Conditions: Hypoglycemia
Keywords: Glucagon Dasiglucagon
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 42
Healthy volunteers: no

Brief summary:
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 type 1 diabetes mellitus (T1DM) treated with insulin

Detailed description:
At least 40 children ≥6 years and \<18 years of age with T1DM were planned to be randomized into the trial (2:1:1 for dasiglucagon:placebo:GlucaGen) and stratified by age intervals: 6 years to \<12 years, and 12 years to \<18 years; and by injection site (abdomen or thigh). A minimum of 16 patients were enrolled into each age group, including a minimum of 8 patients in each age group in the dasiglucagon treatment arm. In Germany only, a staggered approach was applied, whereby a positive safety assessment needed to be available for at least 10 patients in the age group of 12 years to \<18 years who had completed the dosing visit in the overall trial before younger patients (6 to 11 years of age) were allowed to be enrolled.

Arms:
arm 1: Single fixed dose (s.c.injection) of dasiglucagon arm 2: Single fixed dose (s.c.injection) of placebo arm 3: Single fixed dose (s.c.injection) of GlucaGen®

Interventions: intervention 1: dasiglucagon intervention 2: placebo intervention 3: GlucaGen HypoKit
Intervention descriptions: intervention 1: glucagon analog intervention 2: placebo for dasiglucagon intervention 3: native glucagon

Protocol document:
Prot_000.pdf: 
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 
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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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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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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, 
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 
 


 
 
 
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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 
 

SAP_001.pdf: 
CLINICAL TRIAL REPORT  
ZP4207-17086 (ZEA-DNK-02170) 
 
 
Section 16.1.9: Documentation of Statistical Methods 
16.1.9 
DOCUMENTATION OF STATISTICAL METHODS 
 
This appendix includes 
 
Document 
Date, Version 
Statistical Analysis Plan  
Version 1.0 Date 16 August 2019 
 


 
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CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019.docx 
 
 
 
Statistical Analysis Plan 
 
Sponsor: Zealand Pharma A/S 
Protocol Number ZP4207-17086 (ZEA-DNK-02170) 
 
Study 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 
Protocol Version 3.0: 08 January 2019 
 
 
 
Sponsor:  
 
Zealand Pharma A/S 
 
 
 
Smedeland 36 
 
 
 
2600 Glostrup, Copenhagen 
 
 
 
Denmark 
 
 
Prepared by:  
, Synteract  
Albrechtstr.14, 80636 Munich, Germany 
 
 
Version 
Date 
Draft 0.1 
10APR2019 
Draft 0.2 
06JUN2019 
Draft 0.3 
14JUN2019 
Draft 0.4 
28JUN2019 
Draft 0.5 
17JUL2019 
Draft 0.6 – pre-final version 
22JUL2019 
1.0 
16AUG2019 




 
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16 August 2019 
 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ........................................................................................................................................ 5 
1. 
INTRODUCTION ............................................................................................................................................ 7 
2. 
STUDY DOCUMENTS ..................................................................................................................................... 7 
3. 
STUDY OBJECTIVES ....................................................................................................................................... 7 
3.1 PRIMARY OBJECTIVE ................................................................................................................................................. 7 
3.2 SECONDARY OBJECTIVE ............................................................................................................................................. 7 
4. 
STUDY DESIGN AND PLAN ............................................................................................................................. 7 
5. 
DETERMINATION OF SAMPLE SIZE ................................................................................................................ 8 
6. 
GENERAL ANALYSIS CONSIDERATIONS ......................................................................................................... 9 
7. 
NOTATION OF TREATMENT GROUPS AND VISITS ........................................................................................ 10 
8. 
ANALYSIS SETS ............................................................................................................................................ 10 
9. 
STUDY POPULATION ................................................................................................................................... 11 
9.1 
PATIENT DISPOSITION ......................................................................................................................................... 11 
9.2 
PROTOCOL DEVIATIONS ....................................................................................................................................... 11 
9.3 
ELIGIBILITY ........................................................................................................................................................ 11 
9.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................................................................................................... 12 
9.5 
CONCOMITANT MEDICATIONS AND CURRENT DIABETES TREATMENT  ........................................................................... 13 
10. 
EFFICACY ANALYSES .................................................................................................................................... 13 
10.1 
EFFICACY VARIABLES ...................................................................................................................................... 14 
10.2 
BASELINE VALUES .......................................................................................................................................... 14 
10.3 
ADJUSTMENTS FOR COVARIATES ....................................................................................................................... 14 
10.4 
HANDLING OF DROPOUTS OR MISSING DATA ...................................................................................................... 14 
10.5 
INTERIM ANALYSIS AND DATA MONITORING ....................................................................................................... 14 
10.6 
EXAMINATION OF SUBGROUPS ......................................................................................................................... 15 
10.7 
MULTIPLE COMPARISON/MULTIPLICITY ............................................................................................................. 15 
10.8 
MULTICENTER STUDIES ................................................................................................................................... 15 
11. 
METHODS OF EFFICACY ANALYSIS .............................................................................................................. 15 
11.1 
PRIMARY EFFICACY ANALYSES .......................................................................................................................... 15 
11.2 
SECONDARY EFFICACY ANALYSES ...................................................................................................................... 18 
12. 
PHARMACOKINETIC ANALYSES ................................................................................................................... 18 
12.1 
DATA HANDLING ...................................................................................................................................... 19 
12.2 
PRESENTATION OF PLASMA CONCENTRATIONS AND PK METRICS ............................................................. 20 
13. 
PHARMACODYNAMIC ENDPOINTS ............................................................................................................. 21 
14. 
SAFETY ANALYSES ....................................................................................................................................... 22 
14.1 
EXTENT OF EXPOSURE..................................................................................................................................... 22 
14.1.1 
INSULIN ADMINISTRATION PRIOR TO THE HYPOGLYCEMIA INDUCTION PROCEDURE .................................................. 22 
14.1.2 
HYPOGLYCEMIA INDUCTION PROCEDURE ....................................................................................................... 22 
14.1.3 
TRIAL MEDICATION ADMINISTRATION ............................................................................................................ 22 


 
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16 August 2019 
 
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14.1.4 
POST-TREATMENT RESCUE GLUCOSE INFUSION ................................................................................................ 23 
14.2 
LOCAL TOLERABILITY ...................................................................................................................................... 23 
14.3 
ADVERSE EVENTS........................................................................................................................................... 24 
14.3.1 
SUMMARY OF ADVERSE EVENTS ........................................................................................................... 24 
14.3.2 
ADVERSE EVENT TABLES ...................................................................................................................... 25 
14.4 
CLINICAL LABORATORY EVALUATION ................................................................................................................. 26 
14.4.1 
GENERAL .............................................................................................................................................. 26 
14.4.2 
HEMATOLOGY ...................................................................................................................................... 27 
14.4.3 
BIOCHEMISTRY ..................................................................................................................................... 27 
14.4.4 
COAGULATION...................................................................................................................................... 27 
14.4.5 
URINALYSIS .......................................................................................................................................... 27 
14.4.6 
PREGNANCY TEST ................................................................................................................................. 27 
14.4.7 
ALCOHOL BREATH TEST........................................................................................................................ 27 
14.5 
VITAL SIGNS ................................................................................................................................................. 27 
14.6 
PHYSICAL EXAMINATION ................................................................................................................................. 27 
14.7 
ELECTROCARDIOGRAM .................................................................................................................................... 27 
14.8 
IMMUNOGENICITY ......................................................................................................................................... 28 
15. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ........................................................................................... 28 
1. 
REFERENCES ............................................................................................................................................... 29 
2. 
APPENDICES ............................................................................................................................................... 30 
APPENDIX A: PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS .......................................................................... 30 
APPENDIX B: SAS PROGRAMMING QC REQUIREMENTS ...................................................................................................... 33 
APPENDIX C:  LIST OF TABLES, FIGURES, AND LISTINGS ........................................................................................................ 36 
SECTION 14: TABLES, FIGURES, AND GRAPHS .................................................................................................................... 36 
SECTION 16.2: LIST OF DATA LISTINGS ............................................................................................................................ 42 
APPENDIX D: TABLE LAYOUTS ........................................................................................................................................ 45 
APPENDIX E: LISTING LAYOUTS ..................................................................................................................................... 110 


 
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LIST OF ABBREVIATIONS 
 
ADA 
anti-drug antibody 
AE 
adverse event 
BMI 
body mass index 
AESI 
adverse event of special interest 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CSR 
clinical study report 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
ICH 
International Council for Harmonisation  
IMP 
investigational medicinal product 
IV 
intravenous(ly) 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
mean residence time 
NPH 
neutral protamine Hagedorn 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s)  
PPS 
per protocol set 
PR 
PR interval; ie, 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 
QRS 
QRS interval; ie, 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; ie, 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 
QTc 
corrected QT interval 
QTcF 
QTc according to Fridericia’s formula 


 
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SAE 
serious adverse event 
T1DM 
type 1 diabetes mellitus 
TLF 
tables, listings, and figures 
 
 
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 infinitly 
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 
 


 
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1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Zealand Pharma A/S protocol ZP4207-17086. The purpose of this 
plan is to provide specific guidelines from which the statistical analyses will proceed. Any 
deviations from this plan will be documented in the clinical study report (CSR). 
 
2. STUDY DOCUMENTS 
The following study documents are used for the preparation of the statistical analysis plan (SAP): 
 Protocol version 3.0, dated 08 January 2019 
 Annotated electronic case report form (eCRF) version 1.0, 11 September 2018 
 Data management plan version 1.0, 23 August 2018 
 
3. STUDY OBJECTIVES 
3.1 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 type I diabetes mellitus (T1DM) 
3.2 Secondary Objective 
 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 
4. STUDY 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 versus placebo and versus 
GlucaGen® in children with T1DM. At the time of protocol finalisation it was 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 4-1). 
 A screening period from Day -30 to Day -3 


 
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 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 visit at Day 28 (the end-of-trial visit) 
 
Figure 4-1 Overview of the Trial Design 
 
Abbreviation: PK=pharmacokinetic 
The schedule of assessments (refer to the study protocol) gives an overview of the trial 
procedures. Patients should attend all visits on the designated day or as close to it as possible.  
 
5. 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 


 
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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. 
6. GENERAL ANALYSIS CONSIDERATIONS 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). The 
International Council for Harmonisation (ICH) numbering convention will be used for all TLFs. 
Unless otherwise noted, all statistical testing will be 2-sided and will be performed at the 0.05 
significance level. Tests will be declared statistically significant if the calculated P value is 
≤0.05.  
 
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. 
 
Continuous variables will be summarized with means, standard deviations, medians, minimums, 
and maximums and valid cases. Other summaries (eg, quartiles, 5%, 95% intervals) may be used 
as appropriate.  For  PK parameters except Tmax, geometric mean and geometric %  CV will be 
calculated. 
 
Categorical variables will be summarized by counts and by percentage of patients in 
corresponding categories. Percentages for missing values are omitted and do not account for the 
percent calculation of other categories. Percentages are routinely based on the total category 
count excluding the missing category if not otherwise mentioned. Percentages showing a rate 
relative to the total number of patients in this group are given in special tables (eg, adverse event 
[AE] tables). Footnotes will specify the percent basis in those cases. 
 
All summary tables will be presented by treatment group if possible and also include a total 
summary column. 
 
Individual patient data obtained from the eCRFs, external vendors, and any derived data will be 
presented by patient in data listings. 
 
The analyses described in this plan are considered a priori, in that they have been defined prior to 
breaking the blind.  
 
Any analyses performed subsequent to breaking the blind will be considered post hoc and 
exploratory. Post hoc analyses will be labeled as such on the output and identified in the CSR. 
 
All analyses and tabulations will be performed using SAS software Version 9.4 or higher. 
Pharmacokinetic and pharmacodynamic (PD) analyses will be performed using Phoenix® 


 
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WinNonlin Version 6.4 or higher. Tables, listings, and figures will be presented in ASCII or 
RTF format.  
 
