A Two-Period, Open-label Trial Evaluating the Efficacy and Safety of Dasiglucagon for the Treatment of Children With Congenital Hyperinsulinism
Phase: PHASE3
Conditions: Congenital Hyperinsulinism
Sponsor: Zealand Pharma

PROTOCOL TITLE: A Two-Period, Open-label Trial Evaluating the Efficacy and Safety of Dasiglucagon for the Treatment of 
Children with Congenital Hyperinsulinism 
 NCT Number: 
 NCT03777176 
Document name 
Date 
Approval/submission status 
Comments 
Version 1.0 – Global 
14-Dec-2017
Submitted in the US only 
Version 2.0 – Global 
22-May-2018
Submitted in all countries except 
France 
Approved in the US 
Updated based on FDA feedback. First version submitted 
outside the US 
Version 3.0 – UK only 
05-Jul-2018
Approved in the UK 
Minor updates based on MHRA feedback 
Version 4.0 – DE, FR, 
IL only 
25-Jul-2018
Approved (AMG and EC) in DE. 
Approved in IL 
Minor updates based on BfArM feedback 
Version 5.0 – Global 
14-Dec-2018
Approved in the US and UK 
First version submitted in FR in 
Jan-2019  
Not submitted in Germany and 
Israel 
This version includes the updates to the stat section 
regarding primary endpoint (and analysis) and interim 
analysis based on FDA feedback.  
The changes included in the local versions 3.0 and 4.0 
have been included in version 5.0  
Version 6.0 – DE only 
25-Mar-2019
Submitted to MPG Germany 
Device adapted protocol to fulfill the requirements from 
BfArM MPG. New section 19 added + additional device 
related safety reporting added in section 11. 
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Document name 
Date 
Approval/submission status 
Comments 
Version 7.0 – All 
countries except DE 
03-Jun-2019
Submitted in all countries except 
Germany 
Main changes: 
-
Primary analysis changed (FDA requested)
-
Endpoints aligned to 103
-
Clarifications to hypo reporting and electronic
SMPG data
-
Clarified that SOC open label CGM is not allowed
-
Immunogenicity strategy updated
Version 8.0 – DE only 
05-Jul-2019
Submitted in Germany 
Local German protocol combining protocol versions 6.0 
and 7.0. 
Version 9.0 – All 
countries except DE 
19-Sep-2019
Submitted in all countries except 
Germany 
-
Additional ECG and vital signs assessments
(FDA request)
-
Immunogenicity strategy updated (FDA request)
Version 10.0 – DE 
only 
11-Oct- 2019
Submitted in Germany 
Local German protocol combining protocol versions 8.0 
and 9.0. 
Version 11.0 – All 
countries except DE 
06-Mar-2020
Submitted in all countries except 
Germany 
-
Interim analyses taken out
-
Immunogenicity section updated
Version 12.0 – DE 
only 
11-Mar-2020
Submitted in Germany 
Local German protocol combining protocol version 10.0 
and changes according to protocol version 11.0. 
Version 13.0 – All 
countries except DE 
12-Nov-2020
To be submitted in all countries 
except Germany 
-
Second key secondary efficacy endpoint moved
to only be a secondary efficacy endpoint.
-
All endpoints related to intake of gastric
carbohydrates will only described in the subgroup
of patients who have a gastrostomy/NG tube at
screening
Version 14.0 – DE 
only
12-Nov-2020
To be submitted in Germany 
Local German protocol combining protocol versions 12.0 
and 13.0 
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PROTOCOL 
PRODUCT 
NAME/NUMBER: 
Dasiglucagon 
PROTOCOL NUMBER: 
ZP4207-17109 
IND NUMBER: 
135869 
EUDRACT NUMBER: 
2017-004547-21 
DEVELOPMENT PHASE: 
Phase 3 
PROTOCOL TITLE: 
A Two-Period, Open-label Trial Evaluating the Efficacy and 
Safety of Dasiglucagon for the Treatment of Children with 
Congenital Hyperinsulinism 
PROTOCOL DATE: 
Original Protocol Version 1.0, 14-Dec-2017 
Final Version 13.0, 12-Nov-2020 (All countries except Germany) 
SPONSORED BY: 
Zealand Pharma A/S 
Sydmarken 11 
2860 Soeborg (Copenhagen) 
Denmark 
Telephone: +45 88 77 36 00 
CONTRACT RESEARCH 
ORGANIZATION: 
Premier Research  
One Park Drive 
Suite 150 
Durham, NC  27709  USA 
This trial will be performed in compliance with Good Clinical Practices (GCP) and applicable 
regulatory requirements, including the archiving of essential documents. Information contained 
in this protocol is confidential in nature, and may not be used, divulged, published, or otherwise 
disclosed to others, except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that this information is confidential and may not be further 
disclosed without the express permission of Zealand Pharma A/S. 
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REVISION HISTORY 
PROTOCOL TITLE: 
A Two-Period, Open-label Trial Evaluating the Efficacy and 
Safety of Dasiglucagon for the Treatment of Children with 
Congenital Hyperinsulinism 
PROTOCOL DATE: 
Original Protocol Version 1.0, 14-Dec-2017 
This updated protocol version 13.0 is applicable for all 
countries except Germany, and includes: 
AMENDMENT No. 1 
Final Version 2.0, 22-May-2018 (All countries) 
AMENDMENT No. 2 
Final Version 3.0, 05-Jul-2018 (United Kingdom) 
AMENDMENT No. 3 
Final Version 4.0, 25-Jul-2018 (France, Germany, and Israel) 
AMENDMENT No. 4 
Final Version 5.0, 14-Dec-2018 (All countries) 
AMENDMENT No. 5 
Final Version 6.0, 25-Mar-2019 (Germany) 
AMENDMENT No. 6 
Final Version 7.0, 03-Jun-2019 (All countries except 
Germany) 
AMENDMENT No. 7 
Final Version 8.0, 05-Jul-2019 (Germany) 
AMENDMENT No. 8 
Final Version 9.0, 19-Sep-2019 (All countries except 
Germany) 
AMENDMENT No. 9 
Final Version 10.0, 11-Oct-2019 (Germany) 
AMENDMENT No. 10 
Final Version 11.0, 06-Mar-2020 (All countries except 
Germany) 
AMENDMENT No. 11 
Final Version 12.0, 11-Mar-2020 (Germany) 
AMENDMENT No. 12 
Final Version 13.0, 12-Nov-2020 (All countries except 
Germany) 
 
 
 
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1. APPROVAL SIGNATURES 
PROTOCOL 
NUMBER: 
ZP4207-17109 
PROTOCOL TITLE: 
A Two-Period, Open-label Trial Evaluating the Efficacy and Safety of 
Dasiglucagon for the Treatment of Children with Congenital 
Hyperinsulinism 
 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the trial. 
 
 
 
 
 
 
 
 
 
 
 
Clinical Trial Manager 
Zealand Pharma A/S 
 
 
 
 
 
 
Date 
 
 
Medical Director 
Zealand Pharma A/S 
 
 
 
 
 
