Evaluation of the Hypoglycaemia Notification Device Hyposafe H02 - the Pilot 2 Study - in Subjects With Type 1 Diabetes
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Sponsor: UNEEG Medical A/S

16 December 2021
NCT02925676
Pilot 2 diabetes
 
 
 
 
 
 
 
 
UNEEG™ medical A/S 
Borupvang 2 
DK-3450 Allerød  
Denmark 
 
 
CLINICAL INVESTIGATION PLAN 
Including substantial amendment 2 
 
Evaluation of the hypoglycaemia alarm device 
hyposafe H02 – the pilot 2 study – 
in subjects with type 1 diabetes 
 
A 4-month non-controlled observational study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Investigational device 
hyposafe H02 
Sponsor 
UNEEG™ medical A/S 
Borupvang 2 
DK-3450 Allerød 
Denmark 
Manufacturer 
UNEEG™ medical A/S 
Borupvang 2 
DK-3450 Allerød 
Denmark 
Tel : +45 4063 8000 
www.uneeg.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of contents 
List of abbreviations ......................................................................................................................................... 4 
1 
Background information and justification for conducting the study ................................................... 4 
1.1 
Background .................................................................................................................................... 4 
1.1.1 
Hypoglycaemia in patients with type 1 diabetes .......................................................... 4 
1.1.2 
A hypoglycaemia alarm based on electroencephalography ......................................... 5 
1.2 
Rationale for study ......................................................................................................................... 5 
2 
Study objectives and endpoints ................................................................................................................ 6 
2.1 
Objectives ...................................................................................................................................... 6 
2.1.1 
Primary objectives ....................................................................................................... 6 
2.1.2 
Secondary objective ..................................................................................................... 6 
2.2 
Endpoints ....................................................................................................................................... 6 
3 
Study design - overview ............................................................................................................................ 7 
3.1 
Description of study design ........................................................................................................... 7 
4 
Study population ....................................................................................................................................... 8 
4.1 
Definition of the overall subject population .................................................................................. 8 
4.2 
Inclusion criteria ............................................................................................................................ 8 
4.3 
Exclusion criteria ........................................................................................................................... 8 
4.4 
Withdrawal criteria ........................................................................................................................ 9 
5 
Description of the hyposafe H02 device ................................................................................................. 10 
6 
Methods and assessments ....................................................................................................................... 10 
6.1 
Visit procedures ........................................................................................................................... 10 
6.1.1 
Early discontinuation ................................................................................................. 12 
6.1.2 
Adverse events ........................................................................................................... 12 
6.1.2.1 
Definitions ........................................................................................... 12 
6.1.2.2 
Collection, recording and reporting of adverse events ........................ 13 
6.1.2.3 
Follow-up of adverse events ............................................................... 13 
6.1.3 
Concomitant illness/medical history .......................................................................... 13 
6.1.4 
Concomitant medication ............................................................................................ 13 
6.1.5 
Hypoglycaemia awareness status ............................................................................... 13 
6.2 
Case report forms ......................................................................................................................... 14 
6.3 
Traceability and recording of the investigational device ............................................................. 14 
6.4 
Monitoring ................................................................................................................................... 14 
6.5 
Data management ........................................................................................................................ 14 
7 
Statistical considerations and data reporting ....................................................................................... 15 
7.1 
Rational for the choice of sample size ......................................................................................... 15 
7.2 
Definition of analysis populations ............................................................................................... 15 
7.3 
Demographics and baseline characteristics.................................................................................. 15 
7.4 
Handling of missing data ............................................................................................................. 15 
7.5 
Endpoint analysis ......................................................................................................................... 15 
7.5.1 
Performance endpoints .............................................................................................. 15 
7.5.2 
Safety endpoints ......................................................................................................... 17 
7.5.3 
Usability endpoints .................................................................................................... 18 
8 
Ethics ........................................................................................................................................................ 18 

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8.1 
Subject benefit and risks .............................................................................................................. 18 
8.2 
Subject insurance ......................................................................................................................... 19 
8.3 
Informed consent ......................................................................................................................... 19 
8.4 
Early termination or suspension of the investigation ................................................................... 19 
8.5 
Changes to clinical investigation plan or related procedures ....................................................... 19 
8.6 
Deviations from clinical investigation plan ................................................................................. 20 
8.7 
Audit and supervision .................................................................................................................. 20 
8.8 
Data and quality management ...................................................................................................... 20 
8.9 
Safety committee ......................................................................................................................... 20 
8.10 
Reporting of results ...................................................................................................................... 20 
8.11 
Conflict of interest and financial support ..................................................................................... 20 
9 
Reference list ............................................................................................................................................ 21 
 
