The Impact of Self-quarantining on Glycemic Control, Diabetes Self-management and Distress During the Coronavirus Outbreak
Conditions: Type 1 Diabetes, Type 2 Diabetes
Sponsor: Leiden University Medical Center

NL73778.058.20   
 
COVID-19 glycemic control study 
 
 
 
 
 
 
 
 
 
 
 
 
The impact of self-quarantining on  
glycemic control, diabetes self-management 
and distress during the coronavirus outbreak 
 
 
 
 
 

NL73778.058.20   
 
COVID-19 glycemic control study 
 
 
 
PROTOCOL TITLE ‘The impact of self-quarantining on glycemic control, diabetes self-
management and distress during the coronavirus outbreak’ 
 
Protocol ID 
NL73778.058.20 
Short title 
‘The impact of self-quarantining on glycemic control, 
diabetes self-management and distress’ 
EudraCT number  
NA 
Version 
1.1 
Date 
24-04-2020 
Coordinating investigator/project 
leader 
 
Prof. E. J. P. de Koning 
Department of Internal Medicine: Endocrinology 
Leiden University Medical Center 
PO Box 9600 
2300 RC LEIDEN 
The Netherlands 
Tel: +31 71 526 2085 
E-mail: e.j.p.de_koning@lumc.nl 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
Prof. E. J. P. de Koning (diabetologist) 
Tel: +31 71 526 2085 
E-mail: e.j.p.de_koning@lumc.nl 
Dr. S. D. Huisman (clinical psychologist) 
Tel: +31 71 529 8104 
E-mail: s.d.huisman@lumc.nl 
 
Drs. M. M. Ruissen (Clinical researcher) 
Tel: +31 71 529 6993 
E-mail: m.m.ruissen@lumc.nl 
 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Leiden Universitair Medisch Centrum (LUMC) 
 
 
Subsidising party 
Department of Internal Medicine, LUMC 
Independent expert(s) 
Dr. P.J.M. van der Boog (NIERZ) 
pGSM: 98994: p.j.m.van_der_boog@lumc.nl 
 
 
 
 

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Laboratory sites  
Leiden Universitair Medisch Centrum (LUMC) 
 
 
Pharmacy  
NA 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
 
Head of Department: 
 
Department of Internal Medicine: 
Endocrinology, 
Leiden University Medical Center 
 
 
 
 
Coordinating Investigator/Project 
leader/Principal Investigator: 
 
Prof. E. J. P. de Koning, 
diabetologist 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE ................................................................................ 11 
2. 
OBJECTIVES .................................................................................................................... 13 
3. 
STUDY DESIGN ............................................................................................................... 14 
4. 
STUDY POPULATION...................................................................................................... 15 
4.1 
Population (base) ...................................................................................................... 15 
4.2 
Inclusion criteria ......................................................................................................... 15 
4.3 
Exclusion criteria........................................................................................................ 15 
4.4 
Sample size calculation ............................................................................................. 15 
5. 
TREATMENT OF SUBJECTS .......................................................................................... 16 
5.1 
Investigational product/treatment .............................................................................. 16 
5.2 
Use of co-intervention (if applicable) ......................................................................... 16 
5.3 
Escape medication (if applicable) ............................................................................. 16 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................... 17 
6.1 
Name and description of investigational  product(s) ................................................. 17 
6.2 
Summary of findings from non-clinical studies ......................................................... 17 
6.3 
Summary of findings from clinical studies ................................................................. 17 
6.4 
Summary of known and potential risks and benefits ................................................ 17 
6.5 
Description and justification of route of administration and dosage ......................... 17 
6.6 
Dosages, dosage modifications and method of administration ................................ 17 
6.7 
Preparation and labelling of Investigational Medicinal Product ................................ 17 
6.8 
Drug accountability .................................................................................................... 17 
7. 
NON-INVESTIGATIONAL PRODUCT ............................................................................. 18 
7.1 
Name and description of non-investigational product(s) .......................................... 18 
7.2 
Summary of findings from non-clinical studies ......................................................... 18 
7.3 
Summary of findings from clinical studies ................................................................. 18 
7.4 
Summary of known and potential risks and benefits ................................................ 18 
7.5 
Description and justification of route of administration and dosage ......................... 18 
7.6 
Dosages, dosage modifications and method of administration ................................ 18 
7.7 
Preparation and labelling of Non Investigational Medicinal Product ........................ 18 
7.8 
Drug accountability .................................................................................................... 18 
8. 
METHODS ........................................................................................................................ 19 
8.1 
Study parameters/endpoints ..................................................................................... 19 
8.1.1 
Main study parameter/endpoint ......................................................................... 19 
8.1.2 
Secondary study parameters/endpoints (if applicable) ..................................... 19 
8.1.3 
Other study parameters (if applicable) ............................................................... 19 
8.2 
Randomisation, blinding and treatment allocation .................................................... 19 
8.3 
Study procedures ...................................................................................................... 19 
8.4 
Withdrawal of individual subjects .............................................................................. 20 
8.4.1 
Specific criteria for withdrawal (if applicable) ..................................................... 20 
8.5 
Replacement of individual subjects after withdrawal ................................................ 20 
8.6 
Follow-up of subjects withdrawn from treatment ...................................................... 20 