 
Date 
 
 
Manager Biostatistics 
Premier Research 
 
Date 
 
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2. SYNOPSIS 
PRODUCT 
NAME/NUMBER 
Dasiglucagon 
PROTOCOL 
NUMBER 
ZP4207-17109 
EUDRACT NUMBER 
2017-004547-21 
DEVELOPMENT 
PHASE 
Phase 3 
PROTOCOL TITLE 
A Two-Period, Open-label Trial Evaluating the Efficacy and Safety of Dasiglucagon for 
the Treatment of Children with Congenital Hyperinsulinism 
INDICATION 
Congenital hyperinsulinism (CHI) 
OBJECTIVES 
Primary: To evaluate the efficacy of dasiglucagon administered as a subcutaneous (SC) 
infusion in reducing hypoglycemia in children with CHI. 
Secondary:  
• 
To evaluate the safety and tolerability of dasiglucagon administered as an SC 
infusion in children with CHI 
• 
To evaluate the efficacy of dasiglucagon in reducing glucose requirements 
• 
To investigate quality of life and resource utilization 
TRIAL DESIGN 
This is a 2-period, open-label trial to evaluate the efficacy and safety of dasiglucagon in 
children between the ages of 3 months and 12 years (both inclusive) with CHI.  
Patients are to experience frequent (≥3 events per week) episodes of hypoglycemia despite 
standard of care (SOC) medications to be eligible for this trial, and are to have previously 
undergone sub-total pancreatectomy for CHI or be treated with a non-surgical approach, 
having been evaluated as not eligible for pancreatic surgery. 
After screening and eligibility assessments (during which a 2-week baseline for plasma 
glucose [PG] will be established), patients will be randomly assigned in a 1:1 ratio to 
continue receiving SOC alone or SOC plus dasiglucagon for 4 weeks. In 
Treatment Period 2, all patients will receive SOC plus dasiglucagon for 4 weeks. 
At the beginning of Treatment Period 1 (Week 1), all patients will be hospitalized for 
1-2 days. Patients assigned to SOC plus dasiglucagon treatment will have dasiglucagon 
infusion initiated and titrated, and will be trained in the use of the infusion pump, 
continuous glucose monitoring (CGM) sensor, and glucose meter, and supervised. Patients 
assigned to SOC alone will receive a similar degree of supervision alongside the training 
in the use of the CGM sensor and glucose meter. This period can be extended for both 
treatment groups if dasiglucagon titration has not been finalized or if training of the 
family/caregivers has not been completed satisfactorily.  
Patients originally assigned to receive SOC alone in Treatment Period 1 will also be 
hospitalized for the first 2 days of Treatment Period 2 (Week 5), and will have 
dasiglucagon infusion initiated and titrated, and will be trained in the use of the infusion 
pump. This period can be extended if dasiglucagon titration or pump training has not been 
completed. Regardless of whether dasiglucagon is initiated during Treatment Period 1 
or Treatment Period 2, SOC CHI medications should subsequently be kept constant 
throughout the trial. Adjustments to gastric and oral feeds are permitted. 
Patients’ parent(s)/guardian will be trained to perform PG assessments. Events of 
hypoglycemia will be documented by self-monitored PG (SMPG) measurements. The 
extent of hypoglycemia (episodes and percent time below the threshold) will be further 
quantified by CGM measurements during the 2 weeks before randomization (baseline), 
Weeks 2-4 in Treatment Period 1, and Weeks 6-8 of Treatment Period 2. The CGM results 
will be masked.  
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Patients completing the trial will (pending investigator confirmation of continued positive 
benefit-risk balance) be offered to enter a long-term extension trial (Trial ZP4207-17106) 
to continue dasiglucagon treatment. Patients who do not continue in the long-term 
extension trial will have a Follow-up Visit performed 4 weeks after stopping dasiglucagon 
treatment. 
PLANNED NUMBER 
OF PATIENTS 
A sufficient number of patients will be screened to reach a total maximum of 
32 randomized patients with CHI. Patients who withdraw prematurely will not be 
replaced. 
TRIAL ENTRY 
CRITERIA 
Eligible patients will be male or female between 3 months and 12 years of age (both 
inclusive) at screening with an established and documented diagnosis of CHI and who are 
experiencing ≥3 events of hypoglycemia per week (events of PG <70 mg/dL 
[<3.9 mmol/L]) according to investigator’s evaluation. Patients are to have previously 
undergone sub-total pancreatectomy or being treated with a non-surgical approach, having 
been evaluated as not eligible for pancreatic surgery.  
INVESTIGATIONAL 
PRODUCT 
Dasiglucagon injection 4 mg/mL in a 3 mL vial containing 1 mL. 
REFERENCE 
PRODUCT 
None 
TREATMENT 
REGIMENS 
Dosing of dasiglucagon will approximate continuous infusion by delivering small doses at 
frequent intervals via an infusion pump. 
During the trial, PG assessments will be performed regularly (at least 3 times daily, 
preferably before main meals, and as instructed by the investigator); adjustments to the 
gastric dextrose infusion and/or trial drug will occur at the investigator’s discretion. 
Dasiglucagon treatment will be initiated at 10 µg/hr (t=0). Every 2 hours (t=2, 4, 6, etc.), 
the dose will be increased by an additional 10 µg/hr until either: 
1. 
The patient is weaned off entirely from gastric dextrose infusion and/or 
glucose-fortified feeds, or 
2. 
Plasma glucose during the last 2 hours was consistently above 120 mg/dL 
(6.7 mmol/L), or 
3. 
The maximum trial drug product infusion rate of 70 µg/hr is reached, or 
4. 
Adverse events (AEs) emerge that are considered to be related to dasiglucagon 
(e.g., nausea and vomiting) and limit further dose escalation 
The dose of dasiglucagon should not be escalated beyond the treatment objectives of 
PG in the range of 70 to 120 mg/dL (3.9-6.7 mmol/L) while approaching a normal feeding 
regimen according to age.  
The 2-hour dose-adjustment interval will allow plasma drug levels to approach 
approximately steady-state before the dose is further increased. The maximum cumulative 
dose over the first 24 hours is 1.26 mg.  
After the first 24 hours, the dose of dasiglucagon can still be modified to optimize each 
patient’s treatment and to reduce gastric dextrose infusions. The maximum dose of 
dasiglucagon will be 70 µg/hr, corresponding to a maximum of 1.68 mg per day. 
PLANNED TRIAL 
SITES 
Up to 14 sites in the United States, Europe, and Israel. 
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CRITERIA FOR 
EVALUATION 
Primary efficacy endpoint:  
Treatment Period 1 
• 
Hypoglycemia event rate, defined as average weekly number of hypoglycemic 
events (PG <70 mg/dL or 3.9 mmol/L) during Weeks 2-4, as detected by SMPG 
Key secondary efficacy endpoints: 
Treatment Period 1 
• 
Increase in fasting tolerance (time from beginning of meal to the beginning of the 
first continuous 15-minute CGM reading <70 mg/dL [3.9 mmol/L]) 
• 
CGM percent time in range 70-180 mg/dL (3.9-10.0 mmol/L) during Weeks 2-4 
• 
Clinically significant hypoglycemia event rates, defined as average weekly number 
of events <54 mg/dL (3.0 mmol/L), as detected by SMPG during Weeks 2-4 
STATISTICAL 
METHODS 
Continuous endpoints will be summarized with number (n), mean, standard deviation 
(SD), median, minimum, and maximum. In addition, change from baseline values will be 
calculated at each time point and summarized descriptively; the exception to this is the 
time of PG within pre-specified ranges, which will not have a baseline value. For 
categorical endpoints, descriptive summaries will include counts and percentages. 
All data will be presented in the data listings. 
Analysis Populations 
Three analysis populations are defined for this trial: 
The Safety Set: defined as all patients administered any randomized treatment. This 
population will be used to provide descriptive summaries of safety data. Patients will be 
summarized by treatment period according to treatment received. 
The Full Analysis Set (FAS): defined as all patients in the Safety Set who have a valid 
baseline efficacy assessment. This population will be used to analyze efficacy data. 
Patients will be analyzed by treatment period according to planned treatment. 
The Per Protocol (PP) Analysis Set: defined as all patients in the FAS without any major 
protocol deviations. This population will be used to analyze primary and key secondary 
endpoints as a supportive analysis. Patients will be analyzed according to planned 
treatment for the first treatment period only. 
The analysis of efficacy will be separated into 3 categories: 
1. Treatment Period 1, FAS 
2. Treatment Period 1, PP (primary and key secondary endpoints only) 
3. Treatment Period 2, FAS 
In Treatment Period 1 (categories 1 and 2), the 2 treatment arms will be compared by a 
testing procedure starting with the primary and subsequently continuing through the 
key secondary endpoints if the hypotheses are rejected. 
In Treatment Period 2 (category 3), only descriptive analyses will performed. 
Graphical presentations of selected analyses in the 2 treatment periods will be prepared, 
and will be discussed in the formal statistical analysis plan (SAP). 
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Efficacy Analyses  
Primary Endpoint (Treatment Period 1) 
The primary efficacy endpoint is the hypoglycemia event rate during Weeks 2-4 of 
Treatment Period 1. A hypoglycemia event is defined as PG <70 mg/dL or 3.9 mmol/L, as 
detected by SMPG. Baseline is defined as the average weekly number of hypoglycemic 
events during the 2-week baseline period. Weeks 2-4 of Treatment Period 1 is defined as 
the average weekly number of hypoglycemic events across the last 3 weeks of the 
treatment period. The hypoglycemic event rate will be analyzed by using negative 
binomial regression, with treatment group as a fixed effect and baseline hypoglycemic rate 
as a covariate. The null hypothesis is that there is no difference in the incidence of average 
weekly number of hypoglycemic events between the 2 treatment groups, which will be 
tested at the significance level of α = 0.05. 
The primary analysis will estimate the treatment effect based on the de facto (treatment 
policy) estimand. All available data in the form of actual measurements will therefore be 
included in the analysis, irrespective of adherence to treatment or use of subsequent 
therapy. 
As a sensitivity analysis, the primary endpoint will also be analyzed without imputation of 
missing data; however, this analysis will not be included in the fixed-sequence hierarchical 
testing strategy. Similarly, the primary endpoint may be analyzed excluding post-baseline 
data collected after trial drug discontinuation/completion. 
Key Secondary Endpoints (Treatment Period 1) 
The key secondary endpoint of clinically significant hypoglycemia (<54 mg/dL 
[3.0 mmol/L]) event rates will be analyzed using a negative binomial regression, with 
treatment group as a fixed effect and baseline hypoglycemic rate as a covariate. Percent 
time in range (i.e., the percent time between 70 mg/dL [3.9 mmol] and 180 mg/dL [10.0 
mmol], inclusive, as measured by CGM, where percent time is calculated as [number of 
minutes in range/total number of minutes patient is wearing CGM] * 100%) will be 
analyzed by using an ANCOVA, with treatment group and region as fixed effects and 
baseline time in range as a covariate. Increase in fasting tolerance (i.e., change from 
baseline in time from meal to PG <70 mg/dL) will be analyzed similarly using an 
ANCOVA, with treatment group and region as fixed effects and baseline fasting tolerance 
as a covariate. 
For the remaining efficacy endpoints, continuous and categorical endpoints will be 
presented using summary statistics or frequencies, respectively; no inference will be 
performed.  
Safety Analyses 
Adverse events will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Adverse events that begin after the first dose of 
dasiglucagon will be defined as treatment-emergent. The overall incidence of AEs will be 
displayed by system organ class, preferred term, and treatment. The incidence of AEs will 
also be presented by severity and by relationship to the trial drug. Vital signs, clinical 
laboratory measures (including hematology, biochemistry, incidence of anti-drug 
antibodies [ADAs]), electrocardiograms (ECGs), echocardiography, physical 
examinations, and local tolerability data will be summarized by treatment, where 
applicable. Out-of-range safety endpoints may be categorized as low or high where 
applicable. 
A SAP will be prepared to provide further details on the methods for statistical analysis, 
including rules for handling multiplicity and missing data. 
SAMPLE SIZE 
DETERMINATION 
Patients will be randomized into the trial if they have at least 3 events of hypoglycemia on 
average per week, as recorded in the diary during the 2 weeks prior to randomization. It is 
assumed that patients continuing on standard of care will maintain a similar level through 
Treatment Period 1, with the number of hypoglycemia events (PG <70 mg/dL or 
3.9 mmol/L) during Weeks 2-4, as detected by SMPG following a Poisson distribution 
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with a mean of 9. The trial is powered to detect a treatment effect of 50%, hence, 
assuming that the number of hypoglycemia events reported for patients in the 
dasiglucagon group during Weeks 2-4 will follow a Poisson distribution with a mean of 
4.5. At the final analysis, 32 patients will have 99% power testing at a 0.05 significance 
level. The overall alpha level is strongly controlled in this setting, remaining at or below 
0.05. 
TRIAL AND 
TREATMENT 
DURATION 
The overall trial duration is expected to be 15 months. 
The sequence and maximum duration of the trial periods will be as follows: 
1. 
Screening: at least 14 days up to 28 days 
2. 
Treatment Period 1: 4 weeks 
3. 
Treatment Period 2: 4 weeks 
4. 
Follow-up Period: 4 weeks 
The maximum trial duration for each patient is approximately 16 weeks. 
The dasiglucagon treatment duration for each patient is 4 or 8 weeks. 
 
 
 
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3. TABLE OF CONTENTS 
 
 
 
REVISION HISTORY .............................................................................................................2 
1. 
APPROVAL SIGNATURES ...................................................................................................3 
2. 
SYNOPSIS ...............................................................................................................................4 
3. 
TABLE OF CONTENTS .........................................................................................................9 
3.1. LIST OF TABLES ........................................................................................................13 
3.2. LIST OF FIGURES ......................................................................................................13 
4. 
LIST OF ABBREVIATIONS .................................................................................................14 
5. 
INTRODUCTION ..................................................................................................................17 
5.1. Background and Rationale ............................................................................................17 
5.2. Current Treatment and Unmet Medical Need ...............................................................17 
5.3. Dasiglucagon for the Treatment of Congenital Hyperinsulinism .................................18 
5.3.1. Dasiglucagon .....................................................................................................18 
5.3.2. Nonclinical Experience .....................................................................................19 
5.3.3. Clinical Experience ...........................................................................................19 
5.3.4. Literature Data ...................................................................................................21 
5.3.5. Anticipated Medical Benefit of Dasiglucagon in the Treatment of CHI ..........22 
5.3.6. Anticipated Risks of Dasiglucagon in the Treatment of CHI ...........................22 
5.3.7. Summary of Potential Benefits and Risks .........................................................23 
6. 
OBJECTIVES AND ENDPOINTS ........................................................................................24 
6.1. Objectives ......................................................................................................................24 
6.1.1. Primary Objective ..............................................................................................24 
6.1.2. Secondary Objectives ........................................................................................24 
6.2. Endpoints ......................................................................................................................24 
6.2.1. Primary Endpoint ..............................................................................................24 
6.2.2. Key Secondary Efficacy Endpoints ...................................................................24 
6.2.3. Secondary Efficacy Endpoints ..........................................................................24 
6.2.4. Other Efficacy Endpoints ..................................................................................25 
6.2.5. Safety Endpoints ................................................................................................25 
7. 
TRIAL DESIGN .....................................................................................................................26 
7.1. Overall Trial Design and Plan .......................................................................................26 
7.2. Discussion of Trial Design ............................................................................................27 
7.3. Trial Sites ......................................................................................................................27 
7.4. Point of Contact ............................................................................................................27 
8. 
PATIENT POPULATION ......................................................................................................28 
8.1. Selection of Trial Population ........................................................................................28 
8.2. Trial Entry Criteria ........................................................................................................28 
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8.2.1. Inclusion Criteria ...............................................................................................28 
8.2.2. Exclusion Criteria ..............................................................................................29 
8.2.3. Randomization Exclusion Criteria ....................................................................29 
8.3. Premature Patient Withdrawal ......................................................................................30 
8.4. Treatment Discontinuation ............................................................................................30 
8.5. Patient Replacement Criteria.........................................................................................30 
9. 
TREATMENTS ......................................................................................................................31 
9.1. Identification of Investigational Product .......................................................................31 
9.1.1. Packaging and Labeling ....................................................................................31 
9.2. Treatments Administered ..............................................................................................31 
9.3. Trial Supplies ................................................................................................................33 
9.4. Dispensing and Storage .................................................................................................33 
9.5. Method of Assigning Patients to Treatment Groups .....................................................34 
9.6. Blinding and Unblinding Treatment Assignment .........................................................34 
9.7. Selection of Doses in the Trial ......................................................................................34 
9.8. Selection of Timing of Dose for Each Patient ..............................................................35 
9.9. Dose Adjustment Criteria ..............................................................................................35 
9.10. Treatment Compliance ..................................................................................................35 
9.11. Permitted and Prohibited Therapies ..............................................................................35 
9.11.1. Permitted Therapies ...........................................................................................35 
9.11.2. Prohibited Therapies ..........................................................................................35 
9.12. Patients May be Discharged for Home Treatment ........................................................36 
9.13. Treatment After End of Trial ........................................................................................36 
10. TRIAL PROCEDURES ..........................................................................................................37 
10.1. Trial Duration ................................................................................................................37 
10.2. Assessments ..................................................................................................................37 
10.2.1. Efficacy .............................................................................................................37 
10.2.1.1. Plasma Glucose Monitoring ..................................................................37 
10.2.1.2. Continuous Glucose Monitoring ...........................................................37 
10.2.1.3. Quality of Life .......................................................................................38 
10.2.1.4. Other Assessments ................................................................................38 
10.2.1.5. Fasting Tolerance Test/Safety Fast .......................................................39 
10.2.2. Pharmacokinetics/Drug Exposure .....................................................................40 
10.2.3. Safety .................................................................................................................40 
10.2.3.1. Laboratory Safety Assessments ............................................................40 
10.2.3.2. Clinical Examinations ...........................................................................42 
10.2.3.3. Reporting of Hypoglycemia Events ......................................................42 
10.2.3.4. Reporting of Technical Complaints ......................................................43 
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10.2.3.5. Adverse Events .....................................................................................44 
11. ADVERSE EVENTS AND PREGNANCIES .......................................................................44 
11.1. Definitions .....................................................................................................................44 
11.1.1. Adverse Events ..................................................................................................44 
11.1.2. Severity ..............................................................................................................44 
11.1.3. Causality ............................................................................................................45 
11.1.4. Outcome ............................................................................................................45 
11.1.5. Serious Adverse Events .....................................................................................45 
11.1.6. Other Important Events .....................................................................................46 
11.1.7. Non-serious Adverse Events .............................................................................46 
11.1.8. Adverse Events of Special Interest ....................................................................46 
11.1.9. Suspected Unexpected Serious Adverse Reactions ...........................................46 
11.2. Collection, Recording, and Reporting of Adverse Events ............................................46 
11.2.1. Contact Information ..........................................................................................47 
11.3. Follow-up of Adverse Events........................................................................................47 
11.4. Pregnancy ......................................................................................................................48 
11.5. Precautions ....................................................................................................................49 
11.6. Safety Committee ..........................................................................................................49 
11.7. Independent Data Monitoring Committee ....................................................................49 
12. STATISTICS ..........................................................................................................................50 
12.1. Statistical Hypotheses ...................................................................................................50 
12.2. Sample Size Determination ...........................................................................................50 
12.3. Analysis Populations .....................................................................................................51 
12.4. Statistical Analyses .......................................................................................................51 
12.4.1. Trial Patients and Demographics ......................................................................51 
12.4.1.1. Disposition and Withdrawals ................................................................51 
12.4.1.2. Protocol Deviations ...............................................................................51 
12.4.1.3. Demographics and Other Baseline Characteristics ...............................52 
12.4.2. Duration of Exposure and Compliance .............................................................52 
12.4.3. Efficacy Analyses ..............................................................................................52 
12.4.3.1. Primary Analysis ...................................................................................52 
12.4.3.2. Key Secondary Analyses ......................................................................53 
12.4.3.3. Secondary and Other Efficacy Analyses ...............................................53 
12.4.3.4. Imputation of Missing Data ..................................................................54 
12.4.4. Safety and Tolerability Analyses ......................................................................54 
12.4.4.1. Adverse Events .....................................................................................54 
12.4.4.2. Clinical Laboratory Evaluations ...........................................................55 
12.4.4.3. Vital Signs .............................................................................................55 
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12.4.4.4. Twelve-lead Electrocardiograms ..........................................................55 
12.4.4.5. Physical Examination Findings .............................................................55 
12.4.4.6. Local Tolerability ..................................................................................55 
12.4.5. Interim Analysis ................................................................................................55 
13. TRIAL CONDUCT ................................................................................................................56 
13.1. Sponsor and Investigator Responsibilities ....................................................................56 
13.1.1. Sponsor Responsibilities ...................................................................................56 
13.1.2. Investigator Responsibilities .............................................................................56 
13.2. Site Initiation .................................................................................................................57 
13.3. Screen Failures ..............................................................................................................57 
13.4. Trial Documents ............................................................................................................57 
13.4.1. Investigator’s Regulatory Documents ...............................................................57 
13.4.2. Case Report Forms ............................................................................................57 
13.4.3. Source Documents .............................................................................................58 
13.5. Data Quality Control .....................................................................................................58 
13.5.1. Monitoring Procedures ......................................................................................58 
13.5.2. Data Management ..............................................................................................59 
13.5.3. Quality Assurance/Audit ...................................................................................59 
13.6. Trial Termination ..........................................................................................................59 
13.6.1. Regular Trial Termination .................................................................................59 
13.6.2. Premature Trial Termination .............................................................................60 
13.7. Trial Site Closure ..........................................................................................................60 
13.7.1. Record Retention ...............................................................................................60 
13.7.2. Sample Retention ..............................................................................................61 
13.8. Changes to the Protocol ................................................................................................61 
13.9. Use of Information and Publication ..............................................................................61 
14. FINAL CLINICAL TRIAL REPORT ....................................................................................62 
15. ETHICAL AND LEGAL CONSIDERATIONS ....................................................................62 
15.1. Declaration of Helsinki and Good Clinical Practice .....................................................62 
15.2. Patient Information and Informed Consent ...................................................................62 
15.3. Approval by Institutional Review Board and Independent Ethics Committee .............63 
15.4. Finance and Insurance ...................................................................................................63 
16. REFERENCES .......................................................................................................................64 
17. ATTACHMENTS ...................................................................................................................66 
17.1. Schedule of Events ........................................................................................................66 
17.2. Investigator’s Agreement ..............................................................................................69 
18. APPENDICES ........................................................................................................................70 
A. 
Contact Information ......................................................................................................71 
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B. 
Quality of Life Questionnaires ......................................................................................72 
C. 
Regulations and Good Clinical Practice Guidelines .....................................................73 
1. 
Regulations ........................................................................................................73 
2. 
Good Clinical Practice Guidelines ....................................................................73 
 
