesterol levels and blood 
pressure from general practice data (registered for normal care). 
• 
Experience of healthcare providers on COPILOT and MAS-GZ questionnaire  
 
 
4.2 Randomisation, blinding and treatment allocation 
The unit of randomisation will be the general practice (cluster). Practices will be 
randomised to intervention group (10 clusters) or comparator (5 clusters) in a 2:1 
ratio. Five additional clusters will be randomised to the control group by a 2:1 ratio 
randomisation procedure in the parallel cluster RCT named EMBOSS in which the 
GDM programme will be adjusted to the needs of patients with low socioeconomic 
status (SES). In the EMBOSS cluster RCT the adjusted intervention will be provided 
to patients with low SES and at 12 months follow-up the effects will be compared to 
patients with low SES who have received care as usual. Figure 2 illustrates the 
combined randomisation procedure of both the OPTIMA FORMA and the EMBOSS 
cluster RCT. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Randomisation procedures in the OPTIMA FORMA and EMBOSS cluster RCTs 
 
OPTIMA FORMA 
Cluster RCT 
2 : 1 ratio 
EMBOSS 
Cluster RCT 
1 : 2 ratio 
Intervention 
N = 10 clusters 
400 patients 
Control 
N = 10 clusters 
400 patients 
including 140 with 
low SES 
Intervention 
N = 10 clusters  
140 patients with low 
SES 
10 clusters 
5 clusters 
5 clusters 
10 clusters 

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After practices have been recruited, the practices will be randomised to the 
intervention or the usual care group. To avoid an imbalance between the randomised 
groups stratification will take place according to (i) the primary care cooperative, and 
(ii) the socioeconomic status of the practice population. Because of the nature of the 
intervention, it will not be possible to mask intervention allocation from the GPs or the 
patients. The research nurses who will collect the outcome data and the researchers 
who will perform the analyses will be blinded to treatment allocation.  
 
4.3 Study procedures 
Population health 
 
Patient experience 
Category  
Measurement instrument 
Time 
Person-centredness of care 
Person Centred Coordinated Care 
Experiences Questionnaire (P3CEQ) 
Baseline, 6, 12 months 
Experiences  
Focus-group interviews 
12 months 
 
Healthcare provider experience 
Category  
Measurement instrument 
Time 
Positive affect  
CO-PILOT questionnaire  
MAS-GZ questionnaire 
Baseline, 6, 12 months 
Experiences 
Focus-group interviews 
12 months 
Competences 
Focus-group interviews 
Appropriate questionnaire  
12 months 
At baseline and 12 months 
 
Cost-effectiveness 
Category  
Measurement instrument 
Time 
Medication 
Data from medical records 
12 months 
Category  
Measurement instrument 
Time 
Health related quality of life 
EQ-5D-5L 
Baseline, 6, 12 months 
Self-management 
Patient Activation Measure (PAM)      Baseline, 6, 12 months 
Health related quality of life 
PROMIS GLOBAL-10 
Baseline, 6, 12 months 
Unscheduled healthcare 
Data from medical records 
12 months 
Physiological paramenters 
Data from medical records 
12 months 

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Scheduled and 
unscheduled healthcare 
utilisation 
Data from medical records 
12 months 
Referrals 
Data from medical records 
12 months 
Costs 
Data from medical records 
12 months 
 
Medical consumption questionnaire 
Baseline, 3, 6, 9, 12 months 
 
EQ-5D-5L 
Baseline, 6, 12 months 
 
 
4.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences.  
4.5 Replacement of individual subjects after withdrawal 
 
         Subjects will not be replaced after withdrawal 
4.6 Follow-up of subjects withdrawn from treatment 
             For intention-to-treat analyses all available data from patients will be used.      
             Patients who withdraw will be asked to fill the questionnaire for the         
             measurement of the primary outcomes at 12 months.  
4.7   Premature termination of the study 
  The study will be terminated in its current design as recruitment of the necessary      
  number of cluster fails.  
 
 
5. SAFETY REPORTING 
As all patients will at least receive care similar to usual care, we do not expect any safety 
issues for participants. 
 
6. STATISTICAL ANALYSIS 
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 6 
and 12 month follow up will be analysed with mixed three level linear or logistic 
regression, taking into account that the times of measurement (after 6 and 12 months) 
are clustered within patients, and patients within general practices. We will perform a 

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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. Covariates included in the analyses will be age, sex, 
smoking status, education level, and social support.  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. 
 
6.1 Primary study parameter(s) 
Our primary outcome is a dichotomous composite score ( yes / no MCID improvement in 
health-related quality of life or quality of healthcare), which is based on the scores of 
PROMIS dimensions (GPH, GPM) and the P3CEQ-score.  
To test the effect of the intervention over time, we use a three level multilevel logistic model. 
A model with time , group (intervention or control) and the interaction between time and 
group will be performed. With this model we can test the effect of the intervention during the 
entire study period and the intervention effects at 6 months and at 12 months.  
 