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8.7 
Premature termination of the study ........................................................................... 20 
9. 
SAFETY REPORTING...................................................................................................... 21 
 
Error! Bookmark not defined. 
9.2 
AEs, SAEs and SUSARs ........................................................................................... 21 
9.2.1 
Adverse events (AEs) ........................................................................................ 21 
9.2.2 
Serious adverse events (SAEs) ......................................................................... 21 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .......................... 22 
9.3 
Annual safety report .................................................................................................. 22 
9.4 
Follow-up of adverse events ..................................................................................... 22 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ................................... 22 
10. 
STATISTICAL ANALYSIS ............................................................................................. 22 
10.1 
Primary study parameter(s) ....................................................................................... 23 
10.2 
Secondary study parameter(s) .................................................................................. 23 
10.3 
Other study parameters ............................................................................................. 25 
10.4 
Interim analysis (if applicable) ................................................................................... 25 
11. 
ETHICAL CONSIDERATIONS ..................................................................................... 26 
11.1 
Regulation statement ................................................................................................. 26 
11.2 
Recruitment and consent .......................................................................................... 26 
11.3 
Objection by minors or incapacitated subjects (if applicable) ................................... 26 
11.4 
Benefits and risks assessment, group relatedness .................................................. 26 
11.5 
Compensation for injury............................................................................................. 27 
11.6 
Incentives (if applicable) ............................................................................................ 27 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .......................... 28 
12.1 
Handling and storage of data and documents .......................................................... 28 
12.2 
Monitoring and Quality Assurance ............................................................................ 28 
12.3 
Amendments .............................................................................................................. 29 
12.4 
Annual progress report .............................................................................................. 29 
12.5 
End of study report .................................................................................................... 29 
12.6 
Public disclosure and publication policy .................................................................... 29 
13. 
STRUCTURED RISK ANALYSIS ................................................................................. 30 
13.1 
Potential issues of concern ....................................................................................... 30 
13.2 
Synthesis ................................................................................................................... 30 
14. 
REFERENCES .............................................................................................................. 31 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
 
 
AE 
Adverse Event 
AR 
BMI 
Adverse Reaction 
Body Mass Index 
CA 
Competent Authority 
CGM 
COVID-19 
Continuous Glucose Monitoring 
Coronavirus 
CV 
DM 
Curriculum Vitae 
Diabetes Mellitus 
DSMB 
DSMQ-R 
Data Safety Monitoring Board 
Diabetes Self-Management Questionnaire 
EU 
European Union 
EudraCT 
European drug regulatory affairs Clinical Trials  
FGM 
FSL 
GCP 
Flash Glucose Monitoring 
FreeStyleLibre 
Good Clinical Practice 
GDPR 
 
HbA1c 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
Glycated Hemoglobin 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
LUMC 
Investigational Medicinal Product Dossier  
Leiden University Medical Center 
METC  
 
NA 
PAID 
PI 
PSS 
QoL 
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
Not Applicable 
Problem Areas In Diabetes 
Principal investigator 
Perceived Stress Scale 
Quality of Life 
(S)AE 
SDSCA 
SMBG 
(Serious) Adverse Event  
Summary of Diabetes Self-Management Activities 
Self-monitoring of Blood Glucose 
SPC 
Summary of Product Characteristics; in Dutch: officiële productinformatie 

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IB1-tekst 
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. 
SUSAR  
T1DM 
T2DM 
Suspected Unexpected Serious Adverse Reaction 
Type 1 Diabetes Mellitus 
Type 2 Diabetes Mellitus 
UAVG 
 