3.1. LIST OF TABLES 
Table 1 
Initial 24-hour Maximum Dose of Dasiglucagon ..............................................32 
Table 2 
Schedule of Events ............................................................................................66 
 
3.2. LIST OF FIGURES 
Figure 1 
Trial Design .......................................................................................................27 
 
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4. LIST OF ABBREVIATIONS 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AOCglucose 
area over the glucose curve up to 70 mg/dL 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-inf 
area under the plasma concentration-time curve from time zero to infinity 
CGM 
continuous glucose monitoring 
CHI 
congenital hyperinsulinism 
Cmax 
maximum observed concentration 
CRA 
clinical research associate 
CRO 
contract research organization 
CTR 
clinical trial report 
DMC 
data monitoring committee  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ER 
emergency room 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
H 
hypothesis 
HbA1c 
glycated hemoglobin 
HIV 
human immunodeficiency virus 
HNF4A-DM 
hepatocyte nuclear factor 4 alpha diabetes mellitus 
HNF4A-IGT 
hepatocyte nuclear factor 4 alpha impaired glucose tolerance 
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IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IFU 
instructions for use 
IM 
intramuscular(ly) 
IRB 
institutional review board 
ISF 
Investigator Site File 
ISPE  
International Society of Pharmaceutical Engineers 
IV 
intravenous(ly) 
J2C 
jump to control 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MNAR 
missing not at random 
NG 
nasogastric 
PD 
pharmacodynamics(s) 
PedsQL™ 
Pediatric Quality of Life Inventory 
PG 
plasma glucose 
PK 
pharmacokinetic(s) 
PP 
Per protocol 
PT 
preferred term 
QoL 
quality of life 
RBC 
red blood cell 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SEM 
standard error of the mean 
SMPG 
self-monitored plasma glucose 
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SpO2 
blood oxygen saturation level 
SOC 
standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
Zealand 
Zealand Pharma A/S 
 
