Effect of Continuous Glucose Monitoring on Hypoglycemia in Adults With Pancreatogenic Diabetes
Phase: NA
Conditions: Pancreatogenic Type 3C Diabetes Mellitus
Sponsor: Aalborg University Hospital

 
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Characterization of glucose variability and hypoglycaemia in 
patients with post-pancreatitis diabetes mellitus 
 
Aalborg University Hospital 
 
 

 
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Table of contents 
1. Glossary .................................................................................................................................................................. 5 
2. General information ............................................................................................................................................... 6 
3. Funding ................................................................................................................................................................... 8 
4. Roles and responsibilities ....................................................................................................................................... 9 
5. Time schedule ........................................................................................................................................................10 
6. Purpose and scientific background ........................................................................................................................10 
6.1 Introduction and purpose ....................................................................................................................................... 10 
6.2 Scientific background and literature review ........................................................................................................... 11 
6.2.1 Pathophysiology of post-pancreatitis diabetes mellitus ................................................................................. 11 
6.2.2 Continuous glucose monitoring ...................................................................................................................... 12 
6.2.3 Characterization of glucose variability and association with hypoglycaemia risk .......................................... 12 
6.3 Hypotheses ............................................................................................................................................................. 12 
7. Methods I: design, setting, participants, and outcomes .........................................................................................13 
7.1 Study designs .......................................................................................................................................................... 13 
7.2 Study settings ......................................................................................................................................................... 13 
7.3 Eligibility criteria ..................................................................................................................................................... 13 
7.3.1 Inclusion criteria PPDM patients ..................................................................................................................... 13 
7.3.2 Exclusion criteria PPDM patients .................................................................................................................... 13 
7.3.3 Comparator groups for sub studies 1 and 3 (individuals with type 2 diabetes) ............................................. 14 
7.3.4 Comparator group for sub study 2 (individuals with type 2 diabetes) ........................................................... 14 
7.4 Discontinuation or withdrawal from the study ...................................................................................................... 14 
7.5 Concomitant medication and care ......................................................................................................................... 14 
7.6 Outcomes................................................................................................................................................................ 15 
7.6.1 Primary endpoints ........................................................................................................................................... 15 
7.6.2 Secondary endpoints ...................................................................................................................................... 15 
7.6.3 Explorative endpoints ..................................................................................................................................... 15 
7.7 Participant timelines ............................................................................................................................................... 15 
7.7.1 Sub study 1 ...................................................................................................................................................... 15 
7.7.2 Sub study 2 ...................................................................................................................................................... 17 
7.7.3 Sub study 3 ...................................................................................................................................................... 17 
7.8 Sample size considerations ..................................................................................................................................... 17 
7.9 Recruitment ............................................................................................................................................................ 18 
7.10 Information about the study ................................................................................................................................ 18 
8. Methods II: Data collection, management, and analysis ........................................................................................19 
8.1. Data collection methods ........................................................................................................................................ 19 

 
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8.1.1 Continues glucose and activity monitoring ..................................................................................................... 19 
8.1.2 Food diary and monitoring of insulin administration ..................................................................................... 19 
8.1.3 Questionnaires ................................................................................................................................................ 19 
8.1.4 Biochemistry ................................................................................................................................................... 20 
8.1.5 Arginine stimulation test ..................................................................................................................................... 20 
8.1.6 Demographic and clinical parameters ............................................................................................................ 21 
8.2 Data management ................................................................................................................................................. 21 
8.2.1 Case report forms ........................................................................................................................................... 22 
8.2.2 Source data identification and protection ...................................................................................................... 22 
8.3 Plan for statistical analyses .................................................................................................................................... 22 
8.3.1 Statistical methods .......................................................................................................................................... 22 
8.3.2 Criteria for termination of the studies ............................................................................................................ 22 
8.3.3 Missing data .................................................................................................................................................... 22 
8.3.4 Deviations from the original statistical plan ................................................................................................... 23 
9. Ethics and dissemination .......................................................................................................................................23 
9.1 Risk and benefits ..................................................................................................................................................... 23 
9.2 Patient insurance .................................................................................................................................................... 23 
9.3 Consent and confidentiality .................................................................................................................................... 23 
9.4 Declaration of interests .......................................................................................................................................... 23 
9.5 Access to data ......................................................................................................................................................... 24 
9.6 Dissemination policy ............................................................................................................................................... 24 
Reference list .............................................................................................................................................................25 
 

 
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Protocol signature page 
 
Principal investigator’s statement: 
I have read and understand the foregoing protocol entitled “Characterization of glucose variability 
and hypoglycaemia in patients with post-pancreatitis diabetes” protocol version 4.0 and agree to 
conduct the study in compliance with the Research Ethics Committees in Denmark and the Danish 
Data Protection Agency (hereinafter referred to as ”the competent authorities”), and within the 
principles of the Declaration of Helsinki (amended by the 52nd General Assembly, Edinburgh, 
Scotland, October 2000, clarified by the General Assembly in Washington 2002, Tokyo 2004, 
Seoul 2008, and Fortaleza 2013 as outlined herein). 
 
Søren Schou Olesen 
Professor, Chief Consultant 
Principal investigator 
Principal investigator 
23-05-2022 
 
Date 
Principal investigator´s signature 
 
 

 
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1. Glossary 
ADA 
 
American Diabetes Association 
CGM 
 
Continuous glucose monitoring 
CP 
 
Chronic pancreatitis 
CRF 
 
Case report form 
CV 
 
Coefficient of variation 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of 
Life questionnaire  
EPI 
 
Exocrine pancreatic insufficiency 
HbA1c  
 
Haemoglobin A1c  
PP 
 
Pancreatic polypeptide 
PPDM 
 
Post-pancreatitis diabetes mellitus 
PRO 
 
Patient reported outcome 
SARC-F 
 
Strength, assistance with walking, rising from a chair, climbing stairs, 
and falls  
SD 
 
Standard deviation 
SMBG 
 
Self-monitoring of blood glucose 
SOP 
 
Standard operating procedure 
TAR 
 
Time above range 
TBW 
 
Time below range 
TIR 
 
Time in range 
VIM 
 
Variability independent of the mean 
 
 
 
 