WHO-5 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
Well-being questionnaire 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Diabetes mellitus is a chronic disease characterized by the inability of the body to 
maintain normoglycemia. Treatment of diabetes relies mostly on diabetes self-management, 
requiring a large investment of time and energy on a daily basis. Psychological wellbeing, 
behavioral patterns and social context have shown to play a major role in diabetes-self-
management and glycemic control. Self-quarantining may impact glycemic control by 
influencing daily routines, self-measurement behavior, therapy adherence, physical activity 
and eating behaviors. A period of nationwide self-quarantine, such as during the outbreak of 
COVID-19 in the Netherlands, therefore may have a large effect on glycemic control in 
patients with diabetes.  
Objective: We aim to assess the impact of long-term self-quarantine on glycemic control, 
diabetes self-management and distress in patients with type 1 diabetes mellitus (T1DM) and 
type 2 diabetes mellitus (T2DM).  
Study design: This is an observational cross sectional study in Dutch patients with diabetes 
mellitus in tertiary care after self-quarantine for at least 6 weeks as result of the COVID-19 
pandemic. Patients treated at the diabetes outpatient clinic of the Leiden University Medical 
Center (LUMC) will be approached for potential study participation. Measurements will be 
performed during the quarantine period or as soon as possible after. Patients will be asked to 
perform a fingerprick for HbA1c measurement once, which they can send back to the LUMC 
by mail. In addition, data from continuous glucose monitoring (CGM) or flash glucose 
monitoring (FGM) devices will be collected according to standard clinical practice. 
Furthermore, patients will be asked to fill out an online questionnaire once on diabetes self-
management behaviour, well-being and distress, along with questions about health status, 
level of education, medication use, employment, social situation and the impact of self-
quarantine on daily routines. 
Data on demographics, type of diabetes, weight, BMI and HbA1c prior to the COVID-19 
outbreak will be derived from the electronic health dossier of the patient. The most recent 
HbA1c will be used for data analysis.   
Study population: Patients with T1DM and T2DM that are currently in care at the outpatient 
diabetes clinic of the LUMC are eligible for participation. 
Intervention (if applicable): NA 
Main study parameters/endpoints: The main study parameter is glycemic control in 
patients with T1DM and T2DM assessed by HbA1c. We will also determine the change in 
HbA1c per patient group, as well as glucose variability, assessed by the standard deviation 
of glucose values in patients wearing continuous and flash glucose sensors, and the change 
in glucose variability before and after the nation-wide self-quarantine phase for COVID-19. In 

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addition, self-management, well-being and distress will be measured, using the DSMQ-R, 
SDSCA, WHO-5, PSS and PAID questionnaire.  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
The risks associated with participation in this study are limited. The primary potential 
foreseeable risk associated with participation in this study is negative feelings resulting from 
the increased attention to the patient’s illness and distress by filling out the questionnaires. 
Additionally, there is a limited burden of time for the patient for performing the fingerprick and 
filling out the questionnaires, however, this time is limited and the measurement is being 
performed only once. Performing the fingerprick may be another foreseeable risk, however, 
for most patients performing a fingerprick for measurement of blood glucose values is 
already part of their regular daily routine.  
 
 

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1. INTRODUCTION AND RATIONALE 
 
In the early Spring of 2020 the worldwide pandemic viral outbreak of COVID-19 caused a 
rapid increase in morbidity and mortality especially in patients. In an attempt to control the 
outbreak, many countries implemented forms of mass quarantine. Quarantine strategies 
diverged from total lock-down of cities or countries, voluntary home curfews, travel 
restrictions and prohibition of public and social events (1). In all affected countries these 
strategies required major adaptations of behavioral patterns, social activities and 
employment of the population.  
Such sudden and major disruptions from every-day-life are known to influence both mental 
and physical health. Recent studies describing the psychological impact of quarantine, 
showed that experiencing quarantine is related to a wide range of stress and mood related 
symptoms, such as depression, anxiety, irritability, poor concentration, insomnia and post-
traumatic stress disorder (PTSD)(1, 2). Longer periods of quarantine have been associated 
with increased chances of developing PTSD. In addition, several studies suggest that such 
symptoms might even last long after ending quarantine (1, 2).  
Recent studies and global media suggest that individuals with diabetes mellitus (DM) are at 
higher risk for complications and death from COVID-19 (3). Especially patients with T2DM, 
who are frequently overweight and have other comorbidities such as hypertension and 
cardiovascular disease are at a high risk for a complicated course of COVID-19 (4). People 
with diabetes and their relatives may therefore experience increased feelings of stress, fear 
and anxiety regarding the risk of being infected with the coronavirus. And additionally, they 
may put even greater emphasis on the importance of self-quarantine.  
Emotional distress as well as changes in daily structures and behaviors are known to 
influence diabetes self-management and glycemic control (5-8). Maintaining glycemic control 
during self-quarantine can therefore be challenging. Alterations in physical activity, diet and 
daily patterns may result in an imbalance between blood glucose values and the amount of 
insulin injected or other drugs prescribed, resulting in glycemic dysregulation (9-11). 
Furthermore, feelings of anxiety or distress towards the situation may further increase blood 
glucose values and add to the psychological burden of disease (5-8, 12). 
The current study aims to assess the impact of self-quarantine on glycemic control in 
patients with type 1 and type 2 diabetes. In addition, this study describes diabetes self-
management, well-being and distress in Dutch patients with type 1 and type 2 diabetes, 
during a nationwide period of self-quarantine.  
It is hypothesized that experiencing this period of nationwide quarantine influences glycemic 
control and that patients reporting severe distress or low well-being experience more 