The process for SAS program validation and quality control (QC) for programs and outputs is 
documented in the Synteract working instruction “SAS programming quality control.” 
Study-specific QC requirements can be found in Appendix B: SAS Programming QC 
Requirements. 
 
7. NOTATION OF TREATMENT GROUPS AND VISITS 
Notation of treatment groups 
 
The following notation of treatment groups will be used throughout the report: 
Full notation (as used in the study protocol) 
Notation as used throughout all 
tables, listings, and figures 
Dasiglucagon, liquid formulation, 1 mg/mL, 0.6 mL 
dasiglucagon 
1 mg lyophilized powder for reconstitution (GlucaGen®, 
Novo Nordisk) 
GlucaGen 
Placebo treatment: Placebo, liquid formulation, 0.6 mL 
Placebo 
 
Visit terminology 
 
Visit 
Notation as used throughout all tables, 
listings, and figures 
V1 Screening 
Screening 
V2 Dosing 
Dosing 
V3 Follow up 
Follow up 
 
8. ANALYSIS SETS 
For the statistical analysis, the randomized patients will be divided up into the following datasets. 
The following definitions are applicable: 
 
Safety analysis set  
All patients who were randomized and received at least 1 dose 
of trial product. Treatment assignment will be based on the 
treatment actually received.  
Full analysis set (FAS) 
All patients of the safety analysis set. Treatment assignment 
will be based on the randomized treatment. Assignment to the 
stratification factor injection site will be based on the planned 


 
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and not the actual used injection site. 
Per protocol set (PPS) 
All patients of the FAS for whom no relevant protocol 
deviations were documented. Treatment assignment will be 
based on the randomized treatment. Assignment to the 
stratification factor injection site will be based on the planned 
and not the actual used injection site. 
 
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 safety analysis 
set. 
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 before breaking the blind. 
  
9. STUDY POPULATION 
9.1 Patient Disposition 
Patient disposition information will be summarized for all patients by treatment group. 
Summaries will include: the number of patients screened, the number of randomized patients, 
and the number of patients in each analysis set. 
 
The number of patients who completed or discontinued the study will be tabulated by treatment. 
In addition, for patients who discontinued, the primary reason will be tabulated by treatment 
group. 
 
Patient numbers and percentages in each country and patient numbers and percentages in each 
country and center will be presented by treatment group. 
In additon, the number of patient numbers and percentages of US versus non-US countries will 
be tabulated by treatment group. 
 
9.2 Protocol Deviations 
A listing of all protocol deviations including the deviation designation (relevant/non-relevant), 
category, and indication of whether the deviation led to an exclusion of a patient from the PPS 
will be presented in a data listing.   
 
9.3 Eligibility 
A listing of patients not fulfilling any eligibility criteria will be created. This listing will consider 
and differentiate eligibility criteria at screening as well as the re- check of dosing day exclusion 
criteria. 


 
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9.4 Demographic and Baseline Characteristics 
Demographic variables include: age, age group (6-11 years, 12-17 years), sex, childbearing 
potential, ethnicity, and race.  
 
Summary statistics will be presented for the above-mentioned variables by treatment group. 
 
Other baseline characteristics include: diabetes history, medical history and body measurements 
(height, weight, BMI).  
BMI will be additionally classified into the following categories: 
<25 
 25-<30 
30-<35 
>=35 
A summary table for BMI by BMI class and country will be created. In addition, this table will 
show BMI classes of US versus non-US countries. 
 
Diabetes history 
Time since diagnosis of diabetes 1 (based on date of informed consent and start date of diabetes 
1) (years) will be tabulated with descriptive statistics by treatment group. If the day is not 
available, the calculation of duration will be based on month and year only, setting the start day 
to 1. In case only the year is available, the start day will be 1 and the start month will be January. 
 
Body measurements 
 
Separate descriptive statistics will be presented for body measurements (height, weight, BMI) by 
treatment group. 
 
Medical history 
The verbatim term of the medical history condition/event will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA), version 22.0.  
A summary will be prepared by treatment group. The summary will show the system organ class 
and preferred terms ordered by descending order of incidence of system organ class and 
preferred term within each system organ class.  
 
Demographic and baseline characteristics will be summarized for the safety analysis set and 
FAS. If the safety analysis set and FAS are identical, then it will be sufficient to state this in the 
table output section. 
 
Other information documented at screening 
Analyses of other screening or baseline variables as listed below, which are documented at 
screening/baseline and/or have further evaluations after the screening/baseline visit will be 
described in subsequent sections. 
 


 
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 Physical examination  
 Vital signs 
 12-lead electrocardiogram (12-lead ECG)  
 Central safety laboratory (hematology, biochemistry, coagulation, urinalysis) 
 Antibody serum sample for immunogenicity measurements 
9.5 Concomitant Medications and Current Diabetes Treatment  
Concomitant medication and current diabetes treatment verbatim terms in the eCRFs will be 
mapped to Anatomical/Therapeutic/Chemical (ATC) class and preferred names using the 
WHODrug Global (version March 2018). 
 
All concomitant medications and current diabetes treatment will be listed as documented in the 
eCRF. In this listing the WHODrug coding including the drug name as documented in the eCRF, 
the drug name used for the coding, the preferred term, the ATC code and the ATC term will be 
included as well.  
Coding will be done using ATC level 4, which will be presented in the listings.  
 
Concomitant medications and current diabetes treatment will be summarized for each treatment 
by WHO ATC class (level 2) and preferred name. These summaries will present the number and 
percentage of patients using each medication. Patients may have more than 1 medication per 
ATC class and preferred name. At each level of patient summarization, a patient is counted once 
if he/she reported 1 or more medications at that level. Each summary will be ordered by 
descending order of incidence of ATC class and preferred name within each ATC class. 
 
In case the centers also captured true prior medications, this will only be listed and a flag will be 
included in the raw data listing denoting whether the medication is prior or concomitant. 
 
The distinction between previous and concomitant medication will be done as follows: 
 Prior medication is all medication which stopped before the first investigational 
medicinal product (IMP) administration within the trial context, independent from start 
date.  
 Concomitant medication is all medication that started prior to the first IMP administration 
and is still ongoing or stopped at date of first study drug intake - or medication that 
started at/after the date of the first drug intake. 
 If the start or stop date is incomplete and the allocation to previous or concomitant is not 
clear, the medication will be considered to be concomitant. 
10. EFFICACY ANALYSES 
The primary efficacy analysis will be based on the FAS. Analogous supportive sensitivity 
analyses will be conducted in the PPS, but without inference intent. 


 
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10.1 Efficacy Variables 
The primary efficacy variable is: 
 
 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 procedure1 without administration of rescue intravenous (IV) glucose. Time to 
recovery is considered only within the first 45 minutes from baseline. 
In this trial, plasma glucose for pharmacodynamics is reported with the unit ‘mmol/l’. For 
consistency, these results are converted into the unit ‘mg/dl’ by using the conversion 
factor 0.0555 (i.e. Glucose [mg/dl]=Glucose [mmol/l] /0.0555). 
 
Secondary efficacy variables include the following: 
 
 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 at 30 minutes, at 20 minutes, at 15 minutes, and at 
10 minutes after study drug injection or at the time of rescue IV glucose. 
10.2 Baseline Values 
Unless otherwise noted, baseline is defined as the last non-missing value recorded prior to the 
first dose of study drug. Unscheduled visits will be used in the determination of baseline values, 
when applicable. 
10.3 Adjustments for Covariates 
The model for the primary efficacy will include adjustments for the following covariates:  
 Age group: 6-11 years, 12-17 years 
 Injection site: abdomen/thigh 
10.4 Handling of Dropouts or Missing Data 
Only non-missing cases will be analyzed, ie, no imputation technique like last observation 
carried forward will be applied. Summaries will be based on observed data only. 
10.5 Interim Analysis and Data Monitoring 
There are no planned interim analyses for this study. 
                                                 
1 For simplification the addition ‘during the hypoglycemic clamp procedure’ will be omitted further on. 


 
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10.6 Examination of Subgroups 
No subgroup analysis is planned. 
10.7 Multiple Comparison/Multiplicity 
For the confirmatory analyses of the primary and secondary endpoints, patients treated with 
either dasiglucagon 0.6 mg and or placebo 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.  
 
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: 
 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 at 30 minutes, at 20 minutes, at 15 
minutes, and at 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. 
Moreover, the comparison of dasiglucagon versus GlucaGen® is not part of this hierarchial 
testing procedure. 
 
10.8 Multicenter Studies 
This is a multicenter study, having approximately 5 centers participating in the study. The factor 
center will not be accounted for in the primary statistical analysis model. 
 
 
11. METHODS OF EFFICACY ANALYSIS 
11.1 Primary Efficacy Analyses 
The primary endpoint, time to plasma glucose recovery, will be summarized using Kaplan-Meier 
estimates per treatment group.  


 
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The actual time points at 0, 4, 6, 8, 10, 12, 15, 17, 20, 30, 45 and 60 minutes will be used in the 
analyses. 
Kaplan-Meier plots will be created showing the the estimated survival function for each 
treatment in one plot. 
In the primary analysis, recovery cannot be achieved in those subjects where rescue IV glucose 
treatment is administered. Those subjects who receive rescue IV glucose will be censored (and 
set to ‘not recovered’) at 45 minutes after dosing. 
For patients who did not recover within 45 minutes after dosing, time to recovery is censored at 
45 minutes. 
 
The 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®, but not considered for the confirmatory hierarchial testing procedure. 
 
In order to facilitate this, SAS procedure proc lifetest is used. The following code will be used, 
but minor variations can be applied during programming: 
 
proc lifetest data=xx  plots=survival(atrisk=0 10 15 20 30 45); 
   time aval * Status(0); 
   strata age site/ group= treat test=logrank diff=all; 
   run; 
 
 
where “aval” is the time to plasma recovery, and “status” is a censor variable for patients who 
receive IV glucose. Age group and injection site are the stratification variables and “treat” the 
planned treatment assignment. 
 
The unstratified result of the log-rank test can be obtained from the following code: 
proc lifetest data=xx  plots=survival(atrisk=0 10 15 20 30 45); 
   time aval * Status(0); 
   strata treat / test=logrank diff=all; 
   run; 
In sensitivity analyses, the time to plasma glucose recovery will be analyzed  
1) without censoring for those subjects who require rescue IV glucose before 45 minutes and  
2) with censoring at the time of administration of rescue IV glucose before 45 minutes. 
As a supportive analysis to the stratified log-rank test for the time to plasma glucose recovery, 
dasiglucagon will be compared to placebo using a Wilcoxon test stratified by age group and 
injection site. 
To graphically describe recovery in time, a histogram showing the proportion of patients that 
recovered at each time interval will be created, one for each treatment group. 
The primary endpoint will additionally be analyzed using a discrete-time Cox proportional 
hazards (CPH) time to event statistical model, if the hazards by treatment group can be assumed 


 
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proportional using a graphical comparison of log-minus-log survival curves and no more than 
two-thirds of the recovery times are censored in each treatment group. The CPH model will be 
used for descriptive purposes, with treatment group, age group and injection site modeled as 
categorical effects, and baseline plasma glucose modelled as a continuous covariate. The 
treatment group hazard ratios of active versus placebo, will be estimated together with the 95% 
confidence intervals, and pairwise treatment group inferences (dasiglucagon vs placebo, 
GlucaGen vs placebo, dasiglucagon vs GlucaGen) will be evaluated using least-square mean and 
standard deviation estimates. 
Due to the discrete nature of blood sampling in time, and the fact that there must be a true, but 
unmeasured, ordering of the recovery times, the method using the “exact discrete” partial 
likelihood for tied failure times will be applied. In SAS, this is implemented in the phreg 
procedure with the option ties=discrete. The influence of age and injection site on time to 
recovery will also be evaluated in the proportional hazards model by a ‘type 3’ test in the phreg 
procedure. 
 