In a mixed model both fixed and random effects can be analyzed. We perform a model with 
random effect for practice and patients. All other variables will be held fixed. Covariates 
included in the analyses will be age, sex, smoking status, education level, and social support. 
 
6.2 Secondary study parameter(s)  
The relationship between treatment and secondary outcome measures measured at 6 and 
12 month follow up will be analysed with mixed three level linear or logistic regression, taking 
into account that the times of measurement (after 6 and 12 months) are clustered within 
patients, and patients within general practices. A model with time, group (intervention or 
control) and the interaction between time and group will be performed. Covariates included in 
the analyses will be age, sex, smoking status, education level, and social support 
 
6.3 Cost analysis 
We will perform two different approaches for cost analysis. First, we will assess total costs 
per capita per month (triple aim measure). Total costs will be calculated from a healthcare 
and a societal perspective. The healthcare perspective includes all costs covered by the 
healthcare budget, i.e. medication prescriptions, contact with care providers (GP, medical 
specialist, nurse, physiotherapist, dietician, podiatrist, occupational therapist), home care, 
hospital admissions, emergency department visits and rehabilitation. The costs from the 

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societal perspective include travel costs and costs of productivity loss due to absence from 
paid work. Total costs will be calculated per group and then divided by the number of 
patients per group and the length of follow-up to assess the total costs per capita per month. 
Data on healthcare utilization and medication prescriptions will be extracted from the 
electronic medical records of the participating general practices. Additional data on 
healthcare utilization as well as data on travel costs and absence from paid work will be 
retrieved from patients by questionnaire at 6 and 12 months. In addition, we will conduct a 
cost-effectiveness analysis in which cost-effectiveness will be assessed in terms of costs per 
quality-adjusted life years (QALY). QALYs will be based on the EuroQol-5D (EQ-5D) utility 
values using the Dutch value set. 
 
7. ETHICAL CONSIDERATIONS 
7.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki and the 
privacy law (AVG). 
 
7.2 Recruitment and consent 
Eligible patients will be invited by telephone or by e-mail by the practice nurse and will be 
asked for oral permission to approach him/her for participation in the study. If the patient is 
interested in participating, a patient infolder folder is shared and personal details (name, e-
mail address and telephone number, and preference for information by e-mail or on paper) 
will be sent to the research team via a secure mail connection. After five days the patient is 
contacted by the research team to obtain informed consent. The research worker creates a 
study ID, records the data in the Access logistic database in the folder H:sleutelbestanden 
and in CASTOR. The study ID consists of the practice number plus a serial number and 
cannot be traced back to an individual. The researcher sends the CASTOR questionnaire for 
baseline measurement to the participant. A notification is set up in CASTOR so that a 
message is sent to the to the mailbox if a questionnaire has been completed. After receiving 
the notification, the research team informs the practice via secure mail that the participant 
can start with the new method of care.  
 
7.3 Benefits and risks assessment, group relatedness 
• 
The intervention has been developed by the three primary care cooperatives in close 
collaboration with their healthcare professionals and their patient panels and with the 
guidance of our research group. Also, input from the Dutch College of General 
Practitioners (NHG) and from InEen, the branch organisation for primary care 

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cooperatives, has been obtained to ensure that the intervention will suit their vision 
and future plans for reorganising Dutch primary care chronic disease management. 
The intervention is also in line with current movements in healthcare, such as the 
Positive Health concept.  
• 
All three primary care cooperatives are intending to gradually implement the 
intervention throughout their regions in the upcoming years. Thus, the GDM 
programme will be implemented and will replace current SDM, even without the 
current cluster RCT as proposed in this study protocol. 
• 
The burden and risks associated with the intervention are negligible and comparable 
with the usual care, i.e. the current SDM programmes.  
• 
Patients in the control group will continue with their care as usual, i.e. single chronic 
disease management according to the protocols of the SMD programmes that have 
been used in the participating cooperatives since the last decade.  
• 
The additional burden or risk associated with participation in this study is negligible. 
After written informed consent, patients in both groups will fill in a digital or paper 
questionnaire at baseline, 6 months, and 12 months. Estimated time to fill in the 
questionnaire is 20 minutes. A purposive sample of approximately 15 patients will 
participate in focus-groups interviews at the end of follow-up.  
 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
7.4 Handling and storage of data and documents 
7.4.1 
Qualitative data 
Personal data (i.e. name, home address, e-mail address, telephone number) are needed to 
identify subjects when contact is needed. The personal data is stored in an Access database 
(key table) and linked to a personal identification number (pseudonym). Only some 
researchers and the research assistant have access to this database. The database is  
stored in a separate, secure folder on the Radboudumc drive (H:sleutelbetanden/CL-
Ketenzorg Ontketend). The pseudonym is used in ATLAS.ti to identify a test subject. We 
make audio recordings of the focus groups. These will be transcribed in Word and stored on  
These transcripts will not contain the names of the study subjects, only the pseudonyms (if 
necessary). The Word documents are permanently saved as PDF and imported into 
ATLAS.ti. The pseudonymised data are stored for 15 years. 
7.4.2 
Quantitative data 
If the subject has indicated a preference for a paper version of the questionnaires, they will 
be sent by regular mail (including a reply envelope) and the data will be entered into Castor 