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5. INTRODUCTION 
5.1. Background and Rationale 
Congenital hyperinsulinism (CHI) is a rare and challenging disorder in which β-cells in the 
pancreas secrete insulin irrespective of plasma glucose (PG) concentration, resulting in persistent 
and often severe hypoglycemia.1 Congenital hyperinsulinism affects up to 1 in 50,000 newborns. 
It is typically diagnosed on the basis of signs and symptoms of hypoglycemia during the neonatal 
period or in infancy; however, the diagnosis may be made later in childhood. Mutations in 
several different genes have been described to cause CHI, which can be either focal (only a small 
area of the pancreas is affected) or diffuse (most of the pancreas is affected). The condition can 
persist into adulthood; however, the severity generally decreases with age due to the increased 
insulin requirements and/or increased insulin resistance, and CHI is thus primarily a pediatric 
disease with regard to medical treatment needs. Hypoglycemia that results from CHI is of 
particular concern because it is an important cause of brain injury in neonates, infants, and 
children with this disease, which leads to long-term neurological impairments.1,2 Up to 
approximately 50% of children with CHI experience neurodevelopmental abnormalities caused 
by severe hypoglycemia that results from inadequate treatment and/or delays in diagnosis.1,3 
Severe brain damage is the consequence of severe hypoglycemia, which presents as coma and/or 
long-lasting epileptic seizures in neonates. Major intellectual disability is, therefore, most 
frequent in patients with neonatal onset, whereas hypoglycemia is usually less severe and brain 
damage less frequent in children with CHI diagnosed later in childhood.1 Since symptoms and 
severity of hypoglycemia can vary and pose a diagnostic challenge in neonates, infants and 
children with CHI, prompt recognition and treatment of hypoglycemia is critical to reduce the 
risk of long-term neurological consequences. 
5.2. Current Treatment and Unmet Medical Need 
Medical treatment for CHI is focused on chronic therapies to avoid hypoglycemia, as well as on 
rescue therapy during acute episodes of severe hypoglycemia. Available medical therapies 
(mainly diazoxide, octreotide, or glucagon alone or in combination with glucose infusion) are 
often inadequate and accompanied by inability to control PG, as reflected in a large proportion of 
patients requiring sub-total pancreatectomy.4,5,6 With the exception of surgery for focal CHI, 
which is curative in the vast majority of patients, sub-total pancreatectomy for diffuse CHI has 
substantial inadequacies. A recent trial7 showed that 60% of patients who underwent near-total 
pancreatectomy had persistent hypoglycemia after surgery. Moreover, 96% had developed 
insulin-dependent diabetes within 11 years after surgery, indicating the serious and long-term 
consequences of the procedure. 
First-line medical treatment is diazoxide, which is the only EU- and US-approved drug for 
treatment of hyperinsulinemic hypoglycemia. Diazoxide acts to open KATP channels of the 
pancreatic β-cells, thereby inhibiting insulin secretion. Unfortunately, many patients with CHI 
are resistant to diazoxide because of mutations in the genes encoding the KATP channel of the 
pancreatic β-cells.6 For those who respond to diazoxide treatment, the more common side effects 
comprise hypertrichosis, fluid retention, and gastrointestinal (GI) symptoms; however, side 
effects are usually not severe. In diazoxide non-responders, second-line (and off-label) treatment 
is a somatostatin analog (octreotide or lanreotide [long acting]), which (among other effects) 
inhibits secretion of insulin and glucagon from the pancreas and suppresses GLP-1 secretion. 
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Factors that limit their use comprise tachyphylaxis, as well as possible side effects, including 
necrotizing enterocolitis, gallstones, and hepatitis.6 
Glucagon has been shown to be effective in the treatment of CHI. The glycogenolytic effect of 
glucagon and its ability to increase PG levels has been confirmed in children with CHI or 
neonatal hypoglycemia,8,9 and administration of reconstituted glucagon (via intravenous [IV] 
infusion or as repeated subcutaneous [SC] injection) is often used in the initial phase during the 
establishment of CHI diagnosis and to stabilize patients with CHI before surgery or initiation of 
other medical treatments.10 Furthermore, glucagon is administered as single SC doses to treat 
severe hypoglycemic episodes. While IV administration of glucagon to patients with CHI is used 
short-term in the hospital setting, e.g., before pancreatectomy,2,10,11 long-term glucagon treatment 
is complicated by the fact that currently available glucagon products are unstable and form fibrils 
within hours after reconstitution.12 This fibril formation may lead to infusion set clotting, 
catheter obstruction, and dosing errors that may cause acute severe hypoglycemia. Catheter 
obstruction and occlusion because of glucagon fibril formation and aggregation were observed 
daily to 2 to 3 times weekly in a retrospective review of 9 patients with CHI receiving 
continuous SC infusion of glucagon for weeks or months.11 In another series of patients, 60% of 
the patients treated with SC glucagon experienced catheter occlusion.6 In a home-care setting, 
this fibril formation and associated risk of dosing errors carry the risk of hypoglycemic events, 
which is a major barrier for using currently marketed glucagon products for long-term treatment 
of patients with CHI.  
With respect to long-term glucagon treatment in CHI, there are a few reports on home treatment 
with subcutaneously infused glucagon in children with CHI over extended periods (years) that 
suggest benefit in patient care with a potentially good safety profile as compared to diazoxide 
and octreotide.6,11,13 While this attests to the potential clinical relevance of long-term glucagon 
treatment in CHI, the use of SC infusion of currently marketed glucagon is severely limited by 
the issues with fibril formation and solution instability of recombinant glucagon as described 
previously. 
5.3. Dasiglucagon for the Treatment of Congenital Hyperinsulinism 
5.3.1. Dasiglucagon 
Dasiglucagon is a peptide analog of human glucagon that is in development for the treatment and 
prevention of hypoglycemia in patients with diabetes mellitus and CHI via SC or intramuscular 
(IM) administration. Dasiglucagon is a stable analog of glucagon that has been specifically 
designed to overcome the issues with fibril formation and instability in solution observed with 
marketed glucagon products. Compared to native human glucagon, dasiglucagon also comprises 
29 amino acids. As a result of chemical modifications (7 amino acid substitutions compared to 
human glucagon), the pronounced tendency of glucagon to form fibrils and aggregate has been 
effectively prevented in dasiglucagon. In addition, the chemical stability in aqueous media at 
physiological pH has been improved.  
To support the use of dasiglucagon in the pump, compatibility/in-use studies have been 
performed with dasiglucagon 4 mg/mL in the Roche Accu-Chek® Combo pump using the 
Accu-Chek® Spirit 3.15 mL cartridge system and the Accu-Chek® FlexLink infusion set. The 
studies support an in-use time for up to 6 days at 37ºC. 
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Dasiglucagon was granted orphan drug designation by the European Commission on 20 June 
2017 for the ‘treatment of congenital hyperinsulinism.’ Furthermore, the FDA granted an orphan 
drug designation for the ‘treatment of hypoglycemia in patients with congenital hyperinsulinism 
(CHI)’ on 10 August 2017.  
5.3.2. Nonclinical Experience 
The completed nonclinical pharmacology program has determined that dasiglucagon is a specific 
glucagon receptor agonist with comparable in vitro potency to glucagon, promoting a rapid onset 
of PG increase in both normal and insulin-induced hypoglycemic animals, similar to that of 
glucagon. The effects of dasiglucagon and glucagon were investigated in an insulin-induced 
hypoglycemic rat model, which is considered particularly relevant to characterize the use of 
dasiglucagon for the treatment of CHI because it mimics the inappropriate insulin to PG levels in 
CHI and resultant hypoglycemia. The onset of PG increase with dasiglucagon was rapid and 
similar to that observed for glucagon, confirming comparable pharmacodynamics. 
Results of the toxicity studies with dasiglucagon are comparable to what has been reported for 
glucagon. Those from chronic toxicity studies with dasiglucagon in rats and dogs are in line with 
the results of short-term toxicity studies, indicating that long-term treatment with dasiglucagon is 
safe and that the pharmacodynamic (PD) effects noted do not adversely affect organ function 
following chronic use. 
5.3.3. Clinical Experience 
Dasiglucagon is being developed to manage patients with CHI 1) as an initial short-term therapy 
to stabilize PG levels and reduce glucose infusion needs, and 2) as a long-term treatment to help 
maintain euglycemia. Dasiglucagon has not previously been studied in patients with CHI. 
Clinical experience with dasiglucagon comes from the following studies in healthy subjects and 
type 1 diabetics. 
The safety, tolerability, pharmacokinetic (PK), and PD characteristics of dasiglucagon were 
investigated in 2 phase 1 trials and 3 phase 2 trials.  
ZP4207-14013 was a phase 1 randomized, double-blind, 2-part, single-dose trial designed to 
evaluate the pharmacokinetics, PD, safety, and tolerability of dasiglucagon compared to 
GlucaGen®. Part 1 consisted of SC and intramuscular (IM) administration of single ascending 
doses of dasiglucagon in 64 adult healthy volunteers. Part 2 consisted of 20 adult patients with 
type 1 diabetes using a crossover design with IM administration of 0.7 mg dasiglucagon. 
GlucaGen® 1.0 mg was used as a comparator in both parts of the trial. 
ZP4207-15007 was a phase 1 randomized, placebo-controlled, double-blind, multiple-dose trial 
designed to evaluate the PK, PD, safety, and tolerability of repeated doses of dasiglucagon SC in 
24 healthy adult volunteers. The trial included 3 dose cohorts of 8 healthy volunteers each. In 
each cohort, patients were randomly assigned in a 3:1 ratio to receive 5 repeated daily doses of 
0.1, 0.3, and 1.0 mg dasiglucagon (n=6) or placebo (n=2). 
After the 2 phase 1 trials were completed, the composition of the dasiglucagon formulation was 
optimized with respect to its excipients (buffer, tonicity adjusting agent, and stabilizer). The PK 
and PD properties, safety, and tolerability of the optimized formulation were evaluated in the 
phase 2 trial. 
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ZP4207-15126 was a phase 2 randomized, double-blind, single-dose trial designed to evaluate 
the PK, PD, safety, and tolerability of a single SC dose of dasiglucagon in the optimized 
formulation (0.1, 0.3, 0.6, and 1.0 mg) or GlucaGen® (0.5 and 1.0 mg) in 58 adult patients with 
type 1 diabetes. 
ZP4207-16051 was a phase 2 open-label, randomized, crossover trial designed to evaluate the 
feasibility of using dasiglucagon 1 mg/mL SC in conjunction with insulin in a pump setting 
using an iLet algorithm as part of an automated dual hormone pump delivery system in 
12 patients with type 1 diabetes. The primary objective was to evaluate the safety and tolerability 
of dasiglucagon compared to marketed glucagon (Lilly Glucagon™). The trial also aimed to 
demonstrate the functionality and accuracy of the iPhone-based bionic pancreas in a controlled, 
clinical setting. Patients were randomly assigned to two 1-day treatment arms: dasiglucagon or 
Lilly Glucagon™ in the iPhone-based bionic pancreas. 
ZP4207-16098 was a phase 2 randomized, crossover, double-blind trial designed to evaluate the 
safety, tolerability, PK, and PD of dasiglucagon in 23 patients with type 1 diabetes using a 
4 mg/mL formulation of dasiglucagon compared to an active comparator, Lilly Glucagon™. 
Overall, no safety concerns were observed for dasiglucagon at the doses investigated in these 
clinical trials. The most frequently reported adverse event (AE) in each trial was nausea, which is 
a known side effect after administration of glucagon, and appeared at a similar frequency to 
marketed glucagon, which was used as active comparator in some of the trials. No local 
tolerability issues were reported. Injection site reactions were observed only sporadically after 
administration with dasiglucagon, placebo, or marketed glucagon in trials with SC or IM 
administration, and all events were mild and transient. No treatment-induced or 
treatment-boosted anti-drug antibodies (ADAs) were noted in any of the trials, except for trial 
ZP4207-16098, in which 1 patient tested positive for both anti-dasiglucagon and anti-glucagon 
antibodies. Due to the crossover nature of this trial, the induction of ADAs could not be 
associated with a specific treatment. 
Dose-proportionality for dasiglucagon PK using the 1 mg/mL formulation was confirmed in the 
clinical trials, with doses ranging between 0.1 and 1.0 mg, characterized by a fast absorption 
with a peak plasma concentration obtained after 35 minutes. The median time to maximum 
concentration was later for dasiglucagon compared to marketed glucagon (GlucaGen®) 
(35 vs 20 minutes). In the phase 2 trial, doses of 0.3 mg dasiglucagon and 0.5 mg GlucaGen and 
also 0.6 mg dasiglucagon and 1.0 mg GlucaGen were similar with regard to maximum observed 
concentration (Cmax). The total exposure in terms of area under the concentration-time curve 
(AUC) from time zero to infinity (AUC0-inf) was consistently higher for dasiglucagon compared 
to GlucaGen. This was likely due to a higher bioavailability of dasiglucagon since nonclinical 
data consistently show that the bioavailability of dasiglucagon is higher compared to marketed 
glucagon formulations. For the 4 mg/mL formulation, dose-proportionality of dasiglucagon 
doses between 0.03 and 0.6 mg was indicated for AUC0-240min and AUC0-inf. Pharmacokinetic 
parameters were all similar for dasiglucagon administration under both euglycemic and 
hypoglycemic conditions. An approximately 30 to 40% greater exposure in terms of AUC0-inf 
and Cmax was observed with the 4 mg/mL formulation as compared with the 1 mg/mL 
formulation. 
In the phase 2 trial ZP4207-15126, all patients after insulin-induced hypoglycemia achieved a 
PG level of at least 70 mg/dL (3.9 mmol/L) at all dose levels of dasiglucagon, as well as an 
increase in PG by at least 20 mg/dL (1.1 mmol/L) within 30 minutes postdose. The PD responses 
of 0.3 mg of dasiglucagon and 0.5 mg of marketed glucagon (GlucaGen) were similar in the first 
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30 minutes postdose, as were the PD responses of 0.6 mg of dasiglucagon and 1.0 mg of 
GlucaGen. The PD response over the entire observation time (0-360 minutes) was significantly 
greater after dosing with dasiglucagon than with GlucaGen for all pre-specified dose 