In addition, separate CPH models will be calculated to evaluate homogenicity for the following 
factors: 
Sex, BMI class, ethnicity, race, US/non-US. 
 
These additonal homogenicity models are only presented for the primary efficacy analysis, but 
not for subseqent variants of that analysis.  
 
To obtain an estimate of these true, but unassessed, patient recovery times, a linear interpolation 
(between the two time points before and after recovery is observed) will be carried out to 
estimate the patients’ actual time of recovery. These derived recovery times will be described 
and analysed in the same manner as for the discrete times above. 
 
Let t1 and t2 be the 2 time points before and after recovery is observed and y1 and y2 be the 
corresponding changes from baseline in glucose concentrations, where y1 is below 20 mg/dL and 
y2 is greater than 20 mg/dL. 
 
The interpolated time point text is calculated then as: 
 
)
(
)
(
*
)
20
(
1
2
1
2
1
1
y
y
t
t
y
t
text





 
 
This linear interpolation is only used as a supportive analysis to the primary analysis model using 
proc lifetest. 
In this statistical model, ties=exact will be used. 


 
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11.2 Secondary Efficacy Analyses 
The secondary efficacy endpoints are plasma glucose recovery within 10, 15, 20 and 30 minutes 
after trial product injection, ie, achieving a ≥20 mg/dL increase in plasma glucose from baseline 
at 0 to 10, 15, 20, and 30 minutes.  
Actual timepoints of sampling will be used for this calculation.  
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 
dasiglucagon and Placebo will be compared by a Cochran-Mantel-Haenszel test stratified by age 
group and injection site. The treatment responder rates with the 95% confidence intervals will be 
presented for the 10-, 15-, 20-, and 30-minute endpoints. 
 
If due to small or zero cell counts the Cochran-Mantel-Haenszel test fails, non-stratified Fisher 
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.  
The change from baseline is calculated using the nominal sampling time. 
 
Least-square mean adjusted treatment means will be presented with their 95% confidence 
intervals including the 95% confidence intervals for the treatment difference. The analysis of 
variance at each of the 4 time points will also be used to test the difference of dasiglucagon and 
Placebo adjusted for age group and injection site. 
 
  
12. PHARMACOKINETIC ANALYSES 
Plasma dasiglucagon and glucagon concentrations will be described and the following 
parameters are calculated and summarized with descriptive statistics: 
 
PK parameter 
PK parameter 
abbreviation 
Calculation 
Area under the plasma 
dasiglucagon or GlucaGen® 
concentration versus time curve 
from 0 to 30 minutes post-dose  
AUC0-30min 
Linear trapezoidal rule for the ascending 
part of the concentration-time curve, 
logarithmic trapezoidal rule for the 
descending part. 
Area under the plasma 
dasiglucagon or GlucaGen® 
concentration versus time curve 
AUC0-300min 
Linear trapezoidal rule for the ascending 
part of the concentration-time curve, 
logarithmic trapezoidal rule for the 


 
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PK parameter 
PK parameter 
abbreviation 
Calculation 
from 0 to 300 minutes post-
dose  
descending part. 
Area under the plasma 
dasiglucagon or GlucaGen® 
concentration versus time curve 
from 0 to infinitely post-dose  
AUC0-inf 
(AUClast + Clastobs)/ λz, where Clastobs is the 
concentration corresponding to Tlast (time 
of last measurable (positive) concentration). 
Maximum of all valid plasma 
dasiglucagon or GlucaGen® 
concentration measurements 
from 0 to 300 minutes post-
dose  
Cmax 
Taken directly from analytical data, selected 
from individual concentration data. The 
time when the first occurrence of Cmax is 
taken as Tmax. 
Time to maximum of plasma 
dasiglucagon or GlucaGen® 
concentration measurements  
tmax 
Taken directly from analytical data, selected 
from individual concentration data 
Terminal elimination rate 
constant of plasma 
dasiglucagon or GlucaGen®  
λz 
Calculated by linear regression of the 
terminal linear portion of the log 
concentration vs. time curve. At least 3 
concentrations in the terminal elimination 
phase will be required to calculate λz. 
Terminal plasma elimination 
half-life of dasiglucagon or 
GlucaGen®  
t½ 
Ln(2)/ λz 
Total body clearance of plasma 
dasiglucagon or GlucaGen®  
CL/f 
Dose/ AUC0-inf 
Volume of distribution of 
plasma dasiglucagon or 
GlucaGen®  
Vz/f 
Dose/ (λz * AUC0-inf) or CL/f/ λz 
Mean residence time of plasma 
dasiglucagon or GlucaGen®  
MRT 
AUMCinf/ AUC0-inf where AUMCinf is the 
area under the first moment curve as 
estimated by WinNonlin. 
 
 
The PK metrics as listed above will be obtained by non-compartmental analysis using the 
computer programs Phoenix® WinNonlin Version 6.4. 
 
12.1 Data Handling 
Plasma dasiglucagon and GlucaGen® are determined at 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 


 
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minutes between t=140 minutes and t=240 minutes. Pre-dose is defined as within 2 minutes prior 
to dosing). 
 
Summary tables and figures for plasma concentrations: 
 
i.) 
For all pre-dose samples, the sampling time will be set to zero. 
ii.) 
For post-dose samples, the planned sampling time will be used in summary tables 
and the actual sampling times will be used for all figures of individual 
concentrations.  
iii.) 
All concentration values < lower limit of quantification (LLOQ) will be set to zero. 
iv.) 
Missing post-dose values will not be replaced. 
 
Determination of PK metrics: 
 
i.) 
For all pre-dose samples, the sampling time will be set to zero. 
ii.) 
For post-dose samples, the actual sampling time will be used. 
iii.) 
All pre-dose concentration values will be set to zero. 
iv.) 
Post-dose concentration values < LLOQ before tmax will be set to zero if there are 
no further concentrations > LLOQ at later time points. 
v.) 
Post-dose concentration values < LLOQ before tmax will be set to the lower limit of 
quantitation if there are further concentrations > LLOQ at later time points. 
vi.) 
Post-dose concentration values < LLOQ after tmax will be ignored if there are no 
further concentrations > LLOQ at later time points. 
vii.) 
Post-dose concentration values < LLOQ after tmax will be ignored if there are 
further concentrations > LLOQ at later time points. 
viii.) 
Missing post-dose values will not be replaced. 
 
PK metrics will be determined by Synteract. Plasma concentration data will be transferred from 
an external laboratory (York Bioanalytical Solutions (YBS), MLM laboratories) to Synteract as 
detailed in separate data transfer specifications.  
12.2 Presentation of Plasma Concentrations and PK metrics 
Individual plasma concentration results:  
A raw data listing will be provided displaying the concentration as reported, the result used in 
summary tables and mean time-concentration curves, and the change from pre-dose result. 
Results will be displayed using 3 significant digits. 
 
Summary statistics of plasma concentration table:  
Summary statistics of the plasma concentration by treatment group and time point will be 
presented. In addition, the change from pre-dose will be summarized. Results will be displayed 
using 3 significant digits. 
 
PK metrics:  


 
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Summary statistics of PK metrics will be presented by treatment group. Results will be displayed 
using 3 significant digits. 
 
Figures: 
1. Mean concentrations versus nominal time by treatment group using the original 
(untransformed) scale of concentrations. The curves of each treatment group will be put 
into 1 graph, having an overlay plot in the end with 2 curves for each treatment group. 
(Samples from patients receiving placebo will not be analyzed by the laboratories that 
will be analyzing for dasiglucagon and GlucaGen®.) 
2. Mean concentrations versus nominal time by treatment group using the log scale of 
concentrations. The curves of each treatment group will be put into 1 graph, having an 
overlay plot in the end with 2 curves for each treatment group. (Samples from patients 
receiving placebo will not be analyzed by the laboratories that will be analyzing for 
dasiglucagon and GlucaGen®.) 
3. Individual dasiglucagon and glucagon concentrations versus nominal time curves using 
the original concentration scale overlaying all patients per treatment group will be 
prepared.  
 
13. PHARMACODYNAMIC ENDPOINTS 
Plasma glucose is determined at 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 
 
The pharmacodynamic endpoint is the plasma glucose response as area under the effect curve 
above baseline from time 0 to 30 minutes (AUE0-30min). AUE0-30min will be calculated using SAS 
software. 
 
Individual plasma glucose concentration results:  
A raw data listing will be provided displaying the concentration as reported, the result used in 
summary tables and mean time-concentration curves and the change from pre-dose result.  
 
Summary statistics of plasma glucose concentration table:  
Summary statistics of the plasma glucose concentration by treatment group and time point will 
be presented. In addition, the change from pre-dose will be summarized.  
 
Pharmacodynamic metrics:  
Summary statistics of pharmacodynamic metrics will be presented by treatment group.  
 
Figures: 


 
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1. Mean glucose concentrations versus nominal time by treatment group using the original 
(untransformed) scale of concentrations. The curves of each treatment group will be put 
into 1 graph, having an overlay plot in the end with 2 curves for each treatment group.  
2. Individual glucose concentrations versus nominal time curves using the original 
concentration scale overlaying all patients per treatment group will be prepared. 
 
14. SAFETY ANALYSES 
All safety analyses will be based on the safety set. 
14.1 Extent of Exposure 
14.1.1 Insulin administration prior to the hypoglycemia induction procedure 
All details with regard to insulin administration prior to the hypoglycemia induction procedure 
will be listed. This includes whether the patient used multiple daily injections, long-acting 
insulin, short-acting insulin (except insulin glulisine [Apidra®]), insulin NPH, or insulin glulisine 
(Apidra®) or an insulin pump. 
 
A summary table will be prepared showing the number (percentage) of patients who used any of 
the following: 
 Multiple daily injections 
 Insulin NPH  
 Insulin pump  
 Insulin glulisine (Apidra®) 
14.1.2 Hypoglycemia induction procedure 
All details with regard to the hypoglycemia induction procedure will be listed. 
A summary table will be prepared showing the number (percentage) of patients where the 
hypoglycemia induction procedure was performed, the total amount of insulin administered to 
induce hypoglycemia and the total amount of glucose administered during the induction 
procedure. 
14.1.3 Trial medication administration 
All details with regard to the trial medication administration will be listed. 
A summary table will be prepared showing the number (percentage) of patients where the trial 
medication was administered. 


 
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14.1.4 Post-treatment rescue glucose infusion 
All details with regard to the post-treatment rescue glucose infusion will be listed. 
A summary table will be prepared showing the number (percentage) of patients where glucose 
was given as rescue medication. 
 
The time to first IV glucose infusion, after IMP administration (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. 
 
Time to first IV glucose infusion [minutes] is calculated as:  
 
Time of start of first glucose administration – Time of administration of study medication. 
No censoring is done in case no IV glucose infusion is given, ie, the descriptive statistics only 
show data when an infusion was given. 
14.2 Local Tolerability 
Local tolerability at the injection site is assessed at 30, 120, and 300 minutes after dosing and at 
Follow-up. 
The following symptoms are assessed: 
 Spontaneous pain 
 Pain on palpation 
 Itching 
 Redness 
 Edema 
 Induration/Infiltration 
 Other types of reaction 
 
All details of local tolerability assessment are listed. Any local reaction will also be reported as 
AE. 
 
 
The analysis of local tolerability will include a summary table displaying counts and percentages 
of patients experiencing local symptoms by time point, symptom and grade (intensity).  
 
The category “other types of reactions” will not be included in this summary due to lack of a 
distinct unique reaction term. 
 


 
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14.3 Adverse Events 
All AE summaries except for 1 overview table will be restricted to treatment-emergent AEs 
(TEAEs), which are defined as those AEs that occurred after dosing and those existing AEs that 
worsened during the study. A manual check is done for AEs that start prior dosing and continue 
after dosing whether the intensity of the AE worsened. 
 