 
Page 
 

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List of abbreviations 
 
 
ADE:
Adverse device effect
AE:
Adverse event
BG:
Blood glucose
°C:
Centigrade
CA:
Competent authority
CIP:
Clinical investigation plan
CGM:
Continuous glucose monitoring 
CRA:
Clinical research associate
CRF:
Case report form
CRO:
Contract research organisation
EC:
Ethics committee
ECG:
Electrocardiogram
EEG:
Electroencephalogram
FAS:
Full analysis set
HV:
Healthy volunteers
ISO:
International standard organisation
MedDRA:
Medical dictionary for regulatory activities
PG:
Plasma glucose
PP:
Per protocol 
SADE:
Serious adverse device effect
SAE:
Serious adverse event
SOC:
Standard operation classification
TEAE:
Treatment emergent adverse events
V:
Voltage
 
1 
Background information and justification for conducting the 
study 
1.1 
Background 
1.1.1 
Hypoglycaemia in patients with type 1 diabetes 
The near-normalisation of glucose levels has become an established goal in diabetes treatment in 
order to reduce the risk of late complications such as nephropathy, neuropathy, retinopathy and 
cardiovascular disease (1). The fear of hypoglycaemia, the most common adverse event (AE) 
associated with insulin treatment in patients with diabetes (2), discourages patients from 
maintaining tight glycaemic control and only a minority of the patients reach the defined goal of 
glucose control, leading to increased diabetes related morbidity and mortality (3–7). Symptoms of 
hypoglycaemia can be classified as autonomic (warning) symptoms caused by the release of 
catecholamines, or neuroglycopenic symptoms caused by the lack of glucose supply to the brain. 
Following long-term diabetes duration and tight glycaemic control, autonomic symptoms may be 

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compromised due to impaired glucose counter regulatory response. Between 1/4 and 1/3 of patients 
with type 1 diabetes suffer from impaired awareness or unawareness to hypoglycaemia (5,8,9). 
1.1.2 
A hypoglycaemia alarm based on electroencephalography 
The electroencephalogram (EEG) reflects the functional state and metabolism of the brain. The 
brain is critically dependent on a continuous supply of glucose, and when the glucose level is lower 
than the metabolic requirements of the brain, brain function deteriorates. Neuroglycopenic 
hypoglycaemia in insulin-treated patients with diabetes is associated with characteristic changes in 
EEG, including a decrease in alpha activity and an increase in delta and theta activity (10–13). 
These changes are clearly seen at blood glucose level of ~2.0 mmol/L (10,11) preceding the 
development of severe cognitive dysfunction (14). 
Sleep EEG differs significantly from daytime EEG with periods of deep sleep defined by the 
presence of slow wave dominance. Approximately 50% of all hypoglycaemic episodes occur during 
sleep, and prolonged episodes of hypoglycaemia as measured by continuous glucose monitoring 
(CGM) occur in 8.5% of all nights in both children and adults (15). 
For the device to have clinical applicability, it should be able to distinguish hypoglycaemia-induced 
EEG changes from noise, artefacts and physiological variations in the EEG including the low-
frequency waves seen during sleep, with high sensitivity and specificity using an algorithm that 
classifies the EEG in real-time. There should be a timely difference between hypoglycaemia-
induced EEG changes and severe cognitive impairment. The device must be fully compatible with 
everyday activities. Thus, the device should be small, biocompatible and implantable, and the 
monitoring and processing unit should be small and have sufficient battery power. 
1.2 
Rationale for study 
While a finger prick test accurately measures the blood glucose level, it does not provide continuous 
measurements, and hence it is unreliable as a hypoglycaemia alarm. Recent studies have indicated 
that the use of CGM reduces the risk of severe hypoglycaemia (19). However, some find these 
devices troublesome to use and are annoyed by the inaccuracy of the measurements, and even after 
short term use the coverage in subgroups of patients is as low as 50% of the time (20–22). Thus 
there is a medical need for a reliable hypoglycaemia alarm which is easy and convenient to use and 
with high sensitivity and high rate of positive prediction. 
The current protocol describes a clinical study designed to evaluate the sensitivity and the positive 
predictive value of the hyposafe H02 in subjects with type 1 diabetes during everyday activities and 
during insulin-induced hypoglycaemia. In addition, information regarding safety and usability will 
be collected and analysed. This is to verify that the hyposafe H02 is working as intended in subjects 
with type 1 diabetes before proceeding with the planned larger study in subjects with type 1 
diabetes. 