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EDC by the study employee. The papers are kept in a locked cabinet in room 3.20 (technical 
room number M245.03.350) for the duration of the project. Traceable data will be stored 
separately from the questionnaires for the duration of the pilot, i.e. in a different another 
locked cabinet, but in the same room. Afterwards, research data will be entered into the ELG 
archive (technical room number M245.-02.053). Identification Log and Informed Consent 
forms are stored in a closed cabinet in the ELG archive, thus separate from the data. In 
Castor no personal data is stored. The data is exported to SPSS for analysis. The 
pseudonymised data is stored for 15 years. 
 
7.5 Public disclosure and publication policy 
Science: The findings of the project will be published in international health-related scientific 
peer-reviewed journals, and will serve as the basis for the thesis of the GP trainee / PhD 
candidate on the project. Apart from the international papers, a summary paper with the main 
findings will be prepared for Dutch medical journal (Huisarts & Wetenschap, Nederlands 
Tijdschrift voor Geneeskunde). The results will also be presented at at least two international 
conferences on primary care or integrated care. On the national level, the results will be 
presented at the Dutch GP science day (NHG Wetenschapsdag) and the conferences of the 
GPs with special interest groups for respiratory care (CAHAG), diabetes care (DIHAG) and 
cardiovascular disease care (HartVaatHAG), and at least one national conference on 
integrated care.  
 
Clinical practice: During the final phase of the project, when the trial has been finished, the 
data have been analysed and the final results are available, a 1-day national symposium will 
be organized to present and discuss the findings and their implications. All relevant 
stakeholders will be invited for this symposium, i.e. representatives of all integrated general 
practice care groups (‘zorggroepen’) in the country, health policy makers (ministry of health 
(VWS), Zorginstituut Nederland, InEen, others), the professional organisations of GPs (LHV, 
NHG), practice nurses (V&VN Praktijkverpleegkundigen & Praktijkondersteuners), 
physiotherapists (KNGF), medical specialists (especially chest physicians/NVALT and 
internal medicine specialists/NIV), health insurance companies, relevant charities (Lung 
Foundation, Diabetes Foundation, Heart Foundation) and funding bodies (ZonMw, NutsOhra 
Fund), and patient organisations (NPCF) will be invited. The results will also be brought to 
the attention of the bodies responsible for the national clinical practice guidelines (NHG, 
Federation of Medical Specialists, others).  
 

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Education: If the GDM approach for patients with chronic diseases in primary care turns out 
to be effective, the training for practice nurses and GPs that is developed for the project will 
be made available to all (primary) care organisations that want to switch to this new 
approach. The best way to organize broad access to the training will be explored during the 
final year of the project. The preferred approach will probably be to use existing channels for 
postgraduate training of primary care professionals, for instance through the NHG (or its 
special interest groups) and V&VN. In the exploration we will also consider the best way to 
facilitate uptake of (parts of) the training in the vocational training programs for practice 
nurses  
 
Society: Together with the PR/communication department of Radboudumc we will develop a 
strategy to disseminate the findings to the national press, to other popular media and directly 
to organisations that have an interest in the findings (e.g., health insurance companies, 
chronic care groups etc.). The investigators will be prepared to present and discuss the 
findings at non-scientific meetings (e.g., for health policy makers, regional care organisations 
etc., available time allowing) in the year after the project has finished. 
 
The trial will be registered at clinicaltrials.gov 
All data will be made available from the principal investigator, upon reasonable request 
 
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multimorbiditeit/cijfers-context/huidige-situatie#node-aantal-mensen-met-
multimorbiditeit-bekend-bij-de-huisarts. 
2. Jani, B.D., et al., Relationship between multimorbidity, demographic factors and mortality: 
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3. Williams, J.S. and L.E. Egede, The Association Between Multimorbidity and Quality of 
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4. Lehnert, T., et al., Review: health care utilization and costs of elderly persons with multiple 
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6. Nederland), N.H.C.I.Z., [In-depth analyses healthcare costs zvw 2015]. 2018. 
7. van Weel, C. and F.G. Schellevis, Comorbidity and guidelines: conflicting interests. 
Lancet, 2006. 367(9510): p. 550-1. 
8. Hughes, L.D., M.E. McMurdo, and B. Guthrie, Guidelines for people not for diseases: the 
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Barnett, K., et al., Epidemiology of multimorbidity and implications for health care, 
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Leijten, F.R.M., et al., The SELFIE framework for integrated care for multi-morbidity: 
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Lloyd, H., et al., Validation of the person-centred coordinated care experience 
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