Phase 3, Randomized, Double-blind, Placebo/Active-controlled, Parallel-arm Trial to Assess Efficacy, Safety, and Pharmacokinetics of Dasiglucagon Relative to Placebo/GlucaGen® as Rescue Therapy for Severe Hypoglycemia in Children With T1DM Treated With Insulin
Phase: PHASE3
Conditions: Hypoglycemia
Sponsor: Zealand Pharma

CLINICAL TRIAL REPORT 
ZP4207-17086 (ZEA-DNK-02170) 
 
 
Section 16.1.1: Protocol and Protocol Amendments 
16.1  TRIAL INFORMATION 
16.1.1 
PROTOCOL AND PROTOCOL AMENDMENTS  
 
This appendix includes 
 
Document 
Date, Version 
Clinical trial protocol 
 Version 1.0, 08 June 2018  
(valid in Slovenia and the USA) 
 Version 3.0, 08 January 2019 
(valid in Germany) 
 

 
 
 
Clinical Trial Protocol, final version 1.0 
ZP4207-17086 (ZEA-DNK-02170) 
 
08 June 2018  
CONFIDENTIAL 
Page 1/55 
 
Clinical Trial Protocol 
A phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial to 
assess the efficacy, safety, and pharmacokinetics of dasiglucagon relative to placebo 
and GlucaGen® when administered as a rescue therapy for severe hypoglycemia in 
children with T1DM treated with insulin  
Sponsor code: ZP4207-17086 
Synteract: ZEA-DNK-02170 
EudraCT number: 2018-000892-33 
 
 
Coordinating investigator:  
Prof. Dr. med. Thomas Danne 
Allgemeine Kinderheilkunde 
Diabetologie, Endokrinologie, Klinische Forschung 
Diabeteszentrum für Kinder und Jugendliche AUF DER BULT 
Kinder- und Jugendkrankenhaus 
Janusz-Korczak-Allee 12 
30173 Hannover 
Germany 
 
 
Sponsor:  
Zealand Pharma A/S 
Smedeland 36 
2600 Glostrup, Copenhagen 
Denmark 
 
 
 
Version: final version 1.0 
Date: 08 June 2018 
 
 
 
 
 
GCP statement 
This trial will be performed in compliance with Good Clinical Practice,  
the Declaration of Helsinki (with amendments) and local legal and regulatory requirements.

Zealand Pharma A/S
ClinicalTrial Prolocol, final ve¡sion 1.0
zP 42A7 -1 7 A 86 (ZEA-DN K-02 1
L Slgnature¡ and agreoment wlth protocot
Tltle: A phase 3, ¡andomized, double-blind, placebo- and aclivg-controlled, parallel-arm trial to
assess the efficac¡ safety, and pharmacoítinetics of dasiglucagon rela¡ve to placebo and
GlucaGeno when edministered as a rescue thêrapy for sevãre triposivcemia ¡n children w¡th
TlDM treated with insulin
we, the undersigned, agroe to conduct lhls trlal according to lhe Trlal protocol.
we agree that the lrial will be carried oul in accordance with Good clinical p¡actice, with the
Oeclaration of Hetsinki (with amendments) and with the laws and regulations of lhe countries in
which the tríallakes place.
Coordinating
investigator
Statistician
Sponsois
representative
Prof. Dr, med. Thomas Dannê
Senior Director Biometrics
Synteract 9eutschland GmbH
Albrechtstr. 14
80636 Munich, Germany
Clinical Project Director
Zealand Pharma Ái/S
Smedeland 38
2600 Glostrup, Denmark
Dr.
MedlcalDireclor
Zealand Pharma,olS
$medeland 36
?600 Glostrup, Denmark
Date
0B June 2018
CONFIDENTIAL
Page ?55

Zealand Pharma A/S 
Clinical Trial Protocol, final version 1.0 
ZP4207-17086 (ZEA-DNK-02170) 
 
08 June 2018  
CONFIDENTIAL 
Page 3/55 
Title: A phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial to 
assess the efficacy, safety, and pharmacokinetics of dasiglucagon relative to placebo and 
GlucaGen® when administered as a rescue therapy for severe hypoglycemia in children with 
T1DM treated with insulin  
I agree to conduct this trial according to the Trial Protocol.  
I agree that the trial will be carried out in accordance with Good Clinical Practice, with the 
Declaration of Helsinki (with amendments) and with the laws and regulations of the countries in 
which the trial takes place. 
 
 
 
Investigator 
 
 
 
 
 
 
Date 
 
Signature 
 
 
 
 
 
Name and 
address 
 
 
 
 

Zealand Pharma A/S 
Clinical Trial Protocol, final version 1.0 
ZP4207-17086 (ZEA-DNK-02170) 
 
08 June 2018  
CONFIDENTIAL 
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2. Trial synopsis 
Title of the trial: 
A phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial to assess the 
efficacy, safety, and pharmacokinetics of dasiglucagon relative to placebo and GlucaGen® when 
administered as a rescue therapy for severe hypoglycemia in children with T1DM treated with insulin  
EudraCT number: 
2018-000892-33 
Protocol codes: 
Sponsor: ZP4207-17086 
Synteract: ZEA-DNK-02170 
Sponsor or sponsor's representative in the European Union: 
Zealand Pharma A/S, Smedeland 36, 2600 Glostrup (Copenhagen), Denmark 
Coordinating investigator: 
Prof. Dr. med. Thomas Danne, Kinder- und Jugendkrankenhaus AUF DER BULT, Janusz-Korczak-
Allee 12, 30173 Hannover, Germany 
Trial center(s): 
2-3 centers in the EU (Germany, Slovenia) and 1-2 centers in the USA 
Planned trial period: 
First Patient First Visit: September 2018 
Last Patient Last Visit: Second quarter 2019 
Phase of development:  
Phase 3 
Objectives: 
The primary objective is to demonstrate that dasiglucagon is superior to placebo following a single 
injection of 0.6 mg of dasiglucagon in treating hypoglycemia in children with type 1 diabetes mellitus 
(T1DM). 
Secondary objectives are: 
 To confirm that a single dose of dasiglucagon [0.6 mg] is comparable to a single dose of GlucaGen® 
[1 mg/mL] in treating hypoglycemia in children with T1DM, (in accordance with the label, children 
below 25 kg body weight will be administered 0.5 mg GlucaGen®), 
 To assess safety profile of dasiglucagon in children with T1DM, 
 To assess pharmacokinetic (PK) profile of dasiglucagon in children with T1DM. 
Trial design: 
This is a phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial 
designed to assess efficacy, safety and PK of dasiglucagon vs. placebo and vs. GlucaGen® in 
children with diabetes mellitus type 1 (T1DM). Patients will receive a single subcutaneous injection of 
the investigational product during a hypoglycemic clamp procedure. Handling, preparation and 
administration of trial product will be done by unblinded trial personnel. All trial assessments will be 
done by blinded trial personnel. 
The trial design is illustrated in the figure below. 

Zealand Pharma A/S 
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ZP4207-17086 (ZEA-DNK-02170) 
 
08 June 2018  
CONFIDENTIAL 
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Abbreviation: PK=pharmacokinetic 
Planned number of patients: 
At least 40 children ≥6 years and <18 years of age with T1DM will be randomized into the trial (2:1:1 
dasiglucagon/placebo/GlucaGen®) and stratified by age intervals: 6 years to <12 years, and 12 years 
to <18 years and by injection site (abdomen/thigh). A minimum of 16 patients will be enrolled into 
each age group, including a minimum of 8 patients in either of age groups on dasiglucagon treatment 
arm. 
Patients who are dosed will not be replaced. 
Medical condition or disease under investigation: 
This is the first dedicated efficacy and safety trial in children; thus, the target population for this trial is 
children with T1DM ≥6 to <18 years of age. Dasiglucagon is in development for treatment of severe 
hypoglycemia. 
Inclusion criteria: 
To be included in the trial, patients have to fulfill all of the following criteria: 
1. Following receipt of verbal and written information about the trial, patient, parent(s) or guardian(s) 
of the patient must provide signed informed consent before any trial-related activity is carried out* 
2. Female or male patients with T1DM for at least 1 year, diagnostic criteria as defined by the 
American Diabetes Association; and receiving daily insulin 
3. At least 6.0 years of age (inclusive) and less than 18.0 years 
4. Body weight ≥20 kg 
5. Female patients must meet one of the following criteria: 
a.  Participant is of childbearing potential and agrees to use one of the accepted contraceptive 
regimens throughout the entire duration of the trial from screening until last follow-up visit. An 
acceptable method of contraception includes at least one of the following: 
i. Abstinence from heterosexual intercourse 

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ZP4207-17086 (ZEA-DNK-02170) 
 
08 June 2018  
CONFIDENTIAL 
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ii. Systemic contraceptives (birth control pills, injectable/implant/ insertable hormonal birth 
control products, transdermal patch); if the participant is using systemic contraceptives, 
she must use an additional form of acceptable contraception (iii or iv, below) 
iii. Intrauterine device (with and without hormones) 
iv. Condom with spermicide  
or 
b. Participant is of non-childbearing potential due to pre-puberty status or a medical condition 
confirmed by the investigator  
6. Male patients must meet the following criteria: If sexually active, uses condom and partner 
practices contraception during the trial from screening and until last follow-up visit 
7. Willingness to adhere to the protocol requirements 
* Informed consent signatures must be obtained according to local regulations. 
 
Exclusion criteria: 
Patients meeting any of the following criteria during screening evaluations will be excluded from trial 
participation: 
1. Females who are pregnant according to a positive urine pregnancy test, actively attempting to get 
pregnant, or are lactating 
2. Known or suspected allergy to trial product(s) or related products 
3. History of anaphylaxis or symptoms of severe systemic allergy (such as angioedema) 
4. Previous randomization in this trial 
5. History of an episode of severe hypoglycemia that required a third party assistance within a 
month prior to screening visit 
6. History of hypoglycemic events associated with seizures or hypoglycemia unawareness in the last 
year prior to screening 
7. History of epilepsy or seizure disorder 
8. Receipt of any investigational drug within 3 months prior to screening 
9. Active malignancy within the last 5 years 
10. Congestive heart failure, New York Heart Association class II-IV 
11. Current bleeding disorder, including anti-coagulant treatment 
12. Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma (i.e. 
insulin secreting pancreas tumor) 
13. Use of a daily systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs in the 
previous 28 days before Day 1 of this trial 
14. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limit of the 
normal range (ULN), bilirubin >1.5 × ULN, estimated glomerular filtration rate <30 mL/min/1.73 m2 
according to the Modification of Diet in Renal Disease study definition, or altered electrolyte 
values of clinical relevance for cardiac conduction, as judged by the investigator 
15. Clinically significant abnormal electrocardiogram (ECG) at screening as judged by the investigator 
16. Clinically significant illness within 4 weeks before screening as judged by the investigator 
17. Surgery or trauma with significant blood loss within the last 2 months prior to screening 
18. Patients with mental incapacity or language barriers which preclude adequate understanding or 
cooperation, who are unwilling to participate in the trial, or who in the opinion of the investigator 
should not participate in the trial  
19. Any condition interfering with trial participation or evaluation or that could be hazardous to the 
patient 
20. The use of prescription or non-prescription medications known to cause QT prolongation 
 
In addition, the following exclusion criteria at clinic admission on Visit 2, day 0 apply at the time of 
admission to the clinic, which is the day before clamp procedure: 
Patients who meet one or more of the following exclusion criteria at the time of admission to the clinic 
will be excluded from the dosing visit, however, the visit can be rescheduled 1-7 days later. The 
dosing visit can only be rescheduled once. 

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1. Atypically strenuous exercise within 4 days prior to dosing, as judged by the investigator. Exercise 
during the trial should follow patient’s typical routine, and should not exceed a near maximum 
intensity for more than 20 minutes per day, or moderate intensity for more than 90 minutes per 
day 
2. Clinically significant illness within 4 weeks before dosing, as judged by the investigator 
3. Consumption of alcohol within 24 hours prior to dosing visit, determined by positive results from 
an alcohol breath test 
4. Not fasting from 22:00 hours the evening prior to dosing, apart from water. 
5. The use of any non-prescribed systemic or topical medication, except routine vitamins and 
occasional use (as judged by the investigator) of acetylsalicylic acid and paracetamol within 2 
weeks prior to dosing. Treatment with insulin, including analogs, is allowed 
6. Use of insulin degludec or insulin glargine U300 within 72 hours prior to dosing; or use of other 
long-acting insulins (e.g. insulin glargine U100 or insulin detemir) within 48 hours prior to dosing; 
or use of neutral protamine Hagedorn insulin NPH within 22 hours prior to dosing 
7. Use of any short acting (bolus) insulin within 12 hours prior to dosing, except insulin glulisine 
(Apidra®) 
8. Changes in medical history or concomitant medication resulting in fulfillment of clinical exclusion 
criteria, as judged by the investigator 
9. Plasma glucose value <50 mg/dL (2.8 mmol/L) within the last 24 hours or plasma glucose value 
<60 mg/dL (3.3 mmol/L) within the last 5 hours prior to admission to the clinic. 
Test product, dose and mode of administration: 
Dasiglucagon, liquid formulation, 1 mg/mL, 0.6 mL 
Reference product, dose and mode of administration: 
Placebo for dasiglucagon (hereafter referred to as placebo): Placebo, liquid formulation, 0.6 mL  
Active control: Recombinant glucagon hydrochloride, 1 mg lyophilized powder for reconstitution 
(GlucaGen®, Novo Nordisk) in 1 mL sterile water (hereafter referred to as GlucaGen®). In accordance 
with the label, children below 25 kg body weight will be administered 0.5 mg GlucaGen® 
Duration of treatment: 
Patients will receive a single subcutaneous dose of investigational product. Patients will be subjected 
to a hypoglycemic clamp procedure and have to be within a plasma glucose target range of 54-
80 mg/dL at dosing. The total individual trial duration will be a maximum of 63 days (up to 30 days 
screening, 1 dosing, 28 [+5] days of follow-up). 
Criteria for evaluation: 
Primary endpoint 
Time to plasma glucose recovery. Plasma glucose recovery is defined as first increase in plasma 
glucose of ≥20 mg/dL (1.1 mmol/L) from baseline during the hypoglycemic clamp procedure without 
administration of rescue intravenous (IV) glucose.  
Secondary endpoints 
Secondary efficacy endpoints: 
 
Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 minutes, and within 10 
minutes after trial product injection without administration of IV glucose 
 
Plasma glucose changes from baseline within 30 minutes, within 20 minutes, within 15 minutes, 
and within 10 minutes after trial product injection or at the time of rescue IV glucose 
Safety endpoints: 
 
Adverse events (AEs) 
 
Clinical laboratory assessments (biochemistry, hematology, coagulation, urinalysis) 
 
Vital signs 
 
Physical examination 
 
Clinically significant changes in the electrocardiogram 
 
Local tolerability 
 
Administration of IV glucose infusion during the hypoglycemic clamp procedure 

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 
Time to first IV glucose infusion, after trial product administration. (N.B. IV glucose infusion prior 
to trial product administration should not be included, as it is part of hypoglycemic clamp 
procedure) 
 
Immunogenicity endpoint: occurrence of anti-drug antibodies 
Pharmacokinetic endpoints 
PK endpoints will be derived from plasma dasiglucagon and GlucaGen® profiles from 0 to 
300 minutes: 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
30 minutes post-dose (AUC0-30min) 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
300 minutes post-dose (AUC0-300min) 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
infinitely post-dose (AUC0-inf) 
 
Maximum of all valid plasma dasiglucagon or GlucaGen® concentration measurements from 0 to 
300 minutes post-dose (Cmax) 
 
Time to maximum of plasma dasiglucagon or GlucaGen® concentration measurements (tmax) 
 
Terminal elimination rate constant of plasma dasiglucagon or GlucaGen® (λz) 
 
Terminal plasma elimination half-life of dasiglucagon or GlucaGen® (t½) 
 
Total body clearance of plasma dasiglucagon or GlucaGen® (CL/f) 
 
Volume of distribution of plasma dasiglucagon or GlucaGen® (Vz/f) 
 
Mean residence time of plasma dasiglucagon or GlucaGen® (MRT) 
Pharmacodynamic endpoint 
 
Plasma glucose response as area under the effect curve above baseline from time zero to 
30 minutes, AUE0-30min 
Statistical methods: 
All data obtained in this trial and documented in the electronic case report forms (eCRFs) will be listed 
and summarized with statistics or frequency tables as appropriate. In case of termination of the trial, all 
data collected up to that time will be included into the analysis. 
Continuous variables will be summarized with means, standard deviations, medians, minimums, and 
maximums and valid cases.  
Other summaries (e.g. quartiles, 95% confidence intervals) may be used as appropriate. Categorical 
efficacy and safety variables will be summarized by counts and by percentage of patients in 
corresponding categories. The primary endpoint, time to recovery, will be summarized using Kaplan-
Meier estimates for each treatment group in total and stratified by age intervals and injection site. The 
median time to recovery with 95% confidence interval will be estimated by treatment group. 
Log-rank tests will be applied to compare the 2 treatment groups to the placebo group. 
In the primary analysis, recovery cannot be achieved in those patients where IV glucose treatment is 
administered. Those patients who receive IV glucose will be censored (i.e. set to ‘not recovered’) at 45 
minutes after dosing. 
All safety data will be analyzed with descriptive methods. 
AEs will be tabulated by system organ class (SOC) and preferred term (PT) after medical coding using 
the Medical Dictionary for Regulatory Activities. AE summary tables will include counts and percentages 
of patients who experienced AEs summarized by SOC and PT. 
Plasma dasiglucagon and glucagon concentrations will be described and PK metrics determined. 
AUE0-30min will be summarized with descriptive statistics. 
Sample size calculation: 
The primary comparison is between the dasiglucagon and placebo treatment arms. From phase 2 
results, the median time to an increase of 20 mg/dL of the 0.6 mg dose was approximately 10 

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minutes. For placebo-treated patients, the median time to recovery is assumed to be more than 50 
minutes. Assuming an exponential time-to-recovery distribution with median times of 10 and 50 
minutes, a 2-sided log-rank test will be able to detect a difference between dasiglucagon 0.6 mg and 
placebo with 90% power with a follow-up time of 45 minutes at a 5% significance level with 20 
patients randomized to the dasiglucagon arm and 10 patients to placebo. GlucaGen® is included as a 
reference to compare the responses and AE profile to dasiglucagon with those to a marketed product. 
It is expected that 10 patients in the GlucaGen® group will suffice for the comparison. 

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Table 2-1: Schedule of Assessments 
Visit number 
V1 
V2 
V3 
Vx 
Trial day 
-3 
0 and 1 
28 
Unscheduled1 
Visit type 
Screening 
Dosing 
Follow-up 
Unscheduled1 
Window 
-30 to -3 
– 
+5 days 
Unscheduled1 
Patient related information/assessments 
 
 
 
 
Informed consent 
x 
– 
– 
– 
Inclusion/exclusion criteria 
x 
x2,3 
– 
– 
Demography 
x 
– 
– 
– 
Body measurements 
x 
– 
– 
– 
Diabetes diagnosis and current diabetes treatment 
x 
x 
x 
x 
Medical history including concomitant illnesses 
x 
– 
– 
– 
Concomitant medications 
x 
x2 
x 
– 
Randomization 
– 
x2 
– 
– 
Exclusion criteria at clinic admission on Visit 2, day 0 
– 
x2 
– 
– 
Insulin-induced hypoglycemia 
– 
x 
– 
– 
Safety assessments 
 
 
 
 
Physical examination 
x 
x 
x 
x 
Vital signs 
x 
x4 
x 
x 
12-lead ECG 
x 
x5 
x 
– 
Local tolerability  
– 
x6 
x 
– 
Adverse events 
x 
x 
x 
x 
Laboratory 
 
 
 
 
Biochemistry, hematology, coagulation, HbA1c (HbA1c at Visit 1 
only) 
x 
– 
x 
– 
Pregnancy test (women of childbearing potential only) 
x7 
x2,8 
x8 
– 
Urinalysis 
x 
x2 
x 
– 
Alcohol breath test 
– 
x2 
– 
– 
PK/Clinical efficacy 
 
 
 
 
Plasma dasiglucagon/GlucaGen® 
– 
x9 
– 
– 
Plasma glucose 
– 
x10 
– 
– 
Other assessments 
 
 
 
 

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Visit number 
V1 
V2 
V3 
Vx 
Trial day 
-3 
0 and 1 
28 
Unscheduled1 
Visit type 
Screening 
Dosing 
Follow-up 
Unscheduled1 
Window 
-30 to -3 
– 
+5 days 
Unscheduled1 
Antibodies against dasiglucagon/GlucaGen® 
x 
– 
x11 
x 
Trial material 
 
 
 
 
Administration of trial product (during hypoglycemic clamp 
procedure) 
– 
x 
– 
– 
End of trial status 
− 
− 
x 
– 
Abbreviations: ADA=Anti-drug antibody; ECG=Electrocardiogram, HbA1c=Hemoglobin A1c, PK=Pharmacokinetics 
1For ADA-positive patients only. 
2Prior to the start of the insulin-induced hypoglycemic procedure. 
3Only check exclusion criteria at clinic admission on Visit 2, day 0 and changes between screening visit and Visit 2. 
4Prior to the start of the insulin-induced hypoglycemic procedure (within 30 minutes), and at 30, 60 and 300 minutes after dosing. The actual time of the assessment should 
not deviate from the nominal time by more than ±10 minutes. 
5Prior to the start of the insulin-induced hypoglycemic procedure (within 30 minutes), and at 20, 35, 45, 60 and 300 minutes after dosing. The actual time of the assessment 
should not deviate from the nominal time by more than ±5 minutes.  
6Local tolerability assessed at 30, 120, and 300 minutes after dosing. The actual time of the assessment should not deviate from the nominal time by more than ±10 minutes.  
7Serum pregnancy test. 
8Urine stick pregnancy test. 
9Pre-dose, and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing. The actual time of blood sampling should not deviate from the nominal time by more than 
±1 minute between t=5 minutes and t=90 minutes, ±5 minutes between t=150 minutes and t=300 minutes. 
Pre-dose is defined as within 2 minutes prior to dosing. 
10Pre-dose, and at 4, 6, 8, 10, 12, 15, 17, 20, 30 and 45 minutes (as well as 60 minutes if the patient´s body weight is ≥21 kg) after dosing. The actual time of blood sampling 
should not deviate from the nominal time by more than ±30 seconds until the 20-minute collection time point, and by more than ±1 minute for the subsequent collection time 
points. Pre-dose is defined as within 2 minutes prior to dosing. 
11Antibodies against dasiglucagon/GlucaGen® (any treatment-induced or treatment-boosted [titer increase above 5 fold] ADA-positive patients will be monitored until the ADA 
levels return to baseline levels). 
 
 

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3. Table of contents 
1. 
SIGNATURES AND AGREEMENT WITH PROTOCOL ..................................................... 2 
2. 
TRIAL SYNOPSIS ............................................................................................................... 4 
3. 
TABLE OF CONTENTS .................................................................................................... 12 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 15 
4.1 
Abbreviations ..................................................................................................................... 15 
4.2 
Definitions of terms ............................................................................................................ 16 
5. 
INTRODUCTION................................................................................................................ 17 
5.1 
Background of the trial ....................................................................................................... 17 
5.2 
Trial rationale ..................................................................................................................... 19 
5.3 
Assessment of anticipated benefits and risks .................................................................... 19 
6. 
TRIAL OBJECTIVES ......................................................................................................... 21 
7. 
INVESTIGATIONAL PLAN ............................................................................................... 23 
7.1 
Overall trial design and plan .............................................................................................. 23 
7.2 
Discussion of trial design and choice of control groups ..................................................... 24 
7.3 
Selection of trial population ................................................................................................ 24 
7.3.1 
Inclusion criteria ................................................................................................................. 24 
7.3.2 
Exclusion criteria ................................................................................................................ 25 
7.3.3 
Premature withdrawal from trial ......................................................................................... 26 
7.3.3.1 
Possible reasons for patient withdrawal ................................................................... 26 
7.3.3.2 
Center discontinuation .............................................................................................. 27 
7.3.3.3 
Trial termination ........................................................................................................ 27 
7.3.4 
Replacement of patients .................................................................................................... 27 
7.4 
Investigational medicinal product(s)................................................................................... 28 
7.4.1 
Identity of investigational medicinal product(s) .................................................................. 28 
7.4.2 
Treatments administered ................................................................................................... 28 
7.4.3 
Packaging and labelling ..................................................................................................... 28 
7.4.4 
Storage of trial product ....................................................................................................... 29 
7.4.5 
Investigational treatment and dosing conditions ................................................................ 29 
7.4.5.1 
Changes to diabetes management prior to dosing visit ........................................... 29 
7.4.5.2 
Dosing visit ............................................................................................................... 29 
7.4.5.2.1 
Diabetes management .........................................................................................................30 
7.4.5.2.2 
Hypoglycemic clamp procedure and dosing .........................................................................30 
7.4.5.2.3 
Rescue provisions for hypoglycemia ....................................................................................31 
7.4.6 
Selection of doses in the trial ............................................................................................. 31 
7.4.7 
Collection of blood samples ............................................................................................... 32 
7.4.8 
Treatment compliance ....................................................................................................... 32 
7.4.9 
Method of assigning patients to treatments ....................................................................... 32 
7.4.10 
Blinding and breaking the blind........................................................................................ 33 
7.4.11 
Drug accountability and disposal ..................................................................................... 33 
7.4.12 
Prior and concomitant therapy ......................................................................................... 34 
7.4.13 
Treatment after end of trial .............................................................................................. 34 
7.5 
Assessments and schedule of measurements .................................................................. 34 
7.5.1 
Screening visit .................................................................................................................... 34 
7.5.2 
Dosing visit ......................................................................................................................... 34 
7.5.3 
Follow-up visit .................................................................................................................... 35 
7.5.4 
Final examination at the end of the trial ............................................................................. 36 
7.5.5 
Additional (safety) examinations ........................................................................................ 36 
7.5.6 
Efficacy measurements ...................................................................................................... 36 
7.5.7 
Safety and tolerability measurements ................................................................................ 36 

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7.5.7.1 
Safety laboratory tests .............................................................................................. 36 
7.5.7.2 
Safety examinations ................................................................................................. 37 
8. 
ADVERSE EVENTS .......................................................................................................... 38 
8.1 
Definitions .......................................................................................................................... 38 
8.2 
Collection, recording and reporting of adverse events ...................................................... 40 
8.3 
Follow-up of adverse events .............................................................................................. 41 
8.4 
Hypoglycemia ..................................................................................................................... 42 
8.5 
Pregnancy .......................................................................................................................... 42 
8.6 
Precautions ........................................................................................................................ 42 
8.7 
Safety committee ............................................................................................................... 43 
9. 
DATA MANAGEMENT AND QUALITY CONTROL ......................................................... 44 
9.1 
Electronic case report forms .............................................................................................. 44 
9.2 
Quality control .................................................................................................................... 44 
9.3 
Data management ............................................................................................................. 44 
10. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ......................... 45 
10.1 
Statistical analysis plan ...................................................................................................... 45 
10.1.1 
General considerations .................................................................................................... 45 
10.1.2 
Classification of patients to subsets................................................................................. 45 
10.1.3 
Efficacy endpoints ............................................................................................................ 45 
10.1.3.1 
Hierarchical testing procedure .................................................................................. 45 
10.1.3.2 
Primary efficacy endpoint ......................................................................................... 46 
10.1.3.3 
Secondary efficacy endpoints .................................................................................. 46 
10.1.4 
Safety endpoints .............................................................................................................. 46 
10.1.5 
Pharmacokinetic endpoints .............................................................................................. 47 
10.1.6 
Pharmacodynamic endpoints .......................................................................................... 47 
10.1.7 
Further data ..................................................................................................................... 47 
10.1.8 
Withdrawals, drop-outs and missing data ........................................................................ 47 
10.1.9 
Baseline and center comparisons.................................................................................... 48 
10.1.10 
Subgroup analysis ........................................................................................................ 48 
10.1.11 
Interim analysis ............................................................................................................ 48 
10.2 
Determination of sample size ............................................................................................. 48 
11. 
ETHICS AND REGULATIONS .......................................................................................... 49 
11.1 
Independent ethics committees and competent authorities .............................................. 49 
11.2 
Ethical conduct of the trial .................................................................................................. 49 
11.3 
Patient information and consent ........................................................................................ 49 
11.4 
Legal and regulatory requirements .................................................................................... 49 
12. 
TRIAL ADMINISTRATION ................................................................................................ 50 
12.1 
Responsibilities .................................................................................................................. 50 
12.2 
Protocol deviations ............................................................................................................. 50 
12.3 
Protocol changes ............................................................................................................... 50 
12.4 
Reports and publications ................................................................................................... 51 
12.5 
Retention of trial records .................................................................................................... 51 
13. 
REFERENCES................................................................................................................... 53 
 
Appendices: 
(1) 
List of names and addresses 
 
 

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Index of in-text tables 
Table 2-1: Schedule of Assessments ................................................................................................ 10 
Table 7-1: Identity of Investigational Products................................................................................. 28 
 
Index of in-text figures 
Figure 7-1 Overview of the Trial Design ............................................................................................ 23 
 

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4. List of abbreviations and definition of terms 
4.1 
Abbreviations 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CA 
competent authority 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IV 
intravenous(ly) 
IWRS 
interactive web response system 
MRT 
mean residence time 
NPH 
neutral protamine Hagedorn 
ODM 
OpenDocument Master 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s)  
PPS 
per protocol set 
PR 
PR interval; i.e. the measure of the time between the start of the p wave and the 
end of the r wave in the heart’s electrical cycle 
PT 
preferred term 
QRS 
QRS interval; i.e. the measure of the time between the start of the q wave and the 
end of the s wave in the heart’s electrical cycle 
QT  
QT interval; i.e. the measure of the time between the start of the q wave and the 
end of the t wave in the heart’s electrical cycle 
SAE 
serious adverse event 
SAS 
safety analysis set 

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SC 
subcutaneous(ly) 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
T1DM 
type 1 diabetes mellitus 
ULN 
upper limit of normal 
 
 
Plasma concentrations of dasiglucagon/GlucaGen  
AUC0-30min 
Area under the plasma concentration versus time curve from 0 to 30 minutes post-
dose 
AUC0-300min 
Area under the plasma concentration versus time curve from 0 to 300 minutes post-
dose 
AUC0-inf 
Area under the plasma concentration versus time curve from 0 to infinitely post-
dose 
Cmax 
Maximum of all valid plasma concentration measurements from 0 to 300 minutes 
post-dose 
tmax 
Time to maximum of plasma concentration measurements 
λz 
Terminal elimination rate constant 
t½ 
Terminal plasma elimination half-life 
CL/f 
Total body clearance 
Vz/f 
Volume of distribution 
MRT 
Mean residence time 
 
 
Plasma glucose concentrations 
AUE0-30min 
Plasma glucose response as area under the effect curve above baseline from time 
0 to 30 minutes 
 
4.2 
Definitions of terms 
Definition of the end of the trial: The trial ends with the last visit of the last patient participating in 
the trial. 