 
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2. General information 
Principal Investigator: 
Professor Søren Schou Olesen, MD, PhD  
Centre for pancreatic diseases and Mech-Sense, Department of Gastroenterology & Hepatology, 
Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark  
Telephone: +45 97 66 35 10 
E-mail: soso@rn.dk 
 
Co-investigator: 
Morten Hasselstrøm Jensen, MSc, PhD, Senior Researcher & Associate Professor 
Steno Diabetes Center North Denmark, Aalborg University Hospital, Mølleparkvej 4, DK-9000 
Aalborg 
Department of Health Science & Technology, Aalborg University, Fredrik Bajers Vej 7, DK-9210 
Aalborg E 
E-mail: m.hasselstroem@rn.dk 
 
Sub-investigators: 
Srdan Novovic, MD, PhD, Associate professor 
Gastrounit, Hvidovre University Hospital, Hvidovre, Denmark 
Kettegård Alle 30, 2650 Hvidovre 
E-mail: srdan.novovic@regionh.dk 
 
Camilla Nøjgaard, MD, PhD 
Gastrounit, Hvidovre University Hospital, Hvidovre, Denmark 
Kettegård Alle 30, 2650 Hvidovre 
E-mail: camilla.noejgaard@dadlnet.dk 
 
Maiken Thyregod Jørgensen, MD, PhD, Associate professor 
Department of Gastroenterology 
Odense University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark 
J.B. Winsløws Vej 4, 5000 Odense C 
E-mail: maiken.t.joergensen@rsyd.dk 
 
Project group and delegates: 
Professor Filip Krag Knop, MD, PhD 
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, 
Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and 
Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical 
Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 
Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark. 
 
Professor Jens Juel Holst, MD, DMSc 
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of 
Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic 
Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 
Denmark. 
 

 
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Professor Peter Vestergaard, MD, PhD, DMSc 
Steno Diabetes Centre North Denmark, Aalborg University Hospital  
 
 
Professor Asbjørn Mohr Drewes, MD, PhD, DMSc 
Centre for pancreatic diseases and Mech-Sense, Department of Gastroenterology & Hepatology, 
Aalborg University Hospital  
 
Line Davidsen, MD, PhD-student 
Centre for pancreatic diseases and Mech-Sense, Department of Gastroenterology and Hepatology, 
Aalborg University Hospital 
 
Cecilie Siggaard Knoph, MD, PhD-student 
Centre for pancreatic diseases and Mech-Sense, Department of Gastroenterology and Hepatology, 
Aalborg University Hospital 
 
Mette Pilegaard, Project Laboratory Technician  
Department of Endocriniology, Aalborg University Hospital  
 
Lene Holm, Project Laboratory Technician  
Department of Endocriniology, Aalborg University Hospital  
 
Katrine Bruhn Vogensen, Project Laboratory Technician 
Department of Endocriniology, Aalborg University Hospital  
 
Study sites: 
Centre for pancreatic diseases, Department of Gastroenterology & Hepatology, Aalborg University 
Hospital  
Mølleparkvej 4 
9000 Aalborg 
Denmark 
 
Steno Diabetes Center North Denmark (SDCN) 
Mølleparkvej 4 
9000 Aalborg 
Denmark 
 
Gastrounit, Hvidovre University Hospital 
Kettegård Alle 30 
2650 Hvidovre 
Denmark 
 
Department of Gastroenterology, Odense University Hospital 
J.B. Winsløws Vej 4 
5000 Odense C 
Denmark 

 
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3. Funding  
The study was conceived and initiated by professor Søren Schou Olesen, Department of 
Gastroenterology & Hepatology, Aalborg University Hospital. It is economically supported from 
Steno Diabetes Centre North Denmark who will provide equipment and personal for continues 
glucose monitoring (CGM). Various funds will be applied for, to cover any additional financial 
expenses. Potential grants from other funds are deposited in a project account at Aalborg University 
Hospital, which principal investigator Søren Schou Olesen is responsible for. The involved 
researchers conduct the trial of general scientific interest without personal financial gain. All data 
will be publicly available after publication based on reasonable request. 
 
 

 
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4. Roles and responsibilities  
The present studies will be conducted in compliance with this protocol, the guidelines of the World 
Medical Association Declaration of Helsinki in its revised edition (Fortaleza, Brazil, October 2013) 
and designated Standard Operating Procedures. The project will be conducted in collaboration 
between researchers from Centre for Pancreatic Diseases at Aalborg University Hospital and Steno 
Diabetes Centre North Denmark. The researchers have clinical and health technology backgrounds 
and a long track record on research into diabetes, pancreatic diseases, and epidemiology as well as 
major experience with leadership of clinical and epidemiological studies. The principal investigator 
Søren Schou Olesen is clinical professor in pancreatology at Aalborg University and chief physician 
at Aalborg University Hospital where he is the leader of Centre for Pancreatic Diseases. He has a 
long track record of clinical and epidemiological projects within acute and chronic pancreatitis and 
has a special interest in metabolic complications of pancreatic diseases. The co-investigator Morten 
Hasselstrøm Jensen is a senior researcher at Steno Diabetes Centre North Denmark and associate 
professor at Aalborg university. He has a proven track record of epidemiologic and health 
technology studies within type 2 diabetes and a special interest in CGM and management of 
hypoglycaemia. Staff at Steno Diabetes Centre North Denmark and Mech-Sense, Department of 
Gastroenterology and Hepatology will be employed to oversee the studies. For sub study 3, 
associate professors Srdan Novovic, Camilla Nøjgaard and Maiken Thyregod Jørgensen from 
Hvidovre University Hospital and Odense University Hospital will participate. They all have 
extensive experience with clinical management and research in pancreatic diseases. Professors Filip 
Knag Knop and Jens Juel Holst will provide assistance with analysis and interpretation of results 
from the arginine test and analysis of intestinal/pancreatic hormones. Professors Peter Vestergaard 
and Asbjørn Mohr Drewes are international leading experts in endocrinology and gastroenterology 
with extensive experience in research management and will serve as consultants on the project.  
 
 

 
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5. Time schedule 
The project is expected to be initiated (first subject included) in April 2022 and concluded (last 
subject, last visit) by March 2023. An overview is given in the diagram below. 
 