comparisons. This was likely an effect of the higher total drug exposure (AUC0-inf) of 
dasiglucagon mentioned previously. 
No major differences in PD responses were observed between dasiglucagon doses under 
euglycemic or hypoglycemic conditions in phase 2 trial ZP4207-16098. Under euglycemic 
conditions, all patients achieved an increase in PG of at least 20 mg/dL (1.1 mmol/L) within 
30 minutes postdose with 0.08 mg dasiglucagon and above, while this target was reached only 
for 0.2 mg of marketed glucagon (Lilly Glucagon™). Under hypoglycemic conditions, 
dasiglucagon met the target at doses of 0.2 mg and above. The PD response over the entire 
observation time of 240 minutes was significantly higher with dasiglucagon than with Lilly 
Glucagon at the same doses. In the bionic pancreas feasibility trial ZP4207-16051, results 
demonstrated comparable autonomous glycemic control with dasiglucagon compared to Lilly 
Glucagon. This was despite the stressed conditions of the trial in terms of fasted patients being 
on up to twice their basal insulin rate to stimulate glucagon use during the 8-hour test, and 
inclusion of a structured exercise period. With dasiglucagon, patients obtained a glucose value 
within target (70-180 mg/dL [3.9-10.0 mmol/L]) 70.9% of the time vs 65.6% with Lilly 
Glucagon. 
5.3.4. Literature Data 
In a retrospective review of 223 cases of diffuse or focal CHI, glucagon was reported to be used 
in 55% of patients with diffuse CHI and in 31% of patients with focal CHI.10 In an observational 
trial of 55 newborns who received glucagon because of hypoglycemia after birth, applied doses 
were mainly in the range of 0.5 to 1.0 mg/day, and results indicated an increase in PG from a 
mean of 36.3 md/dL to a mean of 93.0 mg/dL, observed within 4 hours after the start of glucagon 
infusion.9 The frequency of hypoglycemic episodes was significantly reduced, and no further 
episodes of severe hypoglycemia were observed. 
The long-term use of glucagon in patients with CHI is limited by the instability of marketed 
glucagon after reconstitution. A literature review on the long-term medical treatment of CHI 
revealed that only 1% of 619 patients identified received glucagon as part of their medical 
management.6 A retrospective review of 9 children with CHI who received continuous SC 
infusion of glucagon for weeks or months showed that introduction of glucagon allowed the 
reduction or discontinuation of central glucose infusion in all patients.11 Six of 9 patients were 
discharged with continued glucagon therapy that their parents were able to continue without 
further symptomatic hypoglycemia, convulsions, or unconsciousness. In 3 children, glucagon 
therapy was continued for 1 to 4 years, which led to stable euglycemia.  
The data reported on marketed glucagon use in patients with CHI indicate that continuous SC 
infusion of a glucagon agonist could provide therapeutic benefit to patients by stabilizing PG 
levels and reducing the frequency of hypoglycemic episodes.5,6,9,10,11 
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5.3.5. Anticipated Medical Benefit of Dasiglucagon in the Treatment of CHI 
With its physio-chemical stability in liquid formulation, dasiglucagon could provide significant 
added benefit in the treatment of CHI relative to currently marketed glucagon by enabling 
long-term reliable IV infusion to control blood glucose. Long-term subcutaneous infusion of 
dasiglucagon through a pump may be an attractive alternative or addition to diazoxide and 
octreotide, as it may reduce the dependency on intensive nutritional support whilst maintaining 
euglycemia by harnessing physiological mechanisms for combating hypoglycemia. It is 
anticipated that reduced need for frequent tube feedings or continuous gastric infusion of 
nutrients, and increased fasting tolerance will be demonstrated, together with improvements in 
the quality of life of the patients and their families/caregivers. If long-term euglycemia is 
achieved with medical therapy, pancreatectomy for the treatment of diffuse CHI could eventually 
be avoided, or at least postponed beyond the neonatal or very young infant period. In one cohort 
of non-surgically treated children, the mean clinical remission rate was 5 (1.5-12) years for 
diffuse CHI.5 This suggests that a significant proportion of infants with CHI could avoid surgery 
if medical treatment allowed for the effective long-term control of hyperinsulinism. 
5.3.6. Anticipated Risks of Dasiglucagon in the Treatment of CHI 
In clinical trials with dasiglucagon conducted up to now, the most frequent treatment-related AEs 
were nausea and vomiting, followed by headache. 
Glucagon exerts positive inotropic and chronotropic effects and may, therefore, cause 
tachycardia and hypertension. Transient increases in heart rate have been observed in clinical 
trials with dasiglucagon, but not hypertension. On the contrary, several episodes of hypotension 
have been noted in the clinical program.  
Accidental overdose may occur due to inappropriate handling of the infusion pump or due to 
pump malfunction. Overdose may result in nausea, vomiting, inhibition of GI tract motility, 
short-term increase in heart rate or blood pressure, and/or hypokalemia. Symptomatic care for 
nausea and vomiting, as well as monitoring of heart rate, blood pressure, and hypokalemia, is 
advised.  
Injection site reactions are observed with many injectable peptides. In the phase 1 and 2 clinical 
trials, injection site reactions occurred with a low frequency in all treatment groups 
(dasiglucagon and marketed glucagons), irrespective of dose.  
Overall, the clinical trial data indicate that dasiglucagon has a low risk for induction of ADAs. 
Out of more than 350 doses of dasiglucagon administered to more than 200 patients, only 
1 low-titer transient ADA incident has been reported to date, in a patient after administration of 
11 SC doses of dasiglucagon or Lilly Glucagon ranging from 0.03 to 0.6 mg, with low binding 
and low in vitro neutralizing capability. No apparent clinical effects on PK, PD, or AEs were 
noted. Due to the crossover trial design, the ADA induction could not be ascribed to a specific 
treatment. Based on the current clinical experience and the product characteristics, the risk of 
dasiglucagon inducing an ADA response is considered low. 
Administration of glucagon or dasiglucagon may be associated with a risk of allergic reactions 
similar to those observed for other therapeutic peptides or proteins.  
Data on the risks of chronic administration of dasiglucagon are not available. From sporadic 
reports of extended SC/IV infusion of marketed glucagon and in glucagonoma patients,14 
sustained exposure to high levels of glucagon may lead to development of skin condition 
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necrolytic migratory erythema (NME), a highly specific migrating, erythematous rash with 
predilection for perioral, perianal, and lower leg distribution.11 
For further information on risks, please refer to the current version of the investigator’s brochure 
(IB). 
5.3.7. Summary of Potential Benefits and Risks 
As with all treatment interventions, the anticipated benefits to trial patients should be balanced 
against the potential risks. The accumulated experience from nonclinical studies and clinical 
trials with dasiglucagon supports that dasiglucagon is a specific glucagon receptor agonist and is 
well tolerated. Glucagon and its analogs belong to a well-known drug class with known mode of 
action. The clinical investigators involved in the trial will all have had experience with use of 
glucagon in patients with CHI.  
The investigator will inform the patients/parents of the potential risks of dasiglucagon treatment 
and other trial-related procedures before they enter the trial. The investigator must become familiar 
with all sections of the dasiglucagon IB before the start of the trial. 
In summary, with its marked improvements in stability in solution and solubility in aqueous 
media compared to currently marketed glucagon products, dasiglucagon is expected to have 
significant clinical benefits in the treatment of CHI and to substantially reduce the disease burden 
in these patients. This includes enabling convenient and reliable long-term treatment via a pump 
device in a home setting, which holds the potential to delay and ultimately avoid pancreatectomy 
and its related exo/endocrine complications, particularly the development of insulin-dependent 
diabetes. 
Dasiglucagon may overall provide significant added benefit in the treatment of CHI relative to 
currently marketed glucagon products by enabling long-term reliable SC infusion to control PG. 
The proposed trial population is still experiencing hypoglycemia despite medical treatments 
being escalated to the highest therapeutically permissible or tolerated doses, or despite having 
undergone subtotal pancreatectomy. Therefore, these patients are dependent on continuous or 
very frequent delivery of carbohydrates, often through invasive routes (NG tube or gastrostomy). 
This limits their ability to lead normal lives, including participating in everyday activities, and 
therefore, impacts their development. For this trial population, the major and clinically relevant 
benefit is the expected reduction in number and volume of nutritional interventions while 
avoiding hypoglycemia. The reduced volume of nutritional interventions should limit the risk of 
volume overload, especially in patients treated with significant doses of diazoxide. Achievement 
of euglycemia could lead to reduction of other CHI medication, further limiting the potential for 
adverse events associated with those treatments. In addition, the need for pancreatectomy, or 
re-surgery in those who already underwent pancreatic surgery is reduced and potentially 
eliminated.  
Overall, the benefit to risk ratio for patients entering the ZP4207-17109 trial is considered 
acceptable.  
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6. OBJECTIVES AND ENDPOINTS 
6.1. Objectives 
6.1.1. Primary Objective 
To evaluate the efficacy of dasiglucagon administered as subcutaneous (SC) infusion in reducing 
hypoglycemia in children with CHI. 
6.1.2. Secondary Objectives 
Secondary objectives are: 
• To evaluate the safety and tolerability of dasiglucagon administered as an SC infusion in 
children with CHI 
• To evaluate the efficacy of dasiglucagon in reducing glucose requirements 
• To investigate quality of life and resource utilization 
6.2. Endpoints 
6.2.1. Primary Endpoint 
Treatment Period 1 
• Hypoglycemia event rate, defined as average weekly number of hypoglycemic events 
(PG <70 mg/dL or 3.9 mmol/L) during Weeks 2-4, as detected by self-monitored PG 
(SMPG) 
6.2.2. Key Secondary Efficacy Endpoints 
Treatment Period 1 
• Increase in fasting tolerance (time from beginning of meal to the beginning of the first 
continuous 15-minute continuous glucose monitoring [CGM] reading <70 mg/dL 
[3.9 mmol/L]) 
• CGM percent time in range 70-180 mg/dL (3.9-10.0 mmol/L) during Weeks 2-4 
• Clinically significant hypoglycemia event rates, defined as average weekly number of 
events <54 mg/dL (3.0 mmol/L), as detected by SMPG during Weeks 2-4 
6.2.3. Secondary Efficacy Endpoints 
Treatment Period 1 
• Total amount of gastric carbohydrates administered (via nasogastric [NG] tube or 
gastrostomy) per week to treat hypoglycemia during Weeks 2-4 
• Rate of gastric carbohydrate administrations (NG tube or gastrostomy) per week to treat 
hypoglycemia during Weeks 2-4 
• Extent of hypoglycemia (area over the glucose curve [AOCglucose] below 70 mg/dL 
[3.9 mmol/L]) as measured by CGM during Weeks 2-4 
• Extent of hypoglycemia (area over the glucose curve [AOCglucose] below 54 mg/dL 
[3.0 mmol/L]) as measured by CGM during Weeks 2-4 
• Amount of nightly (midnight to 6 am) gastric carbohydrates administered (NG tube or 
gastrostomy) per week during Weeks 2-4 
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• Total amount of gastric carbohydrates administered (NG tube or gastrostomy) per week 
during Weeks 2-4 
• CGM percent time in hypoglycemia (<70 mg/dL or 3.9 mmol/L) during Weeks 2-4 
• Rate of hypoglycemic episodes, defined as number of episodes <70 mg/dL (3.9 mmol/L) 
for 15 minutes or more per week, as measured by CGM during Weeks 2-4 
Treatment Period 2 
• CGM percent time in hypoglycemia (<70 mg/dL or 3.9 mmol/L) during Weeks 6-8 
• Rate of weekly number of gastric carbohydrate administrations (NG tube or gastrostomy) 
per week to treat hypoglycemia during Weeks 6-8 
• Rate of hypoglycemic events, defined as number of episodes (PG <70 mg/dL or 
3.9 mmol/L) per week during Weeks 6-8, as detected by SMPG 
• Rate of clinically significant hypoglycemia episodes, defined as number of episodes 
<54 mg/dL (3.0 mmol/L) for 15 minutes or more per week, as measured by CGM during 
Weeks 6-8 
6.2.4. Other Efficacy Endpoints 
• Number of IV glucose infusions to treat hypoglycemia per week during Weeks 2-4 of 
Treatment Period 1 
• Emergency department visits for hypoglycemia 
• Number and length of hospitalizations due to CHI or CHI-related events 
• Number of out-patient visits to health care providers (family doctors, specialist, etc.) 
caused by CHI or CHI-related events 
• Number of home visits by paramedics due to hypoglycemia 
• Quality of life endpoints (PedsQL™ [Total Scale Score, Physical Health Summary Score, 
and Psychosocial Health Summary Score] and CHI-specific questionnaire) 
• Rate of SMPG readings per week during Weeks 2-4 of Treatment Period 1 
6.2.5. Safety Endpoints 
• Adverse events 
• Changes in clinical evaluations: 
o Vital signs 
o Physical examination 
o 12-lead ECG 
• Changes for clinical laboratory assessments: 
o Hematology 
o Biochemistry 
o ADAs 
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7. TRIAL DESIGN 
7.1. Overall Trial Design and Plan 
This is a 2-period, open-label trial to evaluate the efficacy and safety of dasiglucagon in children 
between the ages of 3 months and 12 years (both inclusive) with CHI. To qualify for 
participation, patients must be experiencing ≥3 events of hypoglycemia per week despite 
standard of care (SOC) medications. The determination of hypoglycemia frequency at trial entry 
is according to investigator’s evaluation. Furthermore, patients are to have previously undergone 
sub-total pancreatectomy for CHI or be treated with a non-surgical approach, having been 
evaluated as not eligible for pancreatic surgery.  
The primary objective of this trial is to evaluate whether dasiglucagon can reduce the number 
and severity of hypoglycemic episodes in the investigated population.  
After screening and eligibility assessments, patients will complete a 2-week CGM period to 
establish plasma glucose baseline. Thereafter, patients will be randomly assigned in a 1:1 ratio to 
continue receiving SOC alone, or SOC plus dasiglucagon for 4 weeks. In Treatment Period 2, all 
patients will receive SOC plus dasiglucagon for 4 weeks (see Figure 1). 
At the beginning of Treatment Period 1 (Week 1), all patients will be hospitalized for 1-2 days. 