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2 
Study objectives and endpoints 
2.1 
Objectives 
2.1.1 
Primary objectives 
Performance 
To evaluate the technical performance of the hyposafe H02 during everyday activities and during 
insulin-induced hypoglycaemia in subjects with type 1 diabetes. 
Safety 
To evaluate potential safety issues associated with the implantation and use of the hyposafe H02 in 
subjects with type 1 diabetes. 
2.1.2 
Secondary objective 
Usability 
To evaluate the usability of the hyposafe H02 during everyday activities in subjects with type 1 
diabetes. 
2.2 
Endpoints 
Primary performance endpoints 
 Sensitivity: Proportion of spontaneous hypoglycaemic episodes detected by the hyposafe 
H02 compared to the total number of validated1 spontaneous hypoglycaemic episodes after 
12 weeks of monitoring (from visit 5 to visit 10) 
 Positive predictive value: Proportion of validated1 spontaneous hypoglycaemic episodes 
detected by the hyposafe H02 compared to the total number of alerts from the hyposafe H02 
after 12 weeks of monitoring (from visit 5 to visit 10) 
Secondary performance endpoints 
 Overall sensitivity: Overall proportion of hypoglycaemic episodes detected by the hyposafe 
H02 compared to the total number of validated2 hypoglycaemic episodes after 12 weeks of 
monitoring (from visit 5 to visit 10) 
 Overall positive predictive value: Overall proportion of validated2 hypoglycaemic episodes 
detected by the hyposafe H02 compared to the total number of alerts from the hyposafe H02 
after 12 weeks of monitoring (from visit 5 to visit 10) 
 Sensitivity: Proportion of insulin-induced hypoglycaemic episodes detected by the hyposafe 
H02 compared to the total number of insulin-induced hypoglycaemic episodes 
 
1 Validated by self-measured blood glucose (SMBG) or clinical hypoglycaemia according to subject’s experience  
2 Validated by self-measured blood glucose (SMBG), plasma glucose (PG) or clinical hypoglycaemia according to 
subject’s experience  

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 Positive predictive value: Proportion of insulin-induced hypoglycaemic episodes detected by 
the hyposafe H02 compared to the total number of alerts from the hyposafe H02 
 Number of participants with a satisfactory EEG Quality test 
 Change in impedance (from visit 5 to visit 10) 
 Number of device complaints (from visit 4 to visit 10) 
 Mean glucose level at the time of a hypoglycaemia alarm 
Primary safety endpoint 
 Number of AEs 17 weeks after implantation (from visit 3 to visit 12) 
Secondary safety endpoint 
 Number of adverse device effects (ADEs) 17 weeks after implantation (from visit 3 to visit 
12) 
Secondary usability endpoints 
 
 Development in discomfort over time (visit 5 to visit 10) 
 User satisfaction (visit 8) 
 Mean number of hours of use per hyposafe H02 device (from visit 4 to visit 10) 
 Response to hypoglycaemia alarm (from visit 5 to visit 10) 
 Assessment of alarm fatigue (visit 12) 
 
3 
Study design - overview 
3.1 
Description of study design 
The present study is a 4-month non-controlled observational study in subjects with type 1 diabetes. 
Subjects will attend a screening visit (visit 1) in order to assess their eligibility, followed by an 
inclusion visit (visit 2) which should take place as soon as all screening results (including laboratory 
results) are available, reviewed and the subject is confirmed eligible. 12-20 subjects are planned to 
be enrolled, and withdrawals will be replaced until at least 12 subjects have completed the study. 
The subjects will have the implantable part of the hyposafe H02 device implanted (see Figure 1). 
Subjects will be exposed to insulin-induced hypoglycaemia twice during the study. A device for 
continuous glucose monitoring (CGM) will be mounted for two periods of approximately 5 days. 
They will wear the hyposafe H02 device as much as possible both during daytime and night-time. 
In addition, they will fill out questionnaires and complete an interview regarding use, discomfort 
and satisfaction related to the implantation and the use of the H02 device. 
Subjects will have the implantable part of the hyposafe H02 device implanted at visit 3 by a surgical 
procedure under local anaesthesia. External parts of the hyposafe H02 device will be mounted at 
visit 4 and fitted if needed at each subsequent visit until visit 10 (see flow chart Table 1). 

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The duration of the study from screening (visit 1) to removal of sutures (visit 12) will be 
approximately 18 weeks. 
This study will be conducted in accordance with this investigational plan, ISO 14155:2011, ethics 
committee requirements, the Declaration of Helsinki (23), applicable local governmental 
regulations, and appropriate regulations for clinical studies. 
4 
Study population 
4.1 
Definition of the overall subject population 
Between 12 and 20 subjects with type 1 diabetes and impaired awareness of hypoglycaemia will be 
enrolled in the study to ensure a number of subjects completing the study of at least 12. 
4.2 
Inclusion criteria 
For a subject to be eligible, all inclusion criteria must be answered “yes”: 
1. Informed consent obtained before any study related activities3 
2. Type 1 diabetes diagnosed at least five years prior to inclusion in the study 
3. Age 18-70 years 
4. Impaired awareness, i.e. defined as unaware by the Pedersen-Bjergaard scale (section 6.1.5) 
and/or history of at least one severe hypoglycaemia4 within the preceding year 
4.3 
Exclusion criteria 
For a subject to be eligible, all exclusion criteria must be answered “no”: 
1. Severe cardiac disease 
o History of myocardial infarction 
o Cardiac arrhythmia 
2. History of stroke or cerebral haemorrhage and any other structural cerebral disease 
3. Active cancer or cancer diagnosis within the past 5 years 
4. Uraemia defined as s-creatinine ≥ 3 times upper reference value 
5. Liver disease defined as s-ALAT ≥ 3 times upper reference interval 
6. Epilepsy 
7. Use of antiepileptic drugs for any indication 
8. Clinically important hearing impairment 
9. Use of active implantable medical device including 
o Pacemaker and ICD-unit 
o Cochlear implant 
10. Use of following drugs: 
 