If it cannot be determined whether the AE is treatment emergent due to a partial onset date, then 
it will be counted as such unless the end date is before dosing. Verbatim terms in the eCRFs will 
be mapped to preferred terms and system organ classes using the MedDRA, version 21.0 or 
higher.  
 
Each AE summary will be displayed by treatment group.  
 
Causal relationship: Causal relationship between the occurrence of an AE and the 
administration of the study drug is assessed by the investigator according to classification 
scheme 0=not related, 1=unlikely related, 2=possibly related and 3=probably related. Probable 
and possible relationship are subsumed under the category related. All AEs must have a causal 
relationship assigned. In case of a missing relationship, a query will be raised in order to obtain 
causality assessment. In case no clarification of relationship via query is possible the missing 
relationship will be set to related for the analysis. 
Severity: Severity grading will differ between 1=mild, 2=moderate and 3=severe. For AEs 
having a missing severity, the severity will not be imputed and kept as missing. 
14.3.1 Summary of adverse events 
An overview AE summary table will be prepared showing the number and percentage of patients 
with at least 1 event and the total number of events for the following selections: 
1. AEs during screening 
2. TEAEs  
3. TEAEs, which are adverse events of special interest (AESIs) 
4. TEAEs, which are an other important event 
5. TEAEs, which are injection site reactions based on investigator assessment in CRF 
6. Injection site reactions based on special search category provided by Zealand 
7. Study drug-related TEAEs  
8. Serious TEAEs (SAEs) 
9. Study drug-related serious TEAEs (serious study drug-related TEAEs) 
10. Deaths 
The summary table is based on the number of AE verbatim terms. 


 
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14.3.2 Adverse event tables  
In addition, frequency tables will be prepared by MedDRA terms (system organ class, preferred 
term) showing the following:  
1. All TEAEs 
2. TEAEs, which are AESIs 
3. TEAEs, which are an other important event 
4. TEAEs, which are injection site reactions based on investigator assessment in CRF 
5. Study-drug related TEAEs 
6. TEAEs by causal relationship to study drug 
7. TEAEs by severity 
8. Serious TEAEs (SAEs) 
9. Special search category TEAEs 
The analysis of AEs will include summary tables displaying counts and percentages of patients 
experiencing AEs by system organ class and preferred term. If a patient has more than 1 AE 
which codes to the same preferred term, the patient will be counted only once for that preferred 
term. The total number of events documented per system order class and preferred term will also 
be displayed. Summaries will be ordered by descending order of incidence of system organ class 
and preferred term within each system organ class based on the frequency (proportion of 
patients) in the dasiglucagon group. 
 
The special search category should include the following MedDRA tems: 
 
Events of hypoglycemia 
- 
SMQ Hypoglycemia (narrow)  
 
Hemodynamic events  
- 
Zealand custom search  
- 
External file with PT to be provided by pharmacovigilance 
 
Allergic reactions  
- 
SMQ: Hypersensitivity (narrow) 
 
Events related to QT interval prolongation  
- 
SMQ: Torsade de pointes/QT prolongation (broad) 
 
Renal disorders 
- 
SMQ: Acute renal failure (broad) 
 
Hepatic disorders 


 
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- 
SMQ: Drug related hepatic disorders (broad) 
 
Medication errors 
- 
SMQ: Medication errors (broad) 
 
Rare events 
- 
Zealand custom search  
- 
External file with PTs to be provided by pharmacovigilance 
 
Injection site reactions 
- 
Zealand custom search  
- 
External file with PTs to be provided by pharmacovigilance 
 
 
All details of adverse events will be listed. A separate listing for additional details for AEs of 
special interest is prepared. 
 
14.4 Clinical Laboratory Evaluation 
14.4.1 General 
 High (H)/Low (L) flags will be presented in laboratory listings including the specific lab 
reference range, where appropriate. If normal ranges are not available, the flagging 
cannot be performed. 
 All data will be listed in the CSR as raw data. For the summaries the most recent value 
will be used in case several measurements have been performed at 1 visit. 
 
Tabulations will be prepared for each laboratory parameter by treatment group: 
 
1. Laboratory results with continuous variables will be presented with descriptive statistics 
for each scheduled time point. They will be marked whether they are below (L), within or 
above (H) the respective reference range. The numbers in each category 
(above/below/within reference range) will be counted and percentages presented for each 
laboratory test result, visit and time point. 
2. If laboratory values are categorical, the results (eg, positive/ negative) will be presented 
with counts and percentages for each visit and time point available. 
3. Presentation of “change from baseline” values: Change from baseline will be evaluated 
for all laboratory parameters. The change will be calculated by building the difference 
between the screening visit (V1) and the follow-up visit (V3). Change from baseline 
values will be presented with descriptive statistics in case of continuous parameters.  


 
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14.4.2 Hematology 
Tabulation will follow presentation as suggested in section 14.4.1, items #1 to #3. No figures 
will be prepared.  
14.4.3 Biochemistry 
Tabulation will follow presentation as suggested in section 14.4.1, items #1 to #3. No figures 
will be prepared. 
14.4.4 Coagulation 
Coagulation parameters at screening will be tabulated with descriptive statistics by treatment 
group. 
14.4.5  Urinalysis 
Tabulation will follow presentation as suggested in section 14.4.1, items #1 to #3. No figures 
will be prepared. 
14.4.6 Pregnancy test 
Data results of pregnancy test will be tabulated with counts/percentages for each visit by 
treatment group. 
14.4.7 Alcohol breath test 
Data on alcohol breath test will be listed. 
14.5 Vital Signs 
Vital signs will be summarized using descriptive statistics at baseline and at each postbaseline 
time point.  
Categorical analysis of pulse rate will be done using the following thresholds: 
 
 
Class 1 
Class 2 
Pulse rate 
<=120 bpm 
>120 bpm 
14.6 Physical Examination 
Physical examination results will be included in data listings only.  
14.7 Electrocardiogram 
The number of patients with normal/abnormal clinically significant/abnormal not clinically 
significant investigator assessments of 12-lead ECG will be tabulated with counts/percentages by 
treatment group and visit.  


 
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Descriptive measures by visit for each ECG parameter will be presented by treatment group for 
each visit.  
 
In addition, a categorical summary of corrected QT interval (QTc) values will be presented. At 
each visit, the number of patients with QTc according to Fridericia’s formula (QTcF) values of 
>450 ms, >480 ms, and >500 ms will be presented. At each postbaseline time point, the number 
of patients with change from baseline values in QTcF of >30 ms and >60 ms will be presented.  
 
14.8 Immunogenicity 
Occurrence of ADA will be analyzed descriptively per treatment group. No statistical tests are 
planned. 
 
ADA will be derived from the number of patients having an ADA-positive sample during the 
course of the trial. Determination of the number of patients will include counting: 
 
1. Patients, who were ADA-negative at baseline and ADA-positive after drug administration 
(=treatment-induced ADA patients) 
2. Baseline ADA-positive patients with significant increases (≥5-fold) in ADA titer after 
drug administration (= treatment-boosted ADA patients) 
 
Both patient numbers will be summed up for the overall ADA incidence nominator. The 
nominator will be derived by dividing by the number of evaluable patients (see sec. Definitions: 
Evaluable patients = A patient with at least one sample taken after drug administration during 
the treatment or follow-up that is appropriate for ADA testing (with reportable result).). Patients, 
who were baseline-positive patients without any samples available after drug administration, will 
be excluded from the number of evaluable patients. Note that for ADA-positive patients 
unscheduled dosing visits are performed and results from those visits have to be respected as 
well. 
15. CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
The following changes have been made in the SAP compared to the protocol: 
 
- 
The statistical analyis for the primary efficacy parameter has been reworded and 
additional sensitivity and supportive analysis have been added. 
- 
For the secondary efficacy variables, the terminology was changed from ‘… within 30 
(20 or 15 or 10) min’ to ‘…at 30 (20 or 15 or 10) min’. 
 
 
 


 
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1. REFERENCES 
US Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for industry: E9 Statistical principles for 
clinical trials. September 1998 ICH [cited 2018 Aug 03]. Available from: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
073137.pdf 
 
 


 
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2. APPENDICES 
Appendix A: Presentation of Data and Programming Specifications 
General  
 Specialized text styles, such as bold, italics, borders, shading, superscripted, and 
subscripted text will not be used in tables, figures, and data listings unless they add 
significant value to the table, figure, or data listing. 
 Only standard keyboard characters are to be used in tables and data listings. 
 Special characters, such as non-printable control characters, printer-specific, or font-
specific characters, will not be used on a table, figure, or data listing. 
 Hexadecimal character representations are allowed (eg, µ, , ß). 
 All footnotes will be left justified and at the bottom of a page. Footnotes must be used 
sparingly and must add value to the table, figure, or data listing. 
 
Tables 
 Formal organization of tabulations may be changed during programming, if appropriate, 
eg, tables for the different variables may be combined into a single table, or tables with 
more than 1 variable may be split into several tables. 
 Means and medians will be presented to 1 more decimal place than the raw data. 
Standard deviations will be presented to 2 more decimal places than the raw data. 
Minimums and maximums will be reported with the same number of decimal places as 
the raw data.  
 Percentages will be presented to the tenths place. 
 For frequency counts of categorical variables, categories whose counts are zero will be 
displayed for the sake of completeness. 
 For all inferential analyses, P values will be rounded to 3 decimal places (or at the 
highest level of precision) with a leading zero (0.001). P values less than 0.001 will be 
presented as “<0.001.” 
 The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source table number(s) if applicable (in case aggregated 
results like mean or median are plotted) or the source listing(s) (in case individual responses are 
plotted) and/or source dataset(s) (eg, ADaM).  
- 
“PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date is the date stamp of the data snapshot used. 
Figures 
 Legends will be used for all figures with more than 1 variable or item displayed.  
 Figures will be in black and white but can be in color to add value to the clarity and 
readability of a figure. Lines must be wide enough to see the line after being copied. 
 The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source listing number(s) and/or source dataset(s) (eg, ADaM).  
- 
“PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 


 
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where extract date is the date stamp of the data snapshot used. 
 
Listings 
 Formal organization of the listing may be changed during programming, if appropriate, 
eg, additional variables may be included, change in the column order, or the listing may 
be split into multiple parts due to space constraints. 
 If not otherwise specified, all data listings will be sorted by treatment, center, patient 
number, visit, and date/time, as appropriate.  
 All date values will be presented in a SAS date (eg, 29AUG2001) format.  
 All observed time values will be presented using a 24-hour clock HH:MM:SS format (eg, 
01:35:45 or 11:26). Seconds will only be reported if they were measured as part of the 
study. 
 The last footnote will be 
- 
“PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date is the date stamp of the data snapshot used. 
 
 
 


 
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Missing or incomplete dates (ie, AEs and concomitant medications) 
The most conservative approach will be systematically considered. If the AE onset date is 
missing/incomplete, it is assumed to have occurred during the study treatment phase (ie, 
considered a TEAE) except if the partial onset date or other data, such as the stop date, indicates 
differently. Similarly, a medication with partial start and stop dates could be considered as both a 
prior and concomitant treatment. 
 
Standard Calculations 
 
Variables requiring calculation will be derived using the following formulas: 
 
Days – A duration expressed in days between 1 date (date1) and another later date (date2) is 
calculated using the formula a follows: 
Duration in days = date2 – date1 + 1 
 
Months – A duration expressed in months is calculated using the INTCK function of SAS as 
follows: months=intck('month','date1'd,date2'd, 'continuous'). 
 
Years – A duration expressed in years between 1 date (date1) and another later date (date2) is 
calculated as follows:  
Duration in years = intck(‘year,'date1'd,date2'd, 'continuous'). 
 
Height – Height entries made in inches (in) are converted to centimeters (cm) using the 
following formula: 
Height (cm) = height (in) × 2.54. 
 