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5. Introduction  
5.1 
Background of the trial 
Hypoglycemia  
Hypoglycemia in patients with diabetes is defined as episodes of an abnormally low plasma 
glucose concentration.9 This is a common, unpredictable, and potentially dangerous side effect 
of treatment of diabetes mellitus with especially insulin or sulfonylureas. It is more frequent in 
patients with profound endogenous insulin deficiency, such as occurs in type 1 diabetes mellitus 
(T1DM) and advanced type 2 diabetes mellitus. Treatment of type 2 diabetes mellitus with insulin 
causes hypoglycemia progressively and more frequently over time, whereas in T1DM, 
hypoglycemia is experienced throughout the course of established disease. 
Symptoms and signs of hypoglycemia are not specific. Patients undergoing a hypoglycemic 
episode experience unpleasant symptoms such as anxiety, sweating, hunger, tremors, 
palpitations, paresthesia, nausea and pallor. Depending on its severity, the hypoglycemia may 
lead to mild confusion, behavioral changes, loss of consciousness, seizures, coma, and death.1  
The incidence of hypoglycemic events or even the fear of hypoglycemia influences patients’ 
adherence to prescribed treatment regimens for diabetes mellitus. This leads to inadequate 
glycemic control, which in turn may lead to an increased risk of diabetic complications. 
Glucagon 
Glucagon is a naturally occurring hormone, secreted from the alpha cells of the pancreatic islets. 
Glucagon plays a central role in the regulation of glucose homeostasis and is the counterpart of 
insulin for controlling blood glucose levels (i.e. it acts in opposition to insulin in terms of effects on 
blood glucose levels). Glucagon stimulates hepatic glycogenolysis and gluconeogenesis in 
hypoglycemic states, thereby restoring glucose homeostasis. Glucagon receptor agonism has 
also been shown to exert effects on lipid metabolism, energy balance, body adipose tissue mass 
and food intake.  
Insulin decreases blood glucose levels and cases of hypoglycemia can be reversed by glucagon. 
Therefore, glucagon is indicated for the treatment of severe hypoglycemia.  
Dasiglucagon  
Dasiglucagon (ZP4207) is a stable peptide analog of human glucagon, available in a ready-to-
use liquid formulation and is in development for the treatment of severe hypoglycemia in insulin 
dependent patients with diabetes mellitus. Dasiglucagon is a specific and full glucagon receptor 
agonist designed to mimic the effects of glucagon, having a fast absorption and elimination 
(minutes). It is a peptide of 29 amino acids, with 7 amino acid substitutions compared to native 
glucagon. The main purpose of the substitutions is to increase the physical and chemical stability 
of the glucagon analog compared to marketed glucagon products such as Lilly´s Glucagon or 
GlucaGen®. Dasiglucagon exhibits improved physical and chemical stability and is available in an 
aqueous solution at neutral pH.2 
Five clinical trials have been completed with dasiglucagon: A first human dose trial (ZP4207-
14013), a multiple-dose dose-escalation trial (ZP4207-15007) to evaluate the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD) of dasiglucagon, a phase 2 crossover trial 
to assess the PK and PD of a single dose of an optimized formulation of dasiglucagon 
administered subcutaneously (SC) in patients with T1DM (ZP4207-15126), and a feasibility trial 
testing the bionic pancreas with dasiglucagon was completed (ZP4207-16051).2 Finally, a cross-
over trial (ZP4207-16098) assessing PK and PD responses after micro-doses of dasiglucagon 
administered SC to patients with type 1 diabetes mellitus under euglycemic and hypoglycemic 
conditions, compared to marketed glucagon, was completed. 

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Pharmacokinetics and pharmacodynamics of dasiglucagon  
The results of the phase 1 and 2 clinical trials confirm dose-proportionality for dasiglucagon PK, 
which is characterized by a fast absorption with a peak plasma concentration obtained after 35 
minutes. Thereafter, the plasma concentration rapidly declines with an average half-life of 28 
minutes. The median time to the maximum plasma concentration (Cmax) was later for 
dasiglucagon than for GlucaGen® (35 versus 20 minutes). For Cmax, the results indicated that 
0.3 mg dasiglucagon was comparable to 0.5 mg GlucaGen® (90% confidence interval: 0.8167; 
1.0068) and 0.6 mg dasiglucagon was comparable to 1.0 mg GlucaGen® (90% confidence 
intervaI: 0.8850; 1.1991).2 At these dose levels, the total exposures (AUC0-inf) were higher for 
dasiglucagon compared to GlucaGen®. 
At all dose levels in the phase 2 trial, all patients achieved a plasma glucose level of at least 
70 mg/dL as well as an increase in plasma glucose by at least 20 mg/dL within 30 minutes post-
dose. The maximal observed time to reach the 20 mg/dL plasma glucose increase ranged from 
15 to 27 minutes across doses and decreased as the dose increased. The PD responses of 
0.6 mg of dasiglucagon and 1.0 mg of GlucaGen® were comparable.2 
Safety of dasiglucagon  
The safety data for dasiglucagon did not give rise to any relevant safety concerns for dasiglucagon 
beyond those expected, related to the pharmacological effect of glucagon receptor agonism. All 
adverse events (AEs) recorded in the trials were of mild or moderate severity. The most frequently 
reported systemic AE was nausea, which is a known side effect following administration of 
glucagon. Headache was the next most frequently reported event, occurring in all dose groups in 
the phase 2 trial. Injection site reactions were observed only sporadically after administration with 
either dasiglucagon or GlucaGen® and all were mild and transient. The most frequent injection 
site reaction was erythema, occurring in all treatment groups, including the placebo group, 
irrespective of dose. Therefore, the phase 1 and 2 results and the safety profile described to date 
do not give rise to specific safety concerns. For further information, please refer to the Investigator 
Brochure.2  
Immunogenicity of dasiglucagon  
In adults, anti-drug antibodies (ADA) have been assessed in the completed clinical trials. In one 
of the 5 completed clinical trials (ZP4207-16098) 1 transient ADA incidence have been detected 
in one T1DM patient. The antibodies were able to bind to dasiglucagon and glucagon confirming 
the cross-reactivity potential found in the non-clinical toxicity studies (IND 135869 Section 
2.4.4.6). The antibodies were also capable of neutralizing the in vitro activity of both dasiglucagon 
and glucagon, but could not be associated with any AEs or effects on PK or PD in the patient. 
The trial was a multiple dose trial and completers had received a total of 11 investigational drug 
administrations (8 injections of dasiglucagon and 3 injections of recombinant glucagon) (IND 
135869 Section 2.5.6.3) and indicated that increased exposure will likely increase the risk of ADA 
formation. However, due to the crossover trial design, the induction of ADA cannot be decisively 
attributed to either dasiglucagon or glucagon treatment. The ADA incidence in that trial was 4.3% 
and considered low. From the long-term non-clinical toxicology studies, the detection of antibodies 
was not associated with a change in toxicity profile compared to ADA negative animals. In the 13- 
and 26-week rat studies, an increase in exposure was observed in dose groups ≥8 mg/kg/day, 
which correlates with the dose groups with the highest frequency of ADA-positive animals. So far, 
these findings have not been observed in humans. 
The consequences of an immune response towards endogenous glucagon is not fully known. In 
a recent review summarizing the current physiology of glucagon and learnings from recent 
glucagon antagonist research, it was concluded that although glucagon is an important hormone 
for controlling postprandial glucose levels, it was not essential for the maintenance of fasting 
glucose and glucagon antagonism did not cause hypoglycemia.5 Rather, the lack of glucagon 
signaling induced imbalance in amino acid metabolism leading to elevated amino acid plasma 

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levels. As excess levels of amino acids can be excreted by the kidneys and the detected ADA 
incidence have been transient, the impact is not considered a major risk for the trial population. 
The overall immunogenicity risk of dasiglucagon in a clinical context is therefore considered low 
and the potential effects of induced ADAs judged to be of limited clinical consequence.  
5.2 
Trial rationale 
The SC bolus dose of 0.6 mg dasiglucagon that is the most appropriate dosing to ensure rapid 
rescue from hypoglycemia in adults appears to be appropriate also in children 6 years old and 
above.  
To simulate the potential PK/PD response in children, a previously developed population PK/PD 
model for dasiglucagon was updated with an allometric PK component derived from published 
glucagon pediatric data from weight groups of 25.4±5.2, 43.2±8.9, and 61.2±13.8 kg (mean±SD) 
and adults. The simulations suggested that a 0.3 mg SC bolus dose of dasiglucagon would result 
in a slightly slower increase of blood glucose compared to the 0.6 mg dose in the 3 pediatric body 
weight groups. Considering the intended clinical indication of treating patients for severe 
hypoglycemia where time to PD response is considered essential, the 0.3 mg dose appears less 
attractive than the 0.6 mg dose. 
The higher total drug exposure (AUC and Cmax) predicted in children at lower body weight, relative 
to that observed in adults at a dose of 0.6 mg, is within the tolerable exposure achieved in adults 
administered 2.0 mg dasiglucagon, and the duration of exposure is truncated due to a shorter t½ 
in children. In addition, rapid saturation of the PD response results in similar total and maximum 
glucose response (AUE and CEmax) throughout the body weight range from 25 to 77 kg.  
Based on all data generated to date across 4 clinical trials performed in adults receiving 
dasiglucagon at different dose levels, no clear dose-response for nausea and vomiting was 
observed above a certain threshold. It is therefore not expected that the intensity and frequency 
of nausea and vomiting at a dose of 0.6 mg will differ between adults and children/adolescents. 
This expectation is further consistent with results of the recently conducted trial ZP4207-16098 in 
adults with T1DM, which indicated a similar degree of nausea and vomiting at SC bolus doses of 
0.2 and 0.6 mg dasiglucagon.   
5.3 
Assessment of anticipated benefits and risks 
Glucagon emergency kits are often underutilized in the treatment of patients experiencing severe 
hypoglycemia. Considering the seriousness and potential complications that can arise from 
severe hypoglycemic episodes, it is essential that parents and caregivers receive adequate, 
hands on training for use of glucagon rescue kits to ensure safe, timely, and effective 
administration. Given the challenges with parent/caregiver training and use of current glucagon 
products, Zealand Pharma A/S is developing dasiglucagon as a ready to use rescue treatment 
for severe hypoglycemia. The development of dasiglucagon will provide parents and caregivers 
of children with diabetes mellitus a more efficient alternative for the treatment of severe 
hypoglycemia. The ready-to-use kit addresses an unmet need and may potentially prove to be 
life-saving. 
As glucagon and its analogs belong to a well-known drug class with a known mode of action, 
dasiglucagon is not expected to be a high-risk molecule. 
Treatment with an investigational medicinal product may result in undesired effects or complaints. 
Undesired effects and complaints such as nausea and vomiting are known AEs occurring with 
glucagon administration. Similar AEs have also been observed to a limited degree in the 5 clinical 
studies conducted with dasiglucagon. As with every novel drug substance, new and yet unknown 
side effects also may occur. 
There are limited data available to assess the immunogenic potential of glucagon products 
available on the market, but the data available indicate that marketed glucagon only has a small 

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immunogenic potential. Based on the 5 clinical studies completed with dasiglucagon to date (see 
Section 5.2), no anti-dasiglucagon or anti-glucagon antibodies have been detected, except for 
trial ZP4207-16098, in which there was one transient low titer ADA incidence showing reactivity 
towards both dasiglucagon and glucagon. The patient was tested positive for both anti-
dasiglucagon and anti-glucagon antibodies at the follow-up visit, 24 days after the last drug 
exposure (titer: 35.4 and 33.8, respectively). The patient was also found to be positive for 
dasiglucagon and glucagon in vitro neutralizing activities. The titer of anti-dasiglucagon activity 
was equal to the assay minimum required dilution. Due to the crossover nature of this trial, the 
induction of ADAs could not be associated with a specific treatment. Testing performed 3.5 
months after last dosing confirmed a positive finding for anti-dasiglucagon antibodies (titer of 
38.8), while the test was negative for anti-glucagon antibodies. At a final follow-up visit performed 
7 months after last dosing, the patient was negative for anti-dasiglucagon antibodies. There was 
no evidence for altered PK, PD, or safety profile for this patient. 
Administration of dasiglucagon may be associated with a risk of allergic reactions similar to those 
observed for other therapeutic peptides or proteins. Patients with known or suspected allergies to 
the trial products or related products will be excluded from the trial. Mild or moderate allergic 
reactions may include symptoms of rash, fever, flu-like symptoms, nausea, headache, and 
myalgia. Acute generalized hypersensitivity reactions are usually very rare but may include 
symptoms of flushing, sweating, dizziness, change in blood pressure and difficulties in breathing. 
No severe acute hypersensitivity reactions have been observed in the 4 clinical trials conducted 
with dasiglucagon. Direct access to resuscitation equipment is ensured at the clinical trial centers. 
With the exception of medical examinations, a patient participating in this trial is not likely to derive 
any personal health-related benefits. The results of the trial may contribute to the future use of 
dasiglucagon in patients with diabetes mellitus experiencing severe hypoglycemic reactions. 
Overall, the benefit to risk ratio for patients entering the ZP4207-17086 trial is considered 
acceptable. 

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6.   Trial objectives  
Primary objective 
 
To demonstrate that dasiglucagon is superior to placebo following a single injection of 0.6 mg 
of dasiglucagon in treating hypoglycemia in children with T1DM 
Secondary objectives 
 
To confirm that a single dose of dasiglucagon [0.6 mg] is comparable to a single dose of 
GlucaGen® [1 mg/mL] in treating hypoglycemia in children with T1DM (in accordance with the 
label, children below 25 kg body weight will be administered 0.5 mg GlucaGen®) 
 
To assess safety profile of dasiglucagon in children with T1DM 
 
To assess PK profile of dasiglucagon in children with T1DM  
Primary endpoint 
 
Time to plasma glucose recovery. Plasma glucose recovery is defined as first increase in 
plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline during the hypoglycemic clamp 
procedure without administration of rescue intravenous (IV) glucose 
Secondary endpoints 
Secondary efficacy endpoints 
 
 
Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 minutes, and 
within 10 minutes after study drug injection without administration of rescue IV glucose. 
 
Plasma glucose changes from baseline within 30 minutes, within 20 minutes, within 
15 minutes, and within 10 minutes after study drug injection or at the time of rescue IV 
glucose. 
Safety endpoints 
 
AEs 
 
Clinical laboratory assessments (biochemistry, hematology, coagulation, urinalysis) 
 
Vital signs 
 
Physical examination 
 
Clinically significant changes in the electrocardiogram 
 
Local tolerability 
 
Administration of rescue IV glucose infusion after trial product injection 
 
Time to first IV glucose infusion, after trial product administration (N.B. IV glucose infusion 
prior to trial product administration should not be included, as it is part of hypoglycemic clamp 
procedure) 
 
Immunogenicity endpoint: occurrence of ADAs 
Pharmacokinetic endpoints 
PK endpoints will be derived from plasma dasiglucagon and GlucaGen® profiles from 0 to 
300 minutes: 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
30 minutes post-dose (AUC0-30min) 

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 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
300 minutes post-dose (AUC0-300min) 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 
to infinitely post-dose (AUC0-inf) 
 
Maximum of all valid plasma dasiglucagon or GlucaGen® concentration measurements from 
0 to 300 minutes post-dose (Cmax) 
 
Time to maximum of plasma dasiglucagon or GlucaGen® concentration measurements (tmax) 
 
Terminal elimination rate constant of plasma dasiglucagon or GlucaGen® (λz) 
 
Terminal plasma elimination half-life of dasiglucagon or GlucaGen® (t½) 
 
Total body clearance of plasma dasiglucagon or GlucaGen® (CL/f) 
 
Volume of distribution of plasma dasiglucagon or GlucaGen® (Vz/f) 
 
Mean residence time of plasma dasiglucagon or GlucaGen® (MRT) 
Pharmacodynamics endpoint 
 
Plasma glucose response as area under the effect curve above baseline from time zero to 30 
minutes, AUE0-30min 

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7. Investigational plan 
7.1 
Overall trial design and plan 
This is a phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial 
designed to assess efficacy, safety and PK of dasiglucagon vs. placebo and vs. GlucaGen® in 
children with T1DM. It is currently anticipated that it will be conducted at 2-3 centers in Europe 
and 1-2 centers in the USA. 
The trial will include the following periods (as illustrated in Figure 7-1, below). 
 
A screening period from Day -30 to Day -3 
 
A treatment period, from Day 0 to Day 1 (day of randomization and single dosing with trial 
product). Unblinded trial personnel will do the handling, preparation and administration of trial 
product. All trial assessments will be done by blinded trial personnel 
 
A follow-up visits at Day 28 (the end-of-trial visit) 
 
Figure 7-1 Overview of the Trial Design 
 
Abbreviation: PK=pharmacokinetic 
The schedule of assessments (Table 2-1) gives an overview of the trial procedures. Patients 
should attend all visits on the designated day or as close to it as possible.  
 

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7.2 
Discussion of trial design and choice of control groups 
The trial will be randomized and double-blind to increase trial validity and to reduce bias during 
evaluation of assessments with the treatments. Since the 3 trial products are not identical in 
appearance, (dasiglucagon and placebo are liquid formulations and GlucaGen® is available as a 
powder for reconstitution), unblinded trial personnel, who will not be involved in other trial 
procedures and assessments, will do the handling, preparation and administration of trial product. 
Blinded trial personnel will do all trial assessments performed at the trial center.    
Children with T1DM will be randomized 2:1:1 in order to evaluate the efficacy and safety of 
dasiglucagon compared to placebo and GlucaGen® and PK/PD parameters. The randomized, 
double-blind, parallel arm design with administration of a single dose of randomized trial product 
(dasiglucagon, placebo or GlucaGen®) will allow a relative comparison between the 3 treatment 
arms. 
Dasiglucagon will be administered at fixed doses independent of body weight because this is the 
intended therapeutic dosing regimen in the emergency treatment of hypoglycemia. The selected 
dose of 1 mg GlucaGen® is the recommended dose for treatment of severe hypoglycemia (in 
accordance with the label, children below 25 kg body weight will be administered 0.5 mg 
GlucaGen®). Based on pre-clinical and clinical studies in adult patients, it has been demonstrated 
that 0.6 mg of dasiglucagon results in an initial PD response (i.e. acute glucose mobilization) 
comparable to 1 mg GlucaGen® (see also Section 5.1).  
7.3 
Selection of trial population 
Dasiglucagon is indicated for treatment of severe hypoglycemia in patients with T1DM. As this 
condition also affects children and there is a therapeutic need for them to get access to safe and 
efficacious emergency treatment, the present trial aims to evaluate the efficacy and safety of a 
single dose of SC dasiglucagon compared to placebo and GlucaGen® in children with T1DM in 
experimentally induced hypoglycemia in a hypoglycemic clamp procedure.  
The trial will enroll patients in centers in the EU and in the USA.  
7.3.1 Inclusion criteria 
To be included in the trial, patients have to fulfill all of the following criteria: 
1. 
Following receipt of verbal and written information about the trial, patient, parent(s) or 
guardian(s) of the patient must provide signed informed consent before any trial-related 
activity is carried out* 
2. 
Female or male patients with T1DM for at least 1 year, diagnostic criteria as defined by the 
American Diabetes Association; and receiving daily insulin 
3. 
At least 6.0 years of age (inclusive) and less than 18.0 years 
4. 
Body weight ≥20 kg 
5. 
Female patients must meet one of the following criteria: 
a. 
Participant is of childbearing potential and agrees to use one of the accepted 
contraceptive regimens throughout the entire duration of the trial from screening until 
last follow-up visit. An acceptable method of contraception includes at least one of 
the following: 
i. 
Abstinence from heterosexual intercourse 
ii. 
Systemic contraceptives (birth control pills, injectable/implant/ insertable 
hormonal birth control products, transdermal patch); if the participant is using 
systemic contraceptives, she must use an additional form of acceptable 
contraception (iii or iv, below) 
iii. 
Intrauterine device (with and without hormones) 
iv. 
Condom with spermicide  

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or 
b. Participant is of non-childbearing potential due to pre-puberty status or a medical 
condition confirmed by the investigator  
6. 
Male patients must meet the following criteria: If sexually active, uses condom and partner 
practices contraception during the trial from screening and until last follow-up visit 
7. 
Willingness to adhere to the protocol requirements 
* Informed consent signatures must be obtained according to local regulations. 
7.3.2 Exclusion criteria 
Patients meeting any of the following criteria during screening evaluations will be excluded from 
trial participation: 
1. 
Females who are pregnant according to a positive urine pregnancy test, actively attempting 
to get pregnant, or are lactating 
2. 
Known or suspected allergy to trial product(s) or related products 
3. 
History of anaphylaxis or symptoms of severe systemic allergy (such as angioedema) 
4. 
Previous randomization in this trial 
5. 
History of an episode of severe hypoglycemia that required a third party assistance within 
a month prior to screening visit 
6. 
History of hypoglycemic events associated with seizures or hypoglycemia unawareness in 
the last year prior to screening 
7. 
History of epilepsy or seizure disorder 
8. 
Receipt of any investigational drug within 3 months prior to screening 
9. 
Active malignancy within the last 5 years 
10. 
Congestive heart failure, New York Heart Association class II-IV 
11. 
Current bleeding disorder, including anti-coagulant treatment 
12. 
Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma 
(i.e. insulin secreting pancreas tumor) 
13. 
Use of a daily systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs 
in the previous 28 days before Day 1 of this trial 
14. 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limit 
of the normal range (ULN), bilirubin >1.5 × ULN, estimated glomerular filtration rate 
<30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease study definition, 
or altered electrolyte values of clinical relevance for cardiac conduction, as judged by the 
investigator 
15. 
Clinically significant abnormal electrocardiogram (ECG) at screening as judged by the 
investigator 
16. 
Clinically significant illness within 4 weeks before screening, as judged by the investigator 
17. 
Surgery or trauma with significant blood loss within the last 2 months prior to screening 
18. 
Patients with mental incapacity or language barriers which preclude adequate 
understanding or cooperation, who are unwilling to participate in the trial, or who in the 
opinion of the investigator should not participate in the trial 
19. 
Any condition interfering with trial participation or evaluation or that could be hazardous to 
the patient 
20. 
The use of prescription or non-prescription medications known to cause QT prolongation 
 
In addition, the following exclusion criteria at clinic admission on Visit 2, day 0 apply at the time 
of admission to the clinic, which is the day before clamp procedure: 

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Patients who meet one or more of the following exclusion criteria at the time of admission to the clinic 
will be excluded from the dosing visit, however, the visit can be rescheduled 1-7 days later. The dosing 
visit can only be rescheduled once. 
 
1. 
Atypically strenuous exercise within 4 days prior to dosing, as judged by the investigator. 
Exercise during the trial should follow patient’s typical routine, and should not exceed a near 
maximum intensity for more than 20 minutes per day, or moderate intensity for more than 
90 minutes per day 
2. 
Clinically significant illness within 4 weeks before dosing, as judged by the investigator 
3. 
Consumption of alcohol within 24 hours prior to dosing visit, determined by positive results 
from an alcohol breath test 
4. 
Not fasting from 22:00 hours the evening prior to dosing, apart from water. 
5. 
The use of any non-prescribed systemic or topical medication, except routine vitamins and 
occasional use (as judged by the investigator) of acetylsalicylic acid and paracetamol within 
2 weeks prior to dosing. Treatment with insulin, including analogs, is allowed 
6. 
Use of insulin degludec or insulin glargine U300 within 72 hours prior to dosing; or use of 
other long-acting insulins (e.g. insulin glargine U100 or insulin detemir) within 48 hours prior 
to dosing; or use of neutral protamine Hagedorn (NPH) insulin within 22 hours prior to 
dosing 
7. 
Use of any short acting (bolus) insulin within 12 hours prior to dosing, except insulin glulisine 
(Apidra®) 
8. 
Changes in medical history or concomitant medication resulting in fulfillment of clinical 
exclusion criteria, as judged by the investigator 
9. 
Plasma glucose value <50 mg/dL (2.8 mmol/L) within the last 24 hours or plasma glucose 
value <60 mg/dL (3.3 mmol/L) within the last 5 hours prior to admission to the clinic 
7.3.3 Premature withdrawal from trial 
Participation in the trial is strictly voluntary. A patient has the right to withdraw from the trial at any 
time and for any reason. If the child chooses to withdraw or his/her parents or legal guardians 
choose to have the child withdrawn, the investigator must be informed immediately. The 
investigator has the right to terminate participation of any patient at any time if the investigator 
deems it in the patient's best interest. The reason and circumstances for withdrawal will be 
documented in the electronic case report form (eCRF). 
7.3.3.1 Possible reasons for patient withdrawal 
A patient will be withdrawn if the following applies: 
 
If a protocol deviation occurs which, in the clinical judgment of the investigator, can invalidate 
the trial endpoints, the patient will be withdrawn by the investigator 
 
AEs that are considered unacceptable by the patient or the investigator 
If withdrawal occurs following administration of any trial product, the patient will be asked to return 
and participate in the complete follow-up visit at trial Day 28. In this case, withdrawal relates only 
to blood sampling but not to the safety assessments. Patients should be followed for AEs for the 
same duration as those who are not withdrawn. 
If trial participation is terminated due to an AE possibly related to the trial product (including 
reference product) or trial examinations, the patient must be followed up by additional 
examinations according to the medical judgment of the investigator until the abnormal condition 
is resolved or the investigator deems further observations or examinations to be no longer 
medically indicated. 

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If the patient meets any of the exclusion criteria 1-9 at the time of admission to the clinic at V2, 
he/she will be excluded from the dosing visit but may be rescheduled once 1-7 days later. 
7.3.3.2 Center discontinuation 
The center can be closed and the trial terminated for the following reasons: 
 
The center is unlikely to be able to recruit sufficient patients within the agreed time frame 
 
The center does not respond to trial management requests 
 
Repeat protocol violations 
However, even in case of center discontinuation the center should be kept open as long as 
previously enrolled patients are ongoing. Patients already enrolled should be followed and 
documented for their entire individual trial duration before actually discontinuing the center. 
7.3.3.3 Trial termination 
The sponsor reserves the right to modify or terminate the trial at any time. Possible reasons for 
termination are: 
 
Safety reasons – the incidence of AEs in this or any other trial using the same trial product 
indicates a potential health risk for the patients 
 
New scientific knowledge becomes known that makes the objectives of the trial no longer 
feasible/valid 
 
Unsatisfactory enrollment of patients 
7.3.4 Replacement of patients  
Patients who are dosed will not be replaced. 

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7.4 
Investigational medicinal product(s) 
7.4.1 Identity of investigational medicinal product(s)  
The identity of the investigation products is summarized in Table 7-1. 
Table 7-1: Identity of Investigational Products 
 
Test product 
Placebo 
Reference product 
Name 
Dasiglucagon 
Placebo 
GlucaGen® 
Active substance 
ZP4207  
Not applicable 
Recombinant glucagon 
hydrochloride  
Formulation 
Liquid formulation, 
0.6 mL  
Liquid formulation, 
0.6 mL  
Powder and solvent for 
reconstitution as 1 mL 
solution for injection 
Strength 
1 mg/mL 
Not applicable 
1 mg/mL 
Container 
Single use pre-filled 
syringe 
Single use pre-filled 
syringe 
Powder and solvent for 
reconstitution packed 
together in a plastic 
box. A “hypo-kit”  
Manufacturer 
Zealand Pharma A/S, 
Glostrup 
(Copenhagen), 
Denmark 
Zealand Pharma A/S, 
Glostrup 
(Copenhagen), 
Denmark 
Novo Nordisk A/S, 
Bagsværd, Denmark 
Storage 
requirements 
Store between 2 and 
8°C 
Store between 2 and 
8°C 
Store between 2 and 
8°C 
7.4.2 Treatments administered 
Dasiglucagon, placebo, and GlucaGen® will be administered by SC injection in the abdomen or thigh.  
 
An unblinded person (appropriately trained), authorized to prepare the dose and administer the 
treatment in accordance with the randomization, will prepare the treatment required for each patient on 
each the dosing day. The dose will be administered by the unblinded, trained and qualified person. 
The content of the syringe has to be checked for clarity and absence of bubbles. 
 
Syringes will be discarded after dose administration. Used GlucaGen® vials will be stored in a lockable 
box (separated from unused vials) at ambient temperature. 
7.4.3 Packaging and labelling  
The trial product will be packed by the sponsor. The information on the labels will be in the local language 
and the product label will be compliant with local laws and regulations.  
 
The trial product labels will describe the storage conditions for trial product. The labels will supply no 
information about the patients. Each treatment kit (pre-filled syringe/vial for reconstitution) will have a 
unique Dispensing Unit Number for drug allocation, drug accountability, and traceability purposes. 
 
Labelling will be performed according to Annex 13 of the Good Manufacturing Practice guidelines of the 
European Commission, International Council for Harmonisation (ICH) guidelines on Good Clinical 
Practice (GCP), and local law. 
 

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7.4.4 Storage of trial product 
The investigator must ensure the availability of proper storage conditions. All trial product supplies 
provided for this trial will be stored in the fridge, in a secure area with restricted access at the trial center. 
The trial products ready for use should be separated from any other clinical supplies, to avoid product 
errors. 
The temperature should be monitored by recording the actual, minimum, and maximum temperatures 
using a calibrated thermometer or thermocouple, or by continuous recording using a qualified 
temperature monitoring system. The temperature should be evaluated and documented at least on 
working days on a temperature log. This log must be included in the Investigator Site File upon trial 
termination. 
The unblinded person responsible for trial product handling must contact the unblinded monitor in case 
of temperature deviations outside the acceptable range.  
Please see the trial materials manual for additional information on handling trial product. 
 
7.4.5 Investigational treatment and dosing conditions 
7.4.5.1 Changes to diabetes management prior to dosing visit 
At the screening visit, patients will be instructed by the investigator about the changes in their 
diabetes treatment leading up to and immediately prior to the dosing visits. There should not be 
any changes in their diabetes management until 3 days (72 hours) prior to the planned trial 
product administration except to switch to NPH insulin. The investigator will provide individual 
dosing instructions for this change. Within 72 hours prior to dosing, the use of insulin degludec or 
insulin glargine U300 is prohibited. Within 48 hours prior to dosing, the use of long-acting insulin 
(e.g. insulin glargine U100 or insulin detemir) is prohibited. Within 22 hours prior to dosing, the 
use of insulin NPH is prohibited. Within 12 hours prior to dosing, the use of any short acting (bolus) 
insulin, except insulin glulisine (Apidra®) is prohibited. During the insulin-induced hypoglycemic 
procedure, continuous SC insulin infusion must be stopped. 
7.4.5.2 Dosing visit 
Patients will be admitted to the clinic with their parents in the evening of the day before dosing 
(Day 0). Their eligibility for the trial will be checked, and only those still eligible will continue and 
remain in the clinic overnight.  
If the patient meets any of the exclusion criteria at clinic admission on Visit 2, day 0, he/she will 
be excluded from the dosing visit but may be rescheduled once 1-7 days later. 
An infusion catheter will be inserted into each arm for the manual glucose clamp procedure, with 
the glucose infusion in one arm and the insulin infusion in the opposite arm preferably, but the 
same infusion catheter can also be used. Another IV catheter, separated from infusion catheter(s), 
for blood sampling will be placed in the morning before trial product administration. The hand of 
this arm will be warmed (55-65 ºC) to arterialize venous blood. If there are issues with blood 
sampling from e.g. the metacarpal vein for the purpose of glucose measurements, the investigator 
may use a new and more proximal IV access. 
On the morning of the dosing day (Day 1), patients are required to be in a fasting condition, 
defined as having consumed only water since 22:00 hours the night before. They may consume 
water ad libitum. The patients must not consume any alcohol or smoke within 24 hours prior to 
dosing. 