3 A study related activity is any procedure that would not have been performed during the normal management of the 
subject 
4 Requiring assistance from third person whether being help for carbohydrate ingestion, glucagon injection or contact to 
health care person 

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o Chemotherapeutic drugs of any kind 
o Methotrexate 
o Third generation antipsychotic drugs (aripiprazole, quetiapine, clozapine, 
ziprasidone, paliperidone, risperidone, sertindole, amisulpride, olanzapine) 
11. Contraindications to the local anaesthetic used during implantation (1% xylocain with 
adrenalin) 
12. Known or suspected abuse of alcohol defined as consumption of >250g alcohol5 or any other 
neuro-active substances 
13. Infection at the site of device implantation 
14. Any haemorrhagic disease 
15. Females of childbearing potential who are pregnant or intend to become pregnant or are not 
using adequate contraceptive methods6 throughout the study 
16. Performing extreme sport, including scuba diving (snorkel diving is allowed) or parachute 
jumping 
17. Incapable of understanding the subject information or unlikely to complete the study for any 
reason 
18. Operating MRI scanners 
19. Operating handheld transceivers for communication (e.g. within the police, medical, fire, air 
traffic control, marine or military) 
20. Working at broadcast stations for television or FM/DAB radio 
Subjects who are non-compliant with any of the eligibility criteria, but included in the study, should 
be excluded immediately. If extraordinary circumstances speak in favour of maintaining the subject 
in the study then this is only acceptable if justified and approved by the ethics committee and if 
regulatory authorities are notified. 
4.4 
Withdrawal criteria 
1. The subject may withdraw at will at any time without explanation 
2. The subjects may be withdrawn from the study at the discretion of the investigator due to a 
safety concern or if judged non-compliant with the study procedures 
Subjects must be withdrawn from the study for any of the following reasons: 
3. Included in the study in violation with any of the inclusion and/or exclusion criteria 
4. Use of any drug listed under exclusion criteria 
5. Subject becomes pregnant during the study 
This will not impact the treatment or follow-up of the subject. If a subject is withdrawn from the 
study, the investigator must aim to undertake procedures similar to those for visit 11 and 12: The 
 
5 in Danish: 21 “genstande” per week 
6 Safe anticonceptive methods includes contraceptive pills, intrauterine device including hormone intrauterine device 
and sustained gestagen injection 

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a)
b)
c)
d)
e)
device must be explanted as quickly as possible, the sutures removed when appropriate and the end-
of-study-form in the case report form (CRF) must be filled out. 
Although a subject is not obliged to give his/her reason(s) for withdrawal, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. Any 
reasons obtained must be specified in the subject’s medical file and the appropriate section of the 
CRF. 
5 
Description of the hyposafe H02 device 
The hyposafe H02 device consists of three parts: An implantable part which consists of a 20 mm 
semi-spherical implant house and an electrode (diameter: 1 mm, length 100 mm), see Figure 1b. 
The implant records the EEG signal and transmits the signal wirelessly to the external device. The 
position of the implant is depicted in Figure 1a. The external device is supplied in two versions: An 
ear hanger (Figure 1c) and a disc version (Figure 1d) both wirelessly receiving signals from the 
implant and charging the implant. An insertion needle for the implantation procedure (Figure 1e). 
 
 
 
 
 
 
6 
Methods and assessments 
6.1 
Visit procedures 
Procedure for scheduled visits and telephone contacts are described in the following and in the flow 
chart (Table 1). 
Figure 1 Hyposafe H02 device 

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Table 1 Flow chart 
Visit number 
Visit 
1
Visit 
2
Visit 
3
Visit 
4 
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 
10
Visit 
11
Visit 
12
Time related to time 
of implantation 
(weeks)
-0.5 
01) 
0 
1.5 
3 
4 
5 
7 
11 
15 
16 
17 
Visit window (days)
±22)
±5
±5
±5
±5
±5
±5
±74)
2)
Name of visit 
Screening 
Inclusion 
Implantation 
Device mounting 
Start-up visit 
One-week 
observation 
Two weeks 
observation 
Four weeks 
observation 
Eight weeks 
observation 
End of study 
Device 
explantation 
Follow-up 
Screening, 
Informed consent
X 
 
 
 
 
 
 
 
 
 
 
 
Safety blood 
measurements
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
illness/medical 
history
X 
 
 
 
 
 
 
 
 
 
 
 
Demography
X
Physical 
examination
X 
 
 
 
X 
 
 
 
 
X 
 
 
ECG
X
Concomitant 
medication
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
In/exclusion criteria
X
X
Withdrawal criteria
X
X
X
X
X
X
X
X
Device implantation
X
Suture removal 
X
X
Photography of 
device fitting
 