Patients assigned to SOC plus dasiglucagon treatment will have dasiglucagon infusion initiated 
and titrated, and will be trained and supervised in the use of the infusion pump, CGM sensor, and 
glucose meter. Patients assigned to SOC alone will receive a similar degree of supervision 
alongside the training in the use of the CGM sensor and glucose meter. This period can be 
extended for both treatment groups if dasiglucagon titration has not been finalized or if training 
of the family/caregivers has not been completed satisfactorily.  
Patients originally assigned to receive SOC alone in Treatment Period 1 will also be hospitalized 
for the first 1 to 2 days of Treatment Period 2 (Week 5), and will have dasiglucagon infusion 
initiated and titrated, and will be trained in the use of the infusion pump. This period can be 
extended if dasiglucagon titration or pump training has not been completed. Regardless of 
whether dasiglucagon is initiated during Treatment Period 1 or 2, SOC CHI medications should 
subsequently be kept constant throughout the trial. Adjustments to gastric and oral feeds are 
permitted. 
Patients’ parent(s)/guardian will be trained to perform PG assessments. Events of hypoglycemia 
will be documented by SMPG measurements. The extent of hypoglycemia (episodes and percent 
time below the threshold) will be further quantified by CGM measurements during the 2 weeks 
before randomization (baseline), Weeks 2-4 in Treatment Period 1, and Weeks 6-8 of Treatment 
Period 2. The CGM results will be masked. During the period where the masked trial CGM is 
used, patients are not allowed to use another un-masked CGM. 
Patients completing the trial will (pending investigator confirmation of continued positive 
benefit-risk balance) be offered to enter a long-term extension trial (Trial ZP4207-17106) to 
continue dasiglucagon treatment. Patients who do not continue in the long-term extension trial 
will have a Follow-up visit performed 4 weeks after stopping dasiglucagon treatment. 
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Figure 1 
Trial Design 
7.2. Discussion of Trial Design 
Several sites across multiple geographical regions will be included to ensure results 
representative of the target CHI population.  
A parallel design was chosen rather than a crossover design to avoid the risk of any carry-over 
effect and to limit the total treatment period for the patients included. 
An open-label trial design was chosen because the added burden of a blinded trial design was not 
considered ethically justified. 
7.3. Trial Sites 
This trial will take place at up to 14 sites in the United States and Europe that are experienced in 
the treatment of CHI. A total of up to 32 patients with CHI will be randomized. 
7.4. Point of Contact 
A point of contact will be identified to provide information to each patient’s parent(s)/guardian 
about where to obtain information on the trial, the patient’s rights, and whom to contact in case 
of trial-related injury. This information will be provided in the patient information and informed 
consent form (ICF). 
Week from first treatment
Period
Screening
Treatment Period 1
Treatment Period 2
Follow-up
-4
0
4
8
12
16 children
16 children
1:1 randomization
Standard of Care
Dasiglucagon +
Standard of Care
Dasiglucagon +
Standard of Care
Dasiglucagon +
Standard of Care
Standard of Care or to
Long-term extension trial
Dasiglucagon + Standard of Care
Standard of Care
Screening or Follow-up
0 
--
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8. PATIENT POPULATION 
8.1. Selection of Trial Population 
A screening log of potential trial candidates must be maintained at each trial site. 
8.2. Trial Entry Criteria 
8.2.1. Inclusion Criteria 
A patient will be eligible for trial participation if he or she meets all of the following criteria: 
1. Established and documented diagnosis of CHI based on standard of care. 
2. Male or female between 3 months and 12 years of age (both inclusive) at screening. 
3. Has a negative serum pregnancy test at screening/baseline (only for girls of childbearing 
potential). 
4. Sexually active female patients (and their partners) must continue to use acceptable 
contraception or refrain from sexual activity from screening until 30 days after the last dose 
of trial drug. Females must abstain from sexual activity that could result in pregnancy or 
agree to use acceptable methods of contraception. Abstinence can only be accepted if this is 
true abstinence in line with the preferred and usual lifestyle of the patient. 
Acceptable methods of contraception are: 
a) Hormonal contraceptives (e.g., oral contraceptive pill, depot, patch, intramuscular 
implant or injection, sponge, or vaginal ring), stabilized for at least 30 days if first use 
or 
b) Barrier method, e.g., (i) condom (male or female) and (ii) diaphragm with spermicide 
Germany: Only highly effective methods of birth control are accepted (i.e., one that results 
in less than 1% per year failure rate when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, some intrauterine device), or sexual abstinence. 
5. Experiencing ≥3 events of hypoglycemia per week (PG <70 mg/dL [<3.9 mmol/L]) 
according to the investigator’s evaluation. 
6. Following receipt of oral and written information about the trial, the patient (depending on 
local IRB/IEC requirements) must provide assent and one or both parents* or guardians of 
the patient must provide signed informed consent before any trial-related activity is carried 
out. 
France, Germany, Israel: The consent must correspond to the patient’s presumed will where 
such a will can be ascertained. 
7. Previously undergone near-total pancreatectomy or being treated with a non-surgical 
approach, having been evaluated as not eligible for pancreatic surgery. 
8. If somatostatin analogues or sirolimus are used, the therapy should be well established as 
judged by the investigator, especially when considering their biological half-life. 
* If required by local regulations, both parents must give their permission unless one parent is 
deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal 
responsibility for the care and custody of the child. 
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8.2.2. Exclusion Criteria 
A patient will be excluded from the trial if he or she meets any of the following criteria: 
1. Previous administration of dasiglucagon (previously referred to as ZP4207).
2. Known or suspected allergy to the trial drug or related products.
3. Previous participation (randomization) in this trial.
4. Circulatory instability requiring supportive medication or presence of pheochromocytoma
United Kingdom: Presence of hypertension or hypotension, including circulatory instability
requiring supportive medication or presence of pheochromocytoma.
5. Requires exogenous insulin.
6. Body weight of <4 kg (8.8 lbs).
7. Documented HbA1c ≥7% subsequent to near-total pancreatectomy and within 6 months prior
to screening.
8. Known or suspected presence of significant central nervous system disease/injury such that
in the investigator’s opinion will affect trial participation.
9. Use of systemic corticosteroids, e.g., hydrocortisone >20 mg/mg/m2 body surface area or
equivalent in the 5 days before screening.
10. Use of anti-inflammatory biological agents, or other immune-modulating agents in the
3 months prior to screening.
11. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 X the upper limit
of normal (ULN), or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2
adjusted by a pediatric formula (e.g., Schwartz formula).
12. Any clinically significant abnormality identified on echocardiogram that in the opinion of the
investigator would affect the patient’s ability to participate in the trial.
13. History of laboratory test results obtained before screening that show presence of HIV,
hepatitis B surface antigen, hepatitis C antibody, or hepatitis A immunoglobulin M.
14. Any recognized clotting or bleeding disorders.
15. Has participated in an interventional clinical trial (investigational or marketed product)
within 3 months of screening or 5 half-lives of the drug under investigation (whichever
comes first), or plans to participate in another clinical trial.
16. The use of prescription or non-prescription medications known to cause QT prolongation.
8.2.3. Randomization Exclusion Criteria 
1. Use of glucagon within 24 hours before randomization.
2. Significant changes to CHI medications during screening.
3. An average of <3 events per week of hypoglycemia, as recorded in the diary during the
2 weeks prior to randomization.
The Randomization Visit may be rescheduled if randomization Exclusion Criterion 1 is met. 
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8.3. Premature Patient Withdrawal  
Patients’ parent(s)/guardian will be advised that they are free to withdraw their children from 
participation in this trial at any time, for any reason, and without prejudice. Every reasonable 
attempt should be made by the investigator to keep patients in the trial. However, patients must 
be withdrawn from the trial if their parent(s)/guardian withdraw consent to participate.  
Investigators must attempt to contact patients’ parent(s)/guardian who fail to attend scheduled 
visits by telephone or other means to exclude the possibility of an AE being the cause of 
withdrawal. Attempts to contact the patient must be documented. At least 3 phone calls and 
3 written attempts to contact the patient will be made prior to considering them lost to follow-up. 
Should an AE be the cause of withdrawal, the AE must be documented, reported, and followed 
as described in Section 11.2. 
If a patient/parent(s)/guardian withdraws consent, the reason for withdrawal and the date of 
withdrawal will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion 
of the trial should be performed at the time of premature withdrawal.  
8.4. Treatment Discontinuation 
To prevent missing data, patients should, to the extent possible, be kept in the trial; therefore, 
treatment discontinuation is often the preferred option in case of e.g., substantial noncompliance 
with trial procedures or initiation of prohibited treatment that interferes with the efficacy and 
safety evaluation. If it is an investigator’s decision to discontinue the patient’s treatment, the 
investigator should, whenever possible, discuss the potential discontinuation of the treatment 
with the medical monitor. If the patient is discontinued from trial treatment by the investigator, 
or withdraws consent for trial treatment the reason for treatment discontinuation and the date of 
treatment discontinuation will be recorded on the appropriate page of the eCRF. The patient 
should be asked to continue in the trial by following the planned visit schedule. At a minimum 
the patient will be asked to attend the Follow-up Visit 28 days (± 3 days) after discontinuation of 
trial treatment. 
8.5. Patient Replacement Criteria 
Patients who withdraw from the trial prematurely will not be replaced. If a substantial number of 
patients withdraw prematurely, the sponsor will evaluate the need for developing replacement 
criteria. 
Enrolled patients who subsequently withdraw from the trial may not re-enter. The patient number 
for a withdrawn patient will not be reassigned to another patient. 
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9. TREATMENTS 
9.1. Identification of Investigational Product 
Dasiglucagon injection 4 mg/mL will be supplied by the sponsor in a 3 mL vial containing 1 mL. 
Dasiglucagon will be provided in the form of solution for injection for subcutaneous 
administration through an infusion pump. 
The trial drug product must be transferred from the vial to an Accu-Chek® Spirit Cartridge. The 
amount of test product dosed via the pump will vary among patients. 
Cartridges and infusion sets should be replaced as indicated in the instructions for use. 
9.1.1. Packaging and Labeling 
The trial drug product will be packaged and labeled by the sponsor.  
Dispensing unit configuration: 6 vials containing dasiglucagon, 4 mg/mL, packaged in an outer 
carton. The vial and carton will be packaged and labeled in local language indicating the content 
(open label). 
Detailed information on all labels will be in the local language.  
Storage conditions for the trial drug product will be described on the trial drug product label. The 
labels will supply no information about the patients. Each treatment unit (containing 6 vials) 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) Good 
Clinical Practice (GCP) guidelines, local laws, and regulations. 
9.2. Treatments Administered 
In Treatment Period 1, patients will receive SOC only or SOC plus dasiglucagon for 4 weeks 
based on their treatment assignment. In Treatment Period 2, all patients will receive SOC plus 
dasiglucagon for 4 weeks.  
Dosing of dasiglucagon will approximate continuous infusion by delivering small doses at 
frequent intervals via the infusion pump. 
The pump administers 0.000025 mL/dose ~ 0.1 µg/dose (4 mg/mL formulation): 
• 10 µg/hour ~ 0.5 µg every 3 min 
• 20 µg/hour ~ 1 µg every 3 min 
• 30 µg/hour ~ 1.5 µg every 3 min 
• 40 µg/hour ~ 2 µg every 3 min 
• 50 µg/hour ~ 2.5 µg every 3 min 
• 60 µg/hour ~ 3 µg every 3 min 
• 70 µg/hour ~ 3.5 µg every 3 min 
Plasma glucose assessments will be performed regularly (at least 3 times daily, preferably before 
main meals, and as instructed by the investigator) throughout the trial to guide adjustments to the 
gastric dextrose infusion and/or trial drug product upon the investigator’s discretion.  
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Dasiglucagon treatment will be initiated at 10 µg/hr (t=0). Every 2 hours (t=2, 4, 6, etc.), the 
dose will be increased by an additional 10 µg/hr until either: 
1. 
The patient is weaned off entirely from gastric dextrose infusion and/or 
glucose-fortified feeds, or 
2. 
Plasma glucose during the last 2 hours was consistently above 120 mg/dL 
(6.7 mmol/L), or 
3. 
The maximum trial drug product infusion rate of 70 µg/hr is reached, or 
4. 
Adverse events emerge that are considered to be related to dasiglucagon (e.g., nausea 
and vomiting) and limit further dose escalation 
The dose of dasiglucagon should not be escalated beyond reaching the treatment objectives of 
PG in the range of 70-120 mg/dL (3.9-6.7 mmol/L) while approaching a normal feeding regimen 
according to age.  
The 2-hour dose-adjustment interval will allow plasma drug levels to approach approximately 
steady-state before the dose is further increased. The maximum dose of trial drug product that 
can be administered over the first 24 hours is shown in Table 1. The maximum cumulative dose 
over the first 24 hours is 1.26 mg. 
After the first 24 hours, the dose of dasiglucagon can still be modified to optimize each patient’s 
treatment and to reduce gastric dextrose infusions. The maximum dose of dasiglucagon will be 
70 µg/hr, corresponding to a maximum of 1.68 mg per day.  
Details on the administration instructions and guidelines for preparation and handling of the trial 
drug product are in the pharmacy manual. 
Table 1 Initial 24-hour Maximum Dose of Dasiglucagon 
 