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7.4.5.2.1 Diabetes management 
Last injection or bolus administration via continuous SC insulin infusion of any insulin medication 
should not take place within the 12 hours before dosing. Patients normally using insulin aspart 
will be switched to human soluble insulin or glulisine for the period between 12 and 10 hours prior 
to dosing, if needed. Patients using continuous SC insulin infusion will have their pump switched 
off at 22:00 hours.  
To achieve a target glucose level of 90-160 mg/dL (5.0-8.9 mmol/L) in the morning of dosing, 
patients may be administered insulin glulisine and/or glucose at the discretion of the investigator 
by IV infusion using the following glucose infusion rate and insulin infusion rate as a guidance. 
Deviation from the guidance is allowed at the discretion of the investigator. Plasma glucose levels 
will be checked overnight at regular intervals in order to achieve and maintain the target plasma 
glucose level of 90-160 mg/dL (5.0-8.9 mmol/L). 
A general guidance for administration of insulin IV and/or glucose IV at the dosing visit 
Fluid infusion rate: 
If plasma glucose < 300 mg/dL, then infusion of isotonic solution with 5% glucose: 
 Age 6–10 years: 80 mL/kg/24 h 
 Age >10 years: 60 mL/kg/24 h 
If plasma glucose >300 mg/dL the glucose infusion will be substituted with fluid volume of normal 
saline (0.9% NaCl) at same infusion rate as above. 
Infusion of insulin: 
Insulin infusions should be performed with 0.5 IU insulin glulisine (Apidra®) per kg body weight in 
48 mL NaCl 0.9% according to the following recommendations: 
Glucose  
Infusion rate 
Insulin dose (IU/kg BW/h) 
>200 mg/dL 
10.0 mL/h 
0.1 
150–200 mg/dL 
5.0 mL/h 
0.05 
80-150 mg/dL 
2.5 mL/h 
0.025 
<80 mg/dL 
Insulin infusion stop! 
0 
Abbreviation: BW=Body weight 
7.4.5.2.2 Hypoglycemic clamp procedure and dosing 
At the time of admission to the clinic, which is the day before clamp procedure, the patient’s 
eligibility must be checked. If the patient meets any of the exclusion criteria at the time of 
admission to the clinic at V2, he/she will be excluded from the dosing visit but may be rescheduled 
once 1-7 days later.  
Eligible patients will be randomized to either dasiglucagon, placebo or GlucaGen® in the morning 
of the dosing visit. That morning after 7 o’clock am, the infusion of IV glucose will be stopped. 
This should be at least 30 minutes prior to planned trial product administration. Insulin infusion 
rate and insulin dose are at the discretion of the investigator or can follow the protocol general 
guidance (see above). The investigator may deviate from the guidance. Insulin IV infusion will be 
stopped when glucose level declines to below 80 mg/dL. 
During insulin-induced hypoglycemia, plasma glucose levels will be monitored closely at the site. 
After the start of insulin infusion, plasma glucose should be checked approximately every 10 
minutes while plasma glucose is above 110 mg/dL, approximately every 5 minutes once plasma 
glucose is at or below 110 mg/dL, until after dosing, when the patient’s plasma glucose returns to 
≥70 mg/dL (3.9 mmol/L). From that time on, plasma glucose should be checked approximately 
every 30 minutes until 300 minutes (5 hours) after dosing. Plasma glucose concentrations will be 
measured using the US FDA-approved glucose analyzer YSI 2300, Yellow Springs Instruments, 

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Yellow Springs, Ohio, USA or the Super GL analyzer, Dr. Müller Gerätebau GmbH, Freital, 
Germany. 
At the discretion of the investigator, additional plasma glucose measurements can be taken at 
any time during the trial, for example when there is a suspicion (e.g. symptoms) of a hypoglycemic 
episode. 
Plasma glucose measurements for safety should only be recorded in the eCRF if they are related 
to an AE (e.g. a hypoglycemic episode). 
In case of persistent post-treatment hypoglycemia, patients will receive rescue treatment with an 
IV glucose infusion (see Section 7.4.5.2.3 for details). Blood samples for PD and PK assessments 
should still be taken at the specified time points. 
Once the glucose concentration declines to <80 mg/dL, blood samples for baseline assessment 
of plasma glucose and dasiglucagon/GlucaGen PK will be collected 5 minutes later. The samples 
are the baseline samples and should be collected within 2-5 minutes before trial product 
administration. If plasma glucose is ≥54 mg/dL and <80 mg/dL (3.0-4.4 mmol/L), trial product will 
be administered. 
If plasma glucose is <54 mg/dL (3.0 mmol/L), IV glucose solution will be administered sufficient 
to raise plasma glucose to within the 54-80 mg/dL target range. The run-in period will be 
adequately extended (at least 30 minutes) until the above target is achieved and new baseline 
samples for plasma glucose, dasiglucagon/GlucaGen PK, will be collected. In this case, glucose 
should not be infused within 10 minutes before trial product administration. If plasma glucose is 
not within the target range after the second attempt, the patient should be rescheduled for a new 
treatment visit within 7 days (+ 2 days). 
After 60 minutes, patients will be allowed to eat and drink moderately (appropriate to their body 
size, with a maximum of 50gr carbohydrates) to minimize discomfort in terms of potential nausea. 
The amount and type of food and drink consumed will be recorded. Patients should remain in bed 
until completion of the test procedure 300 minutes after dosing (bathroom visits are allowed). 
7.4.5.2.3 Rescue provisions for hypoglycemia 
During insulin-induced hypoglycemia, plasma glucose levels as well as the patient status will be 
monitored closely throughout the procedure. After administration of trial product, if their glucose 
levels become too low, patients may receive post-treatment IV glucose infusion to ameliorate 
hypoglycemia, as follows: 
1. The IV glucose infusion should be initiated if a patient experiences escalating symptoms of 
hypoglycemia (e.g. start of moderate symptoms of hypoglycemia) at any time during the test 
procedure. Glucose infusion should then be initiated targeting a plasma glucose level 
>70 mg/dL 
2. If plasma glucose is <54 mg/dL between t=8 and t=44 minutes, glucose infusion (e.g. 
1-2 mg/kg administered over 5-10 seconds) should be initiated to maintain plasma glucose 
between 55 mg/dL and 70 mg/dL. Pause glucose infusion if plasma glucose is >70 mg/dL 
3. If plasma glucose is <70 mg/dL at t≥45 minutes, glucose infusion (e.g. 2-3 mg/kg 
administered over 5-10 seconds) should be initiated to maintain plasma glucose between 
70 mg/dL and 90 mg/dL. Pause glucose infusion if plasma glucose is >80 mg/dL 
7.4.6 Selection of doses in the trial 
The selected dose of 1 mg GlucaGen® is the recommended dose for treatment of severe 
hypoglycemia (in accordance with the label, children below 25 kg body weight will be administered 
0.5 mg GlucaGen®). Pre-clinical and adult clinical studies demonstrated that 0.6 mg of 
dasiglucagon results in an initial PD response (i.e. acute glucose mobilization) comparable to 
1 mg GlucaGen®. 

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The estimation of the dasiglucagon dose in the pediatric trial is based on a PK and PD approach6 
where a previously developed population PK/PD model3 for dasiglucagon was extended with an 
allometric scaling component for the PK model4. The PD response was assumed to be similar in 
pediatric and adult patients as organ maturation for patients above 4 years is assumed not to 
have a meaningful impact on dasiglucagon PD. The pediatric PK component was developed by 
allometric scaling of clearance (Cl) and volume (V) by body weight from published glucagon PK 
data obtained from 2 clinical trials following intramuscular administration to pediatric (4 to 17 
years) and adult T1DM patients11,9. 
The conclusion of the modelling was that a dose of 0.6 mg appears appropriate to ensure a fast 
rescue from hypoglycemia for adult patients and children down to a weight of 25 kg. Although the 
dasiglucagon Cmax and AUC is expected to be higher in children, it does not exceed the total Cmax 
and AUC obtained in adults previously administered 2 mg dasiglucagon. The higher total drug 
exposure (AUC and Cmax) at lower weight is partially compensated by the shorter t½ and saturated 
PD response. The resulting total time of drug exposure and PD effect (AEU and CEmax) is similar 
throughout the weight range. 
7.4.7 Collection of blood samples 
The total blood volume to be obtained from any individual child will be about 43 mL. The maximum 
amount per visit is 12 to 17 mL. These values are within the recommended scope provided by the 
EU5. 
The following blood volume will be taken for each sample at each visit: 
Sample type 
Visit 1 (mL) 
Visit 2 (mL) 
Visit 3 (mL) 
Biochemistry/pregnancy 
5.00 
- 
5.00 
Hematology 
2.00 
- 
2.00 
Coagulation 
2.00 
- 
2.00 
HbA1c 
2.00 
- 
- 
ADA 
3.00 
- 
3.00 
PK 
- 
4.00 
- 
PD 
- 
12.00 
- 
Onsite-PG 
- 
1.00 
- 
Sum for each visit 
14.00 
17.00 
12.00 
Total 
43.00 
Abbreviations: ADA=Anti-drug antibodies; HbA1c=Hemoglobin A1c; Onsite-PG=Onsite monitoring of 
plasma glucose; PD=Pharmacodynamics; PK=Pharmacokinetics  
7.4.8 Treatment compliance 
Unblinded trial personnel will handle, prepare and administer all trial products.  
7.4.9 Method of assigning patients to treatments 
Forty patients will be randomized in a 2:1:1 ratio (dasiglucagon/placebo/GlucaGen®) into the 3 
treatment arms and stratified in 2 age groups: 6 to ≤12 years and 12 to ≤18 years and by injection 
site (abdomen/thigh). A minimum of 16 patients will be enrolled into each age group, including a 
minimum of 8 patients in either of age groups on dasiglucagon treatment arm. 
Patients who meet the inclusion and exclusion criteria will be randomized into one of the following 
treatment arms:  
 Dasiglucagon, liquid formulation, 1 mg/mL, 0.6 mL 

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 Placebo treatment: Placebo, liquid formulation, 0.6 mL  
 Active control treatment: Recombinant glucagon hydrochloride, 1 mg lyophilized powder for 
reconstitution (GlucaGen®, Novo Nordisk) in 1 mL sterile water (in accordance with the label, 
children below 25 kg body weight will be administered 0.5 mg GlucaGen®) 
Randomization will be performed using a central, dynamic variance minimization randomization 
method using an interactive web response system (IWRS) that will randomize a patient to one of 
the 3 aforementioned treatment arms and then assign dispensing unit numbers to that patient. 
An unblinded statistician/programmer who is separate from the trial team will generate the 
randomized kit list before the initiation of the trial.  
Treatment assignment will be kept strictly confidential and accessible only to authorized persons 
until after data base lock. However, the investigators can perform an emergency unblinding within 
the IWRS in case of an emergency, see Section 7.4.10. 
7.4.10 Blinding and breaking the blind 
This is a double-blind trial. Dasiglucagon is available as a liquid formulation and GlucaGen® is 
available as a powder for reconstitution; they are therefore not identical in appearance. Unblinded 
trial personnel will be responsible for handling, preparing (according to the prescription from the 
IWRS), and administering the trial product, and the syringes used for administration will be 
wrapped in aluminum foil to maintain the blinding at bedside. Parents being in the room with their 
child must be instructed not to look while the unblinded staff is administering the injection. To 
maintain double-blind conditions, blinded trial personnel not involved in the administration of trial 
products will perform all trial assessments at the trial center and is responsible for keeping the 
records strictly confidential and accessible only to the unblinded staff. However, unblinded 
personnel at the specialty laboratories will perform the exposure assessments and ADA 
assessments to make sure that dasiglucagon or GlucaGen® administration is matched with the 
applicable bioanalytical assay. 
Treatment assignment will be kept strictly confidential and accessible only to authorized persons 
until after the time of unblinding (database lock). Codes with treatment assignment will however 
be readily available in the IWRS to the blinded personnel in case of an emergency.  
The code for a particular patient may be broken in a medical emergency if knowing the identity of 
the treatment allocation would influence the treatment of the patient. The emergency code break 
can be performed using the IWRS. Whenever a code is broken, the person breaking the code 
must record the time, date and reason as well as his/her initials in the source documents.  
The breaking of blinded codes in case of medical emergency for a patient should not unblind the 
trial personnel to the treatment information of other patients. The person performing the unblinding 
should inform as few people as possible about the result of the unblinding. All persons unblinded 
for a specific patient should be documented.  
If the trial center needs to break the code, the medical monitor should, if at all possible, be 
contacted prior to breaking the code and the monitor must be notified within 24 hours after the 
code has been broken. 
7.4.11 Drug accountability and disposal 
Unblinded trial personnel will do the handling, preparation and administration of trial product. Each 
center will keep accurate records of the trial supplies received, stored, and dispensed, using 
appropriate forms. The trial supplies will be stored under appropriate conditions, locked and with 
restricted access. The unblinded monitor will perform the drug accountability to ensure 
compliance. 
All unused supplies and all empty and partially empty containers of trial product will be stored until 
the trial closure visit has been performed and then sent to the sponsor.  

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7.4.12 Prior and concomitant therapy 
All concomitant medications will be recorded in the eCRF at each visit.  
Prior to the start of the clamp procedure, the patient’s eligibility must be checked. If the patient 
has taken any prohibited medication, he/she will be excluded from the dosing visit but may be 
rescheduled 1-7 days later. Each patient may only have their dosing visit rescheduled once. See 
Section 7.3.3.1 for possible reasons for patient discontinuation. 
7.4.13 Treatment after end of trial  
After the end of their trial participation, patients should return to the standard of care that they 
received prior to enrollment in the trial. The treating physician will be responsible for supervising 
patients after the end of the trial. 
7.5 
Assessments and schedule of measurements 
The following assessments and measurements will be carried out at the times specified in the trial 
schedule of assessments (Table 2-1).  
Informed consent will be obtained prior to any trial-related procedures; see Section 11.3. 
7.5.1 Screening visit 
At screening (Visit 1), the following assessments will take place: 
 
Informed consent 
 
Inclusion/exclusion criteria 
 
Demography 
 
Body measurements 
 
Diabetes diagnosis, and current diabetes treatment 
 
Medical history including concomitant illnesses 
 
 
Prior and concomitant medications 
 
History of alcohol/drug abuse 
 
Physical examination 
 
Vital signs 
 
12-lead ECG 
 
AEs 
 
Biochemistry, hematology, coagulation, hemoglobin A1c (at Visit 1 only) 
 
Serum pregnancy test (female patients of childbearing potential only) 
 
Urinalysis 
 
Antibodies against dasiglucagon/GlucaGen® 
7.5.2 Dosing visit 
At Visit 2 (Day 0), patient eligibility is rechecked (check of changes between the screening visit 
and Visit 2) and patient’s eligible to participate will be randomized to treatment with dasiglucagon, 
placebo or GlucaGen®.  

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The following assessments will take place: 
 
Inclusion/exclusion criteria (prior to the start of the insulin-induced hypoglycemic procedure. 
Only check of exclusion criteria at clinic admission on Visit 2, day 0 and changes between 
screening visit and Visit 2) 
 
Concomitant medications (prior to the start of the insulin-induced hypoglycemic procedure) 
 
Current diabetes treatment 
 
Randomization (prior to the start of the insulin-induced hypoglycemic procedure) 
 
Exclusion criteria at clinic admission on Visit 2, day 0 (prior to the start of the insulin-induced 
hypoglycemic procedure) 
 
Urine stick pregnancy test (women of childbearing potential only) (prior to the start of the 
insulin-induced hypoglycemic procedure) 
 
Urinalysis (prior to the start of the insulin-induced hypoglycemic procedure) 
 
Alcohol breath test (prior to the start of the insulin-induced hypoglycemic procedure) 
 
Physical examination (prior to the start of the insulin-induced hypoglycemic procedure) 
 
Insulin-induced hypoglycemia 
 
Vital signs (prior to the start of the insulin-induced hypoglycemic procedure (within 30 
minutes), and at 30, 60 and 300 minutes after dosing. The actual time of the assessment 
should not deviate from the nominal time by more than ±10 minutes) 
 
12-lead ECG (prior to the start of the insulin-induced hypoglycemic procedure (within 30 
minutes), and at 20, 35, 45, 60 and 300 minutes after dosing. The actual time of the 
assessment should not deviate from the nominal time by more than ±5 minutes) 
 
Local tolerability (at 30, 120, and 300 minutes after dosing. The actual time of the assessment 
should not deviate from the nominal time by more than ±10 minutes) 
 
AEs 
 
Plasma dasiglucagon/GlucaGen® (pre-dose, and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 
minutes after dosing. The actual time of blood sampling should not deviate from the nominal 
time by more than ±1 minute between t=5 minutes and t=90 minutes, ±5 minutes between 
t=150 minutes and t=240 minutes. Pre-dose is defined as within 2 minutes prior to dosing) 
 
Plasma glucose (pre-dose, and at 4, 6, 8, 10, 12, 15, 17, 20, 30 and 45 minutes (and as well 
at 60 minutes if the patient´s body weight is ≥21 kg) after dosing. The actual time of blood 
sampling should not deviate from the nominal time by more than ±30 seconds until the 20-
minute collection time point, and by more than ±1 minute for the subsequent collection time 
points. Pre-dose is defined as within 2 minutes prior to dosing 
 
Administration of trial product (during hypoglycemic clamp procedure) 
7.5.3 Follow-up visit 
At 28 (+ 5) days after the hypoglycemic clamp procedure, the follow-up visit is scheduled to collect 
safety data. The following assessments will take place: 
 
Concomitant medications 
 
Current diabetes treatment 
 
Physical examination 
 
Vital signs 

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 
12-lead ECG 
 
Local tolerability 
 
AEs 
 
Biochemistry, hematology, coagulation, HbA1c (HbA1c at Visit 1 only) 
 
Urine stick pregnancy test (women of childbearing potential only) 
 
Urinalysis 
 
Antibodies against dasiglucagon/GlucaGen® (any treatment-induced or treatment-boosted 
[titer increase above 5 fold] ADA-positive patients will be monitored until the ADA levels return 
to baseline levels) 
7.5.4 Final examination at the end of the trial  
The final visit of the trial is Visit 3 (Day 28[+5] of the follow-up period; end-of-trial visit). See Section 
7.5.3 for further details.  
7.5.5 Additional (safety) examinations 
If there are any unclear symptoms or observations the responsible physician in charge may 
perform further medical examinations, other than outlined in this protocol, including further clinical 
laboratory tests, in order to clarify the relevance or to diagnose symptoms.  
7.5.6 Efficacy measurements 
A description of the sample handling and sample processing at the site will be included in the 
laboratory manuals. Validation documentation for the assays must be available prior to sample 
analyses. A bioanalytical report for each analysis of trial PD and PK samples will be prepared. 
Pharmacokinetic measurements 
The exposure to trial medication (dasiglucagon or GlucaGen®) for evaluation of PK will be 
assessed based on plasma concentration data (AUC0-90min, Cmax, tmax) from samples collected at 
the dosing visit (Visit 2). The sampling procedure is described in Section 7.5.2. 
Pharmacodynamic measurements 
The plasma glucose profile for evaluation of the primary and secondary clinical efficacy endpoints 
will be assessed based on plasma concentration data (AUE0-30min) from samples collected at the 
dosing visit (Visit 2). The samples will be sent to the clinical laboratory and analyzed using a 
sensitive and validated assay for glucose measurements. The sampling procedure is described 
in Section 7.5.2. 
7.5.7 Safety and tolerability measurements  
7.5.7.1 Safety laboratory tests 
Routine safety laboratory tests will be performed centrally. Samples for safety laboratory 
parameters will be collected at Visits 1 and 3. Samples for urinalysis will be collected at Visits 1, 
2, and 3. The following parameters will be determined: 
 
Clinical chemistry: sodium, potassium, calcium, glucose, urea, creatinine, total bilirubin, AST, 
ALT, gamma-glutamyltransferase, alkaline phosphatase, total protein, C-reactive protein, 
HbA1c, C-peptide  
 
Hematology: hemoglobin, red blood cell count (erythrocytes), hematocrit, platelet count 
(thrombocytes), total white blood cell count (leucocytes) 

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 
Coagulation: international normalized ratio, fibrinogen (at screening visit only)  
 
Urinalysis: pH, blood (leukocytes and erythrocytes), protein, glucose, ketones, nitrite 
 
Immunogenicity: 
Serum samples for assessment of antibodies against dasiglucagon/GlucaGen® will be 
measured at screening Visit 1 and at follow-up Visit 3 by the special laboratory, York 
Bioanalytical Solutions (York, United Kingdom). A description of the sample handling and 
sample processing, storage and shipment at the center will be included in the laboratory 
manual. Immunogenicity samples will be analyzed after the last patient last visit. 
The clinical ADA assays, one specific for dasiglucagon and another for GlucaGen®, have 
been validated in accordance with existing guidelines and recommendations. 
Confirmed positive anti-dasiglucagon antibody samples from treatment- induced or treatment- 
boosted (titer increase above 5-fold) ADA-positive patients will be evaluated for binding titer, 
neutralizing potential and neutralizing titer as well as cross-reactivity towards endogenous 
glucagon. Any treatment-induced or treatment-boosted ADA-positive patients will be 
monitored until the ADA levels return to baseline levels.  
The in vitro neutralizing effect of the antibodies will be measured using an assay based on 
glucagon receptor expression in transfected human embryonic kidney cells. The calculated 
sensitivity in previous studies was about 51.8 ng/mL. The assay was also validated for 
recombinant glucagon with similar results. In case of a positive result in the neutralizing 
antibody assay, a titer estimation will be performed. The cell-based neutralizing antibody 
analyses will be performed by a special laboratory, BioAgilytix, Durham, North Carolina, USA.  
No further serum sampling will be needed as the ADA samples can be used for neutralizing 
antibody analysis. 
Residual and additional antibody serum samples may be stored until approval of market 
authorization by the health authorities. Further characterization of the antibody response may 
be requested by the health authorities. 
A pregnancy test will be performed at screening and follow-up (Visits 1, 2 and 3) for female 
patients of childbearing potential only. 
An alcohol breath test will be performed at the dosing visit (Visit 2). 
For further details, please refer to the laboratory manual.  
 
7.5.7.2 Safety examinations 
Physical examination is performed at screening (Visit 1), dosing (Visit 2) and end-of-trial (Visit 3).  
AEs are assessed at all visits. Local tolerability is assessed at dosing visit and follow-up visit 
(Visits 2 and 3). ECG and vital signs are assessed at screening, dosing and follow-up visit (Visit 
1, 2 and 3).  
 
Physical examination includes examination of the following body systems: head, ears, eyes, 
nose, throat, including the thyroid gland; heart, lung, chest; abdomen; skin; musculoskeletal 
system; nervous system; lymph nodes 
 
Vital signs include: pulse rate and blood pressure after 5 minutes in sitting position, body 
temperature 
 
Local tolerability: skin reactions will be reported as AEs (see Section 8) 
 
12-lead ECG: Details from ECG assessments will be recorded, including heart rate, PR, QRS, 
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8. Adverse events 
8.1 
Definitions 
Timely, accurate, and complete reporting and analysis of safety information from clinical trials are 
crucial for the protection of patients, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. 
 
Adverse event  
An AE is any untoward medical occurrence in a trial patient administered a trial product and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (for example, an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a trial product, whether or not considered related 
to the trial product.  
Note: This includes events from the first trial-related activity after the patient has signed the 
informed consent.  
AEs include: 
 
A clinically significant worsening of a concomitant illness 
 
A clinical laboratory abnormality that is clinically significant, i.e. any abnormality that suggests 
a disease and/or organ toxicity and is of a severity that requires active management. Active 
management includes active treatment or further investigations, for example change of 
medicine dose or more frequent follow-up due to the abnormality 
 
Hypoglycemic episodes (see Section 8.4) 
 
Injection site reactions 
The following should not be recorded as AEs, if recorded at screening (on Medical History form 
or eCRF): 
 
Pre-planned procedure, unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the patient has signed the informed consent 
 
Pre-existing conditions, including those found because of screening procedures (pre-existing 
conditions should be reported as medical history or concomitant illness) 
 
When assessing an adverse event, the following definitions are use: 
Serious adverse event 
An SAE is any untoward medical occurrence that at any dose results in any of the following:  
 
Results in death  
 
Is life-threatening  
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Is medically important 
Medical judgement must be exercised in deciding whether an AE is believed to be ‘medically 
important’. A medically important event may not be immediately life-threatening or result in 

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death or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. 
Other important events: 
The following events must always be reported to the sponsor according to SAE timelines, 
regardless of whether the event is non-serious or serious:  
 
Risk of liver injury defined as ALT or AST > 3 x ULN and total bilirubin > 2 x ULN, where no 
alternative etiology exist 
 
Suspicion of transmission of infectious agents via the trial product 
 
Overdose of the trial product 
 
Suspected abuse or misuse of the trial product 
 
Medication error involving the trial product 
 
Inadvertent or accidental exposure to the trial product. 
Severity of an adverse event 
The maximum intensity (severity) of all AEs must be assessed by the investigator and 
documented. Severity should be graded when the AE outcome is known: 
 
Mild: No or transient symptoms, no interference with the patient´s daily activities 
 
Moderate: Marked symptoms, moderate interference with the patient´s daily activities 
 
Severe: Considerable interference with the patient´s daily activities, which the patient finds 
unacceptable. A severe reaction does not necessarily deem the AE as serious and an SAE 
is not always severe in nature. 
Causality relationship to trial product 
 
Probable: Good reason and sufficient documentation to assume a causal relationship 
 
Possible: A causal relationship is conceivable and cannot be dismissed 
 
Unlikely: The event is most likely related to etiology other than the trial product 
Outcome of an adverse event 
 
Recovered/resolved: The patient has fully recovered, or by medical or surgical treatment, the 
condition has returned to the level observed at the first trial-related activity after the patient 
signed the informed consent 
 
Recovering/resolving: The condition is improving and the patient is expected to recover from 
the event. This term is only applicable if the patient has completed the trial 
 
Recovered/resolved with sequelae: The patient has recovered from the condition, but with 
lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE 
 
Not recovered/ not resolved: The condition of the patient has not improved and the symptoms 
are unchanged 
 
Fatal: This term is only applicable if the patient died from a condition related to the reported 
AE. Outcomes of other reported AEs in a patient before he/she died should be assessed as 
"recovered/resolved", "recovering/resolving", "recovered/ resolved with sequelae" or "not 
recovered/not resolved". An AE with fatal outcome must be reported as an SAE 
 
Unknown: This term is only applicable if the patient is lost to follow-up 
 

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Suspected unexpected serious adverse reactions 
An AE is considered a suspected unexpected serious adverse reaction (SUSAR) if the nature 
or severity is not consistent with the applicable product Reference Safety Information. For 
dasiglucagon, the expectedness of an AE will be determined by whether or not it is listed in 
the Reference Safety Information section of the Investigator’s Brochure. 
 
Adverse event of special interest (AESI) 
An AESI is an event that, in the evaluation of safety, has a special focus (e.g. required by health 
authorities). In this trial, hemodynamic changes are considered AESIs that are defined as follows: 
 
Post-dose clinical signs, or measured vital signs, indicating a clinically significant drop in 
blood pressure including signs of orthostatic hypotension, vasovagal responses or 
bradycardia.   
 
Post-dose change in pulse or blood pressure considered an event of hypo- or hypertension 
as judged by the investigator. 
AESIs must be reported to the sponsor in the same way and with the same timelines as SAEs 
(see Sections 8.2 and 8.3). 
8.2 
Collection, recording and reporting of adverse events 
All AEs, whether serious or non-serious, will be reported from the time a signed and dated 
informed consent form (ICF) is obtained until the end of the post-treatment follow-up period (which 
may include contacts for follow-up of safety). In addition, patients will be observed for any signs 
or symptoms and asked about their condition by open questioning, such as “How have you been 
feeling since you were last asked?” at each contact with the trial center (visit or telephone). 
Patients will also be encouraged to spontaneously report AEs occurring at any other time during 
the trial.  
All AEs, regardless of seriousness, severity, or presumed relationship to trial product, must be 
recorded and evaluated by the investigator. Whenever possible, diagnoses should be given when 
signs and symptoms are due to a common etiology. If no diagnosis can be made, the investigator 
should record each sign and symptom as individual AEs. Investigators must record their opinion 
concerning the relationship of the AE to the trial product. All measures required for AE 
management must be recorded in the source document and reported according to sponsor 
instructions. 
 
Each AE must be reported on the AE page of the eCRF. 
All AE information should at a minimum include the following: 
 
Date and time of onset and resolution 
 
Date and time of investigator’s first information on the AE 
 
Seriousness 
 
Severity 
 
Causal relationship with trial product 
 
Measures taken due to AE 
 
Date and time of resolution and final outcome 
Each AE will be coded using the latest version of the Medical Dictionary for Regulatory Activities. 
SAEs and AESIs, including those spontaneously reported to the investigator within 30 days after 
the last dose of trial product, must be reported to the appropriate sponsor contact person(s) within 

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24 hours after obtaining knowledge about the event, followed by a complete SAE form as soon 
as more information is available. For each SAE and AESI, a separate SAE form should be 
completed.  
The investigator should report the SAE and AESI in the electronic data capture (EDC) and the 
system will generate an email to the sponsor´s Pharmacovigilance Unit (PharmaLex), informing 
them of the reported SAE. 
It is the responsibility of the sponsor´s Pharmacovigilance Unit (PharmaLex) to report all SUSARs 
that occur in this trial to the respective competent authorities and the institutional review board 
(IRB), or independent ethics committee (IEC) in accordance with the local requirements in force 
and ICH guideline for GCP. 
8.3 
Follow-up of adverse events 
All AEs that are ongoing at the end of the patient’s participation in the trial will be followed up until 
the event is resolved or reaches a satisfactory outcome as deemed by the investigator.  
Follow-up actions for all SAEs will be performed according to appropriate clinical care practices 
and may depend on the nature of the event. These will be determined after internal review and/or 
sponsor review. 
The follow-up information should only include new (updated and/or additional) information that 
reflects the situation at the time of the investigator’s signature. 
Follow-up information on (S)AEs and AESIs will be updated using the (S)AE form. If a non-serious 
event becomes serious during the follow-up, the AE form and SAE form have to be used and 
reporting timelines follow those of a SAE. 
The investigator must forward follow-up information on SAEs and if previously non-serious AEs 
become SAEs to the sponsor immediately (within 24 hours) after obtaining knowledge about the 
new information. 
The investigator must record follow-up information in the eCRF for non-serious AE and on the 
SAE form for SAEs and AESI. Follow-up questions to investigators regarding SAEs are queried 
directly by safety CRO to the investigator.  
Follow-up information must be reported according to the following: 
 
SAEs and AESI: All SAEs and AESI must be followed until the outcome of the events is 
“recovered/resolved,” “recovered/resolved with sequelae,” or “fatal,” and until all queries have 
been resolved. Cases of chronic conditions, cancer, or AEs that are ongoing at time of death 
(where death is due to another AE) may be closed with the outcome “recovering/resolving” or 
“not recovered/not resolved.” Cases can be closed with the outcome of “recovering/resolving” 
when the patient has completed the follow-up period and is expected by the investigator to 
recover. 
The SAE and AESI follow-up information should only include new (eg, corrections or 
additions) information and must be reported within 24 hours of the investigator's first 
knowledge of the information. This is also the case for previously non-serious AEs which 
subsequently become SAEs.  
 
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving,” “recovered/resolved,” or “recovered/resolved with sequelae” or until 
the end of the follow-up period stated in the protocol, whichever comes first, and until all 
queries related to these AEs have been resolved. Cases of chronic conditions, cancer, or AEs 
that are ongoing at time of death (where death is due to another AE) may be closed with the 
outcome of “recovering/resolving” or “not recovered/not resolved.” Cases can be closed with 
the outcome of “recovering/resolving” when a patient has completed the follow-up period and 
is expected by the investigator to recover.  