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problems in regard to diabetes self-management and maintaining glycemic control than 
those without psychological distress or low well-being (13).  
Research hypotheses: 
H1: Experiencing self-quarantine impacts glycemic control and glucose variability  
H2: a) Experiencing high levels of distress is related to (poorer) glycemic control  
H2: b) Experiencing low levels of well-being is related to (poorer) glycemic control  
H3: a) Experiencing high levels of distress is related to suboptimal diabetes self-
management  
H3: b) Experiencing low levels of well-being is related to suboptimal diabetes self-
management  
H4: Experiencing self-quarantine impacts HbA1c, glucose variability, well-being, distress and 
self-management more in patients with type 1 than in patients with type 2 diabetes  
 
 
 
 

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2. OBJECTIVES 
 
Primary Objective:  
- 
To determine the effect of a period of nationwide self-quarantine on glycemic control, 
assessed by HbA1c, in patients with type 1 and type 2 diabetes  
Secondary Objective(s): 
- 
To determine the effect of a period of nationwide self-quarantine on glucose variability 
assessed by the standard deviation (SD) of glucose values (glucose variability) in 
patients with type 1 and type 2 diabetes 
- 
To assess the association between well-being and glycemic control during a period of 
nationwide self-quarantine. Well-being will be measured by the WHO-5. 
- 
To assess the association between (diabetes) distress and glycemic control during a 
period of nationwide self-quarantine. (Diabetes) distress will be measured by 
‘Perceived Stress Scale’(PSS) and ‘Problem Areas in Diabetes’ (PAID). 
- 
To assess the association between diabetes self-management and glycemic during a 
period of nationwide self-quarantine. Self-management behaviour will be measured 
by the ‘Summary of Diabetes Self-Care Activities’ (SDSCA) and ‘Diabetes Self-
Management Questionnaire-rev.’ (DSMQ-R) 
- 
To determine differences HbA1c, glucose variability, well-being, distress and self-
management between patients with type 1 and type 2 diabetes  

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3. STUDY DESIGN 
 
This study is an observational, cross sectional study to assess the impact of self-quarantining 
on glycemic control, diabetes self-management, distress and well-being. Patients with type 1 
and type 2 diabetes mellitus currently in care at the diabetes outpatient clinic of the LUMC 
will be eligible to participate and will receive information about this study and an informed 
consent form. A few days later they will be contacted by phone to resolve any questions they 
may have and ask if the patient wants to participate in the study. If patients want to 
participate, they will sign the informed consent form and send it to the LUMC by mail. Once 
informed consent is provided, patients will be sent an envelope including a fingerprick device 
and a small tube. They will be asked to fill the tube with several drops of blood up to a mark 
on the tube and send the envelope back to the LUMC postage free. At the LUMC the HbA1c 
will be measured by the clinical chemistry lab. If the patients wears a continuous or FSL 
sensor, sensor data will be collected according to standard clinical practice. Furthermore, 
patients will receive a link by e-mail to a set of online questionnaires, containing the DSMQ-
R, SDSCA, PSS, PAID and WHO-5, along with questions about level of education, 
medication use, employment, social situation and the impact of self-quarantine on daily 
routines. The HbA1c measurement and questionnaire will be performed at least 6 weeks 
after starting the quarantine period but still within a period of quarantine measures.  
Questionnaires will assess the extent and impact of the quarantine measures for each 
individual patient and assess the effect on glycemic control, distress and well-being. Data on 
HbA1c measurements in the 12 months prior to the period of nationwide self-quarantine will 
be retrieved from the electronic health record of each patient, if available.  
  
 

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4. STUDY POPULATION 
 
4.1. 
Population (base)  
Patients with type 1 diabetes and type 2 diabetes will be recruited from the diabetes 
outpatient clinic of the LUMC.  
 