 
2021 
2022 
2023 
2024 
 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Writing of protocol  
 
 
 
 
 
 
 
 
 
 
 
 
Regulatory affairs 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct of studies 
 
 
 
 
 
 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
Writing and submitting 
articles 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. Purpose and scientific background  
6.1 Introduction and purpose  
Post-pancreatitis diabetes mellitus (PPDM) is a frequent complication of chronic pancreatitis and 
occurs in up to 80% of patients during their disease course1,2. PPDM prognosis and management 
has not been widely studied as patients with PPDM are typically excluded from observational 
studies and randomized controlled trials of glucose lowering therapies. Therefore, prognosis and 
management strategies have mostly been extrapolated from other diabetes subtypes. Furthermore, 
patients with PPDM are frequently misdiagnosed and treated as type 2 diabetes3,4. This is 
problematic as PPDM has a distinct pathophysiology and clinical presentation. Hence, patients with 
PPDM often have “brittle diabetes” characterized by fluctuating blood glucose levels, frequent 
hypoglycaemic episodes, and poor glycaemic control1,5. However, there is a lack of systematic 
investigations of glucose homeostasis in relation to PPDM. 
 
The use of continuous glucose monitoring (CGM) improves glycaemic control and risk of 
hypoglycaemia compared to self-monitoring of blood glucose (SMBG) in people with type 1 and 
insulin-treated type II diabetes6–9. However, the effect of CGM on hypoglycaemic risk has never 
been investigated in PPDM patients.  
 
 
The overall purpose of this project is to study glucose variability and hypoglycaemia in patients 
with PPDM. The project is organized into three sub studies aiming to: 1) Investigate short-term 
glucose variability assessed by continuous glucose monitoring (CGM) and the effect of CGM on 
hypoglycaemia compared to SMBG, 2) investigate long-term glucose variability based on visit-to-
visit haemoglobin A1c (HbA1c), and 3) investigate the prevalence of, risk factors for and awareness 

 
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of hypoglycaemia using standardized patient-reported outcomes. Patients with type 2 diabetes are 
included as the most clinically relevant comparison group5. The project will provide novel 
information on glucose variability and prevalence of hypoglycaemia among patients with PPDM 
using the most updated classifications and technologies. This information can be used to inform 
prognosis and identify relevant targets for optimization of management.  
 
6.2 Scientific background and literature review 
6.2.1 Pathophysiology of post-pancreatitis diabetes mellitus  
Chronic pancreatitis is characterized by a fibro-inflammatory process that leads to islet cell injury 
with ensuing beta-cell loss and decreased insulin secretion1,10. This has for long been considered the 
primary mechanism of PPDM. However, injury to pancreatic islets also results in impaired 
secretion of pancreatic polypeptide resulting in hepatic insulin resistance and increased hepatic 
glucose production11. Likewise, impaired secretion of glucagon and somatostatin compromise 
glucose counter regulation during hypoglycaemia which may be an important mechanism for the 
frequent hypoglycaemic episodes observed in these patients12. The majority of patients with PPDM 
also have pancreatic exocrine insufficiency and malassimilation of intestinal nutrients, which has 
been associated with a blunted incretin response during oral feeding that are only partly reversed by 
pancreatic enzyme replacement therapy1,13,14. In addition, abdominal pain and other complications 
related to chronic pancreatitis may compromise nutritional intake and lead to malnutrition and 
depleted glycogen stores which again compromise gluconeogenesis during fasting15. Finally, type 2 
diabetes related risk factors may also be implicated in the pathogenesis of PPDM2. The combined 
effects of these mechanisms are believed to result in greatly fluctuating blood glucose levels and 
excess risk of hypoglycaemia i.e., a “brittle diabetic state” - figure 12,16.  
 
 
 
 
 
Figure 1. Pathophysiological mechanisms associated with the “brittleness” in PPDM. PP, pancreatic polypeptide; 
EPI, exocrine pancreatic insufficiency; CP, chronic pancreatitis; PPDM, post-pancreatitis diabetes mellitus 

 
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Notwithstanding the improved understanding of PPDM pathophysiology, most past observations of 
glucose homeostasis in PPDM patients come from small studies in poorly defined patient groups 
and have mostly been based on outdated definitions and technologies1. Also, the problem of “brittle 
diabetes” in relation to PPDM has not been investigated in the era of modern glucose lowering 
medications such as long-acting and ultra-long-acting insulin analogues that may reduce risk of 
hypoglycaemia. 
 
6.2.2 Continuous glucose monitoring 
SMBG using a glucometer and a capillary blood sample drawn via finger-pricking is used by most 
people with diabetes. However, this technique has some disadvantages as it is user-dependent and 
does not capture nocturnal and asymptomatic hypoglycaemia. Also, SMBG cannot be used to 
predict impending hypoglycaemia as it is based on single-instant blood glucose readings. These 
limitations can be overcome by using CGM6. A CGM system is based on a subcutaneous sensor 
that automatically measures an individual’s interstitial glucose levels continuously. Based on trends 
in glucose levels, CGM can predict impending hypoglycaemia and detect fluctuations in blood 
glucose levels17,18. In people with type 1 diabetes and those with type 2 diabetes on multiple daily 
insulin injections, CGM improves glycaemic control and reduces time in hypoglycaemia compared 
to SMBG6–9. It is likely that this effect is also present in patients with pancreatogenic diabetes, but 
this has never been investigated.  
6.2.3 Characterization of glucose variability and association with hypoglycaemia risk 
Variability of glucose homeostasis has been increasingly recognized as an important determinant of 
diabetes-related complications and adverse clinical outcomes beyond HbA1c levels19. It 
encompasses two categories of dysglycaemia: i) short-term daily glucose fluctuations that can be 
assessed by CGM and ii) long-term weekly, monthly or quarterly changes in glucose variability that 
have typically been assessed by changes in visit-to-visit HbA1c levels. Although the evidence for 
the relationship between glucose variability and adverse clinical outcomes is not fully clarified at 
this point, evidence supports a strong association between hypoglycaemic events and both short and 
long-term glucose variability19. To the best of our knowledge short and long-term glucose 
variability and prevalence of hypoglycaemia has not previously been investigated in the context of 
PPDM using modern technologies and definitions.  
 