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If a potential hypersensitivity reaction is observed, additional blood samples, as clinically 
indicated, may be required to further characterize the potential hypersensitivity reaction. If an 
anaphylactic shock is suspected, samples may be taken for the measurement of tryptase. In this 
case, a blood sample should be taken 3 to 4 hours after the event and again approximately 
1 to 2 weeks later to determine tryptase baseline levels. In addition, assessments for elevated 
histamine levels may be considered. 
The investigator must ensure that the worst-case severity and seriousness of an event is kept 
throughout the trial, ie, if the severity of an AE changes over time then it should be reported as 
1 AE with the most severity. A worsening of an unresolved AE must be reported as follow-up with 
re-assessment of severity and/or seriousness of the event. 
If an AE is resolved and re-appears later then it should be reported as a new AE.   
Queries or follow-up requests must be responded within 14 calendar days from the date of receipt 
of the request, unless otherwise specified in the follow-up request.  
8.4 
Hypoglycemia 
Hypoglycemia will be regarded as an AE, recorded, and documented on an AE form (or SAE 
form, if applicable). 
Hypoglycemia is defined as a decline in plasma glucose below 3.9 mmol/L (70 mg/dL). Since 
hypoglycemia will be induced during the dosing visit, in accordance with hypoglycemia clamp 
procedure described in Section 7.4.5.2.2, ONLY plasma glucose below 3.0 mmol/L (54 mg/dL) 
must be reported as an AE, at the dosing visit (V2), and at incidences that IV glucose is given 
after trial product administration. 
8.5 
Pregnancy 
Female patients must be instructed to notify the investigator immediately if they become pregnant 
or if they suspect to be pregnant during the trial. All initial reports of pregnancy in female patients 
must be reported to the sponsor by the trial center personnel within 24 hours of their knowledge 
of the event using the appropriate pregnancy form. Abnormal pregnancy outcomes (e.g. 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs and must be reported using the SAE form. If a patient becomes pregnant during 
the trial, a determination regarding the trial product discontinuation must be made by the 
investigator. 
Because the effect of the trial product on sperm is unknown, pregnancies in partners of male 
patients must be reported by the trial center personnel within 24 hours of their knowledge of the 
event using the appropriate pregnancy form. Male patients must be instructed to notify the 
investigator immediately if their partner becomes pregnant or suspects to be pregnant. 
The investigator must follow the pregnancy until the pregnancy outcome is known and the 
newborn infant is 1 month of age. The investigator must report information about the pregnancy, 
pregnancy outcome, and health of the newborn infant(s), as well as AEs in connection with the 
pregnancy, and AEs in the fetus and newborn infant. 
8.6 
Precautions 
Normal precautions taken for a human trial, including the provision of emergency equipment, will 
be taken during this trial. Qualified and well-trained physicians and medical staff will instruct the 
patients. During a patient’s participation in the trial, the investigator should ensure adequate 
medical care for any AEs, including clinically significant laboratory values related to the trial. The 
investigator should inform the patient when medical care is needed for intercurrent illnesses of 
which the investigator becomes aware.  

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For further information on safety precautions for dasiglucagon and GlucaGen®, please refer to the 
current version of the Investigator’s Brochure2 and the Summary of Product Characteristics for 
GlucaGen®7, respectively. 
8.7 
Safety committee 
An internal Zealand Pharma A/S safety committee is constituted to perform the safety surveillance 
of clinical trials with dasiglucagon, including this trial. 
If safety signals or concerns are observed, whether based on reported SAEs, review of all AEs 
and laboratory parameters reported, or any other notification of significant findings, the safety 
committee will respond appropriately to protect the safety of the patients.   
The safety committee convenes regularly, every quarter, to review the safety information, 
including SAEs, AEs and laboratory data. Additional safety committee meeting may be called at 
the discretion of any safety committee member, should new safety signals occur during this time 
interval. 
 

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9. Data management and quality control 
9.1 
Electronic case report forms 
All the information collected during the trial will be recorded in the eCRFs, which are identified by 
patient number. Synteract will design suitable eCRFs. The investigator will ensure that the eCRFs 
are completed correctly. The investigator will sign all data entered in the eCRF electronically, 
signifying agreement with and responsibility for the recorded data.  
9.2 
Quality control 
The investigator will permit trial-related monitoring, IEC review, and regulatory inspections, 
providing direct access to source data/documents. Sponsor-authorized quality assurance 
personnel may carry out audits for which the investigator must provide support. 
A monitor from Synteract will supervise the trial. The trial monitor will contact the investigator 
regularly to discuss the progress of the trial and to check the trial documents including the 
informed consent forms for completeness and consistency.  
The trial monitor or a representative of the sponsor will cross-check the data entered in the eCRFs 
with the source data at the trial center and observe the trial procedures in order to verify 
adherence to the trial protocol. 
The eCRFs will be checked for completeness and correctness by the monitor and by the data 
management department of Synteract according to the Synteract standard operating procedures, 
and the investigator will resolve any queries. 
All of the clinical data will be captured via EDC using a web-based tool. The software Marvin from 
the company XClinical (www.xclinical.com) is the preferred EDC software. Marvin is compliant 
with all legislation relevant to EDC (Food and Drug Administration USA, 21 Code of Federal 
Regulations [CFR] Part 11, GCP). 
The investigator center staff will enter and edit the data via a secure network, with secure access 
features (username and password). A complete electronic audit trail will be maintained. The 
investigator will approve the data using an electronic signature (Ref: 21 CFR Part 11), and this 
approval is used to confirm the accuracy of the data recorded. 
The eCRFs will be used for all patients. The investigator’s data will be accessible from the 
investigator’s center throughout the trial. The eCRFs must be kept current to reflect patient status 
at each phase during the course of the trial. The eCRF will not capture personalized data. The 
investigator must make a separate confidential record of personalized details (name and initials) 
on the patient identification and enrollment log. The investigator does all changes to data through 
the EDC system.  
It is the responsibility of the Principal Investigator of the respective center to ensure that all patient 
discontinuations or changes in trial or other medications entered in the patient’s eCRF are also 
made on the patient’s medical records. 
The eCRFs for any patient leaving the trial should be completed at the time of the final visit or shortly 
thereafter. 
9.3 
Data management 
Data management will be performed according to Synteract standard operating procedures. 
 

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10. Statistical methods and determination of sample size 
10.1 Statistical analysis plan 
A separate Statistical Analysis Plan will detail the planned statistical analysis and may include 
necessary adaptations to the planned statistical analysis before unblinding of the data.  
Any deviations from the planned analyses will be described and justified in the final integrated 
trial report. 
10.1.1 General considerations 
All data obtained in this trial and documented in the eCRFs will be listed and summarized with 
statistics or frequency tables as appropriate. In case of termination of the trial, all data collected 
up to that time point will be included into the analysis. 
Raw data listings and summary tables will be generated using SAS© software Version 9 or higher 
(SAS Institute, Inc, Cary, North Carolina, USA).  
Continuous variables will be summarized with means, standard deviations, medians, minimums, 
and maximums and valid cases.  
Other summaries (e.g. quartiles, 95% confidence intervals) may be used as appropriate. 
Categorical efficacy and safety variables will be summarized by counts and by percentage of 
patients in corresponding categories.  
10.1.2 Classification of patients to subsets 
For the statistical analysis, the randomized patients will be divided up into the following datasets: 
The following definitions are applicable: 
Safety analysis set 
(SAS) 
all patients who were randomized and received at least 1 dose of 
trial product 
Full analysis set 
(FAS) 
all patients of the SAS 
Per protocol set 
(PPS) 
all patients of the FAS for whom no relevant protocol deviations 
were documented.  
The analysis of the primary endpoint will be based on the FAS. A secondary analysis of the 
primary endpoint will be based on the PPS. Safety analysis will be based on the SAS. 
The decision whether a protocol deviation is relevant or not for the exclusion of patients from the 
PPS will be made case-by-case in a data review meeting. 
10.1.3 Efficacy endpoints 
For the confirmatory analyses, the primary and secondary endpoints for the dasiglucagon 0.6 mg 
and placebo treated patients will be compared. A hierarchical procedure will be applied for the 
control of multiplicity. The primary and secondary endpoints will be evaluated on the FAS. In the 
primary analysis, those patients who require rescue IV glucose will be censored at the time to 
plasma glucose recovery.  In a sensitivity analysis, the time to plasma glucose recovery will be 
analyzed without censoring the patients who received rescue IV glucose.   
10.1.3.1 Hierarchical testing procedure 
For the confirmatory analyses, the following a priori defined hierarchical inferential test order will 
be applied for the control of the type 1 error rate across the planned multiple comparisons. The 
primary endpoint and secondary endpoints will be inferentially evaluated within the FAS in the 
following order, where inference will proceed at the 2-sided 0.05 criterion significance level until 
the first failure to reject the null hypothesis for a dasiglucagon versus placebo comparison: 

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 
Primary:  Time to plasma glucose recovery 
 
Secondary 1-4: Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 
minutes, and within 10 minutes after study drug injection without administration of rescue IV 
glucose. 
 
Secondary 5-8:  Plasma glucose changes from baseline within 30 minutes, within 20 minutes, 
within 15 minutes, and within 10 minutes after study drug injection or at the time of rescue. 
The GlucaGen® versus placebo comparisons will not be included in the inferential testing hierarchy, 
since the efficacy of GlucaGen® is previously established, and these comparisons are intended to 
support the validity of the study for the dasiglucagon versus placebo comparisons. 
Analogous supportive sensitivity analyses will be conducted in the PPS, but without inference intent. 
10.1.3.2 Primary efficacy endpoint 
The primary endpoint, time to plasma glucose recovery, will be summarized using Kaplan-Meier  
estimates for each treatment group in total and stratified by age group and injection site. The median 
time to recovery with 95% confidence interval will be estimated by treatment group, in total and in 
each stratum. 
A stratified log-rank test will be applied to compare the dasiglucagon 0.6 mg treatment group to the 
placebo group. The same method will be applied to compare dasiglucagon 0.6 mg with GlucaGen®. 
In the primary analysis, recovery cannot be achieved in those patients where IV glucose treatment 
is administered. Those patients who receive IV glucose will be censored (i.e. set to ‘not recovered’) 
at 45 minutes after dosing. 
A further sensitivity analysis will be done by censoring data at the actual time when the patients 
received glucose IV. 
10.1.3.3 Secondary efficacy endpoints 
The secondary efficacy endpoints are plasma glucose recovery within 10, 15, 20 and 30 minutes 
after trial product injection, i.e. achieving a ≥20 mg/dL increase in plasma glucose from baseline 
within 0 to 10, 15, 20 and 30 minutes. If a patient has received an IV glucose treatment before 
recovery, the patient is set to ‘not recovered’ in the analysis of the 4 endpoints, corresponding to 
censoring in the time-to-recovery analysis for the primary endpoint. The 10-, 15-, 20- and 30-
minute recovery rates of 2 treatment groups will be compared by a Cochran-Mantel-Haenszel test 
stratified by age group and injection site. The treatment and age group responder rates with the 
95% confidence intervals will be presented for the 10-, 15-, 20- and 30-minute endpoint. 
If due to small or zero cell counts the Cochran-Mantel- Haenszel test fails, non-stratified Fisher’s 
exact tests will be applied instead. 
Plasma glucose changes from baseline at 10, 15, 20 and 30 minutes after trial product injection 
will be analyzed in an analysis of variance with factors treatment (3 levels) age group (2 levels) 
and injection site (2 levels) for each endpoint. If the rescue IV glucose was administered before 
10, 15, 20 or 30 minutes, respectively, the patient’s plasma glucose changes from baseline will 
be determined from the value at the time of rescue IV glucose administration. Adjusted treatment 
means will be presented with their 95% confidence intervals. The 4 analysis of variance will also 
be used to test the difference between treatments adjusted for age group and injection site. 
10.1.4 Safety endpoints 
Clinical laboratory data 
Clinical laboratory test results will be marked whether the result is below, within or above the 
respective reference range. The number of values outside of the reference range will be counted. 

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Adverse events 
Adverse events will be tabulated by system organ class (SOC) and preferred term (PT) after 
medical coding using the Medical Dictionary for Regulatory Activities. AE summary tables will 
include counts and percentages of patients who experienced AEs summarized by SOC and PT. 
Other safety data 
Time to first IV glucose infusion, after IMP administration (N.B. IV glucose infusion prior to IMP 
administration should not be included, as it is part of hypoglycemic clamp procedure) will be 
described with descriptive statistics. No statistical tests will be performed. 
Vital signs, physical examination, ECG and local tolerability data will be summarized with 
descriptive statistics. 
Immunogenicity 
Occurrence of ADA will be analyzed descriptively per treatment group. No statistical tests are 
planned. 
10.1.5 Pharmacokinetic endpoints 
Plasma dasiglucagon and glucagon concentrations will be described and the following 
parameters are calculated and summarized with descriptive statistics: 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
30 minutes post-dose (AUC0-30min) 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 
to 300 minutes post-dose (AUC0-300min) 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 
to infinitely post-dose (AUC0-inf) 
 
Maximum of all valid plasma dasiglucagon or GlucaGen® concentration measurements from 
0 to 300 minutes post-dose (Cmax) 
 
Time to maximum of plasma dasiglucagon or GlucaGen® concentration measurements (tmax) 
 
Terminal elimination rate constant of plasma dasiglucagon or GlucaGen® (λz) 
 
Terminal plasma elimination half-life of dasiglucagon or GlucaGen® (t½) 
 
Total body clearance of plasma dasiglucagon or GlucaGen® (CL/f) 
 
Volume of distribution of plasma dasiglucagon or GlucaGen® (Vz/f) 
 
Mean residence time of plasma dasiglucagon or GlucaGen® (MRT) 
10.1.6 Pharmacodynamic endpoints 
Plasma glucose response as area under the effect curve above baseline from time 0 to 
30 minutes, AUE0-30min, will be summarized with descriptive statistics. 
10.1.7 Further data 
Baseline and demographic data will be summarized using descriptive statistics.  
All other data obtained in this trial and documented in the eCRF will be listed. 
10.1.8 Withdrawals, drop-outs and missing data 
Only valid cases will be analyzed, i.e. no imputation technique like last observation carried forward 
will be applied. 

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10.1.9 Baseline and center comparisons 
Demographic and other baseline characteristics will be compared. 
10.1.10 Subgroup analysis 
No subgroup analysis is currently planned. 
10.1.11 Interim analysis 
No interim analysis is currently planned. 
10.2 Determination of sample size 
The primary comparison is between the dasiglucagon and placebo treatment arms. From phase 
2 results, the median time to an increase of 20 mg/dL of the 0.6 mg dose was approximately 10 
minutes. For placebo-treated patients, the median time to recovery is assumed to be more than 
50 minutes. Assuming an exponential time-to-recovery distribution with median times of 10 and 
50 minutes, a 2-sided log-rank test will be able to detect a difference between dasiglucagon 
0.6 mg and placebo with 90% power with a follow-up time of 45 minutes at a 5% significance level 
with 20 patients randomized to the dasiglucagon arm and 10 patients to placebo. 
GlucaGen® is included as a reference to compare the responses and AE profile to dasiglucagon 
with those to a marketed product. It is expected that 10 patients in the GlucaGen® group will 
suffice for the comparison. 

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11. Ethics and regulations 
11.1 Independent ethics committees and competent authorities 
The clinical trial authorization granted by the competent authority (CA) and a favorable opinion 
from the relevant IEC/IRB(s) will be obtained prior to the start of the trial. The local authorities will 
be notified about the trial as required by law. 
The CA and the IEC/IRB will be notified about the end of the trial and a report summarizing the 
trial results will be sent to the CA and the IEC within 1 year after the end of the trial. If the trial is 
terminated early, the CA and the EC will be notified within 15 days. 
The IECs and/or IRBs meet the requirements of the ICH Harmonised Tripartite Guideline for GCP 
and local legislation. They also meet the requirements of 21 CFR 312.3. 
11.2 Ethical conduct of the trial  
The trial will be conducted in accordance with the ethical principles set forth in the Declaration of 
Helsinki (including amendments).  
11.3 Patient information and consent 
Written informed consent will be obtained from the parents/legal representatives of all patients 
prior to enrollment into the trial. Additionally, the children will be informed about the trial with age-
appropriate information materials, and their assent will be obtained in accordance with local 
regulations. The investigator will explain to each patient and their parents/legal representatives 
orally and in writing (patient information sheet) the nature, significance, risks and implications of 
the trial before inclusion. In particular, the patients will be informed about the following: 
 
The possibility of withdrawing from the clinical trial at any time by revoking the consent and 
without any resulting disadvantage 
 
How personal and health-related data will be collected and used during the trial 
 
Confidentiality, i.e. medical records may be examined by authorized monitors or Clinical 
Quality Assurance auditors appointed by the sponsor, by appropriate IEC/IRB members, and 
by inspectors from regulatory authorities 
All parents/legal representatives and the children will receive a copy of the respective patient 
information sheet and a copy of their signed and dated informed consent/assent form.  
All patients will be insured against injury caused by their participation in the trial according to legal 
requirements. They will be informed about the insurance and the resulting obligations on their 
part. 
11.4 Legal and regulatory requirements 
This trial will be carried out in accordance with: 
 
ICH guidelines for GCP, United States investigational new drug regulations (21 CFR 312), 
the regulations on electronic records and electronic signature (21 CFR 11), the most recent 
guidelines of the Declaration of Helsinki, and the relevant laws and regulations of the country 
in which the trial takes place 
 
Standard operating procedures for clinical investigation and documentation in force at 
Synteract 

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12. Trial administration 
12.1 Responsibilities 
Zealand Pharma A/S is the sponsor of this trial. Synteract, a contract research organization, will 
organize the performance of this trial.  
A list with the names and addresses of the responsible institutions and persons is provided in 
Appendix 1 of this protocol. 
12.2 Protocol deviations 
Before data are released for statistical analysis, a treatment-masked review of all data will take 
place to identify protocol deviations that may potentially affect the results. This review will be 
performed without revealing to which trial product the patients were assigned. The masking of the 
trial products will be maintained for everyone involved in allocating patients to the analysis sets 
until data are released for statistical analysis. Furthermore, spurious outliers will be evaluated. In 
addition, protocol deviations that may potentially affect the results will be identified and it will be 
evaluated if patients and/or data should be excluded from the analysis. Protocol deviations will 
be classified as minor or major in a consistent way. Major deviations from the protocol may lead 
to the exclusion of a patient from the PPS. 
Major protocol deviations may include deviations related to trial inclusion or exclusion criteria, 
conduct of the trial, patient management or patient assessment. Unless explicitly decided 
otherwise during the treatment-masked data review, the following will be considered major 
protocol deviations: 
 
Violation of one or more major inclusion/exclusion criteria 
 
Interruption of administration of trial product 
 
Significant deviation from time windows  
 
Incorrect treatment allocation 
 
Missing primary endpoint. 
The violation of several major inclusion/exclusion criteria or the complete absence of efficacy data 
might lead to exclusion of the patient from the FAS. In that case, the decision should be taken at 
the treatment-masked data review meeting, and the exclusion from efficacy analysis will be 
justified in the signed notes of the meeting. 
Obviously erroneous data points may be excluded from the analyses or re-analyzed (in case of, 
for example, serum concentrations). The decision to re-analyze or exclude data points from the 
statistical analysis is the joint responsibility of the sponsor and the trial statistician.  
The patients or observations to be excluded and the reason for their exclusion will be documented 
and signed by those responsible prior to database release. The documentation will be stored 
together with the remaining trial documentation. The patients and observations excluded from 
analysis sets, and the corresponding reasons, will be described in the clinical trial report.  
12.3 Protocol changes  
This trial protocol may be amended following the procedures specified by local laws and 
regulations. Substantial amendments to this trial protocol may be implemented only if the approval 
of the CA(s) and a favorable opinion of the ethics committee(s) have been obtained. 
Substantial amendments to the conduct of the clinical trial may arise from changes to the protocol 
or from new information relating to the scientific documents in support of the trial. Amendments 
to the trial are regarded as “substantial” where they are likely to have a significant impact on one 
of the following: 

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 
The safety, physical health and mental integrity of the patients 
 
The scientific value of the trial 
 
The conduct or management of the trial 
 
The quality or safety of any investigational medicinal product used in the trial 
If a new event occurs related to the conduct of the trial or the development of the investigational 
product, which may affect the safety of the patients, the sponsor and the investigator will take 
appropriate safety measures to protect the patients against any immediate hazard. The sponsor 
will immediately inform the CA(s) and ethics committee(s) of the new events and the measures 
taken. 
12.4 Reports and publications  
The information obtained during the conduct of this trial is considered confidential and may be 
used by or on behalf of Zealand Pharma A/S for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Zealand Pharma A/S in connection 
with this trial will remain the sole property of Zealand Pharma A/S and is to be considered 
confidential information. 
No confidential information will be disclosed to others without prior written consent from Zealand 
Pharma A/S. Such information will not be used except in the performance of this trial. The 
information obtained during this trial may be made available to other physicians who are 
conducting other clinical trials with the trial product, if deemed necessary by Zealand Pharma A/S. 
Provided that certain conditions are fulfilled, Zealand Pharma A/S may grant access to information 
obtained during this trial to researchers who require access for research projects studying the 
same disease and/or trial product studied in this trial.  
One investigator will be appointed to review and sign the clinical trial report (signatory investigator) 
on behalf of all participating investigators. 
Communication of results 
No permission to publish will be granted to any CRO involved in the trial.  
The results of this trial will be subject to public disclosure on external websites according to 
international and national regulations. 
Zealand Pharma A/S reserves the right to defer the release of data until specified milestones are 
reached, for example when the clinical trial report is available. This includes the right not to release 
the results of interim analyses because the release of such information may influence the results 
of the entire trial. 
At the end of the trial, one or more scientific publications (including abstracts, posters and 
presentations) may be prepared collaboratively by the investigator(s) and Zealand Pharma A/S. 
Zealand Pharma A/S reserves the right to postpone publication and/or communication for up to 
60 days to protect intellectual property. In all cases, the trial results will be reported in an objective, 
accurate and balanced manner. In the event of any disagreement on the content of any 
publication, the opinions of both the investigators and Zealand Pharma A/S will be fairly and 
sufficiently represented in the publication. 
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors. 
12.5 Retention of trial records 
The investigator must retain records and documents pertaining to the conduct of the trial and the 
distribution of the investigational product (e.g. informed consent forms, laboratory slips, 
medication inventory records and other pertinent information) according to local requirements. 

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To meet regulatory requirements, the eCRF data will be electronically stored at centers. The 
CDISC ODM (see http://www.cdisc.org/ for details) will be used to store and archive all electronic 
data at the centers. Since CDISC ODM is also the source for the EDC web-based system, no 
transcription of data is necessary. CDISC ODM is a platform-independent standardized data 
format including the complete trial metadata and audit trail. The data can be reviewed at a later 
stage using off-the-shelf tools. CDISC provides a complete CDISC ODM Viewer for these 
purposes. If needed, PDF files can be created from the ODM file. 
After trial completion at sites in the US, the investigator will retain and preserve 1 copy of all data 
generated in the course of the trial, specifically including, but not limited to, those defined by GCP 
as essential until: 
 
At least 2 years after the last marketing authorization for the trial product has been approved 
or the sponsor has discontinued its research with the trial product, or 
 
At least 2 years have elapsed since the formal discontinuation of clinical development of the 
trial product 
However, these documents should be retained for a longer period if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator will notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor will have 30 days to respond to the investigator’s notice, 
and the sponsor will have a further opportunity to retain such materials at the sponsor’s expense. 
After trial completion at sites in Europe, the sponsor will receive a copy of their data in electronic 
format (e.g. CD) and retain them for at least 25 years. 
One copy will remain with the investigator. The investigator will arrange for the retention of the 
patient identification codes, patient files, and other source data until at least 5 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed since 
the formal discontinuation of the clinical development of the product. These documents need to 
be retained for a longer period of time if required by applicable regulatory authorities or by 
agreement with the sponsor. 
The investigator will keep copies of these trial records (and all trial-related documents, including 
source data) for the maximum period of time permitted by the hospital, institution, or private 
practice. 

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13. References  
1. 
American Diabetes Association. Standards of medical care in diabetes - 2016. Diabetes 
Care 2016; 39 (Suppl. 1):S1-S112. 
2. 
Dasiglucagon Investigator Brochure, Edition 4, 25 Oct 2017. Zealand Pharma A/S. 
3. 
Diderichsen PM. Population PK and population PKPD modeling and simulation of 
dasiglucagon in patients with type I diabetes mellitus. 2016 Zealand Pharma report 16-147. 
4. 
Diderichsen PM. Model-based simulation of paediatric dasiglucagon exposure and glucose 
response. Zealand Pharma report 17-094. 2017 
5. 
European Commission. Ethical considerations for clinical trials on medicinal products 
conducted with minors Revision 1. 18 Sep 2017. Available at: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/2017_09_18_ethical_consid_ct_with_minors.pdf 
6. 
Holst JJ, Albrechtsen NJW, Pedersen J, Knop FK. Glucagon and amino acids are linked in 
mutual feedback cycle: The liver-α-cell axis. Diabetes 2017; 66(2): 235-40. 
7. 
Novo Nordisk. Summary of Product Characteristics. GlucaGen® HypoKit 1 mg powder and 
solvent for solution for injection. Available at: 
http://www.medicines.org.uk/emc/medicine/4258/SPC/GlucaGen®+Hypokit+1+mg. 
8. 
Rickels MR, Ruedy KJ, Foster NC, Piché CA, Dulude H, Sherr JL, et al. Intranasal 
Glucagon for treatment of insulin-induced hypoglycemia in adults with type 1 dabetes: A 
randomized crossover noninferiority study. Diabetes Care. 2016 Feb;39(2):264-70.  
9. 
Seaquist ER, Anderson J., Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: A report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care 2013; 36(5):1384-95. 
10. 
Sherr JL, Ruedy KJ, Foster NC, Piché CA, Dulude H, Rickels MR, et al. Glucagon nasal 
powder: A promising alternative to intramuscular glucagon in youth with type 1 Diabetes. 
Diabetes Care. 2016 Apr; 39(4):555-62.  
11. 
United States. Food and Drug Administration. General clinical pharmacology 
considerations for pediatric studies for drugs and biological products. Guidance for 
industry. Draft guidance. 2014. Available at:  
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/
ucm425885.pdf. 
 
 

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APPENDIX 1: 
List of names and addresses 
Sponsor 
Zealand Pharma A/S 
Smedeland 36 
2600 Glostrup, Copenhagen 
Denmark 
 
Contract Research 
Organization (CRO) 
Synteract Deutschland GmbH 
Albrechtstr. 14 
80636 Munich, Germany 
 
Coordinating investigator 
Prof. Dr. med. Thomas Danne 
Allgemeine Kinderheilkunde 
Diabetologie, Endokrinologie, Klinische Forschung Diabeteszentrum 
für Kinder und Jugendliche AUF DER BULT 
Kinder- und Jugendkrankenhaus 
Janusz-Korczak-Allee 12 
30173 Hannover, Germany 
  
Trial monitor 
To be decided  
Synteract Deutschland GmbH 
Albrechtstr. 14 
80636 Munich, Germany 
 
Statistician 
 
Senior Director Biometrics EMEA 
Synteract Deutschland GmbH 
Albrechtstr. 14 
80636 Munich, Germany 
 
 
Sponsor representative 
 
Clinical Project Director  
Zealand Pharma A/S 
Smedeland 36, 2600 Glostrup, Denmark 
Tel: 
 
 
E-mail: 
 
Sponsor’s medical expert 
Dr. 
 
Medical Director  
Zealand Pharma A/S 
Smedeland 36, 2600 Glostrup, Denmark 
Tel: 
 
E-mail: 
  
 
Sponsor representative for 
pharmacovigilance 
 
PharmaLex A/S Agern Allé 24, 2970 Hørsholm, Denmark 
Tel: 
 (8 a.m. to 4 p.m.) 
 
 (outside 8 a.m. to 4 p.m.)   
Fax:  
 
E-mail: drugsafety@lindeq.com 
 
 
Clinical laboratory 
MLM Medical Labs GmbH  
Dohrweg 63 

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41066 Mönchengladbach 
Germany  
Phone +49 2161 4642 0 
Fax +49 2161 4642 190 
E-mail info@mlm-labs.com 
 
Analytical laboratory 
(ZP4207 PK, ZP4207 ADA, 
Glucagon ADA) 
 
 
 
 
 
 
 
 
(ZP4207 and Glucagon Nab) 
York Bioanalytical Solutions (YBS) 
 (ZP4207 Bioanalysis)  
 (ADA analyses) 
Cedar House  
Northminster Business Park  
Northfield Lane  
York, YO26 6QR 
United Kingdom 
E-mail: 
 
E-mail: 
 
 
 
BioAgilytix Labs 
2300 Englert Drive 
Durham, NC 27713 
USA 
E-mail: 
 
 
Abbreviations: ADA=Anti-drug antibody; Nab=Neutralizing antibody; PK=Pharmacokinetics 
 

 
 
 
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Clinical Trial Protocol 
A phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial to 
assess the efficacy, safety, and pharmacokinetics of dasiglucagon relative to placebo 
and GlucaGen® when administered as a rescue therapy for severe hypoglycemia in 
children with T1DM treated with insulin  
Sponsor code: ZP4207-17086 
Synteract: ZEA-DNK-02170 
EudraCT number: 2018-000892-33 
 
 
Coordinating investigator:  
Prof. Dr. med. Thomas Danne 
Allgemeine Kinderheilkunde 
Diabetologie, Endokrinologie, Klinische Forschung 
Diabeteszentrum für Kinder und Jugendliche AUF DER BULT 
Kinder- und Jugendkrankenhaus 
Janusz-Korczak-Allee 12 
30173 Hannover 
Germany 
 
 
Sponsor:  
Zealand Pharma A/S 
Smedeland 36 
2600 Glostrup, Copenhagen 
Denmark 
 
 
 
Version: final version 3.0 
Date: 08 January 2019 
 
 
 
 
 
GCP statement 
This trial will be performed in compliance with Good Clinical Practice,  
the Declaration of Helsinki (with amendments) and local legal and regulatory requirements.

 
 
 
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2. Trial synopsis 
Title of the trial: 
A phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial to assess the 
efficacy, safety, and pharmacokinetics of dasiglucagon relative to placebo and GlucaGen® when 
administered as a rescue therapy for severe hypoglycemia in children with T1DM treated with insulin  
EudraCT number: 
2018-000892-33 
Protocol codes: 
Sponsor: ZP4207-17086 
Synteract: ZEA-DNK-02170 
Sponsor or sponsor's representative in the European Union: 
Zealand Pharma A/S, Smedeland 36, 2600 Glostrup (Copenhagen), Denmark 
Coordinating investigator: 
Prof. Dr. med. Thomas Danne, Kinder- und Jugendkrankenhaus AUF DER BULT, Janusz-Korczak-
Allee 12, 30173 Hannover, Germany 
Trial center(s): 
2-3 centers in the EU (Germany, Slovenia) and 1-2 centers in the USA 
Planned trial period: 
First Patient First Visit: September 2018 
Last Patient Last Visit: Second quarter 2019 
Phase of development:  
Phase 3 
Objectives: 
The primary objective is to demonstrate that dasiglucagon is superior to placebo following a single 
injection of 0.6 mg of dasiglucagon in treating hypoglycemia in children with type 1 diabetes mellitus 
(T1DM). 
Secondary objectives are: 
• To confirm that a single dose of dasiglucagon [0.6 mg] is comparable to a single dose of GlucaGen® 
[1 mg/mL] in treating hypoglycemia in children with T1DM, (in accordance with the label, children 
below 25 kg body weight will be administered 0.5 mg GlucaGen®), 
• To assess safety profile of dasiglucagon in children with T1DM, 
• To assess pharmacokinetic (PK) profile of dasiglucagon in children with T1DM. 
Trial design: 
This is a phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial 
designed to assess efficacy, safety and PK of dasiglucagon vs. placebo and vs. GlucaGen® in 
children with diabetes mellitus type 1 (T1DM). Patients will receive a single subcutaneous injection of 
the investigational product during a hypoglycemic clamp procedure. Handling, preparation and 
administration of trial product will be done by unblinded trial personnel. All trial assessments will be 
done by blinded trial personnel. 
The trial design is illustrated in the figure below. 