 
Patients who complete this trial will be offered to enter a long-term extension trial 
(Trial ZP4207-17106) to continue dasiglucagon treatment (pending investigator confirmation of 
continued positive benefit-risk balance). Patients who do not continue in the long-term extension 
trial will have a Follow-up visit performed 4 weeks after stopping dasiglucagon treatment. 
Time (hours) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Dose (µg) 
10 
10 
20 
20 
30 
30 
40 
40 
50 
50 
60 
60 
Cumulative 
dose (µg) 
10 
20 
40 
60 
90 
120 
160 
200 
250 
300 
360 
420 
 
 
Time (hours) 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
Dose (µg) 
70 
70 
70 
70 
70 
70 
70 
70 
70 
70 
70 
70 
Cumulative 
dose (µg) 
490 
560 
630 
700 
770 
840 
910 
980 
1050 
1120 
1190 
1260 
0 
I 
I 
I 
I I I I 
I I I I I I 
I 
I 
I 
I I I I 
I I I I I I 
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9.3. Trial Supplies 
The device and ancillaries listed in the following table will be supplied by the sponsor 
throughout the trial. Trained trial personnel will train parent(s)/guardians on the use of the 
infusion pump. 
Instructions for the use of all these supplies will be provided in a separate manual. 
Item 
Name 
Manufacturer 
Pump 
Accu-Chek Spirit Combo 
Hoffman-La Roche AG, Basel, 
Switzerland 
Cartridge 
Accu-Chek Spirit 3.15 mL Cartridge system 
Hoffman-La Roche AG, Basel, 
Switzerland 
Infusion sets 
Accu-Chek FlexLink Infusion set (Accu-Check 
UltraFlex Infusion set in US) 
and 
Accu-Chek Rapid-D Link Infusion set 
Hoffman-La Roche AG, Basel, 
Switzerland 
Infusion set 
inserter 
Accu-Chek LinkAssist Insertion device (can be used 
with FlexLink & UltraFlex) 
Hoffman-La Roche AG, Basel, 
Switzerland 
PG monitoring 
StatStrip Xpress2 
Nova Biomedical, Waltham, MA, 
USA 
CGM 
Dexcom G4 
Dexcom Inc., San Diego, CA, USA 
The infusion pump system is CE marked for the management of diabetes mellitus in persons 
requiring insulin, as prescribed by a physician. In this trial, the pump system is used outside of 
the CE-marked intended use since the pump system will be delivering dasiglucagon to patients 
with CHI. The PG meter is used as intended according to the CE mark, except for the use by a 
lay person in a home care setting. The CGM is used as intended according to the CE mark, 
except for the age group and the disease. 
The pump device will be packaged and labeled for use in investigational trials and will contain a 
unique device number. 
9.4. Dispensing and Storage 
Trial drug product supplied by the sponsor is to be dispensed exclusively for patients enrolled in 
this clinical trial according to the instructions of this protocol and the pharmacy manual. The 
investigator is responsible for dispensing the trial drug product according to the dosage scheme.  
Trial drug product will be allocated using an interactive web response system (IWRS) that has 
been validated for the intended use under the International Society of Pharmaceutical Engineers 
(ISPE) GAMP guidelines, 21CFR Part 11 (FDA regulation for Electronic Records and Electronic 
Signatures), and the ICH Guidance E6 for Industry on Good Clinical Practice.   
Dasiglucagon injection 4 mg/mL must be stored at 2–8°C in a refrigerator. 
The investigator must ensure the availability of proper storage conditions. All trial drug products 
provided for this trial will be stored at the trial site in a secure area with restricted access.  
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 
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documented at least on working days on a temperature log. This log must be included in the 
Investigator Site File (ISF) upon trial termination. 
The investigator must contact the clinical research associate (CRA) in case of temperature 
deviations outside the acceptable range.  
Please refer to the pharmacy manual for additional information on handling of the trial drug. 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the trial drug product including the date, quantity, batch or code number, and 
identification of patients (patient number) who received the trial drug. The investigator will not 
supply the trial drug product to any person except subinvestigators, designated trial personnel, 
and patients in this trial. The trial drug product may not be relabeled or reassigned for use by 
other patients. If any of the trial drug product is not dispensed, is lost, stolen, spilled, unusable, 
or is received in a damaged container, this information must be documented and reported to the 
sponsor and the appropriate regulatory agencies as required. 
9.5. Method of Assigning Patients to Treatment Groups 
In Treatment Period 1, patients will be randomly assigned in a 1:1 ratio to receive either SOC 
only or SOC plus dasiglucagon for 4 weeks using a block randomization scheme stratified by 
region US/non-US). In Treatment Period 2, all patients will receive SOC plus dasiglucagon for 
4 weeks. The stratification by region addresses the difference in practice of treatment for CHI, 
especially the prominent difference in frequency of sub-total pancreatectomy for diffuse CHI 
between US/non-US. 
9.6. Blinding and Unblinding Treatment Assignment 
This is an open-label trial. During parts of Screening, Treatment Period 1, and Treatment 
Period 2, patients will have CGM performed but the results will be masked. 
9.7. Selection of Doses in the Trial 
Both the starting dose and the maximum allowed doses are based on experience with marketed 
glucagon products in this patient population.11  
At present, no pediatric PK data are available for dasiglucagon. However, an approximate 
estimation of expected drug concentration in a 3 kg patient has been made by extrapolation of a 
previously made PK model for pediatric patients with weights between 25 and 45 kg.15  
The predicted plasma concentration is expected to give a low PD response at the lowest dose 
level and be above maximum effect at the highest dose level. The maximum expected plasma 
concentrations of dasiglucagon is in the range of what is achieved following a rescue dose to 
adults. The doses of dasiglucagon will be titrated to meet the needs of the individual patient. The 
titration will stop when no additional PD effects are observed as the infusion rate is increased. 
The infusion rate of dasiglucagon will be monitored and adjusted to meet the needs of the 
individual patient throughout the trial period. 
Since the dasiglucagon dose is titrated individually based on the desired PD response, it does not 
need to be related to any measure of the patient’s size. 
The titration interval of 2 hours was chosen based on the PK data of dasiglucagon showing that 
an approximate steady-state is expected after 2 hours. 
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9.8. Selection of Timing of Dose for Each Patient 
Dosing details are presented in Section 9.2. 
9.9. Dose Adjustment Criteria 
Dose adjustment criteria are presented in Section 9.2. 
9.10. Treatment Compliance 
Compliance data will be collected. Infusion details will be recorded in the patient’s eCRF by trial 
personnel and drug accountability will be performed as detailed in the pharmacy manual. 
9.11. Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
Caution is advised when beta-blockers, indomethacin, anticholinergic drugs, and warfarin are 
prescribed, due to reports of interaction with marketed glucagon products. 
9.11.1. Permitted Therapies 
Concomitant CHI treatments (e.g., somatostatin analogs) that were initiated prior to trial entry 
are permitted throughout the trial. Somatostatin analogs may also be added throughout the trial at 
the investigator’s discretion if the maximum dose level of dasiglucagon (70 µg/hr) has been 
reached or if further titration is not possible due to undesirable side effects.  
Other CHI-specific treatments either prior to trial initiation or added during the trial need to be 
discussed with the medical monitor. 
9.11.2. Prohibited Therapies 
The following therapies are prohibited during the trial: 
• Systemic corticosteroids, e.g., hydrocortisone >20 mg/mg/m2 body surface area or 
equivalent from 5 days before screening and onwards 
• Anti-inflammatory biological agents, or other immune-modulating agents in the 3 months 
prior to screening (except for sirolimus/mTOR inhibitors, as discussed in Section 9.11.1) 
• Exogenous insulin 
• Use of paracetamol/acetaminophen is strongly discouraged for the duration of trial 
because it interferes with CGM accuracy. Parent(s)/guardians should contact the trial site 
before dosing their child with paracetamol/acetaminophen. Both the site staff and the 
parent(s)/guardians should explore other options for treating fever and mild pain before 
deciding that paracetamol/acetaminophen is needed 
• Other investigational agent 
• Marketed glucagon products within the last 24 hours prior to randomization and 
throughout the trial unless necessary for rescue therapy in case of severe hypoglycemia, 
as per local SOC 
• Prescription or non-prescription medications known to cause QT prolongation 
Continuation in the trial after the patient has received excluded therapies will be at the 
investigator’s discretion after consultation with the medical monitor. 
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9.12. Patients May be Discharged for Home Treatment 
Before discharge of patients from hospital care, the investigator will ensure: 
• Appropriate training of patient’s parent(s)/guardians in the use of dasiglucagon in the 
Accu-Chek Spirit Combo pump based on the training material provided. The first pump 
infusion set change should be performed at the hospital 
• Parent(s)/guardian are trained appropriately on the handling of the CGM device 
• Parent(s)/guardian are trained appropriately on how to perform SMPG measurements and 
how to complete the diary. They will check their child’s SMPG at least 3 times daily 
(preferably before main meals) and in case of suspected hypoglycemia 
• Parent(s)/guardian are instructed not to change the dose of trial drug without prior 
consultation with the investigator  
• Parent(s)/guardian are instructed how to recognize and handle signs of hypoglycemia 
• Parent(s)/guardian are instructed to call the investigator/site staff in case of questions  
Patients who are discharged from the hospital will be contacted by the investigator by telephone 
the day after discharge. The investigator will ask the parent(s)/guardian if they have any 
questions about the trial procedures and if their child has experienced any AEs. 
9.13. Treatment After End of Trial 
After completing both treatment periods, patients may be eligible to continue in a long-term 
extension trial (Trial ZP4207-17106) (see Section 9.2). Patients who do not continue in the 
long-term extension trial will not be offered further treatment with dasiglucagon. 
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10. TRIAL PROCEDURES 
Patients’ parents/guardians (according to local law) must provide written informed consent 
before any trial-related procedures are initiated, including the cessation of prohibited 
concomitant therapy. 
France, Germany, Israel: The consent must correspond to the patient’s presumed will where 
such a will can be ascertained. Depending on local IRB/IEC requirements the patient should 
also provide assent before any trial-related procedures are initiated. 
For the timing of assessments and procedures throughout the trial, refer to the Schedule of 
Events (Section 17.1). Throughout the trial, trial personnel should make every reasonable effort 
to follow the timing of assessments and procedures in Section 17.1 for each patient. If a patient 
misses a trial visit for any reason, it should be rescheduled as soon as possible. 
10.1. Trial Duration 
The overall trial duration is expected to be 15 months. 
The sequence and maximum duration of the trial periods will be as follows: 
1. Screening: at least 14 days up to 28 days 
2. Treatment Period 1: 4 weeks 
3. Treatment Period 2: 4 weeks 
4. Follow-up Period: 4 weeks 
The maximum trial duration for each patient is approximately 16 weeks. The dasiglucagon 
treatment duration for each patient is 4 or 8 weeks. 
10.2. Assessments 
Quality of life should be the first assessments performed at each visit according to the Schedule 
of Events (Section 17.1). 
10.2.1. Efficacy 
10.2.1.1. Plasma Glucose Monitoring 
During the trial, SMPG assessments (StatStrip Xpress2) will be performed regularly (at least 
3 times daily, preferably before meals, as instructed by the investigator) to evaluate efficacy.  
At each visit, the investigator will ensure that SMPG data are downloaded from the patient’s 
devices. The investigator will check for patient compliance in number of daily SMPG 
measurements and that hypoglycemic episodes are recorded in the diary. The procedure for 
download of SMPG data will be described in the pharmacy manual.  
10.2.1.2. Continuous Glucose Monitoring 
Additionally, CGM will be used (Dexcom G4) in a blinded manner to evaluate efficacy in terms 
of hypoglycemic episodes. The CGM will be supplied for use throughout the trial, and 
continuous glucose monitoring is required for the 2 weeks up to randomization, during Week 2-4 
of Treatment Period 1, and during Week 6-8 of Treatment Period 2. Short pauses of 1-3 days due 
to skin irritation or discomfort are allowed after consultation with the investigator. 
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At each visit, the investigator will ensure that CGM data are downloaded from the patient’s 
devices. The procedure for download of CGM data will be described in the pharmacy manual. 
Dexcom G4 CGMs configured and labeled for use in this trial will be provided. Each CGM 
device should be calibrated and used according to the manufacturer’s instructions. 
The contract research organization (CRO) or delegate will handle device sourcing, configuration 
for use in the trial, procedures for blinded data extraction, device service, and return handling. 
10.2.1.3. Quality of Life 
Quality of life (Appendix B) will be assessed using the PedsQL and additional CHI 
disease-specific QoL questions (parent-reported versions) according to the Schedule of Events 
(Section 17.1). 
The PedsQL Measurement Model is a modular approach to measuring health-related quality of 
life in healthy children and adolescents and those with acute and chronic health conditions. The 
PedsQL Measurement Model integrates seamlessly both generic core scales and disease-specific 
modules into one measurement system. 
The 23-item PedsQL Generic Core Scales was designed to measure the core dimensions of 
health as delineated by the World Health Organization, as well as role (school) functioning. The 
4 Multidimensional Scales and 3 Summary Scores are: 
Scales 
Summary Scores 
• 
Physical Functioning (8 items) 
• 
Total Scale Score (23 items) 
• 
Emotional Functioning (5 items) 
• 
Physical Health Summary Score (8 items) 
• 
Social Functioning (5 items) 
• 
Psychosocial Health Summary Score (15 items) 
• 
School Functioning (5 items) 
 