6.3 Hypotheses 
• 
Sub study 1: Short-term glucose variability and time in hypoglycaemia, as determined by CGM, is 
increased in patients with PPDM compared to a matched group of individuals with type 2 diabetes; 
the use of CGM will lead to decreased time in hypoglycaemia compared to SMBG in PPDM patients.   
• 
Sub study 2: Long-term glucose variability, as determined by visit-to-visit HbA1c, is increased in 
patients with PPDM compared to a matched group of individuals with type 2 diabetes. 
• 
Sub study 3: Patients with PPDM report high frequencies of self-reported hypoglycaemic events and 
targetable risk factors for hypoglycaemia can be identified. 

 
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7. Methods I: design, setting, participants, and outcomes  
7.1 Study designs 
• 
Sub study 1 is a prospective open-label crossover randomized controlled study of the effect of CGM 
on hypoglycaemia compared to SMBG in PPDM patients 
• 
Sub study 2 is a retrospective cohort study of long-term glucose variability, as determined by visit-
to-visit HbA1c levels, in PPDM patients compared to matched individuals with type 2 diabetes 
• 
Sub study 3 is a multicentre cross-sectional study based on patient-reported outcomes (PROs) 
 
7.2 Study settings  
Sub studies 1 and 2 will be conducted at Centre for Pancreatic Diseases at Aalborg University 
Hospital and Steno Diabetes Centre North Denmark. These centres have comprehensive experience 
in diagnosing, treating, and conducting research on patients with pancreatitis and diabetes. Patients 
with PPDM will primarily be identified and included via the outpatient clinic at Centre for 
Pancreatic Diseases but may also be identified after admission with chronic pancreatitis as 
described in section 7.9 or in the diabetes outpatient clinic. For sub study 2 data are retrieved from 
Diabetesdatabasen in the North Denmark Region. Sub study 3 is a multicentre study that in addition 
to the above-mentioned sites also includes pancreas outpatient clinics at Hvidovre University 
Hospital and Odense University Hospital. 
 
7.3 Eligibility criteria  
7.3.1 Inclusion criteria PPDM patients  
• 
Signed informed consent before any study specific procedures*  
• 
Able to read and understand Danish  
• 
Male or female age ≥ 18 ≤ 80 years  
• 
A definitive diagnosis of chronic pancreatitis based on the M-ANNHEIM criteria20 
• 
A diagnosis of insulin treated PPDM based on the World Health Organization criteria for diabetes 
(HbA1c ≥6.5 % (48 mmol/mol) and/or fasting plasma glucose ≥126 mg/dl (7.0 mmol/l) >3 months 
after diagnosis of pancreatitis 
 
*a signed informed consent is waived for patients in sub study 2 which is a register-based study 
based on data from Diabetesdatabasen in the North Denmark Region. 
 
7.3.2 Exclusion criteria PPDM patients  
• 
Known or suspected abdominal cancer (incl. intestine, pancreas, and the hepato-biliary system) 
• 
Severe pre-existing comorbidities (assessed by investigator upon inclusion) 
• 
Attack of acute on chronic pancreatitis requiring admission within four weeks prior to inclusion   
• 
Use of glucocorticoid medications within four weeks prior to inclusion   
• 
Presence of autoimmune antibodies suggestive of type 1 diabetes 
• 
Prior pancreatic surgery (including total pancreatectomy, pancreaticoduodenectomy, distal 
pancreatectomy, pancreaticojejunostomy, enucleation, or Frey procedure) 
• 
Prior gastric surgery or vagotomy 
• 
Autoimmune pancreatitis 
 

 
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7.3.3 Comparator groups for sub studies 1 and 3 (individuals with type 2 diabetes) 
• 
Individuals with type 2 diabetes enrolled in the DiaMonT study are included as comparator group in 
sub studies 1 and 3. Individuals participating in the DiaMonT study undergo CGM for up to three 
months and provide information on experience with hypoglycaemia and awareness. These data will 
be used for comparison with the data collected in sub studies 1 and 3. The DiaMonT study is already 
approved by relevant regulatory bodies (N-20200068) and participants have provided written 
informed consent upon inclusion and agreed that the collected data can be used for research 
purposes.  
• 
Individuals with type 2 diabetes are matched to PPDM patients based on HbA1c levels and other 
relevant parameters including regimens of glucose lowering therapy. 
• 
The following data from the DiaMonT study will be used: 
o Basic demographic and clinical characteristics 
o Information on glucose lowering therapies and other medications 
o Routine biochemical parameters including Hb1Ac 
o CGM metrics 
o Information on hypoglycaemia and hypoglycaemia awareness  
Patients from the DiaMonT study will not provide any biological material for this project. Data will be used 
in compliance with with the rules on protection of personal data from the the Danish Data Protection 
Agency. 
 
7.3.4 Comparator group for sub study 2 (individuals with type 2 diabetes) 
• 
Individuals with type 2 diabetes enrolled in Diabetesdatabasen are included as comparator group in 
sub study 2. Diabetesdatabasen is a health registry maintained by the Business Intelligence Unit in 
the North Denmark Region and collect anonymised data on individuals with diabetes in the North 
Denmark Region. In agreement with Danish legislation use of anonymised data from Health Registries 
do not require informed consent from involved individuals. 
• 
Individuals with type 2 diabetes are matched to PPDM patients based on HbA1c levels and other 
relevant parameters including regimes of glucose lowering therapy 
 
7.4 Discontinuation or withdrawal from the study  
If a participant is withdrawn from the study, the investigator should always ensure that the end of 
study page in the case report form (CRF) is completed for withdrawn participants. A participant 
should be withdrawn from studies, if at any time:   
• 
It is the wish of the participant for any reason 
• 
The investigator judges it necessary due to medical reasons 
• 
Severe non-compliance to the protocol is judged by the investigator 
 
If a participant does not turn up for a scheduled visit, the study personnel will contact him/her by 
telephone to rearrange the scheduled visit. In any circumstance, every effort should be made to 
document the participant health status. 
 
7.5 Concomitant medication and care  
Along with participation in the studies included patients will continue their usual treatments and 
scheduled visits and examinations in the outpatient clinic according to usual standard of care and 
clinical guidelines.  
 