 
 
 
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Abbreviation: PK=pharmacokinetic 
Planned number of patients: 
At least 40 children ≥6 years and <18 years of age with T1DM will be randomized into the trial (2:1:1 
dasiglucagon/placebo/GlucaGen®) and stratified by age intervals: 6 years to <12 years, and 12 years 
to <18 years and by injection site (abdomen/thigh). A minimum of 16 patients will be enrolled into 
each age group, including a minimum of 8 patients in either of age groups on dasiglucagon treatment 
arm. 
Patients who are dosed will not be replaced. 
Medical condition or disease under investigation: 
This is the first dedicated efficacy and safety trial in children; thus, the target population for this trial is 
children with T1DM ≥6 to <18 years of age. Dasiglucagon is in development for treatment of severe 
hypoglycemia. 
Inclusion criteria: 
To be included in the trial, patients have to fulfill all of the following criteria: 
1. Following receipt of verbal and written information about the trial, patient, parent(s) or guardian(s) 
of the patient must provide signed informed consent before any trial-related activity is carried out* 
2. Female or male patients with T1DM for at least 1 year, diagnostic criteria as defined by the 
American Diabetes Association, and receiving daily insulin and in good and stable medical 
condition 
3. At least 6.0 years of age (inclusive) and less than 18.0 years 
Germany only: A “staggered approach” will be applied, whereby a positive safety assessment 
needs to be available for at least 10 patients who have completed the dosing visit in the overall 
trial before younger patients (6 to 11 years of age) may be enrolled. 
4. Body weight ≥20 kg 
5. Female patients must meet one of the following criteria: 

 
 
 
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a.  Participant is of childbearing potential and agrees to use one of the accepted contraceptive 
regimens throughout the entire duration of the trial from screening until last follow-up visit. An 
acceptable method of contraception includes at least one of the following: 
i. Abstinence from heterosexual intercourse 
ii. Systemic contraceptives (birth control pills, injectable/implant/ insertable hormonal birth 
control products, transdermal patch); if the participant is using systemic contraceptives, 
she must use an additional form of acceptable contraception (iii or iv, below) 
iii. Intrauterine device (with and without hormones) 
iv. Condom with spermicide  
or 
b. Participant is of non-childbearing potential due to pre-puberty status or a medical condition 
confirmed by the investigator  
6. Male patients must meet the following criteria: If sexually active, uses condom and partner 
practices contraception during the trial from screening and until last follow-up visit 
7. Willingness to adhere to the protocol requirements 
* Informed consent signatures must be obtained according to local regulations. 
 
Exclusion criteria: 
Patients meeting any of the following criteria during screening evaluations will be excluded from trial 
participation: 
1. Females who are pregnant according to a positive urine pregnancy test, actively attempting to get 
pregnant, or are lactating 
2. Known or suspected allergy to trial product(s) or related products 
3. History of anaphylaxis or symptoms of severe systemic allergy (such as angioedema) 
4. Previous randomization in this trial 
5. History of an episode of severe hypoglycemia that required a third party assistance within a 
month prior to screening visit 
6. History of hypoglycemic events associated with seizures or hypoglycemia unawareness in the last 
year prior to screening 
7. History of epilepsy or seizure disorder 
8. Receipt of any investigational drug within 3 months prior to screening 
9. Active malignancy within the last 5 years 
10. Congestive heart failure, New York Heart Association class II-IV 
11. Current bleeding disorder, including anti-coagulant treatment 
12. Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma (i.e. 
insulin secreting pancreas tumor) 
13. Use of a daily systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs in the 
previous 28 days before Day 1 of this trial 
14. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limit of the 
normal range (ULN), bilirubin >1.5 × ULN, estimated glomerular filtration rate <30 mL/min/1.73 m2 
according to the Modification of Diet in Renal Disease study definition, or altered electrolyte 
values of clinical relevance for cardiac conduction, as judged by the investigator 
15. Clinically significant abnormal electrocardiogram (ECG) at screening as judged by the investigator 
16. Clinically significant illness within 4 weeks before screening as judged by the investigator 
17. Surgery or trauma with significant blood loss within the last 2 months prior to screening 
18. Patients with mental incapacity or language barriers which preclude adequate understanding or 
cooperation, who are unwilling to participate in the trial, or who in the opinion of the investigator 
should not participate in the trial  
19. Any condition interfering with trial participation or evaluation or that could be hazardous to the 
patient 
20. The use of prescription or non-prescription medications known to cause QT prolongation 

 
 
 
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In addition, the following exclusion criteria at clinic admission on Visit 2, day 0 apply at the time of 
admission to the clinic, which is the day before clamp procedure: 
Patients who meet one or more of the following exclusion criteria at the time of admission to the clinic 
will be excluded from the dosing visit, however, the visit can be rescheduled 1-7 days later. The 
dosing visit can only be rescheduled once. 
1. Atypically strenuous exercise within 4 days prior to dosing, as judged by the investigator. Exercise 
during the trial should follow patient’s typical routine, and should not exceed a near maximum 
intensity for more than 20 minutes per day, or moderate intensity for more than 90 minutes per 
day 
2. Clinically significant illness within 4 weeks before dosing, as judged by the investigator 
3. Consumption of alcohol within 24 hours prior to dosing visit, determined by positive results from 
an alcohol breath test 
4. Not fasting from 22:00 hours the evening prior to dosing, apart from water. 
5. The use of any non-prescribed systemic or topical medication, except routine vitamins and 
occasional use (as judged by the investigator) of acetylsalicylic acid and paracetamol within 2 
weeks prior to dosing. Treatment with insulin, including analogs, is allowed 
6. Use of insulin degludec or insulin glargine U300 within 72 hours prior to dosing; or use of other 
long-acting insulins (e.g. insulin glargine U100 or insulin detemir) within 48 hours prior to dosing; 
or use of neutral protamine Hagedorn insulin NPH within 22 hours prior to dosing 
7. Use of any short acting (bolus) insulin within 12 hours prior to dosing, except insulin glulisine 
(Apidra®) 
8. Changes in medical history or concomitant medication resulting in fulfillment of clinical exclusion 
criteria, as judged by the investigatorPlasma glucose value <50 mg/dL (2.8 mmol/L) within the last 
24 hours or plasma glucose value <60 mg/dL (3.3 mmol/L) within the last 5 hours prior to 
admission to the clinic. 
Test product, dose and mode of administration: 
Dasiglucagon, liquid formulation, 1 mg/mL, 0.6 mL 
Reference product, dose and mode of administration: 
Placebo for dasiglucagon (hereafter referred to as placebo): Placebo, liquid formulation, 0.6 mL  
Active control: Recombinant glucagon hydrochloride, 1 mg lyophilized powder for reconstitution 
(GlucaGen®, Novo Nordisk) in 1 mL sterile water (hereafter referred to as GlucaGen®). In accordance 
with the label, children below 25 kg body weight will be administered 0.5 mg GlucaGen® 
Duration of treatment: 
Patients will receive a single subcutaneous dose of investigational product. Patients will be subjected 
to a hypoglycemic clamp procedure and have to be within a plasma glucose target range of 54-
80 mg/dL at dosing. The total individual trial duration will be a maximum of 63 days (up to 30 days 
screening, 1 dosing, 28 [+5] days of follow-up). 
Criteria for evaluation: 
Primary endpoint 
Time to plasma glucose recovery. Plasma glucose recovery is defined as first increase in plasma 
glucose of ≥20 mg/dL (1.1 mmol/L) from baseline during the hypoglycemic clamp procedure without 
administration of rescue intravenous (IV) glucose.  
Secondary endpoints 
Secondary efficacy endpoints: 
• 
Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 minutes, and within 10 
minutes after trial product injection without administration of IV glucose 

 
 
 
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• 
Plasma glucose changes from baseline within 30 minutes, within 20 minutes, within 15 minutes, 
and within 10 minutes after trial product injection or at the time of rescue IV glucose 
Safety endpoints: 
• 
Adverse events (AEs) 
• 
Clinical laboratory assessments (biochemistry, hematology, coagulation, urinalysis) 
• 
Vital signs 
• 
Physical examination 
• 
Clinically significant changes in the electrocardiogram 
• 
Local tolerability 
• 
Administration of IV glucose infusion during the hypoglycemic clamp procedure 
• 
Time to first IV glucose infusion, after trial product administration. (N.B. IV glucose infusion prior 
to trial product administration should not be included, as it is part of hypoglycemic clamp 
procedure) 
• 
Immunogenicity endpoint: occurrence of anti-drug antibodies 
Pharmacokinetic endpoints 
PK endpoints will be derived from plasma dasiglucagon and GlucaGen® profiles from 0 to 
300 minutes: 
• 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
30 minutes post-dose (AUC0-30min) 
• 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
300 minutes post-dose (AUC0-300min) 
• 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
infinitely post-dose (AUC0-inf) 
• 
Maximum of all valid plasma dasiglucagon or GlucaGen® concentration measurements from 0 to 
300 minutes post-dose (Cmax) 
• 
Time to maximum of plasma dasiglucagon or GlucaGen® concentration measurements (tmax) 
• 
Terminal elimination rate constant of plasma dasiglucagon or GlucaGen® (λz) 
• 
Terminal plasma elimination half-life of dasiglucagon or GlucaGen® (t½) 
• 
Total body clearance of plasma dasiglucagon or GlucaGen® (CL/f) 
• 
Volume of distribution of plasma dasiglucagon or GlucaGen® (Vz/f) 
• 
Mean residence time of plasma dasiglucagon or GlucaGen® (MRT) 
Pharmacodynamic endpoint 
• 
Plasma glucose response as area under the effect curve above baseline from time zero to 
30 minutes, AUE0-30min 
Statistical methods: 
All data obtained in this trial and documented in the electronic case report forms (eCRFs) will be listed 
and summarized with statistics or frequency tables as appropriate. In case of termination of the trial, all 
data collected up to that time will be included into the analysis. 
Continuous variables will be summarized with means, standard deviations, medians, minimums, and 
maximums and valid cases.  
Other summaries (e.g. quartiles, 95% confidence intervals) may be used as appropriate. Categorical 
efficacy and safety variables will be summarized by counts and by percentage of patients in 
corresponding categories. The primary endpoint, time to recovery, will be summarized using Kaplan-
Meier estimates for each treatment group in total and stratified by age intervals and injection site. The 
median time to recovery with 95% confidence interval will be estimated by treatment group. 

 
 
 
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Log-rank tests will be applied to compare the 2 treatment groups to the placebo group. 
In the primary analysis, recovery cannot be achieved in those patients where IV glucose treatment is 
administered. Those patients who receive IV glucose will be censored (i.e. set to ‘not recovered’) at 45 
minutes after dosing. 
All safety data will be analyzed with descriptive methods. 
AEs will be tabulated by system organ class (SOC) and preferred term (PT) after medical coding using 
the Medical Dictionary for Regulatory Activities. AE summary tables will include counts and percentages 
of patients who experienced AEs summarized by SOC and PT. 
Plasma dasiglucagon and glucagon concentrations will be described and PK metrics determined. 
AUE0-30min will be summarized with descriptive statistics. 
Sample size calculation: 
The primary comparison is between the dasiglucagon and placebo treatment arms. From phase 2 
results, the median time to an increase of 20 mg/dL of the 0.6 mg dose was approximately 10 
minutes. For placebo-treated patients, the median time to recovery is assumed to be more than 50 
minutes. Assuming an exponential time-to-recovery distribution with median times of 10 and 50 
minutes, a 2-sided log-rank test will be able to detect a difference between dasiglucagon 0.6 mg and 
placebo with 90% power with a follow-up time of 45 minutes at a 5% significance level with 20 
patients randomized to the dasiglucagon arm and 10 patients to placebo. GlucaGen® is included as a 
reference to compare the responses and AE profile to dasiglucagon with those to a marketed product. 
It is expected that 10 patients in the GlucaGen® group will suffice for the comparison. 

 
 
 
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Log-rank tests will be applied to compare the 2 treatment groups to the placebo group. 
In the primary analysis, recovery cannot be achieved in those patients where IV glucose treatment is 
administered. Those patients who receive IV glucose will be censored (i.e. set to ‘not recovered’) at 45 
minutes after dosing. 
All safety data will be analyzed with descriptive methods. 
AEs will be tabulated by system organ class (SOC) and preferred term (PT) after medical coding using 
the Medical Dictionary for Regulatory Activities. AE summary tables will include counts and percentages 
of patients who experienced AEs summarized by SOC and PT. 
Plasma dasiglucagon and glucagon concentrations will be described and PK metrics determined. 
AUE0-30min will be summarized with descriptive statistics. 
Sample size calculation: 
The primary comparison is between the dasiglucagon and placebo treatment arms. From phase 2 
results, the median time to an increase of 20 mg/dL of the 0.6 mg dose was approximately 10 
minutes. For placebo-treated patients, the median time to recovery is assumed to be more than 50 
minutes. Assuming an exponential time-to-recovery distribution with median times of 10 and 50 
minutes, a 2-sided log-rank test will be able to detect a difference between dasiglucagon 0.6 mg and 
placebo with 90% power with a follow-up time of 45 minutes at a 5% significance level with 20 
patients randomized to the dasiglucagon arm and 10 patients to placebo. GlucaGen® is included as a 
reference to compare the responses and AE profile to dasiglucagon with those to a marketed product. 
It is expected that 10 patients in the GlucaGen® group will suffice for the comparison. 

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Table 2-1: Schedule of Assessments 
Visit number 
V1 
V2 
V3 
Vx 
Trial day 
-3 
0 and 1 
28 
Unscheduled1 
Visit type 
Screening 
Dosing 
Follow-up 
Unscheduled1 
Window 
-30 to -3 
– 
+5 days 
Unscheduled1 
Patient related information/assessments 
 
 
 
 
Informed consent 
x 
– 
– 
– 
Inclusion/exclusion criteria 
x 
x2,3 
– 
– 
Demography 
x 
– 
– 
– 
Body measurements 
x 
– 
– 
– 
Diabetes diagnosis and current diabetes treatment 
x 
x 
x 
x 
Medical history including concomitant illnesses 
x 
– 
– 
– 
Concomitant medications 
x 
x2 
x 
– 
Randomization 
– 
x2 
– 
– 
Exclusion criteria at clinic admission on Visit 2, day 0 
– 
x2 
– 
– 
Insulin-induced hypoglycemia 
– 
x 
– 
– 
Safety assessments 
 
 
 
 
Physical examination 
x 
x 
x 
x 
Vital signs 
x 
x4 
x 
x 
12-lead ECG 
x 
x5 
x 
– 
Local tolerability  
– 
x6 
x 
– 
Adverse events 
x 
x 
x 
x 
Laboratory 
 
 
 
 
Biochemistry, hematology, coagulation, HbA1c (HbA1c at Visit 1 
only) 
x 
– 
x 
– 
Pregnancy test (women of childbearing potential only) 
x7 
x2,8 
x8 
– 
Urinalysis 
x 
x2 
x 
– 
Alcohol breath test 
– 
x2 
– 
– 
PK/Clinical efficacy 
 
 
 
 
Plasma dasiglucagon/GlucaGen® 
– 
x9 
– 
– 
Plasma glucose 
– 
x10 
– 
– 
Other assessments 
 
 
 
 

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Visit number 
V1 
V2 
V3 
Vx 
Trial day 
-3 
0 and 1 
28 
Unscheduled1 
Visit type 
Screening 
Dosing 
Follow-up 
Unscheduled1 
Window 
-30 to -3 
– 
+5 days 
Unscheduled1 
Antibodies against dasiglucagon/GlucaGen® 
x 
– 
x11 
x 
Trial material 
 
 
 
 
Administration of trial product (during hypoglycemic clamp 
procedure) 
– 
x 
– 
– 
End of trial status 
− 
− 
x 
– 
Abbreviations: ADA=Anti-drug antibody; ECG=Electrocardiogram, HbA1c=Hemoglobin A1c, PK=Pharmacokinetics 
1For ADA-positive patients only. 
2Prior to the start of the insulin-induced hypoglycemic procedure. 
3Only check exclusion criteria at clinic admission on Visit 2, day 0 and changes between screening visit and Visit 2. 
4Prior to the start of the insulin-induced hypoglycemic procedure (within 30 minutes), and at 30, 60 and 300 minutes after dosing. The actual time of the assessment should 
not deviate from the nominal time by more than ±10 minutes. 
5Prior to the start of the insulin-induced hypoglycemic procedure (within 30 minutes), and at 20, 35, 45, 60 and 300 minutes after dosing. The actual time of the assessment 
should not deviate from the nominal time by more than ±5 minutes.  
6Local tolerability assessed at 30, 120, and 300 minutes after dosing. The actual time of the assessment should not deviate from the nominal time by more than ±10 minutes.  
7Serum pregnancy test. 
8Urine stick pregnancy test. 
9Pre-dose, and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 minutes after dosing. The actual time of blood sampling should not deviate from the nominal time by more than 
±1 minute between t=5 minutes and t=90 minutes, ±5 minutes between t=150 minutes and t=300 minutes. 
Pre-dose is defined as within 2 minutes prior to dosing. 
10Pre-dose, and at 4, 6, 8, 10, 12, 15, 17, 20, 30 and 45 minutes (as well as 60 minutes if the patient´s body weight is ≥21 kg) after dosing. The actual time of blood sampling 
should not deviate from the nominal time by more than ±30 seconds until the 20-minute collection time point, and by more than ±1 minute for the subsequent collection time 
points. Pre-dose is defined as within 2 minutes prior to dosing. 
11Antibodies against dasiglucagon/GlucaGen® (any treatment-induced or treatment-boosted [titer increase above 5 fold] ADA-positive patients will be monitored until the ADA 
levels return to baseline levels). 
 
 

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3. Table of contents 
1. 
SIGNATURES AND AGREEMENT WITH PROTOCOL ..................................................... 2 
2. 
TRIAL SYNOPSIS ............................................................................................................... 4 
3. 
TABLE OF CONTENTS .................................................................................................... 12 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 15 
4.1 
Abbreviations ..................................................................................................................... 15 
4.2 
Definitions of terms ............................................................................................................ 16 
5. 
INTRODUCTION................................................................................................................ 17 
5.1 
Background of the trial ....................................................................................................... 17 
5.2 
Trial rationale ..................................................................................................................... 19 
5.3 
Assessment of anticipated benefits and risks .................................................................... 19 
6. 
TRIAL OBJECTIVES ......................................................................................................... 23 
7. 
INVESTIGATIONAL PLAN ............................................................................................... 25 
7.1 
Overall trial design and plan .............................................................................................. 25 
7.2 
Discussion of trial design and choice of control groups ..................................................... 26 
7.3 
Selection of trial population ................................................................................................ 26 
7.3.1 
Inclusion criteria ................................................................................................................. 26 
7.3.2 
Exclusion criteria ................................................................................................................ 27 
7.3.3 
Premature withdrawal from trial ......................................................................................... 28 
7.3.3.1 
Possible reasons for patient withdrawal ................................................................... 28 
7.3.3.2 
Center discontinuation .............................................................................................. 29 
7.3.3.3 
Trial termination ........................................................................................................ 29 
7.3.4 
Replacement of patients .................................................................................................... 29 
7.4 
Investigational medicinal product(s)................................................................................... 30 
7.4.1 
Identity of investigational medicinal product(s) .................................................................. 30 
7.4.2 
Treatments administered ................................................................................................... 30 
7.4.3 
Packaging and labelling ..................................................................................................... 30 
7.4.4 
Storage of trial product ....................................................................................................... 31 
7.4.5 
Investigational treatment and dosing conditions ................................................................ 31 
7.4.5.1 
Changes to diabetes management prior to dosing visit ........................................... 31 
7.4.5.2 
Dosing visit ............................................................................................................... 31 
7.4.5.2.1 
Diabetes management .........................................................................................................32 
7.4.5.2.2 
Hypoglycemic clamp procedure and dosing .........................................................................32 
7.4.5.2.3 
Rescue provisions for hypoglycemia ....................................................................................33 
7.4.6 
Selection of doses in the trial ............................................................................................. 34 
7.4.7 
Collection of blood samples ............................................................................................... 34 
7.4.8 
Treatment compliance ....................................................................................................... 35 
7.4.9 
Method of assigning patients to treatments ....................................................................... 35 
7.4.10 
Blinding and breaking the blind........................................................................................ 35 
7.4.11 
Drug accountability and disposal ..................................................................................... 36 
7.4.12 
Prior and concomitant therapy ......................................................................................... 36 
7.4.13 
Treatment after end of trial .............................................................................................. 36 
7.5 
Assessments and schedule of measurements .................................................................. 36 
7.5.1 
Screening visit .................................................................................................................... 37 
7.5.2 
Dosing visit ......................................................................................................................... 37 
7.5.3 
Follow-up visit .................................................................................................................... 38 
7.5.4 
Final examination at the end of the trial ............................................................................. 38 
7.5.5 
Additional (safety) examinations ........................................................................................ 39 
7.5.6 
Efficacy measurements ...................................................................................................... 39 
7.5.7 
Safety and tolerability measurements ................................................................................ 39 

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7.5.7.1 
Safety laboratory tests .............................................................................................. 39 
7.5.7.2 
Safety examinations ................................................................................................. 40 
8. 
ADVERSE EVENTS .......................................................................................................... 41 
8.1 
Definitions .......................................................................................................................... 41 
8.2 
Collection, recording and reporting of adverse events ...................................................... 43 
8.3 
Follow-up of adverse events .............................................................................................. 44 
8.4 
Hypoglycemia ..................................................................................................................... 45 
8.5 
Pregnancy .......................................................................................................................... 45 
8.6 
Precautions ........................................................................................................................ 45 
8.7 
Safety committee ............................................................................................................... 46 
9. 
DATA MANAGEMENT AND QUALITY CONTROL ......................................................... 47 
9.1 
Electronic case report forms .............................................................................................. 47 
9.2 
Quality control .................................................................................................................... 47 
9.3 
Data management ............................................................................................................. 47 
10. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ......................... 48 
10.1 
Statistical analysis plan ...................................................................................................... 48 
10.1.1 
General considerations .................................................................................................... 48 
10.1.2 
Classification of patients to subsets................................................................................. 48 
10.1.3 
Efficacy endpoints ............................................................................................................ 48 
10.1.3.1 
Hierarchical testing procedure .................................................................................. 48 
10.1.3.2 
Primary efficacy endpoint ......................................................................................... 49 
10.1.3.3 
Secondary efficacy endpoints .................................................................................. 49 
10.1.4 
Safety endpoints .............................................................................................................. 49 
10.1.5 
Pharmacokinetic endpoints .............................................................................................. 50 
10.1.6 
Pharmacodynamic endpoints .......................................................................................... 50 
10.1.7 
Further data ..................................................................................................................... 50 
10.1.8 
Withdrawals, drop-outs and missing data ........................................................................ 50 
10.1.9 
Baseline and center comparisons.................................................................................... 51 
10.1.10 
Subgroup analysis ........................................................................................................ 51 
10.1.11 
Interim analysis ............................................................................................................ 51 
10.2 
Determination of sample size ............................................................................................. 51 
11. 
ETHICS AND REGULATIONS .......................................................................................... 52 
11.1 
Independent ethics committees and competent authorities .............................................. 52 
11.2 
Ethical conduct of the trial .................................................................................................. 52 
11.3 
Patient information and consent ........................................................................................ 52 
11.4 
Legal and regulatory requirements .................................................................................... 52 
12. 
TRIAL ADMINISTRATION ................................................................................................ 53 
12.1 
Responsibilities .................................................................................................................. 53 
12.2 
Protocol deviations ............................................................................................................. 53 
12.3 
Protocol changes ............................................................................................................... 53 
12.4 
Reports and publications ................................................................................................... 54 
12.5 
Retention of trial records .................................................................................................... 54 
13. 
REFERENCES................................................................................................................... 56 
 
Appendices: 
(1) 
List of names and addresses 
 
 

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Index of in-text tables 
Table 2-1: Schedule of Assessments ................................................................................................ 10 
Table 7-1: Identity of Investigational Products................................................................................. 30 
 
Index of in-text figures 
Figure 7-1 Overview of the Trial Design ............................................................................................ 25 
 

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4. List of abbreviations and definition of terms 
4.1 
Abbreviations 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CA 
competent authority 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IV 
intravenous(ly) 
IWRS 
interactive web response system 
MRT 
mean residence time 
NPH 
neutral protamine Hagedorn 
ODM 
OpenDocument Master 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s)  
PPS 
per protocol set 
PR 
PR interval; i.e. the measure of the time between the start of the p wave and the 
end of the r wave in the heart’s electrical cycle 
PT 
preferred term 
QRS 
QRS interval; i.e. the measure of the time between the start of the q wave and the 
end of the s wave in the heart’s electrical cycle 
QT  
QT interval; i.e. the measure of the time between the start of the q wave and the 
end of the t wave in the heart’s electrical cycle 
SAE 
serious adverse event 
SAS 
safety analysis set 

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SC 
subcutaneous(ly) 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
T1DM 
type 1 diabetes mellitus 
ULN 
upper limit of normal 
 
 
Plasma concentrations of dasiglucagon/GlucaGen  
AUC0-30min 
Area under the plasma concentration versus time curve from 0 to 30 minutes post-
dose 
AUC0-300min 
Area under the plasma concentration versus time curve from 0 to 300 minutes post-
dose 
AUC0-inf 
Area under the plasma concentration versus time curve from 0 to infinitely post-
dose 
Cmax 
Maximum of all valid plasma concentration measurements from 0 to 300 minutes 
post-dose 
tmax 
Time to maximum of plasma concentration measurements 
λz 
Terminal elimination rate constant 
t½ 
Terminal plasma elimination half-life 
CL/f 
Total body clearance 
Vz/f 
Volume of distribution 
MRT 
Mean residence time 
 
 
Plasma glucose concentrations 
AUE0-30min 
Plasma glucose response as area under the effect curve above baseline from time 
0 to 30 minutes 
 
4.2 
Definitions of terms 
Definition of the end of the trial: The trial ends with the last visit of the last patient participating in 
the trial. 

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5. Introduction  
5.1 
Background of the trial 
Hypoglycemia  
Hypoglycemia in patients with diabetes is defined as episodes of an abnormally low plasma 
glucose concentration.9 This is a common, unpredictable, and potentially dangerous side effect 
of treatment of diabetes mellitus with especially insulin or sulfonylureas. It is more frequent in 
patients with profound endogenous insulin deficiency, such as occurs in type 1 diabetes mellitus 
(T1DM) and advanced type 2 diabetes mellitus. Treatment of type 2 diabetes mellitus with insulin 
causes hypoglycemia progressively and more frequently over time, whereas in T1DM, 
hypoglycemia is experienced throughout the course of established disease. 
Symptoms and signs of hypoglycemia are not specific. Patients undergoing a hypoglycemic 
episode experience unpleasant symptoms such as anxiety, sweating, hunger, tremors, 
palpitations, paresthesia, nausea and pallor. Depending on its severity, the hypoglycemia may 
lead to mild confusion, behavioral changes, loss of consciousness, seizures, coma, and death.1  
The incidence of hypoglycemic events or even the fear of hypoglycemia influences patients’ 
adherence to prescribed treatment regimens for diabetes mellitus. This leads to inadequate 
glycemic control, which in turn may lead to an increased risk of diabetic complications. 
Glucagon 
Glucagon is a naturally occurring hormone, secreted from the alpha cells of the pancreatic islets. 
Glucagon plays a central role in the regulation of glucose homeostasis and is the counterpart of 
insulin for controlling blood glucose levels (i.e. it acts in opposition to insulin in terms of effects on 
blood glucose levels). Glucagon stimulates hepatic glycogenolysis and gluconeogenesis in 
hypoglycemic states, thereby restoring glucose homeostasis. Glucagon receptor agonism has 
also been shown to exert effects on lipid metabolism, energy balance, body adipose tissue mass 
and food intake.  
Insulin decreases blood glucose levels and cases of hypoglycemia can be reversed by glucagon. 
Therefore, glucagon is indicated for the treatment of severe hypoglycemia.  
Dasiglucagon  
Dasiglucagon (ZP4207) is a stable peptide analog of human glucagon, available in a ready-to-
use liquid formulation and is in development for the treatment of severe hypoglycemia in insulin 
dependent patients with diabetes mellitus. Dasiglucagon is a specific and full glucagon receptor 
agonist designed to mimic the effects of glucagon, having a fast absorption and elimination 
(minutes). It is a peptide of 29 amino acids, with 7 amino acid substitutions compared to native 
glucagon. The main purpose of the substitutions is to increase the physical and chemical stability 
of the glucagon analog compared to marketed glucagon products such as Lilly´s Glucagon or 
GlucaGen®. Dasiglucagon exhibits improved physical and chemical stability and is available in an 
aqueous solution at neutral pH.2 
Five clinical trials have been completed with dasiglucagon: A first human dose trial (ZP4207-
14013), a multiple-dose dose-escalation trial (ZP4207-15007) to evaluate the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD) of dasiglucagon, a phase 2 crossover trial 
to assess the PK and PD of a single dose of an optimized formulation of dasiglucagon 
administered subcutaneously (SC) in patients with T1DM (ZP4207-15126), and a feasibility trial 
testing the bionic pancreas with dasiglucagon was completed (ZP4207-16051).2 Finally, a cross-
over trial (ZP4207-16098) assessing PK and PD responses after micro-doses of dasiglucagon 
administered SC to patients with type 1 diabetes mellitus under euglycemic and hypoglycemic 
conditions, compared to marketed glucagon, was completed. 