4.2. 
Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
- 
Age ≥ 18 years 
- 
Diagnosed with type 1 or type 2 diabetes  
- 
Ability to perform fingerpricks 
- 
Sufficient comprehension of the Dutch language 
- 
Ability to fill out online questionnaires 
 
4.3. 
Exclusion criteria 
A potential subject who meets the following criterium will be excluded from participation in 
this study: 
- 
Pregnancy 
- 
Newly diagnosed malignancy, with the exclusion of non-melanoma skin cancer, in the 
previous 6 months 
- 
Chemotherapy or immunotherapy for malignancy 
- 
Admission to hospital or rehabilitation center 
 
4.4. 
Sample size calculation 
Patients with type 1 and type 2 diabetes mellitus are eligible for participation. HbA1c is the 
primary outcome parameter. Blood for HbA1c will be collected at home by a fingerprick and 
send to the LUMC. This is a method to obtain insight in glycemic control that many patients 
perform, and prefer, in clinical practice as it saves them a visit to the hospital. The clinical 
laboratory in the LUMC is set up to analyse these samples. But this method, which is 
appropriate in the context of social distancing and limiting hospital visits during this COVID-
19 outbreak, also has some consequences regarding the number of patients that need to be 
approached. From clinical practice we know that not all patients carry out the blood sampling 
in an appropriate way, despite clear instructions. Also the duration in the postal service 
renders some samples not suitable for analysis. In this COVID-19 period the postal service 

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may take longer than normal. Based on our experience from clinical practice and the current 
COVID-19 situation we estimate that 20% of samples cannot be analysed for HbA1c.     
The aim is to detect a difference in HbA1c of 4.0 mmol/mol (standard deviation 11 mmol/mol) 
in comparison to the HbA1c prior to the period of quarantine, which is considered to be 
clinically relevant in our population of patients with often well regulated diabetes. For an 
alpha error of 0.05 and a power of 90%, the minimum sample needed is 159 patients per 
patient group (type 1 and type 2 diabetes). Taking in consideration an estimated response 
rate of 35% and an estimated proportion of 20% of HbA1c missing measurements as a result 
of logistical, practical or technical problems, 568 patients per patient group (type 1 and type 2 
diabetes) will be invited to participate. This is a total of 1136 patients.  
The numbers of participants mentioned above are much higher than the number that is 
minimally needed (15 per variable) to calculate the hierarchical regression analyses (see 
statistical analyses) on secondary outcomes.   
 
 
5. TREATMENT OF SUBJECTS 
NA. Observational cross-sectional study.  
 
5.1. 
Investigational product/treatment 
NA 
5.2. 
Use of co-intervention (if applicable) 
NA 
5.3. 
Escape medication (if applicable) 
NA  

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6. INVESTIGATIONAL PRODUCT  
NA. Observational cross-sectional study. 
  
6.1. 
Name and description of investigational  product(s) 
 
NA 
6.2. 
Summary of findings from non-clinical studies 
NA 
6.3. 
Summary of findings from clinical studies 
NA 
6.4. 
Summary of known and potential risks and benefits 
NA 
6.5. 
Description and justification of route of administration and dosage 
NA 
6.6. 
Dosages, dosage modifications and method of administration 
NA 
6.7. 
Preparation and labelling of Investigational Medicinal Product 
 
NA 
6.8. 
Drug accountability 
NA 
 

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7. NON-INVESTIGATIONAL PRODUCT 
NA. Observational cross-sectional study. 
  
7.1. 
Name and description of non-investigational product(s) 
NA 
7.2. 
Summary of findings from non-clinical studies 
 
NA 
7.3. 
Summary of findings from clinical studies 
NA 
7.4. 
Summary of known and potential risks and benefits 
NA 
7.5. 
Description and justification of route of administration and dosage 
NA 
7.6. 
Dosages, dosage modifications and method of administration 
NA 
7.7. 
Preparation and labelling of Non Investigational Medicinal Product 
NA 
7.8. 
Drug accountability 
NA 
 

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8. METHODS 
8.1. 
Study parameters/endpoints 
8.1.1. Main study parameter/endpoint 
Glycemic control assessed by HbA1c (mmol/mol)  
8.1.2. Secondary study parameters/endpoints (if applicable) 
- 
Glucose variability assessed by the standard deviation (SD) of glucose values during 
continuous or flash glucose monitoring  
- 
Extent of well-being as assessed by the WHO-5 
- 
Extent of psychological distress as assessed by the ‘Perceived Stress Scale’(PSS) 
and ‘Problem Areas in Diabetes’(PAID) 
- 
Evaluation of self-management behaviour measured by ‘Summary of Diabetes Self-
Care Activities’(SDSCA) and ‘Diabetes Self-Management Questionnaire’ (DSMQ-R) 
8.1.3. Other study parameters (if applicable) 
Baseline characteristics: age, gender, length, weight, type of diabetes, level of education,     
medication use, social situation, employment, impact of self-quarantine on daily routines, and 
health status.  
 