 
 
 
X 
 
 
 
 
 
 
 
EEG quality test
X
X
CGM mounting
X
X
Mounting of 
external device
 
 
 
X 
 
 
 
 
 
 
 
 
Collecting data for 
calibration start
 
 
 
X 
 
 
 
 
 
 
 
 
Hypoglycaemia 
alarm “on”
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Adverse events 
registration
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse device 
effect registration
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Induced 
hypoglycaemia
 
 
 
 
 
 
X 
 
 
X 
 
 
Log book
X
X
X
X
X
X
X
Questionnaire
X
X
X
Device explantation
X
Surgeon 
questionnaire
 
 
X 
 
 
 
 
 
 
 
X 
 
UNEEG™ medical 
staff present
 
 
X7) 
X7) 
X7) 
X7) 
X7) 
X7) 
X7) 
X7) 
X7) 
X 
1) Inclusion should take place as soon as all screening (including laboratory results) are available, reviewed and subject is confirmed eligible 
and no later than two weeks after screening. This visit can be performed as a telephone consultation after reviewing blood samples 
2) Removal of sutures should be within a time window of 8-12 days following implantation and explantation, respectively 
4) The explantation of the implanted device should take place as soon as possible following the end of study visit 
7) Optional 

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6.1.1 
Early discontinuation 
In case of early discontinuation, either requested by the subject or at the discretion of the 
investigator, the end-of-study-form must be completed. The subject must be followed up, as 
appropriate. 
6.1.2 
Adverse events 
6.1.2.1 
Definitions 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a subject whether related 
to the device or not. 
This includes events from the first study related activity after subject has signed the informed 
consent and until removal of sutures (visit 12), see flow chart Table 1. 
A worsening in concomitant illness must be recorded as an AE. A worsening of an ongoing AE 
should be recorded on a new AE form by making a new assessment for seriousness and possible 
relationship to hyposafe H02 device or implantation procedure. 
Adverse device effect 
An adverse device effect (ADE) is defined as any untoward and unintended response to a medical 
device including insufficiencies or inadequacies in instructions for use or deployment, the 
implantation, the operation, or any malfunction of the investigational medical device. This also 
includes any event that is a result of a use error or intentional misuse of the device. 
Serious adverse event 
An serious adverse event (SAE) is defined as an AE that results in any of the following: 
 Death 
 A life-threatening experience7 
 In-subject hospitalisation or prolongation of existing hospitalisation 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
Serious adverse device effect 
Serious adverse device effect (SADE) is defined as an ADE that has resulted in any of the 
consequences characteristics of a SAE or that might have led to any of these consequences if 
suitable action had not been taken, intervention had not been made or if circumstances had been less 
fortunate. These are handled under the SAE reporting system. 
 
7 The term "life-threatening" refers to an event in which the subject was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more severe  

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6.1.2.2 
Collection, recording and reporting of adverse events 
All events meeting the definition of an AE/ADE must be collected and reported. During each 
contact with the site (site visit or telephone contact) the subject must be asked about AEs/ADE. 
The sponsor will discuss with the investigator all SAEs/SADEs and co-ordinate appropriate actions. 
Investigator will be informed of any study related procedure SAEs/SADEs that may warrant a 
change in any study procedure. If the sponsor or the safety committee find continuation of the study 
incompatible with the safety of the study subjects due to any safety issues related to the hyposafe 
H02 or the study procedures, the study will be terminated or postponed until these issues have been 
solved. 
UNEEG™ medical must report all SAEs/SADEs to the ethics committee and the Danish Health and 
Medicines Authority according to the national regulations. 
6.1.2.3 
Follow-up of adverse events 
During and following a subject’s participation in a clinical study, the investigator should ensure that 
adequate medical care is provided for any subject for any AE. 
6.1.3 
Concomitant illness/medical history 
A concomitant illness is any illness that is present at the start of the study (visit 1) or found as a 
result of the screening procedure. Medical history is a medical event that the subject has 
experienced in the past. Any changes in the concomitant illness should be recorded during the 
study. A clinically significant worsening of a concomitant illness must be reported as an AE (see 
section 6.1.2.2). 
6.1.4 
Concomitant medication 
Concomitant medication is any medication, which is taken during the study. Detail on concomitant 
medication must be recorded at visit 1. Changes in concomitant medication must be recorded at 
each visit as they occur. 
6.1.5 
Hypoglycaemia awareness status 
The Pedersen-Bjergaard method (24) and recent history of severe hypoglycaemia will be used to 
assess hypoglycaemia awareness status at visit 1. 
For the Pedersen-Bjergaard method, the subject will be asked: “Do you recognise symptoms when 
you have a hypo?” and can select one of the following answers: 
 Always 
 Usually 
 Occasionally 
 Never 
Subjects answering “occasionally” or “never” (i.e. unaware according to Pedersen-Bjergaard 
method) and/or who has experienced at least one severe hypoglycaemic episode within the 
preceding year will be classified as having impaired awareness of hypoglycaemia. 