Weight – Weight entries made in pounds (lb) are converted to kilograms (kg) using the 
following formula: 
Weight (kg) = weight (lb)* 0.453592. 
 
Temperature – Temperature entries in degrees Fahrenheit are converted to degrees centigrade 
using the following formula: 
Temperature (degrees centigrade) = 5/9 × [temperature (degrees Fahrenheit) – 32]. 
 
Body Mass Index (BMI) – BMI is calculated using height (cm) and weight (kg) using the 
following formula: 
BMI (kg/m2) = weight (kg)/[[height (cm)/100]2]. 
 
Change from baseline – Change from baseline will be calculated as: 
Change = postbaseline value – baseline value. 
 
 


 
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Appendix B: SAS Programming QC Requirements  
Programmer/Validator Review 
 
1. Program Review 
1.1. Program name follows standard naming conventions and is consistent with other 
study program names. 
1.2. Program header uses standard template with all relevant information completed.  
1.3. Program flow is logical (ie, header → initialization code → macro variable definitions 
→ format definitions → main body). 
1.4. Programmer comments are included throughout program to describe purpose of 
individual sections or macros and provide understanding of specific code, if necessary. 
All comments are clear and up-to-date. 
1.5. Hard coding, if any, is implemented correctly and documented in program header 
with: date, reason, and reference to sponsor approval. A comment is also inserted at the 
location of the hard coding. 
1.6. SAP derivation rules, if any, are followed. Significant deviations from mock table or 
SAP text are documented in the SAS Program Header. 
1.7. Permanent intermediate datasets utilized as source data have either been fully 
validated elsewhere or are fully validated within the scope of this QC.  
1.8. Program runs properly and output dataset is generated as intended. 
 
2. SAS Log Review 
2.1. Scan of entire log confirming that each data step and procedure completed properly.  
2.2. Critical messages such as: errors, warnings, merge notes, or uninitialized variables are 
not found in log. Unavoidable critical messages are verified to not adversely affect the 
output and the reasons why they are unavoidable are documented. 
2.3. Other messages such as “PUT” or “INFO” messages (eg, overwritten variables 
following merge) are handled appropriately, if they are found in log. 
 
3. Output Review 
3.1. Output file name follows standard naming conventions and is consistent with other 
study output file names. 
3.2. Titles and footnotes are verified against mock table/listing/figure (if available). 
Discrepancies, including footnotes added for clarification, are noted and verified.  
3.3. Column/row header text is verified against mock table/listing/figure and/or CRF.  
3.4. Format and sorting order are correct relative to mock table/listings/figure and/or 
CRF.  
3.5. Pages breaks are as intended throughout the document. 
3.6. Significant digits are appropriate for summary results (eg, mean is 1 more digit than 
collected on the CRF). 
3.7. Analysis population totals are verified as correct based on SAP definitions and are 
consistent with other tables using the same population(s). 
3.8. Inappropriate data: checked for outliers, invalid numbers, missing results, etc. 
 


 
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4. Dataset Structure (for SDTM/TDM/ADaM) 
4.1. 
Pinnacle 21 validator is run.  Any errors or warnings are updated or explained. 
 
5. Verification of Data  
5.1. SDTM/TDM/Analysis datasets (ADaM or ADaM-Like) 
5.1.1. Programmer 
 Each SDTM/TDM/Analysis dataset is opened and data are reviewed for 
consistency with the protocol, SAP, and/or CRF (no additional QC programming 
is necessary). 
5.1.2. Validator 
 Validation is performed against the protocol, SAP, and/or CRF. A spot-check of 
source data against the output dataset is performed on at least 2 patients. Each 
CRF section/form should be populated at least once for the spot-check. If a 
section/ form is repeated (eg, at several visits) 1 repeat per patient has to be 
spotchecked. 
5.2. Tables 
5.2.1. Program Review 
 Verify that the appropriate datasets, variables, analysis populations, 
parameters/tests, and visits/time points are used. 
 Verify that all keyword and positional parameters of the standardized macro call 
are accurate and are implemented as intended. 
5.2.2. Output Review 
 All expected data (parameters/tests, visits/time points, interventions, totals, etc.) 
are included on the output. 
 Units and the range of values are confirmed to be consistent. 
 Percentages are based on the correct denominator and confirmed to not exceed 
100%. 
 Counts within subgroups or subsets of data are checked for internal consistency 
(eg, subset counts do not exceed overall counts). 
5.3. Listings 
 Listing content is as expected (eg, listing includes all enrolled patients, all 
expected visits) 
 Variables directly from source dataset are spot-checked for accuracy and 
completeness. 
 Derived or calculated variables are compared to corresponding source data and 
manual calculation for at least 2 patients are done. 
5.4. Figures 
 Manual comparison to the corresponding table, where the table is validated and 
at least 25% of the data points on the figure are compared to the corresponding 
value on the table. 
 Manual calculations (if feasible based on small Ns or frequency counts). 
 


 
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6. Documentation 
6.1. The Programmer and Validator must document completion of QC (eg, date of QC and 
method used) in BIO-0205-TMP-002 Program Status Document. 
6.2. Validator findings and/or comments may be tracked in the Program Status Document 
along with a description of how the finding was resolved and resolution date. 
6.3. The following must be retained electronically within the study folder by the Validator 
as supporting documentation:  
 If a spot-check of patient data is performed, output that clearly identifies the 
patients and CRF forms/sections that are checked 
 Pinnacle 21 report generated at time of QC including comments 
 


 
 
 
Zealand Pharma A/S 
 
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Appendix C:  List of Tables, Figures, and Listings 
The following proposal for section 14 and 16.2 is completed according to ICH E3 guidelines. The ICH heading numbers and 
description are in bold. Minor changes from this planned index do not need to be amended in the SAP.   
 
Formal organization of tabulations may be changed during programming, if appropriate, eg, tables for the different variables may be 
combined into a single table, or tables with more than 1 variable may be split into several tables. 
 
  
 
Section 14: Tables, Figures, and Graphs  
Table 
Number 
Table Title 
Analysis 
Set 
Comment 
14 
TABLES, FIGURES, AND GRAPHS REFERRED TO 
BUT NOT INCLUDED IN THE TEXT 
 
 
14.1 
DEMOGRAPHIC DATA 
 
 
14.1.1 
Patient number by country 
All patients  
14.1.2 
Patient number by country and center 
All patients  
14.1.3 
Patient disposition 
All patients  
14.1.4 
Trial termination form 
Safety 
analysis set 
 
14.1.5 
Demographic characteristics 
Safety 
analysis set 
 
14.1.6 
Demographic characteristics 
FAS 
 
14.1.7. 
Baseline characteristics 
 
 
14.1.7.1 
Diabetes history 
Safety 
analysis set 
 
14.1.7.2 
Body measurements (height, weight, BMI) 
Safety 
 


 
 
 
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Table 
Number 
Table Title 
Analysis 
Set 
Comment 
analysis set 
14.1.7.3 
BMI by country 
Safety 
analysis set 
 
14.1.7.4 
Medical history  
Safety 
analysis set 
 
14.1.8 
Concomitant medication/ current diabetes treatment 
Safety 
analysis set 
 
14.2 
Efficacy data 
 
 
14.2.1 
Primary efficacy endpoint 
 
 
14.2.1.1 
Time to plasma glucose recovery - summary table 
FAS 
Patients who receive IV glucose will 
be censored (ie, set to ‘not recovered’) 
at 45 minutes after dosing 
14.2.1.2 
Time to plasma glucose recovery - Kaplan Meier survival 
curve 
FAS 
 
14.2.1.3 
Time to plasma glucose recovery - summary table 
PP 
 
14.2.1.4 
Time to plasma glucose recovery - Kaplan Meier survival 
curve 
PP 
 
14.2.1.5 
Sensitivity analysis - time to plasma glucose recovery without 
censoring for those subjects who require rescue IV glucose 
before 45 minutes - summary table 
FAS 
Without censoring for those subjects 
who require rescue IV glucose before 
45 minutes 
14.2.1.6 
Sensitivity analysis - Time to plasma glucose recovery 
without censoring for those subjects who require rescue IV 
glucose before 45 minutes - Kaplan Meier survival curve 
FAS 
 
14.2.1.7 
Sensitivity analysis - time to plasma glucose recovery with 
censoring data at the actual time when the patients received 
glucose IV - summary table 
FAS 
With censoring data at the actual time 
when the patients received glucose IV. 
14.2.1.8 
Sensitivity analysis - Time to plasma glucose recovery with 
FAS 
 


 
 
 
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Table 
Number 
Table Title 
Analysis 
Set 
Comment 
censoring data at the actual time when the patients received 
glucose IV - Kaplan Meier survival curve 
14.2.1.9 
Time to plasma glucose recovery - histogram 
FAS 
 
14.2.1.10 
Time to plasma glucose recovery – using linear interpolation of 
the time to recovery – summary table 
FAS 
 
14.2.1.11 
Time to plasma glucose recovery – using linear interpolation of 
the time to recovery – Kaplan Meier survival curve 
FAS 
 
14.2.2 
Secondary efficacy endpoints 
 
 
14.2.2.1 
Plasma glucose recovery within 10, 15, 20 and 30 minutes 
after trial product injection 
FAS 
Including p-values from CMH or 
Fisher’s exact test and 95% CIs for 
response rates of each treatment group 
14.2.2.2 
Plasma glucose - untransformed results at 10, 15, 20 and 30 
minutes after trial product injection 
FAS 
 
14.2.2.3 
Plasma glucose - change from baseline results and  inferential 
test statistics at 10, 15, 20 and 30 minutes after trial product 
injection 
FAS 
Results from ANCOVA will be 
displayed here 
 
 
 
 
14.3 
Safety data 
 
 
14.3.1 
Displays of Adverse Events 
 
 
14.3.1.1 
Overall summary of adverse events 
Safety 
analysis set 
 
14.3.1.2 
TEAEs by system organ class and preferred term 
Safety 
analysis set 
 
14.3.1.3 
TEAEs of special interest by system organ class and preferred 
term 
Safety 
analysis set 
 
14.3.1.4 
Other impotant TEAEs by system organ class and preferred 
term 
Safety 
analysis set 
 


 
 
 
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Table 
Number 
Table Title 
Analysis 
Set 
Comment 
14.3.1.5 
TEAEs, which are injection site reactions 
Safety 
analysis set 
 
14.3.1.6 
Study drug-related TEAEs by system organ class and 
preferred term 
Safety 
analysis set 
 
14.3.1.7 
TEAEs by system organ class and preferred term and causal 
relationship 
Safety 
analysis set 
 
14.3.1.8 
TEAEs by system organ class and preferred term and severity 
Safety 
analysis set 
 
14.3.1.9 
SAEs by system organ class and preferred term 
Safety 
analysis set 
 
14.3.1.10 
Special search category TEAEs 
Safety 
analysis set 
 
14.3.2 
Listings of deaths, other serious and significant adverse events 
 
This is a cross-reference to listing 
16.2.7.4 
14.3.3 
Narratives of deaths, other serious and certain other significant 
adverse events 
 
This is a cross-reference to section 
12.3.2 of the CSR 
14.3.4 
Extent of exposure 
 
 
14.3.4.1 
Insulin administration prior to the hypoglycemia induction 
procedure 
Safety 
analysis set 
 
14.3.4.2 
Hypoglycemia induction procedure 
Safety 
analysis set 
 
14.3.4.3 
Trial medication 
Safety 
analysis set 
 
14.3.4.4 
Post-treatment rescue glucose infusion 
Safety 
analysis set 
 
14.3.5 
Other safety data 
 
 
14.3.5.1 
ECG 
 
 


 
 
 
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Table 
Number 
Table Title 
Analysis 
Set 
Comment 
14.3.5.1.1 
ECG, overall interpretation 
Safety 
analysis set 
 