8.2. 
Randomisation, blinding and treatment allocation 
NA 
 
8.3. 
Study procedures 
Eligible patients from the diabetes outpatient clinic will be sent a letter with study 
information and informed consent forms. Within several days after receiving the letter, 
patients will be contacted by phone and will be invited to participate in the study as 
well as given the opportunity to ask questions. If patients are willing to participate they 
will be asked to sign the informed consent form and send it back to the LUMC by 
mail. Once informed consent is provided, patients will be sent a HbA1c fingerprick 
measurement envelope. They will be asked to fill the tube with several drops of blood 
up to a mark on the tube and send the envelope back to the LUMC postage free. At 
the LUMC the HbA1c will be measured by the clinical chemistry lab.  
If patients are using a continuous or flash glucose monitoring device data of the most 
recent 3 months will be collected according to standard clinical practice. 
Additionally, patients will receive a link in their e-mail to a set of online questionnaires, 
containing the DSMQ-R, SDSCA, PSS, PAID and WHO-5, along with questions about 
level of education, medication use, social situation, employment, impact of self-

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quarantine on daily routines, and health status.  
The HbA1c measurement and questionnaire will be performed once two months after 
the start of the nationwide quarantine phase as a result of the COVID-19 outbreak.   
Data on HbA1c measurements in the 6 months prior to the period of nationwide self-
quarantine will be retrieved from the electronic health record of each patient.  
 
8.4. 
Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. 
8.4.1. Specific criteria for withdrawal (if applicable) 
- 
Patient tested COVID-19 positive within 2 weeks after the HbA1c measurement 
- 
Patient diagnosed with a malignancy, potentially resulting in unreliable HbA1c values  
- 
Patient pregnant during HbA1c measurement in retrospect 
 
8.5. 
Replacement of individual subjects after withdrawal 
No replacement of individual subjects will take place after withdrawal. 
 
8.6. 
Follow-up of subjects withdrawn from treatment 
This is an observational cross-sectional study without any follow-up period.  
 
8.7.  Premature termination of the study 
 The study will be terminated prematurely if the nationwide quarantine is unexpectedly lifted 
within a week. In that case, the inclusion of participants will be stopped. Also, the study will 
be terminated if it is temporarily suspended for reasons of subjects’ safety and the accredited 
METC gives a negative decision after assessing the reasons that led to the temporary 
suspension (see below).   
 

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9. SAFETY REPORTING 
9.1. 
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 subject 
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 subjects are kept informed.  
 
9.2. 
AEs, SAEs and SUSARs 
 
 
9.2.1. Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the study procedure. All 
adverse events reported spontaneously by the subject or observed by the investigator 
or his staff will be recorded. 
 
9.2.2. Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
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 of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 

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period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
 
 
9.2.3. Suspected unexpected serious adverse reactions (SUSARs) 
 
         NA.  
 
9.3. 
Annual safety report 
 
         NA.  
 
9.4. 
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 physician or a medical specialist. SAEs need to be 
reported till end of study within the Netherlands, as defined in the protocol.  
 
9.5. 
[Data Safety Monitoring Board (DSMB) / Safety Committee] 
NA. This is an observational cross-sectional study without any follow-up period.  
 
 
 
10. STATISTICAL ANALYSIS 
- 
Categorical data: gender, level of education, type of diabetes, medication use, type of 
blood glucose measurements (fingerprick or glucose sensor (FGM/CGM)) will be 
presented by percentage and standard deviation (SD).  
- 
Continuous variables: age, BMI, weight, height, HbA1c will be presented using the 
mean and the standard deviation (SD). Derived parameters: BMI will be calculated 
from height (m) and weight (kg) using the formula (weight (kg)/(height (m))2 and will 
be presented as continuous variable by mean and standard deviation (SD). Glucose 
variability will be calculated by the standard deviation of the glucose values from the 
continuous and flash glucose monitors obtained during the previous week in the 
quarantine period. This SD will be compared to the SD from the glucose values during 
the last non-quarantine week. Other glycemic measures include time spent in range 
4.0-10.0 mmol/l, time spent in hypoglycaemia (<3.0, 3.0-3,5, and 3.5-3.9 mmol/l), time 
spent in hyperglycemia (≥ 10.0 mmol/l) 
- 
Missing data will be excluded from analyses. 

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- 
Data will be statistically analysed using STATA intercooled 16.0. HbA1c 
measurements and SD measurements prior to and after the quarantine period will be 
compared using a paired-sample t-test in case of normal distribution or Wilcoxon 
Signed Rank Test in case of abnormal distribution. Furthermore, differences in HbA1c 
and glucose variability between patients with type 1 and type 2 diabetes will be 
measured using independent T-tests. Differences in well-being, distress and self-
management between patients with type 1 and type 2 diabetes will be analysed using 
independent T-tests. The association between glucose variability and parameters for 
distress, well-being and self-management will be analysed using multivariate 
regression analysis.   
 