 
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7.6 Outcomes 
7.6.1 Primary endpoints 
• 
Sub study 1: Difference (monitoring with CGM vs. SMBG) in time spent with glucose value <3.0 
mmol/L (level 2 hypoglycaemia) during the last two weeks of each study period 
• 
Sub study 2: Long-term glucose variability (up to 48 months) expressed as difference in visit-to-visit 
HbA1C VIM (Variability Independent of the Mean) between PPDM patients and individuals with type 
2 diabetes patients 
• 
Sub study 3: Proportions of patients with severe hypoglycaemia during the preceding 12 months. 
Hypoglycaemic endpoints are defined according to the latest ADA recommendations21 
 
7.6.2 Secondary endpoints 
Sub study 1:  
• 
Short term (20 days) difference in CGM metrics between PPDM patients and individuals with type 2 
diabetes 
• 
CGM time in range (glucose value >3.9 mmol/L and 10 mmol/L) 
• 
CGM time below range (glucose value 3.9 mmol/L) 
• 
CGM time above range (glucose value >10 mmol/L) 
• 
CGM metrics of glucose variability (SD (Standard deviation) and CV (Coefficient of Variance) of mean 
glucose, mean amplitude of glycaemic excursions [MAGE] and continuous overall net glycaemic 
action [CONGA]) 
 
Sub study 2: 
• 
Difference in HbA1C CV between PPDM and type 2 diabetes patients during up to 48 months follow-
up 
• 
Difference in HbA1C average real variability between PPDM and type 2 diabetes patients during up 
to 48 months follow-up 
• 
Difference in HbA1C level trajectories between PPDM and type 2 diabetes patients during up to 48 
months follow-up 
 
Sub study 3:  
• 
Risk factors for hypoglycaemia including demographics and routine clinical and biochemical 
parameters 
• 
Awareness of hypoglycaemia based on the Clarke hypoglycaemia awareness survey 
• 
Proportions of patients with ketoacidosis during the preceding 12 months 
 
7.6.3 Explorative endpoints 
In sub study 1 an arginine test is employed to study pancreatic endocrine secretory capacity (insulin 
and glucagon). In addition, various baseline characteristics of PPDM patients including pancreatic 
and intestinal hormone profiles are associated with CGM metrics to explore putative mediators of 
short-term glucose variability. 
 
7.7 Participant timelines  
7.7.1 Sub study 1 
Patients with PPDM will primarily be included from the outpatient clinic at Centre for Pancreatic 
Diseases, Alborg University Hospital as outlined below (7.9). Following written informed consent, 

 
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participants are randomized to monitoring with CGM followed by SMBG for 50 days or vice versa. 
Each study period is initiated by 20 days masked CGM (baseline) and patients using SBMG will 
also wear a masked CGM during the last 20 days of the SMBG period to allow comparison of CGM 
based endpoints between the two study periods. A timeline of study activities is illustrated in figure 
2.  
 
Figure 2. Timeline of sub study 1. CGM; Continuous glucose monitoring, SMBG; Self-monitoring of blood glucose. 
 
Participants will undergo a total of 7 study visits, as illustrated in figure 2. The duration of the 
baseline visit (visit 1) is approximately 120 minutes, and the subsequent visits 15-30 minutes, 
making the total time required for participation in the study a maximum of 300 minutes. At the 
baseline visit, height and weight are registered, and body mass index is calculated. Pancreatic 
function (exocrine and endocrine) will be evaluated based on review of patients’ medical records 
and supplemented by routine biochemical tests including autoantibodies and HbA1c. Also, blood is 
drawn for biobanking and assessment of basal intestinal and pancreatic hormone levels. An arginine 
stimulation test is done to assess endocrine pancreatic secretory capacity. Patients are instructed in 
use of an insulin and food diary and fill in questionaries. Finally, the CGM sensor is mounted and 
activated. Every 10 days the CGM glucose sensor is changed by the participant at home based on 
instructions from study staff (or alternatively they can choose to have the censor changed in the 
diabetes outpatient clinic).  After 20±2 days (visit 2), participants meet to either unmask or remove 
the CGM. Then, on day 50±2 (visit 3), the participant with unmasked CGM returns to unload the 
CGM transmitter, while the participants randomized to SMBG come in and the CGM is again 
mounted and masked. The study periods end at day 70±2, where participants meet for a follow-up 
visit (visit 4), where the CGM transmitter is unloaded. The food and insulin diary is collected and 
reviewed together with the patient to ensure accurate registrations of insulin administration and 
food intake. Patients fill in questionaries and adverse events in relation to CGM monitoring or other 
study activities are registered. Since crossover will occur immediately at the end of the first study 
period, visit 4 in period 1 and visit 1 in period 2 are merged. Also, baseline data is only collected at 
the very first visit. In Table 1 an overview of the various study activities in sub study 1 is reported. 
 
 
 
 
 
 
 
 
 

 
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Table 1: Participant timeline and study activities for sub study 1 
 
 
Study period 1 
Study period 2 
Baseline 
Visit 1 
Day 0 
 
Visit 2 
Day 20 
 
Visit 3 
Day 50 
 
Visit 4/1 
Day 70/0 
 
Visit 2 
Day 20 
 
Visit 3 
Day 50 
 
Visit 4 
Day 70 
Anthropometrics 
X 
 
 
 
 
 
 
Biochemistry 
- Faecal elastase 
- HbA1c 
- Routine biochemistry 
- Blood for biobanking 
- Autoantibodies 
- C-peptide 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Arginine stimulation test 
X 
 
 
 
 
 
 
Questionnaires 
X 
 
 
X 
 
 
X 
Registration of adverse events 
 
 
 
X 
 
 
X 
Unloading CGM transmitter 
 
X 
X* 
X 
X 
X* 
X 
 
*Unloading the CGM transmitter applies only when the participants are being monitored using unmasked CGM  
 
7.7.2 Sub study 2 
Sub study 2 is based on data from Diabetesdatabasen in the North Denmark Region and therefore 
no study-related visits or procedures pertain to patients included in sub study 2. The database is 
maintained and managed by the Business Intelligence unit in the North Danish Region. 
 