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Pharmacokinetics and pharmacodynamics of dasiglucagon  
The results of the phase 1 and 2 clinical trials confirm dose-proportionality for dasiglucagon PK, 
which is characterized by a fast absorption with a peak plasma concentration obtained after 35 
minutes. Thereafter, the plasma concentration rapidly declines with an average half-life of 28 
minutes. The median time to the maximum plasma concentration (Cmax) was later for 
dasiglucagon than for GlucaGen® (35 versus 20 minutes). For Cmax, the results indicated that 
0.3 mg dasiglucagon was comparable to 0.5 mg GlucaGen® (90% confidence interval: 0.8167; 
1.0068) and 0.6 mg dasiglucagon was comparable to 1.0 mg GlucaGen® (90% confidence 
intervaI: 0.8850; 1.1991).2 At these dose levels, the total exposures (AUC0-inf) were higher for 
dasiglucagon compared to GlucaGen®. 
At all dose levels in the phase 2 trial, all patients achieved a plasma glucose level of at least 
70 mg/dL as well as an increase in plasma glucose by at least 20 mg/dL within 30 minutes post-
dose. The maximal observed time to reach the 20 mg/dL plasma glucose increase ranged from 
15 to 27 minutes across doses and decreased as the dose increased. The PD responses of 
0.6 mg of dasiglucagon and 1.0 mg of GlucaGen® were comparable.2 
Safety of dasiglucagon  
The safety data for dasiglucagon did not give rise to any relevant safety concerns for dasiglucagon 
beyond those expected, related to the pharmacological effect of glucagon receptor agonism. All 
adverse events (AEs) recorded in the trials were of mild or moderate severity. The most frequently 
reported systemic AE was nausea, which is a known side effect following administration of 
glucagon. Headache was the next most frequently reported event, occurring in all dose groups in 
the phase 2 trial. Injection site reactions were observed only sporadically after administration with 
either dasiglucagon or GlucaGen® and all were mild and transient. The most frequent injection 
site reaction was erythema, occurring in all treatment groups, including the placebo group, 
irrespective of dose. Therefore, the phase 1 and 2 results and the safety profile described to date 
do not give rise to specific safety concerns. For further information, please refer to the Investigator 
Brochure.2  
Immunogenicity of dasiglucagon  
In adults, anti-drug antibodies (ADA) have been assessed in the completed clinical trials. In one 
of the 5 completed clinical trials (ZP4207-16098) 1 transient ADA incidence have been detected 
in one T1DM patient. The antibodies were able to bind to dasiglucagon and glucagon confirming 
the cross-reactivity potential found in the non-clinical toxicity studies (IND 135869 Section 
2.4.4.6). The antibodies were also capable of neutralizing the in vitro activity of both dasiglucagon 
and glucagon, but could not be associated with any AEs or effects on PK or PD in the patient. 
The trial was a multiple dose trial and completers had received a total of 11 investigational drug 
administrations (8 injections of dasiglucagon and 3 injections of recombinant glucagon) (IND 
135869 Section 2.5.6.3) and indicated that increased exposure will likely increase the risk of ADA 
formation. However, due to the crossover trial design, the induction of ADA cannot be decisively 
attributed to either dasiglucagon or glucagon treatment. The ADA incidence in that trial was 4.3% 
and considered low. From the long-term non-clinical toxicology studies, the detection of antibodies 
was not associated with a change in toxicity profile compared to ADA negative animals. In the 13- 
and 26-week rat studies, an increase in exposure was observed in dose groups ≥8 mg/kg/day, 
which correlates with the dose groups with the highest frequency of ADA-positive animals. So far, 
these findings have not been observed in humans. 
The consequences of an immune response towards endogenous glucagon is not fully known. In 
a recent review summarizing the current physiology of glucagon and learnings from recent 
glucagon antagonist research, it was concluded that although glucagon is an important hormone 
for controlling postprandial glucose levels, it was not essential for the maintenance of fasting 
glucose and glucagon antagonism did not cause hypoglycemia.5 Rather, the lack of glucagon 
signaling induced imbalance in amino acid metabolism leading to elevated amino acid plasma 

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levels. As excess levels of amino acids can be excreted by the kidneys and the detected ADA 
incidence have been transient, the impact is not considered a major risk for the trial population. 
The overall immunogenicity risk of dasiglucagon in a clinical context is therefore considered low 
and the potential effects of induced ADAs judged to be of limited clinical consequence.  
5.2 
Trial rationale 
The SC bolus dose of 0.6 mg dasiglucagon that is the most appropriate dosing to ensure rapid 
rescue from hypoglycemia in adults appears to be appropriate also in children 6 years old and 
above.  
To simulate the potential PK/PD response in children, a previously developed population PK/PD 
model for dasiglucagon was updated with an allometric PK component derived from published 
glucagon pediatric data from weight groups of 25.4±5.2, 43.2±8.9, and 61.2±13.8 kg (mean±SD) 
and adults. The simulations suggested that a 0.3 mg SC bolus dose of dasiglucagon would result 
in a slightly slower increase of blood glucose compared to the 0.6 mg dose in the 3 pediatric body 
weight groups. Considering the intended clinical indication of treating patients for severe 
hypoglycemia where time to PD response is considered essential, the 0.3 mg dose appears less 
attractive than the 0.6 mg dose. 
The higher total drug exposure (AUC and Cmax) predicted in children at lower body weight, relative 
to that observed in adults at a dose of 0.6 mg, is within the tolerable exposure achieved in adults 
administered 2.0 mg dasiglucagon, and the duration of exposure is truncated due to a shorter t½ 
in children. In addition, rapid saturation of the PD response results in similar total and maximum 
glucose response (AUE and CEmax) throughout the body weight range from 25 to 77 kg.  
Based on all data generated to date across 4 clinical trials performed in adults receiving 
dasiglucagon at different dose levels, no clear dose-response for nausea and vomiting was 
observed above a certain threshold. It is therefore not expected that the intensity and frequency 
of nausea and vomiting at a dose of 0.6 mg will differ between adults and children/adolescents. 
This expectation is further consistent with results of the recently conducted trial ZP4207-16098 in 
adults with T1DM, which indicated a similar degree of nausea and vomiting at SC bolus doses of 
0.2 and 0.6 mg dasiglucagon.   
5.3 
Assessment of anticipated benefits and risks 
Glucagon emergency kits are often underutilized in the treatment of patients experiencing severe 
hypoglycemia. Considering the seriousness and potential complications that can arise from 
severe hypoglycemic episodes, it is essential that parents and caregivers receive adequate, 
hands on training for use of glucagon rescue kits to ensure safe, timely, and effective 
administration. Given the challenges with parent/caregiver training and use of current glucagon 
products, Zealand Pharma A/S is developing dasiglucagon as a ready to use rescue treatment 
for severe hypoglycemia. The development of dasiglucagon will provide parents and caregivers 
of children with diabetes mellitus a more efficient alternative for the treatment of severe 
hypoglycemia. The ready-to-use kit addresses an unmet need and may potentially prove to be 
life-saving. The trial may also provide a direct benefit to patients and their parent(s)/caregiver by 
allowing patients to experience signs and symptoms of hypoglycemia in a highly specialized 
treatment center where they will be under continuous supervision and medical monitoring. This 
will help the patient and their parent(s)/caregiver recognize the signs and symptoms of 
hypoglycemia and start treatment before the event becomes more serious. 
As glucagon and its analogs belong to a well-known drug class with a known mode of action, 
dasiglucagon is not expected to be a high-risk molecule. 
Treatment with an investigational medicinal product may result in undesired effects or complaints. 
Undesired effects and complaints such as nausea and vomiting are known AEs occurring with 
glucagon administration. Similar AEs have also been observed to a limited degree in the 5 clinical 

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studies conducted with dasiglucagon. As with every novel drug substance, new and yet unknown 
side effects also may occur.  
There are limited data available to assess the immunogenic potential of glucagon products 
available on the market, but the data available indicate that marketed glucagon only has a small 
immunogenic potential. Based on the 5 clinical studies completed with dasiglucagon to date (see 
Section 5.2), no anti-dasiglucagon or anti-glucagon antibodies have been detected, except for 
trial ZP4207-16098, in which there was one transient low titer ADA incidence showing reactivity 
towards both dasiglucagon and glucagon. The patient was tested positive for both anti-
dasiglucagon and anti-glucagon antibodies at the follow-up visit, 24 days after the last drug 
exposure (titer: 35.4 and 33.8, respectively). The patient was also found to be positive for 
dasiglucagon and glucagon in vitro neutralizing activities. The titer of anti-dasiglucagon activity 
was equal to the assay minimum required dilution. Due to the crossover nature of this trial, the 
induction of ADAs could not be associated with a specific treatment. Testing performed 3.5 
months after last dosing confirmed a positive finding for anti-dasiglucagon antibodies (titer of 
38.8), while the test was negative for anti-glucagon antibodies. At a final follow-up visit performed 
7 months after last dosing, the patient was negative for anti-dasiglucagon antibodies. There was 
no evidence for altered PK, PD, or safety profile for this patient. 
Administration of dasiglucagon may be associated with a risk of allergic reactions similar to those 
observed for other therapeutic peptides or proteins. Patients with known or suspected allergies to 
the trial products or related products will be excluded from the trial. Mild or moderate allergic 
reactions may include symptoms of rash, fever, flu-like symptoms, nausea, headache, and 
myalgia. Acute generalized hypersensitivity reactions are usually very rare but may include 
symptoms of flushing, sweating, dizziness, change in blood pressure and difficulties in breathing. 
No severe acute hypersensitivity reactions have been observed in the 4 clinical trials conducted 
with dasiglucagon. Direct access to resuscitation equipment is ensured at the clinical trial centers. 
The results of the trial may contribute to the future use of dasiglucagon in patients with diabetes 
mellitus experiencing severe hypoglycemic reactions. 
Overall, the benefit to risk ratio for patients entering the ZP4207-17086 trial is considered 
acceptable. The trial design subjects the patients concerned to as little burden and other 
foreseeable risks as possible. 
Germany only: With the exception of medical examinations, a patient participating in this trial is 
not likely to derive any personal health-related benefits. The results of the trial may contribute to 
the future use of dasiglucagon in patients with diabetes mellitus experiencing severe 
hypoglycemic reactions. The perceived risks and burden of the trial will be discussed with the 
patients and their parent(s)/guardian(s) prior to the trial, and it is therefore expected that a given 
patient will not be enrolled if there are concerns about the risks or burden of the trial. A patient 
can be withdrawn if the burden of trial procedures is considered unacceptable by the patient, their 
parent(s)/guardian(s) or the investigator; see Section 7.3.3.1. Therefore, the investigator will need 
to monitor the burden of the trial activities for each patient. 
To minimize the burden for the pediatric participants, the trial will be conducted in highly 
specialized centers for clinical research studies in patients with T1DM having specific experience 
and expertise in the conduct of pediatric trials. In Germany, this trial will be conducted at the 
Diabetes Center for Children and Adolescents, Children's Hospital AUF DER BULT, Hannover 
under supervision of Professor Thomas Danne. All trial nurses, trial coordinators and sub-
investigators are specially trained in conducting pediatric trials and in the management of diabetes 
in children. All patients that will be included in the trial are familiar with the site and staff. Following 
diagnosis of T1DM, they have all attended information meetings about their illness and training 
sessions about controlling their diabetes, measuring blood glucose levels, injecting insulin and 
treating hypoglycemia (based on a monitored provocation) at the trial site. This trial gives another 
opportunity to the patients and their parents to learn about hypoglycemia signs and symptoms in 
a well-controlled environment and to learn how to treat hypoglycemia in a real-life emergency 
situation. 

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Facilities at the site allow for overnight stays with 2 patients (and their parents) in a room. The 
patients will be allocated to rooms based on age and their relationships with other patients. Age-
appropriate entertainment will be provided for all patients. The participating patients will be 
investigated with two being present in the same room as this has proven to distract the participants 
from the burden of the trial and allows for interaction with peers, which makes the experience 
much more pleasurable. As only otherwise healthy participants are eligible for inclusion in the 
trial, the risk of transmitting an infection from one participant to another is negligible. The 
participating patients will be separated from other in-patients at the hospital to ensure a minimum 
degree of risk to the trial patients from potential infections as well as any bias this may cause in 
the outcome of the trial. 
The interaction between the trial staff and the other patients during the overnight stay helps 
reduce the stress/anxiety felt by the patients prior to the procedure. Parents and patients also 
have the opportunity to discuss day-to-day issues with other participants or staff. In addition, the 
staff can control the patients’ blood glucose values during the night and ensure the patients are 
ready to participate in the trial. Following the procedures, the patients will remain under 
observation in their rooms for 5 hours. Age-appropriate entertainment will be provided for all 
patients during this period of observation, which is similar to that occurring after an event of 
hypoglycemia.  
Currently, there is no plan to include any additional sites in Germany. Should any other sites be 
included, the sponsor will ensure that the same standards and qualifications are applied to these 
sites as well. 
The Kinder- und Jugendkrankenhaus AUF DER BULT is an institution which is dedicated to the 
care of sick and handicapped children, and was founded for this purpose more than 150 years 
ago. The mission statement of the institution expressively states the importance of research for 
pediatric care with focus on creating an acceptable environment for children and their families. 
For example, the patient’s age and personal preference is considered when appointments are 
made, as patients often know each other from the outpatient ward or diabetes camps and choose 
to do studies at the same time as others. Age-appropriate entertainment and leisure activities are 
available to reduce the stress of being treated as an in-patient and lying in a bed. The trial 
personnel are experienced in pediatric medical procedures. For example, all patients are offered 
a local anesthetic (EMLA®) to reduce the potential pain of venous punctures.  
The patients will be examined prior to the trial visit to ensure that patients with health issues are 
identified in time and no health issues are overlooked, which could be aggravated through 
participation in the trial procedures.  
The trial protocol has been adapted to be appropriate for children between 6 and 17 years of age. 
The trial patients will be exposed to minimal invasive procedures, which include insertion of two 
pediatric catheters for a clamp procedure and blood draw. To ensure a minimum of burden to the 
children, the number of catheters has been reduced compared with the adult trials. The site offers 
use of topical anesthetic as part of their standard of care when placing catheters. The use of 
catheters allows injection of insulin/glucose to quickly control blood glucose levels and blood 
samples can be drawn without the need for finger pricks or other sampling methods. 
The number and volume of blood samples do not exceed what is required for a successful trial 
and do not exceed the limits permitted by Health Authorities. In accordance with guidance and 
directive of the European Medicines Agency (EMA), blood sampling should not exceed 1% of the 
total blood volume at each visit (i.e. approximately 18 mL for a patient with a body weight of 
20 kg), and should not exceed 3% of the total blood volume during a period of four weeks (i.e. 
approximately 54 mL for a 20 kg patient).  
Insulin induced-hypoglycemia is commonly used to assess the safety and efficacy of glucagon or 
similar products in this class. Compared with the trials conducted with dasiglucagon in adults, the 
children in the ZP4207-17086 trial will have a higher target plasma glucose concentration prior to 
treatment with dasiglucagon and a lower rate of insulin infusion. Both of these measures increase 

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the level of control and reduce the risk for plasma glucose concentrations below the expected 
range (54-80 mg/dL; 3.0-4.4 mmol/L) prior to treatment. 
Patients will be in a controlled setting with access to immediate intervention, should this be 
required. If any child reacts differently than expected, rescue provisions based on the type of 
reaction and the timing relative to the clamp procedure are available (see Section 7.4.5.2.3). 
With the close monitoring of patients at the clinical site, the considerable experience with the 
insulin induction technique at the clinical site and the pre-defined thresholds for administering IV 
glucose described in the protocol, the risk of the insulin induction technique to patients is 
considered to be minimal and well controlled. 
The burden associated with nausea and vomiting is considered minimal (slight and temporary 
impairment of the health of the patient) and any discomfort is temporary. The trial was designed 
based on a large amount of data generated in adults, thereby limiting the number of pediatric 
patients needed to be dosed to provide adequate and conclusive data on the safety and efficacy 
of dasiglucagon in this age group. It is not possible to treat the patients prophylactically with anti-
emetics, as this will bias the tolerability profiles of the treatments. However, treatment of any 
adverse events will be provided when it is needed. In order to reduce the effects of nausea, the 
children will be given a small meal 1 hour after the clamp procedure is completed. 
The potential risks associated with allergic reactions are similar to those for other therapeutic 
peptides or proteins. Patients with known or suspected allergies to the trial products or related 
products will be excluded from the trial. No severe acute hypersensitivity reactions have been 
observed in the clinical trials conducted to date with dasiglucagon and the risk of such an event 
is assessed as low. However, direct access to resuscitation equipment is ensured at the clinical 
trial sites. 
ADAs have been assessed in all completed clinical trials in adults (n=448). Only one transient 
ADA incidence has been detected in one patient with T1DM in one of the completed clinical trials 
(ZP4207-16098). The trial was a multiple-dose trial and completers had received a total of 11 
investigational drug doses (8 injections of dasiglucagon and 3 injections of recombinant 
glucagon). The antibodies were able to bind to dasiglucagon and glucagon and were also capable 
of neutralizing the in vitro activity of both dasiglucagon and glucagon, but were not associated 
with any AEs or effects on PK or PD in the patient. Due to the cross-over trial design, the induction 
of ADA could not be decisively attributed to either dasiglucagon or glucagon treatment. Since the 
potential of dasiglucagon to induce ADAs at clinically relevant doses is considered to be low, the 
sponsor considers the risk of developing ADA in this trial as minimal. To ensure minimal burden 
on the trial population ADA assessment will only be performed at the screening and the end of 
trial visit. 
In balancing the risk and benefit of the trial, it has to be taken into consideration that this age 
group is at highest risk of severe hypoglycemia due to unplanned physical activities and the eating 
behaviors frequently encountered in pediatric patients.  

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6.   Trial objectives  
Primary objective 
 
To demonstrate that dasiglucagon is superior to placebo following a single injection of 0.6 mg 
of dasiglucagon in treating hypoglycemia in children with T1DM 
Secondary objectives 
 
To confirm that a single dose of dasiglucagon [0.6 mg] is comparable to a single dose of 
GlucaGen® [1 mg/mL] in treating hypoglycemia in children with T1DM (in accordance with the 
label, children below 25 kg body weight will be administered 0.5 mg GlucaGen®) 
 
To assess safety profile of dasiglucagon in children with T1DM 
 
To assess PK profile of dasiglucagon in children with T1DM  
Primary endpoint 
 
Time to plasma glucose recovery. Plasma glucose recovery is defined as first increase in 
plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline during the hypoglycemic clamp 
procedure without administration of rescue intravenous (IV) glucose 
Secondary endpoints 
Secondary efficacy endpoints 
 
 
Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 minutes, and 
within 10 minutes after study drug injection without administration of rescue IV glucose. 
 
Plasma glucose changes from baseline within 30 minutes, within 20 minutes, within 
15 minutes, and within 10 minutes after study drug injection or at the time of rescue IV 
glucose. 
Safety endpoints 
 
AEs 
 
Clinical laboratory assessments (biochemistry, hematology, coagulation, urinalysis) 
 
Vital signs 
 
Physical examination 
 
Clinically significant changes in the electrocardiogram 
 
Local tolerability 
 
Administration of rescue IV glucose infusion after trial product injection 
 
Time to first IV glucose infusion, after trial product administration (N.B. IV glucose infusion 
prior to trial product administration should not be included, as it is part of hypoglycemic clamp 
procedure) 
 
Immunogenicity endpoint: occurrence of ADAs 
Pharmacokinetic endpoints 
PK endpoints will be derived from plasma dasiglucagon and GlucaGen® profiles from 0 to 
300 minutes: 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
30 minutes post-dose (AUC0-30min) 

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 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
300 minutes post-dose (AUC0-300min) 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 
to infinitely post-dose (AUC0-inf) 
 
Maximum of all valid plasma dasiglucagon or GlucaGen® concentration measurements from 
0 to 300 minutes post-dose (Cmax) 
 
Time to maximum of plasma dasiglucagon or GlucaGen® concentration measurements (tmax) 
 
Terminal elimination rate constant of plasma dasiglucagon or GlucaGen® (λz) 
 
Terminal plasma elimination half-life of dasiglucagon or GlucaGen® (t½) 
 
Total body clearance of plasma dasiglucagon or GlucaGen® (CL/f) 
 
Volume of distribution of plasma dasiglucagon or GlucaGen® (Vz/f) 
 
Mean residence time of plasma dasiglucagon or GlucaGen® (MRT) 
Pharmacodynamics endpoint 
 
Plasma glucose response as area under the effect curve above baseline from time zero to 30 
minutes, AUE0-30min 

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7. Investigational plan 
7.1 
Overall trial design and plan 
This is a phase 3, randomized, double-blind, placebo- and active-controlled, parallel-arm trial 
designed to assess efficacy, safety and PK of dasiglucagon vs. placebo and vs. GlucaGen® in 
children with T1DM. It is currently anticipated that it will be conducted at 2-3 centers in Europe 
and 1-2 centers in the USA. 
The trial will include the following periods (as illustrated in Figure 7-1, below). 
 
A screening period from Day -30 to Day -3 
 
A treatment period, from Day 0 to Day 1 (day of randomization and single dosing with trial 
product). Unblinded trial personnel will do the handling, preparation and administration of trial 
product. All trial assessments will be done by blinded trial personnel 
 
A follow-up visits at Day 28 (the end-of-trial visit) 
 
Figure 7-1 Overview of the Trial Design 
 
Abbreviation: PK=pharmacokinetic 
The schedule of assessments (Table 2-1) gives an overview of the trial procedures. Patients 
should attend all visits on the designated day or as close to it as possible.  
 

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7.2 
Discussion of trial design and choice of control groups 
The trial will be randomized and double-blind to increase trial validity and to reduce bias during 
evaluation of assessments with the treatments. Since the 3 trial products are not identical in 
appearance, (dasiglucagon and placebo are liquid formulations and GlucaGen® is available as a 
powder for reconstitution), unblinded trial personnel, who will not be involved in other trial 
procedures and assessments, will do the handling, preparation and administration of trial product. 
Blinded trial personnel will do all trial assessments performed at the trial center.    
Children with T1DM will be randomized 2:1:1 in order to evaluate the efficacy and safety of 
dasiglucagon compared to placebo and GlucaGen® and PK/PD parameters. The randomized, 
double-blind, parallel arm design with administration of a single dose of randomized trial product 
(dasiglucagon, placebo or GlucaGen®) will allow a relative comparison between the 3 treatment 
arms. 
Dasiglucagon will be administered at fixed doses independent of body weight because this is the 
intended therapeutic dosing regimen in the emergency treatment of hypoglycemia. The selected 
dose of 1 mg GlucaGen® is the recommended dose for treatment of severe hypoglycemia (in 
accordance with the label, children below 25 kg body weight will be administered 0.5 mg 
GlucaGen®). Based on pre-clinical and clinical studies in adult patients, it has been demonstrated 
that 0.6 mg of dasiglucagon results in an initial PD response (i.e. acute glucose mobilization) 
comparable to 1 mg GlucaGen® (see also Section 5.1).  
7.3 
Selection of trial population 
Dasiglucagon is indicated for treatment of severe hypoglycemia in patients with T1DM. As this 
condition also affects children and there is a therapeutic need for them to get access to safe and 
efficacious emergency treatment, the present trial aims to evaluate the efficacy and safety of a 
single dose of SC dasiglucagon compared to placebo and GlucaGen® in children with T1DM in 
experimentally induced hypoglycemia in a hypoglycemic clamp procedure.  
The trial will enroll patients in centers in the EU and in the USA.  
7.3.1 Inclusion criteria 
To be included in the trial, patients have to fulfill all of the following criteria: 
1. 
Following receipt of verbal and written information about the trial, patient, parent(s) or 
guardian(s) of the patient must provide signed informed consent before any trial-related 
activity is carried out* 
2. 
Female or male patients with T1DM for at least 1 year, diagnostic criteria as defined by the 
American Diabetes Association, and receiving daily insulin and in good and stable medical 
condition 
3. 
At least 6.0 years of age (inclusive) and less than 18.0 years 
Germany only: A “staggered approach” will be applied, whereby a positive safety 
assessment needs to be available for at least 10 patients who have completed the dosing 
visit in the overall trial before younger patients (6 to 11 years of age) may be enrolled. 
4. 
Body weight ≥20 kg 
5. 
Female patients must meet one of the following criteria: 
a. 
Participant is of childbearing potential and agrees to use one of the accepted 
contraceptive regimens throughout the entire duration of the trial from screening until 
last follow-up visit. An acceptable method of contraception includes at least one of 
the following: 
i. 
Abstinence from heterosexual intercourse 
ii. 
Systemic contraceptives (birth control pills, injectable/implant/ insertable 
hormonal birth control products, transdermal patch); if the participant is using 

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systemic contraceptives, she must use an additional form of acceptable 
contraception (iii or iv, below) 
iii. 
Intrauterine device (with and without hormones) 
iv. 
Condom with spermicide  
or 
b. Participant is of non-childbearing potential due to pre-puberty status or a medical 
condition confirmed by the investigator  
6. 
Male patients must meet the following criteria: If sexually active, uses condom and partner 
practices contraception during the trial from screening and until last follow-up visit 
7. 
Willingness to adhere to the protocol requirements 
* Informed consent signatures must be obtained according to local regulations. 
7.3.2 Exclusion criteria 
Patients meeting any of the following criteria during screening evaluations will be excluded from 
trial participation: 
1. 
Females who are pregnant according to a positive urine pregnancy test, actively attempting 
to get pregnant, or are lactating 
2. 
Known or suspected allergy to trial product(s) or related products 
3. 
History of anaphylaxis or symptoms of severe systemic allergy (such as angioedema) 
4. 
Previous randomization in this trial 
5. 
History of an episode of severe hypoglycemia that required a third party assistance within 
a month prior to screening visit 
6. 
History of hypoglycemic events associated with seizures or hypoglycemia unawareness in 
the last year prior to screening 
7. 
History of epilepsy or seizure disorder 
8. 
Receipt of any investigational drug within 3 months prior to screening 
9. 
Active malignancy within the last 5 years 
10. 
Congestive heart failure, New York Heart Association class II-IV 
11. 
Current bleeding disorder, including anti-coagulant treatment 
12. 
Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma 
(i.e. insulin secreting pancreas tumor) 
13. 
Use of a daily systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs 
in the previous 28 days before Day 1 of this trial 
14. 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limit 
of the normal range (ULN), bilirubin >1.5 × ULN, estimated glomerular filtration rate 
<30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease study definition, 
or altered electrolyte values of clinical relevance for cardiac conduction, as judged by the 
investigator 
15. 
Clinically significant abnormal electrocardiogram (ECG) at screening as judged by the 
investigator 
16. 
Clinically significant illness within 4 weeks before screening, as judged by the investigator 
17. 
Surgery or trauma with significant blood loss within the last 2 months prior to screening 
18. 
Patients with mental incapacity or language barriers which preclude adequate 
understanding or cooperation, who are unwilling to participate in the trial, or who in the 
opinion of the investigator should not participate in the trial 
19. 
Any condition interfering with trial participation or evaluation or that could be hazardous to 
the patient 
20. 
The use of prescription or non-prescription medications known to cause QT prolongation 
 

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In addition, the following exclusion criteria at clinic admission on Visit 2, day 0 apply at the time 
of admission to the clinic, which is the day before clamp procedure: 
Patients who meet one or more of the following exclusion criteria at the time of admission to the clinic 
will be excluded from the dosing visit, however, the visit can be rescheduled 1-7 days later. The dosing 
visit can only be rescheduled once. 
 
1. 
Atypically strenuous exercise within 4 days prior to dosing, as judged by the investigator. 
Exercise during the trial should follow patient’s typical routine, and should not exceed a near 
maximum intensity for more than 20 minutes per day, or moderate intensity for more than 
90 minutes per day 
2. 
Clinically significant illness within 4 weeks before dosing, as judged by the investigator 
3. 
Consumption of alcohol within 24 hours prior to dosing visit, determined by positive results 
from an alcohol breath test 
4. 
Not fasting from 22:00 hours the evening prior to dosing, apart from water. 
5. 
The use of any non-prescribed systemic or topical medication, except routine vitamins and 
occasional use (as judged by the investigator) of acetylsalicylic acid and paracetamol within 
2 weeks prior to dosing. Treatment with insulin, including analogs, is allowed 
6. 
Use of insulin degludec or insulin glargine U300 within 72 hours prior to dosing; or use of 
other long-acting insulins (e.g. insulin glargine U100 or insulin detemir) within 48 hours prior 
to dosing; or use of neutral protamine Hagedorn (NPH) insulin within 22 hours prior to 
dosing 
7. 
Use of any short acting (bolus) insulin within 12 hours prior to dosing, except insulin glulisine 
(Apidra®) 
8. 
Changes in medical history or concomitant medication resulting in fulfillment of clinical 
exclusion criteria, as judged by the investigator 
9. 
Plasma glucose value <50 mg/dL (2.8 mmol/L) within the last 24 hours or plasma glucose 
value <60 mg/dL (3.3 mmol/L) within the last 5 hours prior to admission to the clinic 
7.3.3 Premature withdrawal from trial 
Participation in the trial is strictly voluntary. A patient has the right to withdraw from the trial at any 
time and for any reason. If the child chooses to withdraw or his/her parents or legal guardians 
choose to have the child withdrawn, the investigator must be informed immediately. The 
investigator has the right to terminate participation of any patient at any time if the investigator 
deems it in the patient's best interest. The reason and circumstances for withdrawal will be 
documented in the electronic case report form (eCRF). 
7.3.3.1 Possible reasons for patient withdrawal 
A patient will be withdrawn if the following applies: 
 
If a protocol deviation occurs which, in the clinical judgment of the investigator, can invalidate 
the trial endpoints, the patient will be withdrawn by the investigator 
 
AEs that are considered unacceptable by the patient or the investigator 
 
If the burden of study procedures is considered unacceptable by the patient, their parent(s) 
or the investigator 
If withdrawal occurs following administration of any trial product, the patient will be asked to return 
and participate in the complete follow-up visit at trial Day 28. In this case, withdrawal relates only 
to blood sampling but not to the safety assessments. Patients should be followed for AEs for the 
same duration as those who are not withdrawn. 

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If trial participation is terminated due to an AE possibly related to the trial product (including 
reference product) or trial examinations, the patient must be followed up by additional 
examinations according to the medical judgment of the investigator until the abnormal condition 
is resolved or the investigator deems further observations or examinations to be no longer 
medically indicated. 
If the patient meets any of the exclusion criteria 1-9 at the time of admission to the clinic at V2, 
he/she will be excluded from the dosing visit but may be rescheduled once 1-7 days later. 
7.3.3.2 Center discontinuation 
The center can be closed and the trial terminated for the following reasons: 
 
The center is unlikely to be able to recruit sufficient patients within the agreed time frame 
 
The center does not respond to trial management requests 
 
Repeat protocol violations 
However, even in case of center discontinuation the center should be kept open as long as 
previously enrolled patients are ongoing. Patients already enrolled should be followed and 
documented for their entire individual trial duration before actually discontinuing the center. 
7.3.3.3 Trial termination 
The sponsor reserves the right to modify or terminate the trial at any time. Possible reasons for 
.termination are: 
 
Safety reasons – the incidence of AEs in this or any other trial using the same trial product 
indicates a potential health risk for the patients 
 
New scientific knowledge becomes known that makes the objectives of the trial no longer 
feasible/valid 
 
Unsatisfactory enrollment of patients 
7.3.4 Replacement of patients  
Patients who are dosed will not be replaced. 

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7.4 
Investigational medicinal product(s) 
7.4.1 Identity of investigational medicinal product(s)  
The identity of the investigation products is summarized in Table 7-1. 
Table 7-1: Identity of Investigational Products 
 
Test product 
Placebo 
Reference product 
Name 
Dasiglucagon 
Placebo 
GlucaGen® 
Active substance 
ZP4207  
Not applicable 
Recombinant glucagon 
hydrochloride  
Formulation 
Liquid formulation, 
0.6 mL  
Liquid formulation, 
0.6 mL  
Powder and solvent for 
reconstitution as 1 mL 
solution for injection 
Strength 
1 mg/mL 
Not applicable 
1 mg/mL 
Container 
Single use pre-filled 
syringe 
Single use pre-filled 
syringe 
Powder and solvent for 
reconstitution packed 
together in a plastic 
box. A “hypo-kit”  
Manufacturer 
Zealand Pharma A/S, 
Glostrup 
(Copenhagen), 
Denmark 
Zealand Pharma A/S, 
Glostrup 
(Copenhagen), 
Denmark 
Novo Nordisk A/S, 
Bagsværd, Denmark 
Storage 
requirements 
Store between 2 and 
8°C 
Store between 2 and 
8°C 
Store between 2 and 
8°C 
7.4.2 Treatments administered 
Dasiglucagon, placebo, and GlucaGen® will be administered by SC injection in the abdomen or thigh.  
 
An unblinded person (appropriately trained), authorized to prepare the dose and administer the 
treatment in accordance with the randomization, will prepare the treatment required for each patient on 
each the dosing day. The dose will be administered by the unblinded, trained and qualified person. 
The content of the syringe has to be checked for clarity and absence of bubbles. 
 
Syringes will be discarded after dose administration. Used GlucaGen® vials will be stored in a lockable 
box (separated from unused vials) at ambient temperature. 
7.4.3 Packaging and labelling  
The trial product will be packed by the sponsor. The information on the labels will be in the local language 
and the product label will be compliant with local laws and regulations.  
 
The trial product labels will describe the storage conditions for trial product. The labels will supply no 
information about the patients. Each treatment kit (pre-filled syringe/vial for reconstitution) will have a 
unique Dispensing Unit Number for drug allocation, drug accountability, and traceability purposes. 
 
Labelling will be performed according to Annex 13 of the Good Manufacturing Practice guidelines of the 
European Commission, International Council for Harmonisation (ICH) guidelines on Good Clinical 
Practice (GCP), and local law. 
 

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7.4.4 Storage of trial product 
The investigator must ensure the availability of proper storage conditions. All trial product supplies 
provided for this trial will be stored in the fridge, in a secure area with restricted access at the trial center. 
The trial products ready for use should be separated from any other clinical supplies, to avoid product 
errors. 
The temperature should be monitored by recording the actual, minimum, and maximum temperatures 
using a calibrated thermometer or thermocouple, or by continuous recording using a qualified 
temperature monitoring system. The temperature should be evaluated and documented at least on 
working days on a temperature log. This log must be included in the Investigator Site File upon trial 
termination. 
The unblinded person responsible for trial product handling must contact the unblinded monitor in case 
of temperature deviations outside the acceptable range.  
Please see the trial materials manual for additional information on handling trial product. 
 