14.3.5.1.2 
ECG, descriptive statistics of all ECG parameters 
Safety 
analysis set 
 
14.3.5.1.3 
ECG, categorical analysis of QTc results 
Safety 
analysis set 
 
14.3.5.1.4 
ECG, categorical analysis of QTc results, change from 
baseline 
Safety 
analysis set 
 
14.3.5.2 
Laboratory data 
 
 
14.3.5.2.1 
Hematology 
Safety 
analysis set 
 
14.3.5.2.2 
Clinical chemistry 
Safety 
analysis set 
 
14.3.5.2.3 
Coagulation 
Safety 
analysis set 
 
14.3.5.2.4 
Urinalysis - pH 
Safety 
analysis set 
 
14.3.5.2.5 
Urinalysis - quantitative results, count of abnormal results 
Safety 
analysis set 
 
14.3.5.2.6 
Pregnancy test 
 
 
14.3.5.3 
Local tolerability 
Safety 
analysis set 
 
14.3.5.4 
Vital signs 
 
 
14.3.5.5 
Pulse rate  – categorical analysis 
Safety 
analysis set 
 
14.3.5.6 
Immunogenicity - occurrence of ADA 
Safety 
analysis set 
 


 
 
 
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Table 
Number 
Table Title 
Analysis 
Set 
Comment 
14.4 
Pharmacokinetic (PK) and pharmacodynamic (PD) 
 
 
14.4.1 
Pharmacokinetics 
 
 
14.4.1.1 
Summary statistics of plasma dasiglucagon and GlucaGen 
concentration table 
FAS 
 
14.4.1.2 
PK metrics 
FAS 
 
14.4.1.3 
Figure: Mean analyte concentrations versus time - original scale 
FAS 
 
14.4.1.4 
Figure: Mean analyte concentrations versus time - log scale 
FAS 
 
14.4.1.5 
Figure: Individual analyte concentrations versus time curves - 
original scale 
FAS 
 
14.4.2 
Pharmacodynamics 
 
 
14.4.2.1 
PD metrics 
FAS 
 
14.4.2.2 
Figure: Mean glucose concentrations versus time - original 
scale 
FAS 
 
14.4.2.3 
Figure: Individual glucose concentrations versus time curves - 
original scale 
FAS 
 
 
  


 
 
 
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Section 16.2: List of Data Listings 
ICH Listing 
Number 
 
Listing Title 
Comment 
16.2 
PATIENT DATA LISTINGS 
 
16.2.1 
Discontinued patients 
 
16.2.1.1 
Patient disposition 
 
16.2.1.2 
Trial termination 
 
16.2.2 
Protocol deviations 
 
16.2.2.1 
Patients not fulfilling any inclusion/exclusion criteria 
 
16.2.3 
Patients excluded from the efficacy analysis 
 
16.2.3.1 
Patients Excluded from analysis 
 
16.2.4 
Demographic data 
 
16.2.4.1 
Informed consent and demographics 
 
16.2.4.2 
Baseline characteristics (body measurements) 
 
16.2.4.3 
Diabetes history 
 
16.2.4.4 
Medical history 
 
16.2.5 
Compliance and/or drug concentration data  
 
16.2.5.1 
Visit dates 
 
16.2.5.2 
Randomisation 
 
16.2.5.3 
Insulin administration prior to the hypoglycemia induction procedure 
 
16.2.5.4 
Hypoglycemia induction procedure 
 
16.2.5.5 
Study drug administration 
 
16.2.5.6 
Post-treatment rescue glucose infusion 
 
16.2.5.7 
Plasma dasiglucagon/GlucaGen sampling and concentrations 
 
16.2.5.8 
Plasma dasiglucagon/GlucaGen pharmacokinetic metrics 
 
16.2.6 
Individual efficacy response data 
 
16.2.6.1 
Plasma glucose sampling and concentrations 
 


 
 
 
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ICH Listing 
Number 
 
Listing Title 
Comment 
16.2.6.2 
Plasma glucose pharmacodynamic metrics 
 
16.2.6.3 
Time to plasma glucose recovery 
Derived 
including 
derived 
parameters 
16.2.7 
Adverse events listings 
 
16.2.7.1 
Adverse events - CRF entries 
 
16.2.7.2 
Adverse events - MedDRA coding 
 
16.2.7.3 
Adverse Event of Special Interest - additional details 
 
16.2.7.4 
Death and serious adverse events 
 
16.2.7.5 
Adverse events – leading to withdrawal from study 
 
16.2.7.6 
Adverse events – patients with positive ADA result 
 
16.2.7.7 
Adverse events - plasma glucose measurements in case of hypogylcemia 
 
16.2.8 
Listing of individual laboratory measurements by patient, when required by regulatory 
authorities 
 
16.2.8.1 
Hematology 
incl. derived data CFB 
16.2.8.2 
Biochemistry 
incl. derived data CFB 
16.2.8.3 
Coagulation 
incl. derived data CFB 
16.2.8.4 
Urinalysis 
 
16.2.8.5 
Pregnancy test 
 
16.2.8.6 
Alcohol breath test 
 
16.2.9 
Other data 
 
16.2.9.1 
Vital signs 
 
16.2.9.2 
Physical examination 
 
16.2.9.3 
Electrocardiogram 
incl. derived data CFB 
16.2.9.4 
Concomitant medication and current diabetes treatment 
 
16.2.9.5 
Local tolerability 
 


 
 
 
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ICH Listing 
Number 
 
Listing Title 
Comment 
16.2.9.6 
Immunogenicity results 
 
 


 
 
 
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Appendix D: Table Layouts 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.1.1: Patient number by country, all patients 
 
Country 
Sreening Failure 
(N=xxx) 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 Country 1 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Country 2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
... 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
 US 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 NON-US 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
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Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.1.2: Patient number by country and center, all patients 
 
Country 
Center Number 
Sreening Failure 
 (N=xxx) 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 Country 1 
xx 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
xx 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
Country 2 
xx 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
xx 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
... 
 
 
 
 
 
 
 
 
 
 
 
 Country xx 
xx 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
xx 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 
 
 


 
 
 
Zealand Pharma A/S 
 
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Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.1.3: Patient disposition, all patients 
 
Number of 
Sreening Failure 
 (N=xxx) 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 patients screened 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
patients randomised 
    
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
patients in safety analysis set 
   
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 patients in full analysis set 
   
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 patients in per protocol set 
   
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy 
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
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Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.1.4: Trial termination, Safety analysis set 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
Did the patient complete the study? 
 No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Primary reason for non-completion 
 Adverse event 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Death 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
... 
 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy 
RUN DATE: ddmmyyy hh:mm CET 
Programmer Note: Populate all possible reasons for non-completion from e-CRF


 
 
 
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ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 2 
14.1.5: Demographic characteristics, Safety analysis set 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Age 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 Age groups 
 
 
 
 
 
 6-11 years 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
12-17 years 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Gender 
 
 
 
 
 
 Male 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Female 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Child bearing potential 
 
 
 
 
 
 No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 50/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 2 of 2 
14.1.5 Demographic characteristics, Safety analysis set 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Race 
 
 
 
 
 
American indian or alaska native 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Asian 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
... 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
... 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
... 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
... 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
... 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Ethnic 
 
 
 
 
 
Hispanic or latino 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Nothispanic or latino 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 Not allowed to ask per  local regulations 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
Programmer Note: Populate all possible races from e-CRF 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 51/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Protocol Number: ZP4207-17086 
Page 1 of 2 
14.1.6: Demographic characteristics, FAS 
 
 
Repetiton of table 14.1.5 with different selection of population. 
 
If identical (like expected) it will be sufficient to state they are identical. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 52/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.1.7.1: Diabetes history, Safety analysis set 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Time since diagnosis of diabetes 1 [years] 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 53/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.1.7.2: Body measurements (height, weight, BMI), Safety analysis set 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Height [cm] 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 Weight [kg] 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 Body mass index [kg/m2] 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 Body mass index class 
 
 
 
 
 
<25 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
25-<30 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
30-<35 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
>35 kn/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 54/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.1.7.3: BMI by country, Safety analysis set 
 
Country 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 
 
Country 1 
<25 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
25-<30 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
30-<35 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
>35 kn/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 ... 
 
 
 
 
 
 
 
 
 
 
 
 
Country xx 
<25 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
25-<30 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
30-<35 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
>35 kn/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
 
US 
<25 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
25-<30 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
30-<35 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
>35 kn/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
 
NON-US 
<25 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
25-<30 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
30-<35 kg/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
>35 kn/m2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 55/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.1.8: Medical history, Safety analysis set 
 
 
Number of Patients (%) Event Count 
 
System organ class 
Preferred term 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Any medical history 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 SOC class 1 
 
 
 
 
 
PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 SOC class 2 
 
 
 
 
 
PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 SOC class xx 
 
 
 
 
 
PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
... 
 
 
 
 
Note: At each level of summation (SOC class, preferred name), patients reporting more than 1 event are counted only once for the patient count.  
Table is sorted by descending patientcount on the PT level 
Percentages are based on total no. of patients in each treatment group 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 56/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.1.8: Concomitant Medications/ Current Diabetes Treatment, Safety analysis set 
 
 
Number of Subjects (%) Medication Count 
 
ATC class (level 2) 
Preferred name 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Any medication/ treatment 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 ATC class 1 
 
 
 
 
 
PT Name 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Name 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Name 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Name xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 ATC class 2 
 
 
 
 
 
PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Name 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Name 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Name xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 ATC class xx 
 
 
 
 
 
PT Name 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Name 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Name 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Name xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
... 
 
 
 
 
 
Note: At each level of summation (overall, ATC class, preferred name) patients reporting more than 1 medication/ treatment are counted only once. 
Table is sorted by descending total patient count  
Percentages are based on total no. of subjects in each treatment group 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 57/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 2 
14.2.1.1: Time to plasma glucose recovery - summary table, FAS 
Primary model 
 
Treatment 
 
 
dasiglucagon  
(N=xxx) 
GlucaGen  
(N=xx) 
placebo 
(N=xx) 
 
p-values 
 
 
 
 
 
Status (N) 
Xx 
xx 
xx 
 
Recovered1  
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Censored2 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
 
 
 
 
 
Time to recovery (minutes) 
 
 
 
 
25th percentile 
xx.x 
xx.x 
xx.x 
 
Median (95% CI) 
xx.x (xx.x ; xx.x) 
xx.x (xx.x ; xx.x) 
xx.x (xx.x ; xx.x) 
 
75th percentile 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Dasiglucagon versus Placebo   P-value (log-
rank test – stratified) 
 
 
 
 
x.xxxx 
  P-value (log-rank test – non-stratified) 
 
 
 
x.xxxx 
  P-value (Wilcoxon test) - stratified 
 
 
 
x.xxxx 
 
 
 
 
 
Dasiglucagon versus GlucaGen  
  P-value (log-rank test – stratified) 
 
 
 
 
x.xxxx 
  P-value (log-rank test – non-stratified) 
 
 
 
x.xxxx 
  
 
 
 
 
Cox proportional hazards3  
 
 
 
 
Hazard ratio 
xx.xx 
xx.xx 
1 
 
95% profile CL 
(xx.xxx ; xx.xxx) 
(xx.xxx ; xx.xxx) 
 
 
P-values 
 
 
 
 
Dasiglucagon versus Placebo 
 
 
 
x.xxxx 
Dasiglucagon versus Glucagen 
 
 
 
x.xxxx 
Glucagen versus Placebo  
 
 
 
x.xxxx 
Type 3 test for Age 
 
 
 
x.xxxx 
Type 3 test for injection site 
 
 
 
x.xxxx 
1: Increase of plasma glucose of 20 mg/dL within 45 min without iv glucose 
2: Did not recover within 45 min or received iv glucose before 45 min 
3: Cox proportional hazard model with treatment, age and injection site as fixed effects and baseline plasma glucose as covariate 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 58/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 2 of 2 
 
Homogenicity models 
 
 
 
Treatment 
 
 
dasiglucagon  
(N=xxx) 
GlucaGen  
(N=xx) 
placebo 
(N=xx) 
 
 
 
 
Cox proportional hazards1  
 
 
 
<Sub-group level 1> 
 
 
 
Hazard ratio 
xx.xx 
xx.xx 
1 
95% profile CL 
(xx.xxx ; xx.xxx) 
(xx.xxx ; xx.xxx) 
 
<Sub-group level 2> 
 
 
 
Hazard ratio 
xx.xx 
xx.xx 
1 
95% profile CL 
(xx.xxx ; xx.xxx) 
(xx.xxx ; xx.xxx) 
 
.. . 
 