7.7.3 Sub study 3 
Patients with PPDM will primarily be included from the outpatient clinics of participating centres as 
outlined above. Following written informed consent, patients are asked to fulfil the relevant 
questionaries as described below. The required time to fulfil the questionaries is approximately 30 
minutes, making total time required for participation in the study a maximum of 60 minutes. 
Patients can either choose to fill in the questionaries in the outpatient clinic or bring the 
questionnaires to their home and return them via postal service (stamped envelopes are provided for 
free) or alternatively use digital questionnaires linked to the individual subject’s CRF in REDCap 
(see section 8.2.1). 
 
7.8 Sample size considerations 
• 
Sub study 1: The sample size calculation is based on the primary endpoint described for sub study 1 
(time in level 2 hypoglycaemia). A sample size of 24 patients is determined to have at least 80% 
power to detect a reduction in the percentage of time spent with a glucose value <3.0 mmol/l (level 
2 hypoglycaemia), assuming a relative treatment reduction of 50% from a percentage of time spent 
with glucose value <3.0 mmol/l of 3%, standard error of 2.5%, and type I error rate (2 sided) of 5%. 
To account for approximately 25% dropouts, the final sample size is set to 30 patients. As there are 
currently no adequate data on CGM in patients with pancreatogenic diabetes to inform sample size 
calculations, assumptions are based on findings in older adults with long-standing type 1 diabetes 
who have an increased risk of hypoglycaemia7. 
• 
Sub study 2: This is a retrospective cohort study based on data already collected in 
Diabetesdatabasen and the sample size will therefore be dictated by the number of individuals in the 

 
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database. Previous population-based studies from our group have shown that the proportion of 
patients with PPDM among patients clinically diagnosed type 1 or type 2 diabetes is approximately 
1.5%4,22. In Diabetesdatabasen there are currently >5000 unique adult individuals registered, and 
thus we expect to identify at least 75 PPDM cases which should provide sufficient statistical power 
to the planned analyses according to a previous study from our group22.  
• 
Sub study 3: This is a cross-sectional survey. No previous studies have evaluated the prevalence of 
self-reported severe hypoglycaemia and related risk factors in patients with PPDM. However, 
according to recent population-based registry data from our group, patients with PPDM have a risk 
of hospitalization for hypoglycaemia comparable to that observed for individuals with type 1 diabetes 
(unpublished data). In type 1 diabetes, the yearly prevalence of self-reported severe hypoglycaemia 
range between 10–53%23. Thus, we consider a sample size of 200 patients will provide sufficient 
power to obtain prevalence estimates with reasonable precision and allow for multivariate modelling 
of putative risk factors associated with severe hypoglycaemia.  
 
7.9 Recruitment 
Eligible patients with PPDM from the outpatient clinic are contacted during scheduled clinical visits 
in the outpatient clinic. Information regarding medical history and previous treatment can be passed 
on from the treatment-responsible physician from medical records to study personnel. Potentially 
eligible patients from the outpatient clinic, may subsequently be contacted by study personnel, but 
only if permission has been granted by the treatment-responsible physician. This will be conducted 
in accordance with “Sundhedsloven § 46, stk 1”, under the responsibility of the primary 
investigator. Patients can be included, four weeks after discharge from an acute on chronic 
pancreatitis attack if they are clinically stable at the time of inclusion. We expect to enrol about 1 to 
2 patients per week for sub study 1 and 5-10 patients per week for sub study 3.  
 
7.10 Information about the study 
All patients will be informed both oral and written before they decide whether they want to 
participate in the study. Furthermore, they will be informed that they can withdraw from the study 
at any given time without giving a reason. The participants are also allowed to have an assessor 
with them to the interview. Competent delegated personnel (medical doctors affiliated with the 
study or trained site staff) will give the oral information according to the Research Ethics 
Committee’s guidelines. The information interview will take place in quiet surroundings at one of 
our respective inclusion sites. During the interview, the participant will be informed thoroughly 
about the purpose of the study, the specific procedures the study entails, and potential benefits and 
risks. Any questions the participant have, will also be answered here. The written information 
(“Deltagerinformation”) is given or sent (in the case they contact us first) to the participants so they 
have it at least one day before the oral information takes place. After the interview where the 
participant has received information (oral and written) about the study, they are encouraged to go 
home and consider whether they want to participate in the study or not, for a minimum period of 24 
hours. They may also sign the informed consent immediately if they are ready. After the participant 
has signed the informed consent and is included in the study, they will be receiving an ID-number. 
For additional information on informed consent and confidentiality see section 9.3. 

 
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8. Methods II: Data collection, management, and analysis 
8.1. Data collection methods 
8.1.1 Continues glucose and activity monitoring  
Participants in sub study 1 will be provided with a CGM and an activity tracker. The CGM device 
consists of three components: A sensor, a transmitter, and a receiver. The receiver can be a mobile 
phone app or a dedicated device. The sensor penetrates the skin and is localized in the subcutaneous 
tissue on the upper arm or the abdomen and measures the interstitial glucose levels continuously. 
The signal is processed by the receiver and an interstitial glucose value is shown every 5 minutes. 
The participants will be trained in using the provided technologies at study initiation and use the 
devices continuously at home to measure and log tissue glucose levels, activity, and sleep for the 
entire study duration. Participants are in periods blinded to the results from both CGM and are 
informed that they remain responsible for monitoring and managing their blood glucose levels 
according to their usual standard of care, despite the telemonitoring. For technical challenges, 
participants can contact Steno Diabetes Centre by phone via a technical support line. Use of the 
devices do not restrict the daily activities of the participants. 
 
8.1.2 Food diary and monitoring of insulin administration 
Participants in sub study 1 are instructed to register their daily food intake and insulin 
administration (both basal and bolus) in a “food and insulin diary” during the CGM monitoring 
period. A diary provided by Diabetesforeningen is used. Thorough instructions on how to use and 
fill in the diary is provided by study staff. An example of the “food and insulin diary” is provided in 
the appendix. 
 
8.1.3 Questionnaires  
All questionaries will be filled in by participants in sub studies 1 and 3. 
 
8.1.3.1 Clarke hypoglycaemia awareness survey 
The Clarke questionnaire for assessment of hypoglycemia awareness comprises eight questions 
characterizing the participant's exposure to episodes of moderate and severe hypoglycemia. It also 
examines the glycemic threshold for, and symptomatic responses to, hypoglycemia. A score of four 
or more implies impaired awareness of hypoglycemia. 
 