7.4.5 Investigational treatment and dosing conditions 
7.4.5.1 Changes to diabetes management prior to dosing visit 
At the screening visit, patients will be instructed by the investigator about the changes in their 
diabetes treatment leading up to and immediately prior to the dosing visits. There should not be 
any changes in their diabetes management until 3 days (72 hours) prior to the planned trial 
product administration except to switch to NPH insulin. The investigator will provide individual 
dosing instructions for this change. Within 72 hours prior to dosing, the use of insulin degludec or 
insulin glargine U300 is prohibited. Within 48 hours prior to dosing, the use of long-acting insulin 
(e.g. insulin glargine U100 or insulin detemir) is prohibited. Within 22 hours prior to dosing, the 
use of insulin NPH is prohibited. Within 12 hours prior to dosing, the use of any short acting (bolus) 
insulin, except insulin glulisine (Apidra®) is prohibited. During the insulin-induced hypoglycemic 
procedure, continuous SC insulin infusion must be stopped. 
7.4.5.2 Dosing visit 
Patients will be admitted to the clinic with their parents in the evening of the day before dosing 
(Day 0). Their eligibility for the trial will be checked, and only those still eligible will continue and 
remain in the clinic overnight.  
If the patient meets any of the exclusion criteria at clinic admission on Visit 2, day 0, he/she will 
be excluded from the dosing visit but may be rescheduled once 1-7 days later. 
An infusion catheter will be inserted into each arm for the manual glucose clamp procedure, with 
the glucose infusion in one arm and the insulin infusion in the opposite arm preferably, but the 
same infusion catheter can also be used. Another IV catheter, separated from infusion catheter(s), 
for blood sampling will be placed in the morning before trial product administration. The hand of 
this arm will be warmed (55-65 ºC) to arterialize venous blood. If there are issues with blood 
sampling from e.g. the metacarpal vein for the purpose of glucose measurements, the investigator 
may use a new and more proximal IV access. 
On the morning of the dosing day (Day 1), patients are required to be in a fasting condition, 
defined as having consumed only water since 22:00 hours the night before. They may consume 
water ad libitum. The patients must not consume any alcohol or smoke within 24 hours prior to 
dosing. 

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7.4.5.2.1 Diabetes management 
Last injection or bolus administration via continuous SC insulin infusion of any insulin medication 
should not take place within the 12 hours before dosing. Patients normally using insulin aspart 
will be switched to human soluble insulin or glulisine for the period between 12 and 10 hours prior 
to dosing, if needed. Patients using continuous SC insulin infusion will have their pump switched 
off at 22:00 hours.  
To achieve a target glucose level of 90-160 mg/dL (5.0-8.9 mmol/L) in the morning of dosing, 
patients may be administered insulin glulisine and/or glucose at the discretion of the investigator 
by IV infusion using the following glucose infusion rate and insulin infusion rate as a guidance. 
Deviation from the guidance is allowed at the discretion of the investigator. Plasma glucose levels 
will be checked overnight at regular intervals in order to achieve and maintain the target plasma 
glucose level of 90-160 mg/dL (5.0-8.9 mmol/L). 
A general guidance for administration of insulin IV and/or glucose IV at the dosing visit 
Fluid infusion rate: 
If plasma glucose < 300 mg/dL, then infusion of isotonic solution with 5% glucose: 
 Age 6–10 years: 80 mL/kg/24 h 
 Age >10 years: 60 mL/kg/24 h 
If plasma glucose >300 mg/dL the glucose infusion will be substituted with fluid volume of normal 
saline (0.9% NaCl) at same infusion rate as above. 
Infusion of insulin: 
Insulin infusions should be performed with 0.5 IU insulin glulisine (Apidra®) per kg body weight in 
48 mL NaCl 0.9% according to the following recommendations: 
Glucose  
Infusion rate 
Insulin dose (IU/kg BW/h) 
>200 mg/dL 
10.0 mL/h 
0.1 
150–200 mg/dL 
5.0 mL/h 
0.05 
80-150 mg/dL 
2.5 mL/h 
0.025 
<80 mg/dL 
Insulin infusion stop! 
0 
Abbreviation: BW=Body weight 
7.4.5.2.2 Hypoglycemic clamp procedure and dosing 
At the time of admission to the clinic, which is the day before clamp procedure, the patient’s 
eligibility must be checked. If the patient meets any of the exclusion criteria at the time of 
admission to the clinic at V2, he/she will be excluded from the dosing visit but may be rescheduled 
once 1-7 days later.  
Eligible patients will be randomized to either dasiglucagon, placebo or GlucaGen® in the morning 
of the dosing visit. That morning after 7 o’clock am, the infusion of IV glucose will be stopped. 
This should be at least 30 minutes prior to planned trial product administration. Insulin infusion 
rate and insulin dose are at the discretion of the investigator or can follow the protocol general 
guidance (see above). The investigator may deviate from the guidance. Insulin IV infusion will be 
stopped when glucose level declines to below 80 mg/dL. 
During insulin-induced hypoglycemia, plasma glucose levels will be monitored closely at the site. 
After the start of insulin infusion, plasma glucose should be checked approximately every 10 
minutes while plasma glucose is above 110 mg/dL, approximately every 5 minutes once plasma 
glucose is at or below 110 mg/dL, until after dosing, when the patient’s plasma glucose returns to 
≥70 mg/dL (3.9 mmol/L). From that time on, plasma glucose should be checked approximately 
every 30 minutes until 300 minutes (5 hours) after dosing. Plasma glucose concentrations will be 
measured using the US FDA-approved glucose analyzer YSI 2300, Yellow Springs Instruments, 

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Yellow Springs, Ohio, USA or the Super GL analyzer, Dr. Müller Gerätebau GmbH, Freital, 
Germany. 
At the discretion of the investigator, additional plasma glucose measurements can be taken at 
any time during the trial, for example when there is a suspicion (e.g. symptoms) of a hypoglycemic 
episode. 
Plasma glucose measurements for safety should only be recorded in the eCRF if they are related 
to an AE (e.g. a hypoglycemic episode). 
In case of persistent post-treatment hypoglycemia, patients will receive rescue treatment with an 
IV glucose infusion (see Section 7.4.5.2.3 for details). Blood samples for PD and PK assessments 
should still be taken at the specified time points. 
Once the glucose concentration declines to <80 mg/dL, blood samples for baseline assessment 
of plasma glucose and dasiglucagon/GlucaGen PK will be collected 5 minutes later. The samples 
are the baseline samples and should be collected within 2-5 minutes before trial product 
administration. If plasma glucose is ≥54 mg/dL and <80 mg/dL (3.0-4.4 mmol/L), trial product will 
be administered. 
If plasma glucose is <54 mg/dL (3.0 mmol/L), IV glucose solution will be administered sufficient 
to raise plasma glucose to within the 54-80 mg/dL target range. The run-in period will be 
adequately extended (at least 30 minutes) until the above target is achieved and new baseline 
samples for plasma glucose, dasiglucagon/GlucaGen PK, will be collected. In this case, glucose 
should not be infused within 10 minutes before trial product administration. If plasma glucose is 
not within the target range after the second attempt, the patient should be rescheduled for a new 
treatment visit within 7 days (+ 2 days). 
After 60 minutes, patients will be allowed to eat and drink moderately (appropriate to their body 
size, with a maximum of 50gr carbohydrates) to minimize discomfort in terms of potential nausea. 
The amount and type of food and drink consumed will be recorded. Patients should remain in bed 
until completion of the test procedure 300 minutes after dosing (bathroom visits are allowed). 
Germany only: Trial staff will be instructed on pediatric aspects of hypoglycemia according to the 
Clinical Practice Consensus Guidelines of the International Society for Pediatric and Adolescent 
Diabetes (ISPAD) 2018 (https://www.ispad.org/page/ISPADGuidelines2018). As the blood 
glucose falls, the initial symptoms result from activation of the autonomic nervous system and 
include shakiness, sweating, pallor and palpitation. In healthy individuals with no diabetes, these 
symptoms occur at a blood glucose level of approximately 70 mg/dL (3.9 mmol/L) in children and 
54 mg/dL (3.0 mmol/L) in adults. However, this threshold in individuals with diabetes will depend 
on their glycemic control, with an adaptive shift of the glycemic threshold for symptom onset to a 
higher glucose level with chronic hyperglycemia and lower glucose level with chronic 
hypoglycemia. Neuroglycopenic symptoms result from brain glucose deprivation and include 
headache, difficulty concentrating, blurred vision, difficulty hearing, slurred speech and confusion. 
Behavioral changes such as irritability, agitation, quietness, stubbornness and tantrums may be 
the prominent symptom particularly for the preschool child, and may result from a combination of 
neuroglycopenic and autonomic responses. The patient’s blood glucose values will be monitored 
via Point of Care plasma calibrated blood glucose measurements every 10 minutes or per 
investigator discretion from the start of the hypoglycemia induction protocol. Frequency of glucose 
testing will be according to investigator discretion based on the patient’s condition, the glucose 
values and their rate of change. 
The investigator must terminate the experiment immediately if he/she feels at any point that a 
patient’s burden is not acceptable or safety may be at risk. 
7.4.5.2.3 Rescue provisions for hypoglycemia 
During insulin-induced hypoglycemia, plasma glucose levels as well as the patient status will be 
monitored closely throughout the procedure. After administration of trial product, if their glucose 

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levels become too low, patients may receive post-treatment IV glucose infusion to ameliorate 
hypoglycemia, as follows: 
1. The IV glucose infusion should be initiated if a patient experiences escalating symptoms of 
hypoglycemia (e.g. start of moderate symptoms of hypoglycemia) at any time during the test 
procedure. Glucose infusion should then be initiated targeting a plasma glucose level 
>70 mg/dL 
2. If plasma glucose is <54 mg/dL between t=8 and t=44 minutes, glucose infusion (e.g. 
1-2 mg/kg administered over 5-10 seconds) should be initiated to maintain plasma glucose 
between 55 mg/dL and 70 mg/dL. Pause glucose infusion if plasma glucose is >70 mg/dL 
3. If plasma glucose is <70 mg/dL at t≥45 minutes, glucose infusion (e.g. 2-3 mg/kg 
administered over 5-10 seconds) should be initiated to maintain plasma glucose between 
70 mg/dL and 90 mg/dL. Pause glucose infusion if plasma glucose is >80 mg/dL 
7.4.6 Selection of doses in the trial 
The selected dose of 1 mg GlucaGen® is the recommended dose for treatment of severe 
hypoglycemia (in accordance with the label, children below 25 kg body weight will be administered 
0.5 mg GlucaGen®). Pre-clinical and adult clinical studies demonstrated that 0.6 mg of 
dasiglucagon results in an initial PD response (i.e. acute glucose mobilization) comparable to 
1 mg GlucaGen®. 
The estimation of the dasiglucagon dose in the pediatric trial is based on a PK and PD approach6 
where a previously developed population PK/PD model3 for dasiglucagon was extended with an 
allometric scaling component for the PK model4. The PD response was assumed to be similar in 
pediatric and adult patients as organ maturation for patients above 4 years is assumed not to 
have a meaningful impact on dasiglucagon PD. The pediatric PK component was developed by 
allometric scaling of clearance (Cl) and volume (V) by body weight from published glucagon PK 
data obtained from 2 clinical trials following intramuscular administration to pediatric (4 to 17 
years) and adult T1DM patients11,9. 
The conclusion of the modelling was that a dose of 0.6 mg appears appropriate to ensure a fast 
rescue from hypoglycemia for adult patients and children down to a weight of 25 kg. Although the 
dasiglucagon Cmax and AUC is expected to be higher in children, it does not exceed the total Cmax 
and AUC obtained in adults previously administered 2 mg dasiglucagon. The higher total drug 
exposure (AUC and Cmax) at lower weight is partially compensated by the shorter t½ and saturated 
PD response. The resulting total time of drug exposure and PD effect (AEU and CEmax) is similar 
throughout the weight range. 
7.4.7 Collection of blood samples 
The total blood volume to be obtained from any individual child will be about 43 mL. The maximum 
amount per visit is 12 to 17 mL. These values are within the recommended scope provided by the 
EU5. 
The following blood volume will be taken for each sample at each visit: 

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Sample type 
Visit 1 (mL) 
Visit 2 (mL) 
Visit 3 (mL) 
Biochemistry/pregnancy 
5.00 
- 
5.00 
Hematology 
2.00 
- 
2.00 
Coagulation 
2.00 
- 
2.00 
HbA1c 
2.00 
- 
- 
ADA 
3.00 
- 
3.00 
PK 
- 
4.00 
- 
PD 
- 
12.00 
- 
Onsite-PG 
- 
1.00 
- 
Sum for each visit 
14.00 
17.00 
12.00 
Total 
43.00 
Abbreviations: ADA=Anti-drug antibodies; HbA1c=Hemoglobin A1c; Onsite-PG=Onsite monitoring of 
plasma glucose; PD=Pharmacodynamics; PK=Pharmacokinetics  
7.4.8 Treatment compliance 
Unblinded trial personnel will handle, prepare and administer all trial products.  
7.4.9 Method of assigning patients to treatments 
Forty patients will be randomized in a 2:1:1 ratio (dasiglucagon/placebo/GlucaGen®) into the 3 
treatment arms and stratified in 2 age groups: 6 to ≤12 years and 12 to ≤18 years and by injection 
site (abdomen/thigh). A minimum of 16 patients will be enrolled into each age group, including a 
minimum of 8 patients in either of age groups on dasiglucagon treatment arm. 
Patients who meet the inclusion and exclusion criteria will be randomized into one of the following 
treatment arms:  
 Dasiglucagon, liquid formulation, 1 mg/mL, 0.6 mL 
 Placebo treatment: Placebo, liquid formulation, 0.6 mL  
 Active control treatment: Recombinant glucagon hydrochloride, 1 mg lyophilized powder for 
reconstitution (GlucaGen®, Novo Nordisk) in 1 mL sterile water (in accordance with the label, 
children below 25 kg body weight will be administered 0.5 mg GlucaGen®) 
Randomization will be performed using a central, dynamic variance minimization randomization 
method using an interactive web response system (IWRS) that will randomize a patient to one of 
the 3 aforementioned treatment arms and then assign dispensing unit numbers to that patient. 
An unblinded statistician/programmer who is separate from the trial team will generate the 
randomized kit list before the initiation of the trial.  
Treatment assignment will be kept strictly confidential and accessible only to authorized persons 
until after data base lock. However, the investigators can perform an emergency unblinding within 
the IWRS in case of an emergency, see Section 7.4.10. 
7.4.10 Blinding and breaking the blind 
This is a double-blind trial. Dasiglucagon is available as a liquid formulation and GlucaGen® is 
available as a powder for reconstitution; they are therefore not identical in appearance. Unblinded 
trial personnel will be responsible for handling, preparing (according to the prescription from the 
IWRS), and administering the trial product, and the syringes used for administration will be 
wrapped in aluminum foil to maintain the blinding at bedside. Parents being in the room with their 
child must be instructed not to look while the unblinded staff is administering the injection. To 
maintain double-blind conditions, blinded trial personnel not involved in the administration of trial 

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products will perform all trial assessments at the trial center and is responsible for keeping the 
records strictly confidential and accessible only to the unblinded staff. However, unblinded 
personnel at the specialty laboratories will perform the exposure assessments and ADA 
assessments to make sure that dasiglucagon or GlucaGen® administration is matched with the 
applicable bioanalytical assay. 
Treatment assignment will be kept strictly confidential and accessible only to authorized persons 
until after the time of unblinding (database lock). Codes with treatment assignment will however 
be readily available in the IWRS to the blinded personnel in case of an emergency.  
The code for a particular patient may be broken in a medical emergency if knowing the identity of 
the treatment allocation would influence the treatment of the patient. The emergency code break 
can be performed using the IWRS. Whenever a code is broken, the person breaking the code 
must record the time, date and reason as well as his/her initials in the source documents.  
The breaking of blinded codes in case of medical emergency for a patient should not unblind the 
trial personnel to the treatment information of other patients. The person performing the unblinding 
should inform as few people as possible about the result of the unblinding. All persons unblinded 
for a specific patient should be documented.  
If the trial center needs to break the code, the medical monitor should, if at all possible, be 
contacted prior to breaking the code and the monitor must be notified within 24 hours after the 
code has been broken. 
7.4.11 Drug accountability and disposal 
Unblinded trial personnel will do the handling, preparation and administration of trial product. Each 
center will keep accurate records of the trial supplies received, stored, and dispensed, using 
appropriate forms. The trial supplies will be stored under appropriate conditions, locked and with 
restricted access. The unblinded monitor will perform the drug accountability to ensure 
compliance. 
All unused supplies and all empty and partially empty containers of trial product will be stored until 
the trial closure visit has been performed and then sent to the sponsor.  
7.4.12 Prior and concomitant therapy 
All concomitant medications will be recorded in the eCRF at each visit.  
Prior to the start of the clamp procedure, the patient’s eligibility must be checked. If the patient 
has taken any prohibited medication, he/she will be excluded from the dosing visit but may be 
rescheduled 1-7 days later. Each patient may only have their dosing visit rescheduled once. See 
Section 7.3.3.1 for possible reasons for patient discontinuation. 
7.4.13 Treatment after end of trial  
After the end of their trial participation, patients should return to the standard of care that they 
received prior to enrollment in the trial. The treating physician will be responsible for supervising 
patients after the end of the trial. 
7.5 
Assessments and schedule of measurements 
The following assessments and measurements will be carried out at the times specified in the trial 
schedule of assessments (Table 2-1).  
Informed consent will be obtained prior to any trial-related procedures; see Section 11.3. 

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7.5.1 Screening visit 
At screening (Visit 1), the following assessments will take place: 
 
Informed consent 
 
Inclusion/exclusion criteria 
 
Demography 
 
Body measurements 
 
Diabetes diagnosis, and current diabetes treatment 
 
Medical history including concomitant illnesses 
 
 
Prior and concomitant medications 
 
History of alcohol/drug abuse 
 
Physical examination 
 
Vital signs 
 
12-lead ECG 
 
AEs 
 
Biochemistry, hematology, coagulation, hemoglobin A1c (at Visit 1 only) 
 
Serum pregnancy test (female patients of childbearing potential only) 
 
Urinalysis 
 
Antibodies against dasiglucagon/GlucaGen® 
7.5.2 Dosing visit 
At Visit 2 (Day 0), patient eligibility is rechecked (check of changes between the screening visit 
and Visit 2) and patient’s eligible to participate will be randomized to treatment with dasiglucagon, 
placebo or GlucaGen®.  
The following assessments will take place: 
 
Inclusion/exclusion criteria (prior to the start of the insulin-induced hypoglycemic procedure. 
Only check of exclusion criteria at clinic admission on Visit 2, day 0 and changes between 
screening visit and Visit 2) 
 
Concomitant medications (prior to the start of the insulin-induced hypoglycemic procedure) 
 
Current diabetes treatment 
 
Randomization (prior to the start of the insulin-induced hypoglycemic procedure) 
 
Exclusion criteria at clinic admission on Visit 2, day 0 (prior to the start of the insulin-induced 
hypoglycemic procedure) 
 
Urine stick pregnancy test (women of childbearing potential only) (prior to the start of the 
insulin-induced hypoglycemic procedure) 
 
Urinalysis (prior to the start of the insulin-induced hypoglycemic procedure) 
 
Alcohol breath test (prior to the start of the insulin-induced hypoglycemic procedure) 
 
Physical examination (prior to the start of the insulin-induced hypoglycemic procedure) 
 
Insulin-induced hypoglycemia 

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 
Vital signs (prior to the start of the insulin-induced hypoglycemic procedure (within 30 
minutes), and at 30, 60 and 300 minutes after dosing. The actual time of the assessment 
should not deviate from the nominal time by more than ±10 minutes) 
 
12-lead ECG (prior to the start of the insulin-induced hypoglycemic procedure (within 30 
minutes), and at 20, 35, 45, 60 and 300 minutes after dosing. The actual time of the 
assessment should not deviate from the nominal time by more than ±5 minutes) 
 
Local tolerability (at 30, 120, and 300 minutes after dosing. The actual time of the assessment 
should not deviate from the nominal time by more than ±10 minutes) 
 
AEs 
 
Plasma dasiglucagon/GlucaGen® (pre-dose, and at 10, 20, 30, 40, 60, 90, 140, 220, and 300 
minutes after dosing. The actual time of blood sampling should not deviate from the nominal 
time by more than ±1 minute between t=5 minutes and t=90 minutes, ±5 minutes between 
t=150 minutes and t=240 minutes. Pre-dose is defined as within 2 minutes prior to dosing) 
 
Plasma glucose (pre-dose, and at 4, 6, 8, 10, 12, 15, 17, 20, 30 and 45 minutes (and as well 
at 60 minutes if the patient´s body weight is ≥21 kg) after dosing. The actual time of blood 
sampling should not deviate from the nominal time by more than ±30 seconds until the 20-
minute collection time point, and by more than ±1 minute for the subsequent collection time 
points. Pre-dose is defined as within 2 minutes prior to dosing 
 
Administration of trial product (during hypoglycemic clamp procedure) 
7.5.3 Follow-up visit 
At 28 (+ 5) days after the hypoglycemic clamp procedure, the follow-up visit is scheduled to collect 
safety data. The following assessments will take place: 
 
Concomitant medications 
 
Current diabetes treatment 
 
Physical examination 
 
Vital signs 
 
12-lead ECG 
 
Local tolerability 
 
AEs 
 
Biochemistry, hematology, coagulation, HbA1c (HbA1c at Visit 1 only) 
 
Urine stick pregnancy test (women of childbearing potential only) 
 
Urinalysis 
 
Antibodies against dasiglucagon/GlucaGen® (any treatment-induced or treatment-boosted 
[titer increase above 5 fold] ADA-positive patients will be monitored until the ADA levels return 
to baseline levels) 
7.5.4 Final examination at the end of the trial  
The final visit of the trial is Visit 3 (Day 28[+5] of the follow-up period; end-of-trial visit). See Section 
7.5.3 for further details.  

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7.5.5 Additional (safety) examinations 
If there are any unclear symptoms or observations the responsible physician in charge may 
perform further medical examinations, other than outlined in this protocol, including further clinical 
laboratory tests, in order to clarify the relevance or to diagnose symptoms.  
7.5.6 Efficacy measurements 
A description of the sample handling and sample processing at the site will be included in the 
laboratory manuals. Validation documentation for the assays must be available prior to sample 
analyses. A bioanalytical report for each analysis of trial PD and PK samples will be prepared. 
Pharmacokinetic measurements 
The exposure to trial medication (dasiglucagon or GlucaGen®) for evaluation of PK will be 
assessed based on plasma concentration data (AUC0-90min, Cmax, tmax) from samples collected at 
the dosing visit (Visit 2). The sampling procedure is described in Section 7.5.2. 
Pharmacodynamic measurements 
The plasma glucose profile for evaluation of the primary and secondary clinical efficacy endpoints 
will be assessed based on plasma concentration data (AUE0-30min) from samples collected at the 
dosing visit (Visit 2). The samples will be sent to the clinical laboratory and analyzed using a 
sensitive and validated assay for glucose measurements. The sampling procedure is described 
in Section 7.5.2. 
7.5.7 Safety and tolerability measurements  
7.5.7.1 Safety laboratory tests 
Routine safety laboratory tests will be performed centrally. Samples for safety laboratory 
parameters will be collected at Visits 1 and 3. Samples for urinalysis will be collected at Visits 1, 
2, and 3. The following parameters will be determined: 
 
Clinical chemistry: sodium, potassium, calcium, glucose, urea, creatinine, total bilirubin, AST, 
ALT, gamma-glutamyltransferase, alkaline phosphatase, total protein, C-reactive protein, 
HbA1c, C-peptide  
 
Hematology: hemoglobin, red blood cell count (erythrocytes), hematocrit, platelet count 
(thrombocytes), total white blood cell count (leucocytes) 
 
Coagulation: international normalized ratio, fibrinogen (at screening visit only)  
 
Urinalysis: pH, blood (leukocytes and erythrocytes), protein, glucose, ketones, nitrite 
 
Immunogenicity: 
Serum samples for assessment of antibodies against dasiglucagon/GlucaGen® will be 
measured at screening Visit 1 and at follow-up Visit 3 by the special laboratory, York 
Bioanalytical Solutions (York, United Kingdom). A description of the sample handling and 
sample processing, storage and shipment at the center will be included in the laboratory 
manual. Immunogenicity samples will be analyzed after the last patient last visit. 
The clinical ADA assays, one specific for dasiglucagon and another for GlucaGen®, have 
been validated in accordance with existing guidelines and recommendations. 
Confirmed positive anti-dasiglucagon antibody samples from treatment- induced or treatment- 
boosted (titer increase above 5-fold) ADA-positive patients will be evaluated for binding titer, 
neutralizing potential and neutralizing titer as well as cross-reactivity towards endogenous 
glucagon. Any treatment-induced or treatment-boosted ADA-positive patients will be 
monitored until the ADA levels return to baseline levels.  

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The in vitro neutralizing effect of the antibodies will be measured using an assay based on 
glucagon receptor expression in transfected human embryonic kidney cells. The calculated 
sensitivity in previous studies was about 51.8 ng/mL. The assay was also validated for 
recombinant glucagon with similar results. In case of a positive result in the neutralizing 
antibody assay, a titer estimation will be performed. The cell-based neutralizing antibody 
analyses will be performed by a special laboratory, BioAgilytix, Durham, North Carolina, USA.  
No further serum sampling will be needed as the ADA samples can be used for neutralizing 
antibody analysis. 
Residual and additional antibody serum samples may be stored until approval of market 
authorization by the health authorities. Further characterization of the antibody response may 
be requested by the health authorities. 
A pregnancy test will be performed at screening and follow-up (Visits 1, 2 and 3) for female 
patients of childbearing potential only. 
An alcohol breath test will be performed at the dosing visit (Visit 2). 
For further details, please refer to the laboratory manual.  
 
7.5.7.2 Safety examinations 
Physical examination is performed at screening (Visit 1), dosing (Visit 2) and end-of-trial (Visit 3).  
AEs are assessed at all visits. Local tolerability is assessed at dosing visit and follow-up visit 
(Visits 2 and 3). ECG and vital signs are assessed at screening, dosing and follow-up visit (Visit 
1, 2 and 3).  
 
Physical examination includes examination of the following body systems: head, ears, eyes, 
nose, throat, including the thyroid gland; heart, lung, chest; abdomen; skin; musculoskeletal 
system; nervous system; lymph nodes 
 
Vital signs include: pulse rate and blood pressure after 5 minutes in sitting position, body 
temperature 
 
Local tolerability: skin reactions will be reported as AEs (see Section 8) 
 
12-lead ECG: Details from ECG assessments will be recorded, including heart rate, PR, QRS, 
QT and QTc corrected by Fridericia´s formula intervals 

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8. Adverse events 
8.1 
Definitions 
Timely, accurate, and complete reporting and analysis of safety information from clinical trials are 
crucial for the protection of patients, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. 
 
Adverse event  
An AE is any untoward medical occurrence in a trial patient administered a trial product and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (for example, an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a trial product, whether or not considered related 
to the trial product.  
Note: This includes events from the first trial-related activity after the patient has signed the 
informed consent.  
AEs include: 
 
A clinically significant worsening of a concomitant illness 
 
A clinical laboratory abnormality that is clinically significant, i.e. any abnormality that suggests 
a disease and/or organ toxicity and is of a severity that requires active management. Active 
management includes active treatment or further investigations, for example change of 
medicine dose or more frequent follow-up due to the abnormality 
 
Hypoglycemic episodes (see Section 8.4) 
 
Injection site reactions 
The following should not be recorded as AEs, if recorded at screening (on Medical History form 
or eCRF): 
 
Pre-planned procedure, unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the patient has signed the informed consent 
 
Pre-existing conditions, including those found because of screening procedures (pre-existing 
conditions should be reported as medical history or concomitant illness) 
 
When assessing an adverse event, the following definitions are use: 
Serious adverse event 
An SAE is any untoward medical occurrence that at any dose results in any of the following:  
 
Results in death  
 
Is life-threatening  
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Is medically important 
Medical judgement must be exercised in deciding whether an AE is believed to be ‘medically 
important’. A medically important event may not be immediately life-threatening or result in 

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death or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. 
Other important events: 
The following events must always be reported to the sponsor according to SAE timelines, 
regardless of whether the event is non-serious or serious:  
 
Risk of liver injury defined as ALT or AST > 3 x ULN and total bilirubin > 2 x ULN, where no 
alternative etiology exist 
 
Suspicion of transmission of infectious agents via the trial product 
 
Overdose of the trial product 
 
Suspected abuse or misuse of the trial product 
 
Medication error involving the trial product 
 
Inadvertent or accidental exposure to the trial product. 
Severity of an adverse event 
The maximum intensity (severity) of all AEs must be assessed by the investigator and 
documented. Severity should be graded when the AE outcome is known: 
 
Mild: No or transient symptoms, no interference with the patient´s daily activities 
 
Moderate: Marked symptoms, moderate interference with the patient´s daily activities 
 
Severe: Considerable interference with the patient´s daily activities, which the patient finds 
unacceptable. A severe reaction does not necessarily deem the AE as serious and an SAE 
is not always severe in nature. 
Causality relationship to trial product 
 
Probable: Good reason and sufficient documentation to assume a causal relationship 
 
Possible: A causal relationship is conceivable and cannot be dismissed 
 
Unlikely: The event is most likely related to etiology other than the trial product 
Outcome of an adverse event 
 
Recovered/resolved: The patient has fully recovered, or by medical or surgical treatment, the 
condition has returned to the level observed at the first trial-related activity after the patient 
signed the informed consent 
 
Recovering/resolving: The condition is improving and the patient is expected to recover from 
the event. This term is only applicable if the patient has completed the trial 
 
Recovered/resolved with sequelae: The patient has recovered from the condition, but with 
lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE 
 
Not recovered/ not resolved: The condition of the patient has not improved and the symptoms 
are unchanged 
 
Fatal: This term is only applicable if the patient died from a condition related to the reported 
AE. Outcomes of other reported AEs in a patient before he/she died should be assessed as 
"recovered/resolved", "recovering/resolving", "recovered/ resolved with sequelae" or "not 
recovered/not resolved". An AE with fatal outcome must be reported as an SAE 
 
Unknown: This term is only applicable if the patient is lost to follow-up 
 

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Suspected unexpected serious adverse reactions 
An AE is considered a suspected unexpected serious adverse reaction (SUSAR) if the nature 
or severity is not consistent with the applicable product Reference Safety Information. For 
dasiglucagon, the expectedness of an AE will be determined by whether or not it is listed in 
the Reference Safety Information section of the Investigator’s Brochure. 
 
Adverse event of special interest (AESI) 
An AESI is an event that, in the evaluation of safety, has a special focus (e.g. required by health 
authorities). In this trial, hemodynamic changes are considered AESIs that are defined as follows: 
 
Post-dose clinical signs, or measured vital signs, indicating a clinically significant drop in 
blood pressure including signs of orthostatic hypotension, vasovagal responses or 
bradycardia.   
 
Post-dose change in pulse or blood pressure considered an event of hypo- or hypertension 
as judged by the investigator. 
AESIs must be reported to the sponsor in the same way and with the same timelines as SAEs 
(see Sections 8.2 and 8.3). 
8.2 
Collection, recording and reporting of adverse events 
All AEs, whether serious or non-serious, will be reported from the time a signed and dated 
informed consent form (ICF) is obtained until the end of the post-treatment follow-up period (which 
may include contacts for follow-up of safety). In addition, patients will be observed for any signs 
or symptoms and asked about their condition by open questioning, such as “How have you been 
feeling since you were last asked?” at each contact with the trial center (visit or telephone). 
Patients will also be encouraged to spontaneously report AEs occurring at any other time during 
the trial.  
All AEs, regardless of seriousness, severity, or presumed relationship to trial product, must be 
recorded and evaluated by the investigator. Whenever possible, diagnoses should be given when 
signs and symptoms are due to a common etiology. If no diagnosis can be made, the investigator 
should record each sign and symptom as individual AEs. Investigators must record their opinion 
concerning the relationship of the AE to the trial product. All measures required for AE 
management must be recorded in the source document and reported according to sponsor 
instructions. 
 