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6.2 
Case report forms 
Case report forms (CRFs) are provided in a uniform design, each form heading requires 
identification of the hospital, subject and investigator and each visit must be dated. The investigator 
must ensure that data are recorded in the CRF as soon as possible after the visit. Completed CRFs 
must be reviewed and signed by the local investigators. The CRF must be kept on site until the 
designated CRA has performed verification of all data entries. 
6.3 
Traceability and recording of the investigational device 
At the site, a device accountability system will be maintained during the study, documenting device 
shipment and receipt, storage at the site, use, and return to the sponsor of used/unused devices, as 
applicable. 
6.4 
Monitoring 
The sponsor will appoint a qualified, experience and trained Clinical Research Associate (CRA) 
from the Contract Research Organisation (CRO) who will visit the study centre periodically during 
the study. The CRA is to ensure adherence to the clinical investigation plan, including verification 
of subject informed consent, letter of authorisation, inclusion and exclusion criteria etc. The CRA 
should also verify and review all AEs/ADEs and SAEs/SADEs. 
Investigators must provide access to the hospital files and any other medical source document 
containing subject’s clinical/medical information, to the CRA for them to perform source document 
verification. The CRA is responsible for verifying the data entered into the CRFs against hospital 
source documents to ensure accuracy and completeness of the data, prior to retrieving the CRFs, 
from the study centre. 
During the study CRA must check that appropriate written informed consents and power of attorney 
have been obtained. The CRA must inform the sponsor about any problems relating to facilities, 
technical equipment or medical staff at the study centre. The CRA must notify such deficiencies in 
writing to the related clinical centre’s principal investigator and convene with the study centre 
personnel appropriate and timely corrective actions. The CRA must make written reports to the 
sponsor, after each visit or contact with the investigator or centre. 
6.5 
Data management 
Data management is the responsibility of UNEEG™ medical but may be delegated under an 
agreement of transfer of responsibilities to a CRO. Data collected via the CRFs will be subject to 
data quality control measures in compliance with all applicable data management procedures. All 
CRFs will be audited against corresponding database output to ensure accuracy. Data management 
will correct obvious errors, and a query will be sent to the CRA for confirmation of the correction 
by the investigator, as will queries for omission and discrepancies or other errors. The CRFs will be 
corrected as required and the corrected data entered into the database. The copy of the signed query 
form will be filed with the CRFs. 

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Prior to database lock the database will be validated. When all queries have been resolved, the 
database will be locked. Any changes to the database after that time will require joint written 
agreement between the investigator, the biostatistician and the sponsor. 
7 
Statistical considerations and data reporting 
Tabulations and cross-tabulations will be performed as outlined in the endpoint analysis section. No 
comparative statistical analyses are planned. Any deviations from the planned statistical analysis 
will be justified in the study report. 
7.1 
Rational for the choice of sample size 
This is not a comparative endpoint study. It is assumed that sufficient information about the 
performance, safety and the use of the hyposafe H02 to support any potential optimisation of the 
algorithm or adjustment of procedures will be obtained with approximately 12 subjects with 
type 1 diabetes. The total number will depend on the results of the study and number of 
withdrawals, and it is planned to enrol 12-20 subjects with type 1 diabetes to ensure a number of 
subjects completing the study of at least 12. 
7.2 
Definition of analysis populations 
The following analysis set are defined according: Full analysis set (FAS) are all subjects included in 
the study will be included in the FAS. Per protocol (PP) analysis set are all subjects of the FAS who 
completed the trial without major protocol violations will be included in the PP analysis set. Safety 
analysis set are all subjects in whom the investigational device was implanted will be included in 
the safety analysis set 
7.3 
Demographics and baseline characteristics 
Demographic and baseline characteristics will be summarised according to the type of data. 
Summaries will be provided for entire study population. 
7.4 
Handling of missing data 
Subjects who withdraw from the study due to reasons not related to the hyposafe H02 device will be 
tabulated with the reasons for the withdrawal. 
7.5 
Endpoint analysis 
7.5.1 
Performance endpoints 
All performance endpoints will be analysed using the FAS as well as the PP analysis set. 
Primary performance endpoint 
The primary performance endpoints are defined as the sensitivity and positive predictive value of 
the hyposafe H02 based on spontaneous hypoglycaemic episodes. 