8.1.3.2 The Comprehensive Pain Assessment Tool Short Form (COMPAT-SF) 
The Comprehensive Pain Assessment Tool Short Form is a questionary that has been specifically 
developed and validated for pain assessment in patients with chronic pancreatitis. It comprises of 6 
questions describing 5 pain dimensions: a) pain severity, b) pain pattern, c) factors provoking pain, 
d) widespread pain, and e) a qualitative pain-describing dimension. The questionary can be 
summarized in a total score in addition to the 5 pain dimension sub scores24. 
 
8.1.3.3 Strength, assistance with walking, rising from a chair, climbing stairs, and falls (SARC-F) questionnaire 
The SARC-F questionnaire is a screening tool that can be rapidly implemented by clinicians to 
identify probable sarcopenic patients. The questionnaire screens patients for self-reported signs 
suggestive of sarcopenia, which include deficiencies in strength, walking, rising from a chair, 
climbing stairs, and experiencing falls. Each of the self-reported parameters receives a minimum 
and maximum score of 0 and 2, respectively, with the greatest maximum SARC-F score being 1025. 

 
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8.1.3.4 EORTC QLQ-C30 questionnaire 
The EORTC QLQ-C30 questionnaire is used to document life quality, physical function, and a 
number of other health-related parameters26 and will be filled in by participants in sub study 1 at 
baseline. The questionnaire has been validated for assessment of quality of life in patients with 
chronic pancreatitis and is composed of single-item measures and multi-item scales with scores 
ranging from 0 to 100 after linear transformation of the raw score27. A high score for a functional 
scale represents a high level of functioning, as does a high score for the global health status, while a 
high score for the symptom items represents a high level of symptomatology.  
 
8.1.4 Biochemistry  
Patients in sub studies 1 and 3 will have their pancreatic exocrine function evaluated by means of 
faecal-elastase test at baseline. At the same time, they will have routine clinical blood sample tests 
performed (including HbA1C, electrolytes, creatinine, albumin, haemoglobin, liver tests, pancreas 
specific amylase, c-peptide and autoantibodies) corresponding to approximately 20 ml blood. The 
blood samples are analysed immediately as part of routine clinical practice. Patients in sub study 1 
will also have extra blood tests drawn to detect circulating levels of pancreatic hormones (insulin, 
glucagon, pancreatic polypeptide) and intestinal hormones (GLP-1 and GIP) as well as markers of 
hypoglycaemia and postprandial glucose excursions corresponding to approximately 30 ml blood. 
These blood samples will be separated by centrifugation and processed as plasma, serum, buffy 
coat, and full blood and subsequently transferred in aliquots to vials labelled with the protocol 
number (PPDM-CGM_2022), subject number, and date of sample collection. Samples will be 
frozen and stored at approximately -80°C or cooler in a freezer at Aalborg University Hospital until 
analysis. The samples will be batch analysed at a central laboratory to measure the analytes of 
interest. After the analyses, spare blood will be kept in the biobank for future research purposes and 
destroyed at the latest 15 years after termination of the study. Ethics according to 
“databeskyttelsesforordningen” and” databeskyttelsesloven” will be ensured in this regard. Based 
on the blood samples drawn at baseline (20 ml + 30 ml blood) a total of 50 ml blood will be drawn 
from each participant in sub study 1 and 20 ml from each participant in sub study 3. 
 
8.1.5 Arginine stimulation test 
An intravenous catheter is inserted into the cubital vein for blood sampling and arginine infusion 
with arterialization of the venous blood using the heated hand technique. At time -1 min 5 g 
argininehydrochlorid (100 mg/mL) is infused over 1 minute. Blood samples are drawn at time -15, 
0, 2, 5, 10, 15 and 30 min for the analysis of blood glucose, plasma C-peptide and glucagon. These 
blood samples will be kept on ice and immediately separated by centrifugation and processed as 
plasma and subsequently transferred in aliquots to vials labelled with the protocol number (PPDM-
CGM_2022), subject number, and date of sample collection. Samples will be frozen and stored at 
approximately -80°C or cooler in a freezer at Aalborg University Hospital until analysis. The 
samples will be batch analysed at a central laboratory to measure the analytes of interest. After the 
analyses, spare blood will be kept in the biobank for future research purposes and destroyed at the 
latest 15 years after termination of the study. Ethics according to “databeskyttelsesforordningen” 
and” databeskyttelsesloven” will be ensured in this regard. In total, 56 ml blood will be drawn from 
each participant during the arginine stimulation test. 
 

 
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8.1.6 Demographic and clinical parameters 
For all sub studies, demographic and clinical information are obtained from medical records and 
patient interviews (sub studies 1 and 3) or Diabetesdatabasen (sub study 2). The following clinical 
information is registered: 
 
 
Demographic information: 
• 
Age and sex 
• 
Height and weight 
• 
Body mass index 
 
Information on chronic pancreatitis: 
• 
Duration and aetiology 
• 
Smoking and drinking history 
• 
Complications including exocrine pancreatic insufficiency and pain 
• 
Treatment (medical treatment including pancreatic enzyme replacement therapy, history of 
endoscopic treatment or surgery) 
 
Information on diabetes: 
• 
Duration of diabetes 
• 
Information on past hypoglycaemic episodes according to the ADA definitions of hypoglycaemia21 
• 
Presence of micro- and macrovascular complications 
• 
Glucose lowering therapy including insulin regime and daily insulin units 
• 
HbA1c and other relevant biochemical parameters in Diabetesdatabasen (sub study 2 only) 
 
Information on comorbidity is registered using the Charlson Comorbidity index. 
 
Information on demographic and clinical parameters including comorbidities are registered for two 
reasons: First, the information is obtained to ensure the suitability of the subjects in relation to 
inclusion in the study. Second, the information must be used for later analysis in an anonymized 
form.  
 