 
 
 
 
 
 
<Sub-group level i> 
 
 
 
Hazard ratio 
xx.xx 
xx.xx 
1 
95% profile CL 
(xx.xxx ; xx.xxx) 
(xx.xxx ; xx.xxx) 
 
 
 
 
 
 
1: Cox proportional hazard model with treatment, age and injection site as fixed effects and baseline plasma glucose as covariate 
 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 59/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.2.1.2: Time to plasma glucose recovery - Kaplan Meier survival curve, FAS 
 
 
 
 
 
Note: this is a generic example using example data from SAS Institute; number of patients at risk are adapted to 0, 10, 15, 20, 30 and 45min. 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 60/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.2.1.3: Time to plasma glucose recovery - summary table, PP 
 
 
 
 
Repetiton of table 14.2.1.1 with different selection of population. Only page 1 output presented here. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 61/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.2.1.4: Time to plasma glucose recovery - Kaplan Meier survival curve, PP 
 
 
 
 
Repetiton of table 14.2.1.2 with different selection of population. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 62/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.2.1.5: Sensitivity analysis - time to plasma glucose recovery without censoring for those subjects who require rescue IV glucose before 45 minutes - 
summary table, FAS 
 
 
 
 
Repetiton of table 14.2.1.1 with different selection of population. Only page 1 output presented here. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 63/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.2.1.6: Sensitivity analysis - time to plasma glucose recovery without censoring for those subjects who require rescue IV glucose before 45 minutes - 
Kaplan Meier survival curve, FAS 
 
 
 
 
Repetiton of table 14.2.1.2 with different selection of population. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 64/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.2.1.7: Sensitivity analysis - time to plasma glucose recovery with censoring for those subjects who require rescue IV glucose before 45 minutes - 
summary table, FAS 
 
 
 
 
Repetiton of table 14.2.1.1 with different selection of population. Only page 1 output presented here. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 65/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.2.1.8: Sensitivity analysis - time to plasma glucose recovery with censoring for those subjects who require rescue IV glucose before 45 minutes - 
Kaplan Meier survival curve, FAS 
 
 
 
 
Repetiton of table 14.2.1.2 with different selection of population. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 66/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.2.1.9: Time to plasma glucose recovery - histogram, FAS 
 
 
 
Layout will be established during programming 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 67/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.2.1.10: Time to plasma glucose recovery - using linear interpolation of the time to recovery, FAS 
 
 
 
 
Repetiton of table 14.2.1.1 using linear interpolated time to recovery data. Only page 1 output presented here. 
 
 


 
 
 
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                                                                                                 Statistical Analysis Plan 
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Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.2.2.1: Plasma glucose recovery within 10, 15, 20 and 30 minutes after trial product injection, FAS 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
p-value1 
dasiglucgon  
versus  
Placebo 
 
 
 
 
 
 Plasma glucose recovery within 10min 
 
 
 
 
  No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
   
  Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
95% CIs for response rate (Category ‘Yes’) 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
x.xxxx 
 
 
 
 
 
 Plasma glucose recovery within 15min 
 
 
 
 
  No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
   
  Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
95% CIs for response rate (Category ‘Yes’) 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
x.xxxx 
 
 
 
 
 
 Plasma glucose recovery within 20min 
 
 
 
 
  No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
   
  Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
95% CIs for response rate (Category ‘Yes’) 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
x.xxxx 
 
 
 
 
 
 Plasma glucose recovery within 30min 
 
 
 
 
  No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
   
  Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
95% CIs for response rate (Category ‘Yes’) 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
x.xxxx 
 
 
 
 
 
 
 
 
If a patient has received an IV glucose treatment before recovery, the patient is set to ‘not recovered’. 
1 p-values calculated using a Cochran-Mantel-Haenszel test stratified by age group and injection site. 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
 
14.2.2.2: Plasma glucose - untransformed results at 10, 15, 20 and 30 minutes after trial product injection 
 
Variable 
Time Point 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
Result 
Pre-dose 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
10 min after dosing 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
15 min after dosing 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
20 min after dosing 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
30 min after dosing 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
If the rescue IV glucose was administered before 10, 15, 20, or 30 minutes, respectively, the patient’s plasma glucose changes from baseline is determined from the 
value at the time of rescue IV glucose administration. 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 2 of 2 
 
14.2.2.2: Plasma glucose - change from baseline results and inferential test statistics at 10, 15, 20 and 30 minutes after trial product 
injection 
Variable 
Time Point 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
p-value1 
(95% CI) 
dasiglucgon  
versus  
Placebo 
 
 
 
 
 
Change from Baseline 
10 min after dosing 
n 
xx 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
x.xxxx 
LS-mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
95%CI (LS-mean) 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
15 min after dosing 
N 
xx 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
x.xxxx 
LS-mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
95%CI (LS-mean) 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
20 min after dosing 
n 
xx 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
x.xxxx 
LS-mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
95%CI (LS-mean) 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
30 min after dosing 
n 
xx 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
x.xxxx 
LS-mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
95%CI (LS-mean) 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
If the rescue IV glucose was administered before 10, 15, 20, or 30 minutes, respectively, the patient’s plasma glucose changes from baseline is determined from the 
value at the time of rescue IV glucose administration. 
1 p-values calculated using an analysis of variance (ANOVA) with factors treatment, age group and injection site 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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Protocol Number: ZP4207-17086 
Page 1 of 1 
14.3.1.1: Overall summary of adverse events, Safety analysis set 
 
 
Number of Subjects (%) Event Count 
 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Adverse events during screening 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 Treatment-emergent AEs (TEAEs) 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 TEAEs, which are adverse events of special interest (AESIs) 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 TEAEs, which are another important event 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 TEAEs, which are injection site reactions 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 Study drug-related TEAEs 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 Serious TEAEs (SAEs) 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 Study drug-related serious TEAEs 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 Deaths 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 
... 
 
 
 
 
 
 
¹ Study drug-related TEAEs: TEAEs which were assessed by the investigator as possibly related or probably related, or without assessment of relationship. 
Table is based on number of verbatims. 
Patients reporting more than 1 event are counted only once for the patient count.  
Percentages are based on total no. of subjects in each treatment group 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.1.2: TEAEs by system organ class and preferred term, Safety analysis set 
 
 
Number of Subjects (%) Event Count 
 
System organ class 
Preferred term 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Any adverse event 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 SOC class 1 
 
 
 
 
 
PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 SOC class 2 
 
 
 
 
 
PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 SOC class xx 
 
 
 
 
 
PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
... 
 
 
 
 
 
Note: At each level of summation (SOC class, preferred name) patients reporting more than 1 event are counted only once for the patient count.  
Table is sorted by descending subject count on the PT level in the dasiglucagon group. 
Percentages are based on total no. of subjects in each treatment group 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.1.3: TEAEs of special interest by system organ class and preferred term, Safety analysis set 
 
 
Repetiton of table 14.3.1.2 with different selection of the AE analysis dataset. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.1.4: Other important TEAEs by system organ class and preferred term, Safety analysis set 
 
 
Repetiton of table 14.3.1.2 with different selection of the AE anaylsisy dataset. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.1.5: TEAEs, which are injection site reactions, Safety analysis set 
 
 
Repetiton of table 14.3.1.2 with different selection of the AE analysis dataset. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.1.6: Study drug-related TEAEs by system organ class and preferred term, Safety analysis set 
 
 
Repetiton of table 14.3.1.2 with different selection of the AE anaylsisy dataset. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.1.7: TEAEs by system organ class and preferred term and causal relationship, Safety analysis set 
 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
System organ class 
Preferred term 
Related1 
Not Related2 
Related1 
Not Related2 
Related1 
Not Related2 
 
 
 
 
 
 
 
 
 Any adverse event 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 
 
 SOC class 1 
 
 
 
 
 
 
 
PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 
 
 SOC class 2 
 
 
 
 
 
 
 
PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
PT Term xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
Note: At each level of summation (SOC class, preferred name) patients reporting more than 1 event are counted only once for the patient count.  
[1] Includes all events reported as ‘Possible’, ‘Probable’ or missing relationship. 
[2] Includes all events reported as ‘Not related or ‘Unlikely’. 
Table is sorted by descending subject count on the PT level in the dasiglucagon group. 
Percentages are based on total no. of subjects in each treatment group. 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.1.8: TEAEs by system organ class and preferred term and severity, Safety analysis set 
 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
System organ class 
Preferred term 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
 
 
 
 
 
 
 
 
 
 
 Any adverse event 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 
 
 
 
 
 SOC class 1 
 
 
 
 
 
 
 
 
 
 PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 PT Term 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 PT Term 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 PT Term xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 
 
 
 
 
 SOC class 2 
 
 
 
 
 
 
 
 
 
 PT Term 1 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 PT Term 2 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 PT Term 3 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 PT Term xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
xx ( xx.x) xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: At each level of summation (SOC class, preferred name) patients reporting more than 1 event are counted only once for the patient count.  
Table is sorted by descending subject count on the PT level in the dasiglucagon group. 
Percentages are based on total no. of subjects in each treatment group. 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
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Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.1.9: SAEs by system organ class and preferred term, Safety analysis set 
 
 
Repetiton of table 14.3.1.2 with different selection of the AE anaylsisy dataset. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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16 August 2019 
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CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.1.10: Special search category TEAEs, Safety analysis set 
 
 
Repetiton of table 14.3.1.2 with different selection of the AE anaylsisy dataset. 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
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ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.2: Listings of deaths, other serious and significant adverse events, Safety analysis set 
 
Please refer to listing 16.2.7.4. 
 
 
 
 
 
 
 
 
Programmer Note: Create a empty table with that reference as message  
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 82/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.3: Narratives of deaths, other serious and certain other significant adverse events, Safety analysis set 
 
Please refer to listing 16.2.7.4. 
 
 
 
 
 
 
 
 
Programmer Note: Create a empty table with that reference as message  
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 83/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.3.4.1: Insulin administration prior to the hypoglycemia induction procedure, Safety analysis set 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
Is the subject using multiple daily injections? 
 
No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Missing 
  n           
  n           
  n           
  n           
 
 
 
 
 
Has the subject taken insulin NPH? 
 
No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Missing 
  n           
  n           
  n           
  n           
 
 
 
 
 
Is the subject using an insulin pump? 
 
No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Missing 
  n           
  n           
  n           
  n           
 
 
 
 
 
Was insulin glulisine (Apidra) administered in the 
last 5 hours prior to initiation of the hypoglycemic 
induction procedure? 
 