10.1. Primary study parameter(s) 
HbA1c 
HbA1c will be assessed in whole blood obtained by a fingerprick. The HbA1c will be 
compared to the last HbA1c in the non-quarantine period.   
   
10.2. Secondary study parameter(s)  
Standard deviation (SD) of glucose values 
In patients who wear a continuous or flash glucose sensor the SD of the glucose values 
will be determined in the previous week before uploading the glucose data during the 
quarantine period. The SD will be compared to the SD during the last non-quarantine 
week.  
 
Well-being (WHO-5) 
To measure the extent of well-being we will administer the WHO-5 Well-Being Index 
(WHO-5). The WHO-5 is one of the most widely used questionnaires assessing well-
being and consists of five simple, non-invasive questions (14). The five items are 
assessed on a 6-point Likert scale  ranging from 0 to 5 and the individual item scores are 
added together and transformed into a 100 point scale with lower scores indicating worse 
well-being.  The WHO-5 has been found to correlate moderately to strongly with diabetes 
specific measures of distress and depression in both T1DM and T2DM (15, 16).  
 
Stress: PSS 
Perceived Stress Scale (PSS): The PSS is a 10 item scale designed to measure the 
degree to which situations’ in one’s life are appraised as stressful (17).  Participants rate 
each item based on their recall of the past month and the degree to which they perceived 

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events as being stressful on a 5 point scale (never –almost never – sometimes – fairly 
often – very often). Four positively stated items are the reverse scored and then all scores 
are summed for an overall perceived stress score with higher score representing more 
perceived stress. A validated Dutch version is available.  
 
Diabetes Distress: PAID 
The Problem Areas in Diabetes (PAID) questionnaire is a 20-item measure of 
psychosocial adjustment to diabetes (18). Each of the 20 items represents a unique area 
of diabetes-related distress which are rated on a 5 point Likert scale (range = 0-4). These 
individual items are then added together and multiplied by 1.25 to transform the raw score 
into a 0-100 scale with higher scores representing increased emotional distress. The 
PAID was developed for routine clinical usage in both T1DM and T2DM. The PAID has 
been validated in Dutch (19).  
 
 
Diabetes Self-Management: SDSCA and DSMQ-R  
The Summary of Diabetes Self-Care Activities (SDSCA) .The SDCSA is a short 
questionnaire that covers basic aspects of diabetes self-care in regards to general diet, 
specific diet, exercise, blood-glucose testing, foot care, and smoking (20). The core 
questionnaire consists of 11 questions but it can be expanded and adapted to specific 
needs using the additional self-care items published with the original instrument. The core 
set of questions has been validated in Dutch. 
The Diabetes Self-Management Questionnaire-Revised (DSMQ-R) questionnaire is a 
revision of the original Diabetes Self-Management Questionnaire and contains 20- items 
that asks the patient about their self-management based on the previous days (21). 
These items can be grouped into four subscales  (glucose management, dietary control, 
physical activity, and physician contact) from which an overall sum score for ‘diabetes 
self-management’ can be calculated. All subscales as well as the overall sum score have 
shown to be highly correlated with levels of HbA1c. Additionally, the revised version has 
an additional 7-item subscale containing questions specific to insulin usage intended for 
patients using insulin.  
 
Relationship between well-being/distress and glycemic control  
To assess the relationship between well-being/distress and glycemic control, a (stepwise) 
hierarchical regression analysis will be performed, with HbA1c during self-quarantine as 
dependent variable and demographics (age, gender, education), diabetes/treatment 
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stress (PSS) and distress (PAID) as independent variables. 
 
Relationship between well-being/distress and diabetes self-management 
To assess the relationship between well-being/distress and self-management, five 
separate (stepwise) hierarchical regression analyses will be performed, with the total 
DSMQ-R self-management score, and four (DSMQ-R) diabetes self-management 
subscale scores (glucose management, dietary control, physical activity, physician 
contact) as five separate dependent variables. Independent variables are: demographics 
(age, gender, education) and diabetes/treatment related variables (type of diabetes, 
medication), well-being, stress (PSS) and distress (PAID). 
 
10.3. Other study parameters 
NA 
 
10.4. Interim analysis (if applicable) 
NA. This is a observational cross-sectional study.  

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11. ETHICAL CONSIDERATIONS 
11.1. Regulation statement 
The study will be conducted according to the principles of the ‘declaration of Helsinki' (as 
amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013) and in 
accordance with the Medical Research Involving Human Subjects Act (WMO). 
 