8.2 Data management  
The study will be submitted to the Northern Region of Denmark (“Forskningsanmeldelse Region 
Nordjylland – Registrering af forskningsprojekter”). Standard operating procedures (SOPs) for data 
handling and record keeping exists within the research centres and these will be followed. The 
principal investigator must maintain complete and accurate records to ensure that study execution is 
fully documented, and the study data can be subsequently verified. REDCap, a secure browser-
based software, will be used for filling an electronic case report form for each participant (sub 
studies 1 and 3). REDCap meets all regulatory safety requirements and is approved for data 
collection by the North Danish Region. Data recording will begin when a participant is included and 
will occur gradually to the end of the study. Any corrections will be made in such a way that 
information from the original version is still available. Putative changes are endorsed by initials and 
date. All forms are filled out during (or immediately after) the assessment of a participant and must 
be legible. Data will be stored at Aalborg University Hospital, Department of Gastroenterology and 
Hepatology, for a minimum of 5 years after the study has ended. Relevant information from the 
participants’ medical records will be given to the investigator if needed to assess the in- and 

 
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exclusion criteria. After five years all data will be anonymized. The principal investigator allows 
direct access to all source data and documents at monitoring, auditing, and inspection from the 
competent authorities. A participant identification list is created for all persons included in the 
study. This list contains patient number, full name, and civil registration number. The list is 
populated and updated by a study nurse or other competent person and is stored at Department of 
Gastroenterology, Aalborg University Hospital. 
 
8.2.1 Case report forms  
All data from sub studies 1 and 3 are entered directly into electronic CRFs using REDCap, licensed 
by Aalborg University Hospital, and saved electronically. All forms are filled out during (or 
immediately after) the assessment of a subject and must be legible. Errors and corrections are 
logged as provided by the REDCap interface. It is possible to export validated data from REDCap 
to e.g., a statistical program (e.g., STATA) for further statistical analysis. When data have been 
entered, reviewed, and verified the data will be frozen to prevent editing. Digitalized data are 
backed up and stored on specific drives at each site under the responsibility of the principal 
investigators for a minimum of 5 years after the study has ended.  
 
8.2.2 Source data identification and protection 
Patient Identification List containing patient number, full name, civil registration number for all 
participants included in sub studies 1 and 3 are created, and ethics according to 
“databeskyttelsesforordningen” and ”databeskyttelsesloven” is ensured. The list is populated and 
updated by a project nurse or other competent person. A list of all source documents will be devised 
at the initiation of the study. All source documentation will be stored on a secure drive under the 
responsibility of the principal investigator. 
 
8.3 Plan for statistical analyses 
8.3.1 Statistical methods  
• 
Sub study 1: CGM metrics collected in periods with monitoring using CGM vs. SMBG are compared 
using multiple linear regression models. Further, regression models are fitted to investigate 
associations between baseline characteristics and measures of glucose variability. 
• 
Sub study 2: HbA1c variability metrics are compared between PPDM and type 2 diabetes patients 
using multiple linear regression models. Hb1Ac level trajectories are visually characterized and latent 
class analysis is used to define distinct patient clusters.  
• 
Sub study 3: Prevalence estimates of hypoglycaemia are reported as point prevalence estimates with 
95% confidence intervals. Logistic and Poisson regression models are fitted to investigate 
associations between patient characteristics and hypoglycaemia risk. 
 
8.3.2 Criteria for termination of the studies 
The sub studies are terminated when observations corresponding to planned sample sizes have been 
collected.  
 
8.3.3 Missing data 
Handling of missing data will be defined in the final statistical analysis plan and finalized before 
unblinding of data.  
 

 
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8.3.4 Deviations from the original statistical plan 
It will be reported if any deviations from the original statistical plan occur. 
9. Ethics and dissemination  
The studies will be conducted in compliance with the principles of the Declaration of Helsinki 
(amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013). The studies will 
only be initiated once they are approved by the competent authorities. Any significant modifications 
to the protocol, will be submitted as protocol amendments and subsequently approved by the 
competent authorities before implementation.  
 
9.1 Risk and benefits  
The risks and potential side effects associated with participation in the study are considered to be 
limited. Biochemical tests including blood samples and fecal-elastase1 as well as CGM bear little risk 
for the patients and furthermore are all part of the standard evaluation/management of the disease. 
Potential side effects include the inconvenience and slight discomfort associated with blood sampling. 
Furthermore, use of the CGM can rarely cause local skin irritation and increased risk of infection. 
The potential benefit, on the other hand, is significant, as the proposed studies are expected to 
provide insight into modifiable risk factors for hypoglycaemia and to identify targets for improved 
glycaemic control in PPDM. As many of parameters under investigation are available through routine 
clinical management, it will be straightforward to implement findings into clinical practice. It is 
envisioned that information from the proposed studies can be used to identify patients at excess risk 
of hypoglycaemia and thus to optimize clinical management including intensified outpatient 
monitoring strategies. Accordingly, most patients with PPDM are currently treated by general 
practitioners that may have limited knowledge of the special considerations for management of 
PPDM. Identification of PPDM patients with high risk of complications would facilitate a rational 
triage of patients to specialized outpatient clinics with special interest in PPDM management. 
 
9.2 Patient insurance  
Clinical responsibility befalls Aalborg University Hospital. All participants will be covered by the 
patient insurance of Aalborg University Hospital.  
 
9.3 Consent and confidentiality     
The informed consent will be obtained following oral and written information has been given by 
competent delegated study personnel as previously described in section 7.8. Once informed consent 
is signed, this allows investigators and other local competent authorities to assess patients’ medical 
records with the purpose of retrieving information necessary for study conduction, monitoring and 
inspection. Detailed clinical characterization of the patient, complementary information in relation 
to the study will be made available from medical records so that sponsor and monitor can control 
the quality of the study regarding “informationsbekendtgørelsen”. Information about participants is 
protected by ”databeskyttelsesforordningen”, ”databeskyttelsesloven” and ”sundhedsloven”. 
 
9.4 Declaration of interests  
None.  
 

 
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9.5 Access to data  
All results will be published as open access whenever possible using both scientific and public 
media. When the studies end, the anonymized data will be made available to other researchers upon 
reasonable request. 
 
9.6 Dissemination policy 
Results, positive as well as negative and inconclusive, will be released to the public, and may be 
published in peer-reviewed scientific journals. Results may also be used in submission to regulatory 
authorities. The first author will be appointed according to the Vancouver system. The investigator 
will inform the competent authorities after the termination of the studies. The Research Ethics 
Committee will be notified of results from this study. Published articles are sent to the competent 
authorities. 

 
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