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Spontaneous hypoglycaemic episodes are recorded by subjects in the log book throughout the study. 
This includes information on blood glucose measurements before treating the episode, alarms given 
by the hyposafe H02 device and information on whether the subjects was able to treat him/herself or 
was asleep when the episode occurred. 
A hypoglycaemic episode will be characterised as treatment emergent if the onset of the episode is 
on or after the first day the hyposafe H02 device switched to “alarm on”-mode and no later than the 
last day of the wearing the external device. Data on treatment emergent hypoglycaemic episodes are 
presented in terms of the number of subjects with at least one episode (N) and the number of 
episodes (E). 
Hypoglycaemic episodes will be defined as nocturnal (i.e. during night-time) if they occur during 
sleep (as reported by the subject) and/or are registered by the hyposafe H02 night device. 
Data from blood glucose measurement and clinical hypoglycaemia (according to subject’s 
experience) will be used by UNEEG™ medical to classify a hypoglycaemic alarm according to 
categorisation displayed in Table 2 (true and false, positive and negative hypoglycaemia alarms). 
As blood glucose values are lower than plasma values, a constant factor of 1.11 is used to convert 
concentration in whole blood to the equivalent concentration in plasma (25). 
Sensitivity and positive predictive value will be calculated for daytime and night-time, separately. 
Secondary performance endpoints 
Insulin-induced hypoglycaemia is performed twice for each subject, with frequent assessments of 
plasma glucose levels. As the number of spontaneous hypoglycaemic episodes reported during the 
study may be relatively small, data from the insulin-induced hypoglycaemia will be added to 
calculate the overall sensitivity and positive predictive value of the hyposafe H02 (spontaneous 
and insulin-induced hypoglycaemia episodes) after 12 weeks of monitoring (from visit 5 to 
visit 10). 
The sensitivity and positive predictive value will also be calculated based data from the insulin-
induced hypoglycaemic episodes only. 
The hypoglycaemic alarms will be classified according to categorisation displayed in Table 2 (true 
and false, positive and negative hypoglycaemia alarms), and presented as described for primary 
performance endpoint. 

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Table 2 Categorisation of hypoglycaemic episodes 
Episodes categorised as 
PG > 3.9mmol/l 
+ alarm 
+/- clinical hypoglycaemiaa) 
False positive □ 
- alarm 
+/- clinical hypoglycaemia a) 
True negative □ 
PG 2.0 – 3.9mmol/l 
+ alarm 
+/- clinical hypoglycaemia a) 
True positive □ 
- alarm 
+ clinical hypoglycaemia a) 
False negative □ 
- clinical hypoglycaemia a) 
True negative □ 
PG < 2.0mmol/l 
+ alarm 
+/- clinical hypoglycaemia a) 
True positive □ 
- alarm 
+/- clinical hypoglycaemia a) 
False negative □ 
PG not measured 
+ alarm 
+ clinical hypoglycaemia a) 
True positive □ 
- clinical hypoglycaemia a) 
Not categorised □ 
- alarm 
+ clinical hypoglycaemia a) 
 
Not categorised 
False negativeb)  
a) According to subject (No strict definition is given) 
b) If hypoglycaemic episode was severe (i.e. requiring assistance from third person whether being help for carbohydrate 
ingestion, glucagon injection or contact to health care person), the episodes should be characterised as false negative 
PG; plasma glucose 
Data from EEG quality test at the visit 4 and visit 10 will be compared graphically. 
The impedance is expected to be below 5 kOhm at all times. No trend in the measurements for 
each subject should be apparent over time, except perhaps a small decline in the beginning. Any 
change in impedance over time (from visit 5 to visit 10) will be summarised descriptively and 
presented by subject. 
The number of device complaints will be tabulated and presented by device part. 
Mean blood, plasma or interstitial glucose level at the time of an alarm will be summarised for 
insulin-induced hypoglycaemia and spontaneous hypoglycaemic episodes, separately. 
7.5.2 
Safety endpoints 
All safety endpoints will be analysed using the safety analysis set. 
Primary safety endpoint 
The primary safety endpoint is defined as the number of AEs 17 weeks after implantation. 
All AEs will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA). 
Secondary safety endpoint 
The number of ADEs 17 weeks after implantation will be summarised as described for AEs. 

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7.5.3 
Usability endpoints 
All usability endpoints will be analysed using the FAS. 
Development in discomfort over time 
Data from questionnaires regarding discomfort related to the implanted device will be tabulated and 
presented by week and discomfort category and compared over time (visit 5 to visit 10). 
Assessment of alarm fatigue 
Data from questionnaire regarding alarm fatigue at visit 12 will be tabulated and presented by 
category of sensitivity and false alarm(s). 
User satisfaction 
Subject user satisfaction at visit 8 will be summarised based on the specific questionnaire. 
Usage of external device 
The mean number of hours the hyposafe H02 day or night device has been connected to the implant 
from visit 4 to visit 10 will be summarised. Summaries will be presented for daytime and night-
time, separately. 
Response to hypoglycaemia alarm 
The number of preventive actions, i.e. the number of hypoglycaemia alarms where subject was able 
to take preventive action as instructed (acknowledge the alarm by key press, measure blood glucose, 
and in case of low blood glucose; ingest a carbohydrate rich meal) compared to the total number of 
hypoglycaemia alarms from visit 5 to visit 10 will be tabulated. 
8 
Ethics 
The study will be conducted according to the Declaration of Helsinki (23) and approved by the local 
ethical committee before commencement. The use of the hyposafe H02 must be approved by the 
Danish Health and Medicines Agency before initiation. Only information relevant for the study will 
be collected. As UNEEG™ medical is a private data responsible the current private health research 
project will not been notified to the Danish Data Protection Agency. Data will be handled in 
accordance with the Act on Processing of Personal Data. 
8.1 
Subject benefit and risks 
A risk analysis according to ISO 14971 “Application of risk management to medical devices” has 
been conducted. Risks have been minimised or eliminated through appropriate design control. 
Impaired awareness of hypoglycaemia associated with increased morbidity and mortality, is a 
serious problem for many patients with type 1 diabetes, and it is believed that the potential benefit 
of a hypoglycaemia alarm system overweighs the potential risks in the current study. 