11.2. Recruitment and consent 
Patients with type 1 and type 2 diabetes that are currently in care at the diabetes 
outpatient clinic will be sent a letter with study information and informed consent forms. 
Within several days after receiving the letter, patients will be contacted by phone by a 
member of the study team and invited to participate in the study as well as given the 
opportunity to ask questions. If patients are willing to participate they will be asked to sign 
the informed consent form and send it back to the LUMC by post. Once informed consent 
is provided, patients will be sent an envelope with a lancet, small tube and instructions to 
collect blood with a fingerprick. They will be asked to fill the tube that is in the envelope 
with several drops of blood until the mark on the tube is reached and send the envelope 
(special envelope for medical samples) back to the LUMC. At the LUMC the HbA1c will 
be measured by the clinical chemistry lab.  
If patients are using a continuous or flash glucose monitor, data will be collected 
according to standard clinical practice and will be covering the last non-quarantine week 
and the quarantine period. 
Additionally, patients will receive a link in their e-mail to a set of online questionnaires, 
containing the DSMQ-R, SDSCA, PSS, PAID and WHO-5, along with questions about 
level of education, medication use, social situation, employment, impact of self-quarantine 
on daily routines.  
The HbA1c measurement and questionnaire will be performed once at the predicted end 
of the nationwide quarantine phase as a result of the COVID-19 outbreak.  
 
11.3. Objection by minors or incapacitated subjects (if applicable) 
NA. Minors and incapacitated subjects are not eligible to participate.  
 
11.4. Benefits and risks assessment, group relatedness 
The risks associated with participation in this study are limited. The primary potential 
foreseeable risk associated with participation in this study is negative feelings resulting from 

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the increased attention to the patient’s illness and distress by filling out the questionnaires. 
Additionally, there is a burden of time for the patient for performing the fingerprick and filling 
out the questionnaires, however, this time is limited and the measurement is being performed 
only once. Performing the fingerprick may be another forseeable risk, however, for most 
patients performing the fingerprick for measurement of blood glucose values is already part 
of their regular daily routine. 
 
11.5. Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the 
WMO. The sponsor (also) has an insurance which is in accordance with the legal 
requirements in the Netherlands (Article 7 WMO). This insurance provides cover for damage 
to research subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
11.6. Incentives (if applicable) 
Not applicable 
 
 
 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1. Handling and storage of data and documents 
- 
All data will be handled confidentially and will be coded, according to the EU General 
Data Protection Regulation and Dutch Act on Implementation of the General Data 
Protection Regulation (AVG/UAVG). All data will be preserved for 15 years. A secure 
datasafe folder is used for all output and storage of all data. Only the researchers 
have access to this folder.  
- 
Consent forms will be stored securely in a locked cabinet at the at the Leiden 
University Medical Center by the researchers. After giving consent, each patient will 
be provided with an unique study code. This unique study code contains no traceable 
data, such as birth date or names. This will be generated by a secured online 
database (CASTOR). CASTOR will be used to gather questionnaire data. No 
traceable data is stored in CASTOR. Access to CASTOR is restricted to only the 
researchers conducting the study. Two factor authorization is used to enter the 
database. After filling out the questionnaires, the export of the coded data is stored by 
the researcher in the datasafe. A secured list with restricted access (HIX eigen lijsten) 
will be used to enable coupling of the patient ID to the CASTOR study code, to ensure 
that HbA1c measurements can be matched to the questionnaire outcomes. Only the 
researchers of this study will have access to this list. The management of the key HIX 
and study ID is the responsibility of the PI. In the analysis phase of the study, the 
researchers do not have access to this key file.  
- 
Patients’ continuous or flash glucose measurements (FSL) will be collected according 
to standard clinical practice. They will be stored by study ID in the datasafe with 
access restricted to the researchers.  
- 
HbA1c measurements will be done by the clinical laboratory of the LUMC and data 
will be stored in the electronic health dossier (HIX) using the patient ID. The blood 
sample is destroyed by the clinical laboratory immediately after use.  
 
 
 
12.2. Monitoring and Quality Assurance  
Monitoring will be executed by (internal) monitors of the LUMC according to the 
monitoring plan.   
 

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12.3. 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 and the competent authority, but will be recorded and filed by the sponsor.  
 
12.4. Annual progress report 
 
N.A. 
 
12.5. 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 'completion of the report on primary 
and secondary outcomes'.  
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.  
 
12.6. Public disclosure and publication policy 
Results will be presented at national and international (diabetes) conferences, and 
published in peer reviewed (inter)national journals. 

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13. STRUCTURED RISK ANALYSIS  
NA. This study is a cross-sectional study, based on self-report data.  
 
13.1. Potential issues of concern 
NA. 
 
13.2. Synthesis 
NA 
 
 
 
 

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