Each AE must be reported on the AE page of the eCRF. 
All AE information should at a minimum include the following: 
 
Date and time of onset and resolution 
 
Date and time of investigator’s first information on the AE 
 
Seriousness 
 
Severity 
 
Causal relationship with trial product 
 
Measures taken due to AE 
 
Date and time of resolution and final outcome 
Each AE will be coded using the latest version of the Medical Dictionary for Regulatory Activities. 
SAEs and AESIs, including those spontaneously reported to the investigator within 30 days after 
the last dose of trial product, must be reported to the appropriate sponsor contact person(s) within 

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24 hours after obtaining knowledge about the event, followed by a complete SAE form as soon 
as more information is available. For each SAE and AESI, a separate SAE form should be 
completed.  
The investigator should report the SAE and AESI in the electronic data capture (EDC) and the 
system will generate an email to the sponsor´s Pharmacovigilance Unit (PharmaLex), informing 
them of the reported SAE. 
It is the responsibility of the sponsor´s Pharmacovigilance Unit (PharmaLex) to report all SUSARs 
that occur in this trial to the respective competent authorities and the institutional review board 
(IRB), or independent ethics committee (IEC) in accordance with the local requirements in force 
and ICH guideline for GCP. 
8.3 
Follow-up of adverse events 
All AEs that are ongoing at the end of the patient’s participation in the trial will be followed up until 
the event is resolved or reaches a satisfactory outcome as deemed by the investigator.  
Follow-up actions for all SAEs will be performed according to appropriate clinical care practices 
and may depend on the nature of the event. These will be determined after internal review and/or 
sponsor review. 
The follow-up information should only include new (updated and/or additional) information that 
reflects the situation at the time of the investigator’s signature. 
Follow-up information on (S)AEs and AESIs will be updated using the (S)AE form. If a non-serious 
event becomes serious during the follow-up, the AE form and SAE form have to be used and 
reporting timelines follow those of a SAE. 
The investigator must forward follow-up information on SAEs and if previously non-serious AEs 
become SAEs to the sponsor immediately (within 24 hours) after obtaining knowledge about the 
new information. 
The investigator must record follow-up information in the eCRF for non-serious AE and on the 
SAE form for SAEs and AESI. Follow-up questions to investigators regarding SAEs are queried 
directly by safety CRO to the investigator.  
Follow-up information must be reported according to the following: 
 
SAEs and AESI: All SAEs and AESI must be followed until the outcome of the events is 
“recovered/resolved,” “recovered/resolved with sequelae,” or “fatal,” and until all queries have 
been resolved. Cases of chronic conditions, cancer, or AEs that are ongoing at time of death 
(where death is due to another AE) may be closed with the outcome “recovering/resolving” or 
“not recovered/not resolved.” Cases can be closed with the outcome of “recovering/resolving” 
when the patient has completed the follow-up period and is expected by the investigator to 
recover. 
The SAE and AESI follow-up information should only include new (eg, corrections or 
additions) information and must be reported within 24 hours of the investigator's first 
knowledge of the information. This is also the case for previously non-serious AEs which 
subsequently become SAEs.  
 
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving,” “recovered/resolved,” or “recovered/resolved with sequelae” or until 
the end of the follow-up period stated in the protocol, whichever comes first, and until all 
queries related to these AEs have been resolved. Cases of chronic conditions, cancer, or AEs 
that are ongoing at time of death (where death is due to another AE) may be closed with the 
outcome of “recovering/resolving” or “not recovered/not resolved.” Cases can be closed with 
the outcome of “recovering/resolving” when a patient has completed the follow-up period and 
is expected by the investigator to recover.  

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If a potential hypersensitivity reaction is observed, additional blood samples, as clinically 
indicated, may be required to further characterize the potential hypersensitivity reaction. If an 
anaphylactic shock is suspected, samples may be taken for the measurement of tryptase. In this 
case, a blood sample should be taken 3 to 4 hours after the event and again approximately 
1 to 2 weeks later to determine tryptase baseline levels. In addition, assessments for elevated 
histamine levels may be considered. 
The investigator must ensure that the worst-case severity and seriousness of an event is kept 
throughout the trial, ie, if the severity of an AE changes over time then it should be reported as 
1 AE with the most severity. A worsening of an unresolved AE must be reported as follow-up with 
re-assessment of severity and/or seriousness of the event. 
If an AE is resolved and re-appears later then it should be reported as a new AE.   
Queries or follow-up requests must be responded within 14 calendar days from the date of receipt 
of the request, unless otherwise specified in the follow-up request.  
8.4 
Hypoglycemia 
Hypoglycemia will be regarded as an AE, recorded, and documented on an AE form (or SAE 
form, if applicable). 
Hypoglycemia is defined as a decline in plasma glucose below 3.9 mmol/L (70 mg/dL). Since 
hypoglycemia will be induced during the dosing visit, in accordance with hypoglycemia clamp 
procedure described in Section 7.4.5.2.2, ONLY plasma glucose below 3.0 mmol/L (54 mg/dL) 
must be reported as an AE, at the dosing visit (V2), and at incidences that IV glucose is given 
after trial product administration. 
8.5 
Pregnancy 
Female patients must be instructed to notify the investigator immediately if they become pregnant 
or if they suspect to be pregnant during the trial. All initial reports of pregnancy in female patients 
must be reported to the sponsor by the trial center personnel within 24 hours of their knowledge 
of the event using the appropriate pregnancy form. Abnormal pregnancy outcomes (e.g. 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs and must be reported using the SAE form. If a patient becomes pregnant during 
the trial, a determination regarding the trial product discontinuation must be made by the 
investigator. 
Because the effect of the trial product on sperm is unknown, pregnancies in partners of male 
patients must be reported by the trial center personnel within 24 hours of their knowledge of the 
event using the appropriate pregnancy form. Male patients must be instructed to notify the 
investigator immediately if their partner becomes pregnant or suspects to be pregnant. 
The investigator must follow the pregnancy until the pregnancy outcome is known and the 
newborn infant is 1 month of age. The investigator must report information about the pregnancy, 
pregnancy outcome, and health of the newborn infant(s), as well as AEs in connection with the 
pregnancy, and AEs in the fetus and newborn infant. 
8.6 
Precautions 
Normal precautions taken for a human trial, including the provision of emergency equipment, will 
be taken during this trial. Qualified and well-trained physicians and medical staff will instruct the 
patients. During a patient’s participation in the trial, the investigator should ensure adequate 
medical care for any AEs, including clinically significant laboratory values related to the trial. The 
investigator should inform the patient when medical care is needed for intercurrent illnesses of 
which the investigator becomes aware.  

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For further information on safety precautions for dasiglucagon and GlucaGen®, please refer to the 
current version of the Investigator’s Brochure2 and the Summary of Product Characteristics for 
GlucaGen®7, respectively. 
8.7 
Safety committee 
An internal Zealand Pharma A/S safety committee is constituted to perform the safety surveillance 
of clinical trials with dasiglucagon, including this trial. 
If safety signals or concerns are observed, whether based on reported SAEs, review of all AEs 
and laboratory parameters reported, or any other notification of significant findings, the safety 
committee will respond appropriately to protect the safety of the patients.   
The safety committee convenes regularly, every quarter, to review the safety information, 
including SAEs, AEs and laboratory data. Additional safety committee meeting may be called at 
the discretion of any safety committee member, should new safety signals occur during this time 
interval. 
 

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9. Data management and quality control 
9.1 
Electronic case report forms 
All the information collected during the trial will be recorded in the eCRFs, which are identified by 
patient number. Synteract will design suitable eCRFs. The investigator will ensure that the eCRFs 
are completed correctly. The investigator will sign all data entered in the eCRF electronically, 
signifying agreement with and responsibility for the recorded data.  
9.2 
Quality control 
The investigator will permit trial-related monitoring, IEC review, and regulatory inspections, 
providing direct access to source data/documents. Sponsor-authorized quality assurance 
personnel may carry out audits for which the investigator must provide support. 
A monitor from Synteract will supervise the trial. The trial monitor will contact the investigator 
regularly to discuss the progress of the trial and to check the trial documents including the 
informed consent forms for completeness and consistency.  
The trial monitor or a representative of the sponsor will cross-check the data entered in the eCRFs 
with the source data at the trial center and observe the trial procedures in order to verify 
adherence to the trial protocol. 
The eCRFs will be checked for completeness and correctness by the monitor and by the data 
management department of Synteract according to the Synteract standard operating procedures, 
and the investigator will resolve any queries. 
All of the clinical data will be captured via EDC using a web-based tool. The software Marvin from 
the company XClinical (www.xclinical.com) is the preferred EDC software. Marvin is compliant 
with all legislation relevant to EDC (Food and Drug Administration USA, 21 Code of Federal 
Regulations [CFR] Part 11, GCP). 
The investigator center staff will enter and edit the data via a secure network, with secure access 
features (username and password). A complete electronic audit trail will be maintained. The 
investigator will approve the data using an electronic signature (Ref: 21 CFR Part 11), and this 
approval is used to confirm the accuracy of the data recorded. 
The eCRFs will be used for all patients. The investigator’s data will be accessible from the 
investigator’s center throughout the trial. The eCRFs must be kept current to reflect patient status 
at each phase during the course of the trial. The eCRF will not capture personalized data. The 
investigator must make a separate confidential record of personalized details (name and initials) 
on the patient identification and enrollment log. The investigator does all changes to data through 
the EDC system.  
It is the responsibility of the Principal Investigator of the respective center to ensure that all patient 
discontinuations or changes in trial or other medications entered in the patient’s eCRF are also 
made on the patient’s medical records. 
The eCRFs for any patient leaving the trial should be completed at the time of the final visit or shortly 
thereafter. 
9.3 
Data management 
Data management will be performed according to Synteract standard operating procedures. 
 

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10. Statistical methods and determination of sample size 
10.1 Statistical analysis plan 
A separate Statistical Analysis Plan will detail the planned statistical analysis and may include 
necessary adaptations to the planned statistical analysis before unblinding of the data.  
Any deviations from the planned analyses will be described and justified in the final integrated 
trial report. 
10.1.1 General considerations 
All data obtained in this trial and documented in the eCRFs will be listed and summarized with 
statistics or frequency tables as appropriate. In case of termination of the trial, all data collected 
up to that time point will be included into the analysis. 
Raw data listings and summary tables will be generated using SAS© software Version 9 or higher 
(SAS Institute, Inc, Cary, North Carolina, USA).  
Continuous variables will be summarized with means, standard deviations, medians, minimums, 
and maximums and valid cases.  
Other summaries (e.g. quartiles, 95% confidence intervals) may be used as appropriate. 
Categorical efficacy and safety variables will be summarized by counts and by percentage of 
patients in corresponding categories.  
10.1.2 Classification of patients to subsets 
For the statistical analysis, the randomized patients will be divided up into the following datasets: 
The following definitions are applicable: 
Safety analysis set 
(SAS) 
all patients who were randomized and received at least 1 dose of 
trial product 
Full analysis set 
(FAS) 
all patients of the SAS 
Per protocol set 
(PPS) 
all patients of the FAS for whom no relevant protocol deviations 
were documented.  
The analysis of the primary endpoint will be based on the FAS. A secondary analysis of the 
primary endpoint will be based on the PPS. Safety analysis will be based on the SAS. 
The decision whether a protocol deviation is relevant or not for the exclusion of patients from the 
PPS will be made case-by-case in a data review meeting. 
10.1.3 Efficacy endpoints 
For the confirmatory analyses, the primary and secondary endpoints for the dasiglucagon 0.6 mg 
and placebo treated patients will be compared. A hierarchical procedure will be applied for the 
control of multiplicity. The primary and secondary endpoints will be evaluated on the FAS. In the 
primary analysis, those patients who require rescue IV glucose will be censored at the time to 
plasma glucose recovery.  In a sensitivity analysis, the time to plasma glucose recovery will be 
analyzed without censoring the patients who received rescue IV glucose.   
10.1.3.1 Hierarchical testing procedure 
For the confirmatory analyses, the following a priori defined hierarchical inferential test order will 
be applied for the control of the type 1 error rate across the planned multiple comparisons. The 
primary endpoint and secondary endpoints will be inferentially evaluated within the FAS in the 
following order, where inference will proceed at the 2-sided 0.05 criterion significance level until 
the first failure to reject the null hypothesis for a dasiglucagon versus placebo comparison: 

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 
Primary:  Time to plasma glucose recovery 
 
Secondary 1-4: Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 
minutes, and within 10 minutes after study drug injection without administration of rescue IV 
glucose. 
 
Secondary 5-8:  Plasma glucose changes from baseline within 30 minutes, within 20 minutes, 
within 15 minutes, and within 10 minutes after study drug injection or at the time of rescue. 
The GlucaGen® versus placebo comparisons will not be included in the inferential testing hierarchy, 
since the efficacy of GlucaGen® is previously established, and these comparisons are intended to 
support the validity of the study for the dasiglucagon versus placebo comparisons. 
Analogous supportive sensitivity analyses will be conducted in the PPS, but without inference intent. 
10.1.3.2 Primary efficacy endpoint 
The primary endpoint, time to plasma glucose recovery, will be summarized using Kaplan-Meier  
estimates for each treatment group in total and stratified by age group and injection site. The median 
time to recovery with 95% confidence interval will be estimated by treatment group, in total and in 
each stratum. 
A stratified log-rank test will be applied to compare the dasiglucagon 0.6 mg treatment group to the 
placebo group. The same method will be applied to compare dasiglucagon 0.6 mg with GlucaGen®. 
In the primary analysis, recovery cannot be achieved in those patients where IV glucose treatment 
is administered. Those patients who receive IV glucose will be censored (i.e. set to ‘not recovered’) 
at 45 minutes after dosing. 
A further sensitivity analysis will be done by censoring data at the actual time when the patients 
received glucose IV. 
10.1.3.3 Secondary efficacy endpoints 
The secondary efficacy endpoints are plasma glucose recovery within 10, 15, 20 and 30 minutes 
after trial product injection, i.e. achieving a ≥20 mg/dL increase in plasma glucose from baseline 
within 0 to 10, 15, 20 and 30 minutes. If a patient has received an IV glucose treatment before 
recovery, the patient is set to ‘not recovered’ in the analysis of the 4 endpoints, corresponding to 
censoring in the time-to-recovery analysis for the primary endpoint. The 10-, 15-, 20- and 30-
minute recovery rates of 2 treatment groups will be compared by a Cochran-Mantel-Haenszel test 
stratified by age group and injection site. The treatment and age group responder rates with the 
95% confidence intervals will be presented for the 10-, 15-, 20- and 30-minute endpoint. 
If due to small or zero cell counts the Cochran-Mantel- Haenszel test fails, non-stratified Fisher’s 
exact tests will be applied instead. 
Plasma glucose changes from baseline at 10, 15, 20 and 30 minutes after trial product injection 
will be analyzed in an analysis of variance with factors treatment (3 levels) age group (2 levels) 
and injection site (2 levels) for each endpoint. If the rescue IV glucose was administered before 
10, 15, 20 or 30 minutes, respectively, the patient’s plasma glucose changes from baseline will 
be determined from the value at the time of rescue IV glucose administration. Adjusted treatment 
means will be presented with their 95% confidence intervals. The 4 analysis of variance will also 
be used to test the difference between treatments adjusted for age group and injection site. 
10.1.4 Safety endpoints 
Clinical laboratory data 
Clinical laboratory test results will be marked whether the result is below, within or above the 
respective reference range. The number of values outside of the reference range will be counted. 

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Adverse events 
Adverse events will be tabulated by system organ class (SOC) and preferred term (PT) after 
medical coding using the Medical Dictionary for Regulatory Activities. AE summary tables will 
include counts and percentages of patients who experienced AEs summarized by SOC and PT. 
Other safety data 
Time to first IV glucose infusion, after IMP administration (N.B. IV glucose infusion prior to IMP 
administration should not be included, as it is part of hypoglycemic clamp procedure) will be 
described with descriptive statistics. No statistical tests will be performed. 
Vital signs, physical examination, ECG and local tolerability data will be summarized with 
descriptive statistics. 
Immunogenicity 
Occurrence of ADA will be analyzed descriptively per treatment group. No statistical tests are 
planned. 
10.1.5 Pharmacokinetic endpoints 
Plasma dasiglucagon and glucagon concentrations will be described and the following 
parameters are calculated and summarized with descriptive statistics: 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 to 
30 minutes post-dose (AUC0-30min) 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 
to 300 minutes post-dose (AUC0-300min) 
 
Area under the plasma dasiglucagon or GlucaGen® concentration versus time curve from 0 
to infinitely post-dose (AUC0-inf) 
 
Maximum of all valid plasma dasiglucagon or GlucaGen® concentration measurements from 
0 to 300 minutes post-dose (Cmax) 
 
Time to maximum of plasma dasiglucagon or GlucaGen® concentration measurements (tmax) 
 
Terminal elimination rate constant of plasma dasiglucagon or GlucaGen® (λz) 
 
Terminal plasma elimination half-life of dasiglucagon or GlucaGen® (t½) 
 
Total body clearance of plasma dasiglucagon or GlucaGen® (CL/f) 
 
Volume of distribution of plasma dasiglucagon or GlucaGen® (Vz/f) 
 
Mean residence time of plasma dasiglucagon or GlucaGen® (MRT) 
10.1.6 Pharmacodynamic endpoints 
Plasma glucose response as area under the effect curve above baseline from time 0 to 
30 minutes, AUE0-30min, will be summarized with descriptive statistics. 
10.1.7 Further data 
Baseline and demographic data will be summarized using descriptive statistics.  
All other data obtained in this trial and documented in the eCRF will be listed. 
10.1.8 Withdrawals, drop-outs and missing data 
Only valid cases will be analyzed, i.e. no imputation technique like last observation carried forward 
will be applied. 

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10.1.9 Baseline and center comparisons 
Demographic and other baseline characteristics will be compared. 
10.1.10 Subgroup analysis 
No subgroup analysis is currently planned. 
10.1.11 Interim analysis 
No interim analysis is currently planned. 
10.2 Determination of sample size 
The primary comparison is between the dasiglucagon and placebo treatment arms. From phase 
2 results, the median time to an increase of 20 mg/dL of the 0.6 mg dose was approximately 10 
minutes. For placebo-treated patients, the median time to recovery is assumed to be more than 
50 minutes. Assuming an exponential time-to-recovery distribution with median times of 10 and 
50 minutes, a 2-sided log-rank test will be able to detect a difference between dasiglucagon 
0.6 mg and placebo with 90% power with a follow-up time of 45 minutes at a 5% significance level 
with 20 patients randomized to the dasiglucagon arm and 10 patients to placebo. 
GlucaGen® is included as a reference to compare the responses and AE profile to dasiglucagon 
with those to a marketed product. It is expected that 10 patients in the GlucaGen® group will 
suffice for the comparison. 

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11. Ethics and regulations 
11.1 Independent ethics committees and competent authorities 
The clinical trial authorization granted by the competent authority (CA) and a favorable opinion 
from the relevant IEC/IRB(s) will be obtained prior to the start of the trial. The local authorities will 
be notified about the trial as required by law. 
The CA and the IEC/IRB will be notified about the end of the trial and a report summarizing the 
trial results will be sent to the CA and the IEC within 1 year after the end of the trial. If the trial is 
terminated early, the CA and the EC will be notified within 15 days. 
The IECs and/or IRBs meet the requirements of the ICH Harmonised Tripartite Guideline for GCP 
and local legislation. They also meet the requirements of 21 CFR 312.3. 
11.2 Ethical conduct of the trial  
The trial will be conducted in accordance with the ethical principles set forth in the Declaration of 
Helsinki (including amendments).  
11.3 Patient information and consent 
Written informed consent will be obtained from the parents/legal representatives of all patients 
prior to enrollment into the trial. Additionally, the children will be informed about the trial with age-
appropriate information materials, and their assent will be obtained in accordance with local 
regulations. The investigator will explain to each patient and their parents/legal representatives 
orally and in writing (patient information sheet) the nature, significance, risks and implications of 
the trial before inclusion. In particular, the patients will be informed about the following: 
 
The possibility of withdrawing from the clinical trial at any time by revoking the consent and 
without any resulting disadvantage 
 
How personal and health-related data will be collected and used during the trial 
 
Confidentiality, i.e. medical records may be examined by authorized monitors or Clinical 
Quality Assurance auditors appointed by the sponsor, by appropriate IEC/IRB members, and 
by inspectors from regulatory authorities 
All parents/legal representatives and the children will receive a copy of the respective patient 
information sheet and a copy of their signed and dated informed consent/assent form.  
All patients will be insured against injury caused by their participation in the trial according to legal 
requirements. They will be informed about the insurance and the resulting obligations on their 
part. 
11.4 Legal and regulatory requirements 
This trial will be carried out in accordance with: 
 
ICH guidelines for GCP, United States investigational new drug regulations (21 CFR 312), 
the regulations on electronic records and electronic signature (21 CFR 11), the most recent 
guidelines of the Declaration of Helsinki, and the relevant laws and regulations of the country 
in which the trial takes place 
 
Standard operating procedures for clinical investigation and documentation in force at 
Synteract 

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12. Trial administration 
12.1 Responsibilities 
Zealand Pharma A/S is the sponsor of this trial. Synteract, a contract research organization, will 
organize the performance of this trial.  
A list with the names and addresses of the responsible institutions and persons is provided in 
Appendix 1 of this protocol. 
12.2 Protocol deviations 
Before data are released for statistical analysis, a treatment-masked review of all data will take 
place to identify protocol deviations that may potentially affect the results. This review will be 
performed without revealing to which trial product the patients were assigned. The masking of the 
trial products will be maintained for everyone involved in allocating patients to the analysis sets 
until data are released for statistical analysis. Furthermore, spurious outliers will be evaluated. In 
addition, protocol deviations that may potentially affect the results will be identified and it will be 
evaluated if patients and/or data should be excluded from the analysis. Protocol deviations will 
be classified as minor or major in a consistent way. Major deviations from the protocol may lead 
to the exclusion of a patient from the PPS. 
Major protocol deviations may include deviations related to trial inclusion or exclusion criteria, 
conduct of the trial, patient management or patient assessment. Unless explicitly decided 
otherwise during the treatment-masked data review, the following will be considered major 
protocol deviations: 
 
Violation of one or more major inclusion/exclusion criteria 
 
Interruption of administration of trial product 
 
Significant deviation from time windows  
 
Incorrect treatment allocation 
 
Missing primary endpoint. 
The violation of several major inclusion/exclusion criteria or the complete absence of efficacy data 
might lead to exclusion of the patient from the FAS. In that case, the decision should be taken at 
the treatment-masked data review meeting, and the exclusion from efficacy analysis will be 
justified in the signed notes of the meeting. 
Obviously erroneous data points may be excluded from the analyses or re-analyzed (in case of, 
for example, serum concentrations). The decision to re-analyze or exclude data points from the 
statistical analysis is the joint responsibility of the sponsor and the trial statistician.  
The patients or observations to be excluded and the reason for their exclusion will be documented 
and signed by those responsible prior to database release. The documentation will be stored 
together with the remaining trial documentation. The patients and observations excluded from 
analysis sets, and the corresponding reasons, will be described in the clinical trial report.  
12.3 Protocol changes  
This trial protocol may be amended following the procedures specified by local laws and 
regulations. Substantial amendments to this trial protocol may be implemented only if the approval 
of the CA(s) and a favorable opinion of the ethics committee(s) have been obtained. 
Substantial amendments to the conduct of the clinical trial may arise from changes to the protocol 
or from new information relating to the scientific documents in support of the trial. Amendments 
to the trial are regarded as “substantial” where they are likely to have a significant impact on one 
of the following: 

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 
The safety, physical health and mental integrity of the patients 
 
The scientific value of the trial 
 
The conduct or management of the trial 
 
The quality or safety of any investigational medicinal product used in the trial 
If a new event occurs related to the conduct of the trial or the development of the investigational 
product, which may affect the safety of the patients, the sponsor and the investigator will take 
appropriate safety measures to protect the patients against any immediate hazard. The sponsor 
will immediately inform the CA(s) and ethics committee(s) of the new events and the measures 
taken. 
12.4 Reports and publications  
The information obtained during the conduct of this trial is considered confidential and may be 
used by or on behalf of Zealand Pharma A/S for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Zealand Pharma A/S in connection 
with this trial will remain the sole property of Zealand Pharma A/S and is to be considered 
confidential information. 
No confidential information will be disclosed to others without prior written consent from Zealand 
Pharma A/S. Such information will not be used except in the performance of this trial. The 
information obtained during this trial may be made available to other physicians who are 
conducting other clinical trials with the trial product, if deemed necessary by Zealand Pharma A/S. 
Provided that certain conditions are fulfilled, Zealand Pharma A/S may grant access to information 
obtained during this trial to researchers who require access for research projects studying the 
same disease and/or trial product studied in this trial.  
One investigator will be appointed to review and sign the clinical trial report (signatory investigator) 
on behalf of all participating investigators. 
Communication of results 
No permission to publish will be granted to any CRO involved in the trial.  
The results of this trial will be subject to public disclosure on external websites according to 
international and national regulations. 
Zealand Pharma A/S reserves the right to defer the release of data until specified milestones are 
reached, for example when the clinical trial report is available. This includes the right not to release 
the results of interim analyses because the release of such information may influence the results 
of the entire trial. 
At the end of the trial, one or more scientific publications (including abstracts, posters and 
presentations) may be prepared collaboratively by the investigator(s) and Zealand Pharma A/S. 
Zealand Pharma A/S reserves the right to postpone publication and/or communication for up to 
60 days to protect intellectual property. In all cases, the trial results will be reported in an objective, 
accurate and balanced manner. In the event of any disagreement on the content of any 
publication, the opinions of both the investigators and Zealand Pharma A/S will be fairly and 
sufficiently represented in the publication. 
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors. 
12.5 Retention of trial records 
The investigator must retain records and documents pertaining to the conduct of the trial and the 
distribution of the investigational product (e.g. informed consent forms, laboratory slips, 
medication inventory records and other pertinent information) according to local requirements. 

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To meet regulatory requirements, the eCRF data will be electronically stored at centers. The 
CDISC ODM (see http://www.cdisc.org/ for details) will be used to store and archive all electronic 
data at the centers. Since CDISC ODM is also the source for the EDC web-based system, no 
transcription of data is necessary. CDISC ODM is a platform-independent standardized data 
format including the complete trial metadata and audit trail. The data can be reviewed at a later 
stage using off-the-shelf tools. CDISC provides a complete CDISC ODM Viewer for these 
purposes. If needed, PDF files can be created from the ODM file. 
After trial completion at sites in the US, the investigator will retain and preserve 1 copy of all data 
generated in the course of the trial, specifically including, but not limited to, those defined by GCP 
as essential until: 
 
At least 2 years after the last marketing authorization for the trial product has been approved 
or the sponsor has discontinued its research with the trial product, or 
 
At least 2 years have elapsed since the formal discontinuation of clinical development of the 
trial product 
However, these documents should be retained for a longer period if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator will notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor will have 30 days to respond to the investigator’s notice, 
and the sponsor will have a further opportunity to retain such materials at the sponsor’s expense. 
After trial completion at sites in Europe, the sponsor will receive a copy of their data in electronic 
format (e.g. CD) and retain them for at least 25 years. 
One copy will remain with the investigator. The investigator will arrange for the retention of the 
patient identification codes, patient files, and other source data until at least 5 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed since 
the formal discontinuation of the clinical development of the product. These documents need to 
be retained for a longer period of time if required by applicable regulatory authorities or by 
agreement with the sponsor. 
The investigator will keep copies of these trial records (and all trial-related documents, including 
source data) for the maximum period of time permitted by the hospital, institution, or private 
practice. 

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13. References  
1. 
American Diabetes Association. Standards of medical care in diabetes - 2016. Diabetes 
Care 2016; 39 (Suppl. 1):S1-S112. 
2. 
Dasiglucagon Investigator Brochure, Edition 4, 25 Oct 2017. Zealand Pharma A/S. 
3. 
Diderichsen PM. Population PK and population PKPD modeling and simulation of 
dasiglucagon in patients with type I diabetes mellitus. 2016 Zealand Pharma report 16-147. 
4. 
Diderichsen PM. Model-based simulation of paediatric dasiglucagon exposure and glucose 
response. Zealand Pharma report 17-094. 2017 
5. 
European Commission. Ethical considerations for clinical trials on medicinal products 
conducted with minors Revision 1. 18 Sep 2017. Available at: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/2017_09_18_ethical_consid_ct_with_minors.pdf 
6. 
Holst JJ, Albrechtsen NJW, Pedersen J, Knop FK. Glucagon and amino acids are linked in 
mutual feedback cycle: The liver-α-cell axis. Diabetes 2017; 66(2): 235-40. 
7. 
Novo Nordisk. Summary of Product Characteristics. GlucaGen® HypoKit 1 mg powder and 
solvent for solution for injection. Available at: 
http://www.medicines.org.uk/emc/medicine/4258/SPC/GlucaGen®+Hypokit+1+mg. 
8. 
Rickels MR, Ruedy KJ, Foster NC, Piché CA, Dulude H, Sherr JL, et al. Intranasal 
Glucagon for treatment of insulin-induced hypoglycemia in adults with type 1 dabetes: A 
randomized crossover noninferiority study. Diabetes Care. 2016 Feb;39(2):264-70.  
9. 
Seaquist ER, Anderson J., Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: A report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care 2013; 36(5):1384-95. 
10. 
Sherr JL, Ruedy KJ, Foster NC, Piché CA, Dulude H, Rickels MR, et al. Glucagon nasal 
powder: A promising alternative to intramuscular glucagon in youth with type 1 Diabetes. 
Diabetes Care. 2016 Apr; 39(4):555-62.  
11. 
United States. Food and Drug Administration. General clinical pharmacology 
considerations for pediatric studies for drugs and biological products. Guidance for 
industry. Draft guidance. 2014. Available at:  
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/
ucm425885.pdf. 
 
 

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APPENDIX 1: 
List of names and addresses 
Sponsor 
Zealand Pharma A/S 
Smedeland 36 
2600 Glostrup, Copenhagen 
Denmark 
 
Contract Research 
Organization (CRO) 
Synteract Deutschland GmbH 
Albrechtstr. 14 
80636 Munich, Germany 
 
Coordinating investigator 
Prof. Dr. med. Thomas Danne 
Allgemeine Kinderheilkunde 
Diabetologie, Endokrinologie, Klinische Forschung Diabeteszentrum 
für Kinder und Jugendliche AUF DER BULT 
Kinder- und Jugendkrankenhaus 
Janusz-Korczak-Allee 12 
30173 Hannover, Germany 
  
Trial monitor 
To be decided  
Synteract Deutschland GmbH 
Albrechtstr. 14 
80636 Munich, Germany 
 
Statistician 
 
Senior Director Biometrics EMEA 
Synteract Deutschland GmbH 
Albrechtstr. 14 
80636 Munich, Germany 
 
 
Sponsor representative 
 
Clinical Project Director  
Zealand Pharma A/S 
Smedeland 36, 2600 Glostrup, Denmark 
Tel: 
 
E-mail: 
 
Sponsor’s medical expert 
Dr. 
 
Medical Director  
Zealand Pharma A/S 
Smedeland 36, 2600 Glostrup, Denmark 
Tel: 
 
E-mail: 
  
 
Sponsor representative for 
pharmacovigilance 
 
PharmaLex A/S Agern Allé 24, 2970 Hørsholm, Denmark 
Tel: 
 (8 a.m. to 4 p.m.) 
 
 (outside 8 a.m. to 4 p.m.)   
Fax:  
 
E-mail: drugsafety@lindeq.com 
 
 
Clinical laboratory 
MLM Medical Labs GmbH  
Dohrweg 63 

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41066 Mönchengladbach 
Germany  
Phone +49 2161 4642 0 
Fax +49 2161 4642 190 
E-mail info@mlm-labs.com 
 
Analytical laboratory 
(ZP4207 PK, ZP4207 ADA, 
Glucagon ADA) 
 
 
 
 
 
 
 
 
(ZP4207 and Glucagon Nab) 
York Bioanalytical Solutions (YBS) 
 (ZP4207 Bioanalysis)  
 (ADA analyses) 
Cedar House  
Northminster Business Park  
Northfield Lane  
York, YO26 6QR 
United Kingdom 
E-mail: 
 
E-mail: 
 
 
 
BioAgilytix Labs 
2300 Englert Drive 
Durham, NC 27713 
USA 
E-mail: 
 
 
Abbreviations: ADA=Anti-drug antibody; Nab=Neutralizing antibody; PK=Pharmacokinetics