No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Missing 
  n           
  n           
  n           
  n           
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy 
RUN DATE: ddmmyyy hh:mm CET 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 84/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.3.4.2: Hypoglycemia induction procedure, Safety analysis set 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
Was the hypoglycemia induction procedure performed? 
 No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 Missing 
  n           
  n           
  n           
  n           
 
 
 
 
 
Total amount of insulin administered to induce hypoglycemia [IU] 
 n  
xx 
xx 
xx 
xx 
 Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 Median 
xx.x 
xx.x 
xx.x 
xx.x 
 Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
Total amount of glucose administered during the induction procedure [mL] 
 n  
xx 
xx 
xx 
xx 
 Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 Median 
xx.x 
xx.x 
xx.x 
xx.x 
 Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy 
RUN DATE: ddmmyyy hh:mm CET 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 85/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.3.4.3: Trial medication, Safety analysis set 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
Was the trial medication administered? 
 No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 Missing 
  n           
  n           
  n           
  n           
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy 
RUN DATE: ddmmyyy hh:mm CET 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 86/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.3.4.4: Post-treatment rescue glucose infusion, Safety analysis set 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
Was glucose given for rescue? 
 No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 Missing 
  n           
  n           
  n           
  n           
 
 
 
 
 
Time to first IV glucose infusion [min] 
 Mean (SD) 
n 
xx 
xx 
xx 
 Median 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 Min, Max 
Median 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy 
RUN DATE: ddmmyyy hh:mm CET 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 87/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 2 
14.3.5.1.1: ECG, overall interpretation, Safety analysis set 
 
Visit 
Time Point 
Result 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Screening 
NORMAL 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / NOT CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
Pre-dose 
NORMAL 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / NOT CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
20min post dose 
NORMAL 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / NOT CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
35min post dose 
NORMAL 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / NOT CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
45min post dose 
NORMAL 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / NOT CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
60min post dose 
NORMAL 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / NOT CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
300min post dose 
NORMAL 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / NOT CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 88/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 2 of 2 
14.3.5.1.1: ECG, overall interpretation, Safety analysis set 
 
Visit 
Time Point 
Result 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Follow up 
NORMAL 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / NOT CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
ABNORMAL / CLIN. SIG. 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 89/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.1.2: ECG, descriptive statistics of all ECG parameters, Safety analysis set 
 
 
Parameter 
Visit/ TimePoint 
Result 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 
Mean heart rate 
[bpm] 
 Screening 
n 
xx 
xx 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 Dosing/ Pre-dose 
n 
xx 
xx 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 Dosing/20 min 
after dosing 
n 
xx 
xx 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ... 
 
 
 
 
 
 
 
 
 
 
 
 Follow up 
n 
xx 
xx 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
Programmer Note: This table is continued for each of the following ECG parameter: PR Interval Aggregate [msec], QRS Duration 
Aggregate[msec], QT Interval Aggregate[msec], QTcF Interval Aggregate[msec] 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 90/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.1.3: ECG, categorical analysis of QTc results, Safety analysis set 
 
Visit 
Time Point 
Result 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Screening 
QTcF values of >450 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF values of >480 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF values of >500 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
Pre-dose 
QTcF values of >450 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF values of >480 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF values of >500 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
20min post dose 
QTcF values of >450 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF values of >480 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF values of >500 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 ... 
 
 
 
 
 Follow up 
QTcF values of >450 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF values of >480 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF values of >500 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 91/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.1.4: ECG, categorical analysis of QTc results, change from baseline, Safety analysis set 
 
Visit 
Time Point 
Result 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Dosing 
20min post dose 
QTcF CFB >30 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF CFB >60 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
35min post dose 
QTcF CFB >30 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF CFB >60 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 ... 
 
 
 
 
 Follow up 
QTcF CFB >30 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
QTcF CFB >60 ms 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
Programmer Note: Baseline is the pre-dose result at  visit 1 Screening 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 92/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.2.1: Hematology, Safety analysis set 
Treatment 
Visit 
n 
Mean 
Median 
SD 
Min 
Max 
CFB -Mean 
CFB- SD 
Below reference 
range  
n(%) 
Within reference 
range  
n(%) 
Above reference 
range  
n(%) 
Laboratory parameter test name 1 
 
dasiglucagon Screening 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
- 
- 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
 
Follow up 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
xx.xx 
xx.xxx 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
Placebo 
Screening 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
- 
- 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
 
Follow up 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
xx.xx 
xx.xxx 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
Glucagon 
Screening 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
- 
- 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
 
Follow up 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
xx.xx 
xx.xxx 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
Total 
Screening 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
- 
- 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
 
Follow up 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
xx.xx 
xx.xxx 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
 
Laboratory parameter test name 2 
 
dasiglucagon Screening 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
- 
- 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
 
Follow up 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
xx.xx 
xx.xxx 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
Placebo 
Screening 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
- 
- 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
 
Follow up 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
xx.xx 
xx.xxx 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
Glucagon 
Screening 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
- 
- 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
 
Follow up 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
xx.xx 
xx.xxx 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
Total 
Screening 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
- 
- 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
 
Follow up 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.x 
xx.x 
xx.xx 
xx.xxx 
n ( xx.x%)  
n ( xx.x%)  
n ( xx.x%)  
... 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
Programmer Note: Each laboratory test parameter is either displayed one per page or as shown here two on 1 page if possible. 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.2.2: Clinical chemistry, Safety analysis set 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 93/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Repetiton of table 14.3.5.2.1 with different selection of the lab analysis dataset. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 94/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.2.3: Coagulation, Safety analysis set 
 
 
Repetiton of table 14.3.5.2.1 with different selection of the lab analysis dataset. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 95/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.2.4: Urinalysis - pH, Safety analysis set 
 
 
Repetiton of table 14.3.5.2.1 with different selection of the lab analysis dataset. 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 96/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.2.5: Urinalysis - quantitative results, count of abnormal results, Safety analysis set 
 
Urine parameter 
Visit 
Result 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Urine parameter 1 
Screening 
Below reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Within reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Above reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
Dosing 
Below reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Within reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Above reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
Follow up 
Below reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Within reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Above reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Urine parameter 2 
Screening 
Below reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Within reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Above reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
Dosing 
Below reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Within reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Above reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
Follow up 
Below reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Within reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Above reference range 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 ... 
 
 
 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 97/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.2.6: Pregnancy test, Safety analysis set 
 
Visit 
Result 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
Screening 
Negative 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Positive 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
Dosing 
Negative 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Positive 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
Follow up 
Negative 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Positive 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
Screening: Serum pregnancy test 
Dosing,Follow up: Urine stick pregnancy test. Prior to the start of the insulin-induced hypoglycemic procedure. 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 98/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.3: Local tolerability, Safety analysis set 
 
Local Symptom 
Visit/ Time point 
Grade (Intensity) 
 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 
 
 
Spontaneous Pain 
30min after dosing 
 
None 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Mild 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Moderate 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Severe 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
 
 
 
 
 
 
120min after dosing 
 
None 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Mild 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Moderate 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Severe 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
 
 
 
 
300min after dosing 
 
None 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Mild 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Moderate 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Severe 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
 
 
 
 
Follow up 
 
None 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Mild 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Moderate 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
Severe 
 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x)  
xx ( xx.x)  
 
 
 
 
 
 
 
 
Percentages are based on total no. of subjects in each treatment group 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
Programmer Note: Table is produced with same SAS macro like Aes (npcttab). 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 99/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.4: Vital signs, Safety analysis set 
 
 
Parameter  
Visit/Time Point 
Result 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
Screening 
 
 
 
 
 Systolic blood 
pressure [mmHg] 
n 
xx 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Dosing/ Prior start of hypoglycemic procedure 
n 
xx 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Dosing/ 30min post dose 
n 
xx 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 ... 
 
 
 
 
 
 
 
 
 
 
Follow up 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
n 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
Programmer Note: This table is continued for each of the following Vital signs parameter: Systolic blood pressure  [mmHg], Pulse rate [bpm] and 
body temparature [°C]  
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 100/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.3.5.5: Pulse rate - categorical analysis, Safety analysis set 
 
Visit 
Time Point 
Class 
dasiglucagon 
(N=xxx) 
GlucaGen 
(N=xxx) 
Placebo 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Screening 
Class1 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Class2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
Prior start of hypoglycemic procedure 
Class1 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Class2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 Dosing 
30min post dose 
Class1 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Class2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
 
 
 
 
 ... 
 
 
 
 
 
 
 
 
 
 Follow up 
Class1 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
Class2 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
Programmer Note: This table is repeated (as byvars) for each of the following Vital signs parameter: Systolic blood pressure  [mmHg], Pulse rate 
[bpm] and body temparature [°C]  
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 101/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.3.5.6: Immunogenicity - occurrence of ADA, Safety analysis set 
 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
Occurrence of ADA 
 No 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
Yes 
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
  n ( xx.x%)  
 Missing 
  n           
  n           
  n           
  n           
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy 
RUN DATE: ddmmyyy hh:mm CET 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 102/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of 1 
14.4.1.1: Summary statistics of plasma dasiglucagon and GlucaGen concentration table, FAS 
 
Treatment 
Variable 
Pre- 
dose 
10min 
20min 
30min 
 
40min 
 
60min 
 
90min 
 
140min 
 
220min 
 
300min 
 
 
 
 
 
 
 
 
 
 
 
 Glucagon 
Result 
n 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
Change from baseline n 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 dasiglucagon Result 
n 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
Change from baseline n 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose results LLOQ are set to 0 pmol/mL 
Results are rounded to 3 significant digits 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
Programmer Note: The mean (SD) column above is broken into 2 lines above, but if possible put it in one row 
 
  
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.4.1.2: PK metrics, FAS 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 103/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
PK Parameter 
dasiglucagon 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 Cmax [pmol/L] 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
Geom. Mean 
xx, xx 
xx, xx 
xx, xx 
 
Gem. Mean CV % 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 Tmax [h] 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 ... 
 
 
 
 
 
 
 
 
 
Results are rounded to 3 significant digits 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 104/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.4.1.3: Figure: Mean analyte concentrations versus time - original scale, FAS 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
NOTE: This is a generic example using example data not real data 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 105/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.4.1.4: Figure: Mean analyte concentrations versus time - log scale, FAS 
 
 
Repetiton of figure 14.4.1.3 using logarithmic y-scale 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 106/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.4.1.5: Figure: Individual analyte concentrations versus time curves- original scale, FAS 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
NOTE: This is a generic example using example data not real data and coloring will be the same as in the figure before; x-axis and sampling scheme 
will be adapted to the study specifics 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 107/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.4.2.1: PD metrics, FAS 
 
 
PK Parameter 
dasiglucagon 
(N=xxx) 
Placebo 
(N=xxx) 
GlucaGen 
(N=xxx) 
Total 
(N=xxx) 
 
 
 
 
 
 Cmax [pmol/L] 
n 
xx 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 Tmax [h] 
n 
xx 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 ... 
 
 
 
 
 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 108/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.4.2.2: Figure: Mean glucose concentrations versus time - original scale, FAS 
 
 
 
Repetiton of figure 14.4.1.3 using glucose concentration and adapted sampling scheme 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 109/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
Zealand Pharma A/S 
Clinical Study Report Section 14 
Protocol Number: ZP4207-17086 
Page 1 of x 
14.4.2.3: Figure: Individual glucose concentrations versus time curves - original scale, FAS 
 
 
 
Repetiton of figure 14.4.1.4 using glucose concentration and adapted sampling scheme 
 
 
 
 


 
 
 
Zealand Pharma A/S 
 
                                                                                                 Statistical Analysis Plan 
ZP4207-17086 (ZEA-DNK-02170) 
  
16 August 2019 
TMP-SOP-0202-001-03_SAP Template 
Page 110/110 
CONFIDENTIAL 
ZEA-DNK-02170_SAP_Vers.1.0_clean_16AUG2019 
 
Appendix E: Listing Layouts 
 
Zealand Pharma A/S 
Clinical Study Report Section 16.2 
Protocol Number: ZP4207-17086 
Page 1 of x 
 
 
 
 
Listing 16.2.x 
Title, Population (if applicable) 
 
Treatment 
Subject  
ID 
Parameter 
Visit 
Time Point 
Variable 1 
Variable 2 
Variable 3 
Variable 4 
Variable xxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROGRAM SOURCE:###, DATA CUT OFF DATE: ddmmmyyyy  
RUN DATE: ddmmyyy hh:mm CET 
 
 
 
 
 
 
Programmer Note:  
- 
Listings are sorted by treatment, Subject ID, Parameter, Visit and timepoint as applicable and available. 
- 
Listings usually will display all data avaiölable and not restricted to any analysis set if not defined otherwise in the SAP