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The subject participating in this study cannot be guaranteed benefits of the participation. If the 
hypoglycemia alarm works as intended, subjects with the alarm function switched on may 
experience an increased security at hypoglycaemia. 
An external energy source powers the implant via an inductive link. There is no risk of transfer of 
power from the energy source to the surrounding tissue of the subject. No radioactive substances are 
used in the study. 
Foreseeable AEs and anticipated ADEs are infection (estimated risk: 0.5%), headache (estimated 
risk: 10%), seizures (estimated risk: 0.5%), and phlebitis (estimated risk: 1-2%). 
8.2 
Subject insurance 
Product liability and no fault clinical trial assurance covering the duration of the study are in place, 
to enable compensation in the event of an injury to a participating subject. 
8.3 
Informed consent 
Study subjects will be recruited by advertising or by personal contact to the subject in the outpatient 
clinics. The information sheet will be sent to or given to the participant at least 3 days before the 
screening visit. Participants will be encouraged to bring a friend or a family member for the 
screening visit at the study site. The study procedures will be explained to the participant by 
qualified personnel and the information sheet will be reviewed with the participant under 
undisturbed conditions in a quiet room reserved for this purpose. A voluntary, signed and dated 
informed consent form must be obtained from the subject prior to any study related activities. 
The investigator is responsible for ensuring that no subject is subjected to any study related 
examination or activity before the subject has given his/her written informed consent. The written 
informed consent must be signed and dated by the person who seeks the consent. 
8.4 
Early termination or suspension of the investigation 
If the sponsor or the safety committee find continuation of the study incompatible with the safety of 
the study subjects due to any safety related issues of the study product or the study procedure the 
study will be terminated or postponed until these issues have been solved. 
If a study is prematurely terminated or suspended, the investigator should promptly inform the 
subjects and assure appropriate follow-up. Furthermore, the investigator and/or UNEEG™ medical 
should promptly inform the ethics committee and provide a detailed written explanation. The 
regulatory authorities should be informed according the regulations. 
8.5 
Changes to clinical investigation plan or related procedures 
All substantial changes to the clinical investigational plan must not be implemented before 
approval/favourable opinion unless necessary to eliminate immediate hazards to the subjects. All 
changes to the clinical investigation plan require notification to the ethics committee and the 

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competent authority. No changes in the study procedures must be implemented without mutual 
agreement of the investigator and the sponsor. 
8.6 
Deviations from clinical investigation plan 
Deviation to the clinical investigational plan should be avoided. If deviations occur, the investigator 
must inform the sponsor who is responsible for analysing and assessing the implication of the 
deviation. Any deviation from the clinical investigation plan must be documented stating the 
explanation for the deviation, the date and any actions taken. 
Significant deviations compromising or potentially compromising the safety of the subjects, 
enrolment of non-eligible subjects or any deviation, which significantly compromises the outcome 
of the study, must be reported to the ethics committee within the appropriate timelines indicated by 
the ethics committee. 
8.7 
Audit and supervision 
Investigator sites and study documentation may be subject to quality assurance audits during the 
course of the study. In addition, regulatory bodies at their discretion may conduct inspections, 
during and after study completion. 
8.8 
Data and quality management 
CRF data collected will be subject to data quality control measures in compliance with all 
applicable data management procedures. Edit checks will be applied to identify discrepant data. All 
CRFs will be audited against corresponding database output to ensure accuracy. Data management 
documentation will be generated and maintained throughout the process including the data 
management plan and associated project binders. 
8.9 
Safety committee 
UNEEG™ medical will constitute an internal safety committee to perform ongoing safety 
surveillance. 
8.10 
Reporting of results 
The results of the investigation will be summarised in a report to be used in the further development 
and approval of the device. The report will be forwarded to the ethics committee and competent 
authorities at the end of the investigation. The main findings of study will be submitted for 
publication in a peer reviewed journal or made public available www.clinicaltrials.gov. 
8.11 
Conflict of interest and financial support 
The study is initiated by UNEEG™ medical and financed by UNEEG™ medical. The principal 
investigator is not affiliated with UNEEG™ medical and has full scientific integrity.  
 

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9 
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