The CHI disease-specific questions have been developed by the patient association, Congenital 
Hyperinsulinism International, and taken from the patient-reported registry, the HI Global 
Registry. The HI Global Registry questions are grouped mostly under general quality of life; 
however, some questions relate specifically to diet and feeding, surgical management, glucose 
monitoring, and child development. The HI Global Registry is governed by a Global Steering 
Committee, including key global clinical experts.  
10.2.1.4. Other Assessments 
Resource Utilization 
• Emergency department visits for hypoglycemia 
• Number and length of hospitalizations due to CHI or CHI-related events 
• Number of outpatient visits to health care providers (family doctors, specialist, etc.) 
caused by CHI or CHI-related events 
• Number of home visits by paramedics due to hypoglycemia 
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Diary 
The patient’s parent(s)/guardian will be provided with a paper diary at all visits except at Visit 7 
and the Follow-up Visit. The investigator will instruct the patient’s parent(s)/guardian on how to 
complete the diary. The diary should be completed throughout the trial until the end of treatment 
visit (Visit 7). The following information should be recorded in the diary: 
• Type and volume of fluid administered through NG tube/gastrostomy (if applicable)  
• Hypoglycemic events, including related SMPG measurements 
• Concomitant medications 
• AEs 
• Hospitalizations, visits to health care providers or ER, and visit by paramedics 
• Data regarding suspicion of NME and neurological findings 
Diary entries should be reviewed at each visit and the review documented in the diary. Data 
from the diary should be transcribed to the eCRF on an ongoing basis. 
10.2.1.5. Fasting Tolerance Test/Safety Fast 
During the screening period and at the end of Treatment Period 1, all patients will undergo a 
fasting tolerance test. This test must be performed when the CGM is active, and not the first day 
of CGM sensor, e.g., the day before randomization. This fasting tolerance test will be initiated 
according to the site’s normal clinical practice and the anticipated duration of the test will be at 
investigator’s discretion.  
The test will commence after the patient’s normal meal (t=0 will be the beginning of the meal). 
The meals have to be the same for both tests for the same individual. The frequency of 
PG sampling using the PG meter will be conducted according to site’s normal practice and the 
individual patient’s needs. This test is planned to last for 12 hours but will be stopped when 
PG is ≤60 mg/dL (3.3 mmol/L) and then ketones, insulin, and free fatty acids will be measured. 
The child will then be fed. If this value has not been reached at 12 hours, the test should be 
extended until it is reached.  
The investigator will record the type and size of the meal, the date, start time, all PG 
measurements obtained, ketone measurement, and the end time of the test in a dedicated eCRF 
page.  
The duration of fasting tolerance will be measured from the beginning of the normal meal until 
the beginning of the first continuous 15-minute CGM reading of <70 mg/dL (3.9 mmol/L). 
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10.2.2. Pharmacokinetics/Drug Exposure 
Blood samples will be collected twice during the trial to measure for dasiglucagon levels at 
steady-state (Schedule of Events; Section 17.1). 
Details on sampling/collection, shipment, and analysis will be provided in the laboratory manual. 
10.2.3. Safety 
Safety assessments will include the evaluation of AEs, clinical laboratory assessments 
(hematology, biochemistry, and ADAs), vital signs, physical examinations; electrocardiograms 
(ECGs), echocardiography, and local tolerability issues. 
10.2.3.1. Laboratory Safety Assessments 
Trial procedures require a maximum total of 12 mL blood in a 30-day period. Where this 
exceeds the 2.5 mL/kg maximum,16,17 safety laboratory tests (2 mL per sampling) will be 
prioritized over immunogenicity (1 mL) and drug exposure (0.4 mL) samples. 
All measurements described in this section are recognized standard methods. 
Laboratory Tests to be Performed 
Samples for hematology and chemistry will be collected at the time points specified in the 
Schedule of Events (Section 17.1). 
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular volume, mean corpuscular 
hemoglobin concentration, platelet count (or estimate), white blood cell 
count, including differential 
Biochemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea 
nitrogen, creatinine, sodium, potassium, chloride, eGFR, urea, insulin, 
ketones (measured at the local laboratory or with the PG meter), free 
fatty acids 
Standard of care blood samples can be used as screening samples if they were collected within 
1 week of screening.  
Laboratory specimens will be analyzed at local laboratories. 
Immunogenicity 
Blood samples will be collected to test for antibodies against dasiglucagon at Visit 2 (Day 1, 
prior to dosing ), Visit 5 (Week 5, prior to dosing), Visit 7 (Week 9) and at the Follow-up Visit 
(Visit 8, Week 12) (Section 17.1) and processed and shipped according to instructions provided 
in the laboratory manual. The samples will be stored until the ADA screening and confirmatory 
assays have been approved by the FDA.  
Patients completing the trial before the ADA screening and confirmatory assays have been 
approved by the FDA and who do not continue treatment in the long-term extension trial will 
have an additional ADA Follow-up Visit (not included in the Schedule of Events) approximately 
16 weeks after the End of Trial visit (Visit 8). 
Upon ADA assay approval, the ADA samples will be analyzed in batches during the trial. The 
ADA samples will be analyzed at a special laboratory. 
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The clinical ADA assays for dasiglucagon have been validated in accordance with existing 
guidelines and recommendations.18,19,20 
Samples will be measured in anti-dasiglucagon antibody screening and confirmatory assays. Due 
to the limited sample volume in the CHI pediatric patients, the ADA characterization of 
confirmed positive samples will be conducted according to the following priority: 
• Cross-reactivity against endogenous glucagon (cross-reactivity Yes/No) 
• Establishment of anti-dasiglucagon binding titer 
• Dasiglucagon in-vitro neutralizing potential of the antibodies 
• Glucagon in-vitro neutralizing potential of the antibodies (only if positive for cross-
reactivity) 
• Neutralizing antibody titers, in case of a positive result in the in-vitro neutralizing 
antibody assays 
The in-vitro neutralizing effects of antibodies will be measured using an assay based on glucagon 
receptor-transfected human embryonic kidney cells. The assays were validated for both 
dasiglucagon and recombinant glucagon neutralizing antibodies. The cell-based neutralizing 
antibody analyses will be performed by a special laboratory. 
Anti-dasiglucagon antibody-positive patients (treatment induced or treatment boosted [titer 
increase above 4 fold]) will be monitored until the ADA level returns to pre-dose level. 
Any residual serum samples will be stored until approval of market authorization by the health 
authorities. 
In addition to the above, the neutralizing potential in samples from ADA-positive patients will be 
evaluated in relation to PK/PD data. 
Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all trial personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of patient samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and 
shipping of infectious samples are outlined in the laboratory manual. The investigator is 
responsible for ensuring that all trial samples that are to be transported to another location are 
packed and shipped appropriately according to the applicable regulations.  
Evaluation of Laboratory Values 
The normal ranges of values for the laboratory assessments in this trial will be provided by the 
responsible laboratory and submitted to the sponsor before the beginning of the trial. They will 
be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, the investigator must evaluate if the value is 
clinically significant and record his or her assessment in the appropriate eCRF. 
All laboratory values that in the investigator’s opinion are clinically significant during or after 
termination of the treatment have to be reported as AEs and followed, as described in 
Section 11.3. 
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10.2.3.2. Clinical Examinations 
Vital Signs 
Vital signs, including blood pressure, heart rate, respiratory rate, and SpO2 will be measured 
according to the Schedule of Events (Section 17.1). 
Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed while the child is in a sleeping or calm state 
according to the time points specified in the Schedule of Events (Section 17.1). If it is not 
practical or possible, then a 2-lead may be used.21 If arrhythmia is detected on a 2-lead ECG, this 
should be followed by a 12-lead ECG. All ECG recordings will be identified with the patient 
number, date, and time of the recording and will be attached to his or her medical record. 
The ECG parameters (heart rate, PQ, QRS, QT, and QTcF) and any abnormality will be recorded 
and described in the eCRF, including the investigator’s assessment of clinical significance 
(Abnormal, Clinically Significant; or Abnormal, or Not Clinically Significant). At subsequent 
visits, any clinically significant deterioration of a pre-existing condition, as well as any new 
clinically significant findings, will be recorded as AEs. 
Echocardiogram 
An echocardiogram will be performed according to the time points specified in the Schedule of 
Events (Section 17.1).  
Physical Examination and Neurological Examination 
A complete physical examination of body systems (excluding breast and genitourinary 
examinations) according to standard of care and a neurological examination (including cranial 
nerves, muscle strength and tone, reflexes, coordination, sensory function, and gait, all as 
applicable for the patient’s age) will be performed according to the Schedule of Events 
(Section 17.1). 
Local Tolerability 
Local tolerability data will be collected separately from AEs. Within the eCRF, data will be 
collected on the nature of any reaction (erythema, pain, swelling, etc.), the severity (mild, 
moderate, or severe), and any action take (e.g., no action, interruption of infusion). The likely 
cause of the reaction will also be collected (e.g., insertion site, drug, or adhesive dressing). 
Other skin findings will be collected along other AEs. If clinical suspicion of NME is made, data 
describing the lesion(s) will be collected as an AE of special interest (AESI) (see Section 11.1.8), 
together with a photograph or series of photographs of the lesion(s) uploaded to a central 
repository. 
10.2.3.3. Reporting of Hypoglycemia Events 
All hypoglycemic episodes are to be reported via the dedicated hypoglycemia eCRF form. 
Hypoglycemic episodes that fulfill the definition of an SAE should furthermore be recorded as 
an SAE. The following information should be collected: 
• Date, start time 
• PG start value 
• Selected symptoms (e.g., unconsciousness, seizures) 
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• Intervention, type, and amount of food; route of administration (oral vs. 
NG tube/gastrostomy); and use of marketed glucagon as rescue therapy 
• Subsequent PG measurements 
• End time (time when PG exceeded a threshold of 70 mg/dL [3.9 mmol/L] or 60 minutes 
after the start of the event) and PG value, if available  
• Contact to trial doctor or emergency services, paramedic visit, ER admission, 
hospitalization, if applicable 
A single hypoglycemia episode is defined as up until 60 minutes from the start of the episode 
even if normoglycemia (>70 mg/dL) is not reached within this time. A new episode of 
hypoglycemia is to be reported when the next PG value below 70 mg/dL (3.9 mmol/L) is 
measured. 
10.2.3.4. Reporting of Technical Complaints 
Technical complaints should be reported to the sponsor on any of the following products if 
technical issues occur between their first and last use: 
• Dasiglucagon 4 mg/mL vial containing 1 mL 
• Accu-Chek Spirit pump 
• Accu-Chek Spirit 3.15 mL Cartridge system, Accu-Chek FlexLink Infusion set 
(Accu-Check UltraFlex Infusion set in the US), and Accu-Check Rapid-D Link infusion 
set 
• Accu-Chek Link-Assist Insertion device 
• SMPG meter, StatStrip Xpress2 
• Dexcom G4 system 
The investigator must report whether the technical complaint is associated with any AEs or 
SAEs. Any AE/SAE associated with a technical complaint must be reported in accordance with 
Section 11.2; the relationship between the technical complaint and the AE/SAE must be assessed 
by the investigator. 
Technical complaints must be reported on a dedicated technical complaint form.  
The investigator must complete the technical complaint form in the eCRF according to the 
following timelines, starting from the time the trial site becomes aware of the technical 
complaint: 
• Technical complaint assessed as related to an SAE within 24 hours 
• All other technical complaints within 5 calendar days 
Use the paper technical complaint form when reporting a technical complaint for an item that is 
not yet allocated to a patient. The form should be sent by e-mail to sponsor QA, refer to 
Appendix A for contact details. 
Collection, Storage, and Shipment of Technical Complaint Item(s) 
The investigator must collect and store the item(s) that is the subject of the technical complaint 
and notify the CRA (including photo documentation) within 5 calendar days of obtaining the 
item at the trial site. Upon request, the CRA must coordinate the shipment as per instruction from 
the sponsor. 
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10.2.3.5. Adverse Events 
The definitions and management of and special considerations for AEs are provided in 
Section 11. 
11. ADVERSE EVENTS AND PREGNANCIES 
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. 
11.1. Definitions 
11.1.1. Adverse Events 
An AE is any untoward medical occurrence in a clinical trial patient administered a medicinal 
(investigational or non-investigational) product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a product, whether or not related to the product. 
AEs include: 
• A clinically significant worsening of a concomitant illness 
• A clinical laboratory AE: a clinical abnormality which 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, e.g., change of dose or more frequent follow-up due to the abnormality 
The following should not be considered as AEs: 
• Pre-existing conditions, including those found as a result of screening procedures 
(pre-existing conditions should be reported as medical history or concomitant illness) 
• 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 
11.1.2. Severity 
When assessing the severity of an AE, the following definitions are used: 
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 find 
unacceptable. A severe reaction does not necessarily deem the AE as serious (SAE), and an SAE 
is not always severe in nature. 
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11.1.3. Causality 
When assessing the cause of an AE, the following definitions are used: 
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 product 
Not related: No relationship to product. 
Causality will take into consideration whether the cause of the AE was related to the trial drug, 
device, or procedures. 
11.1.4. Outcome 
When assessing the outcome of an AE, the following definitions are used: 
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 ICF. 
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 or has died from 
another AE 
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, or the outcome is not known 
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. 
11.1.5. Serious Adverse Events 
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 otherwise medically important and may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when (based on appropriate medical 
judgement) it may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in the definition of an SAE. Examples could be 
emergency room or home treatment of allergic bronchospasm or convulsion 
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11.1.6. Other Important Events 
The following events must always be reported in the electronic data capture (EDC) system on a 
dedicated form, regardless of whether it is related to an AE:  
• suspicion of transmission of infectious agents via the trial product 
• overdose of the trial product 
• medication error involving the trial product 
• inadvertent or accidental exposure to the trial product 
11.1.7. Non-serious Adverse Events 
A non-serious AE is any AE that does not fulfill the definition of an SAE. 
11.1.8. Adverse Events of Special Interest 
For this trial, the following events are to be regarded as AEs of special interest (AESI events or 
AESIs), with data collected under a specific eCRF form:  
• Suspicion of NME 
• Risk of liver injury defined as ALT or AST >3 x UNL AND total bilirubin >2 x UNL, 
where no alternative etiology exists (Hy’s law) 
• Loss of consciousness, partial and generalized seizures 
• Clinically significant changes in blood pressure or heart rate  
11.1.9. 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 (RSI). For 
dasiglucagon, the expectedness of an AE will be determined by whether or not it is listed in the 
RSI section of the investigator’s brochure. 
11.2. Collection, Recording, and Reporting of Adverse Events 
All AEs, whether serious or non-serious, will be reported from the time a signed and dated ICF is 
obtained until the end of the posttreatment follow-up period (which may include contacts for 
follow-up of safety) or inclusion in the ZP4207-17106 trial. Parent(s)/guardian will be asked 
about their child’s condition by open questioning, such as “How has your child been feeling 
since you were last asked?” at each contact with the trial site (visit or telephone). 
Parent(s)/guardian will also be encouraged to spontaneously report AEs occurring at any other 
time during the trial. In addition, patients will be observed for any signs or symptoms. 
All AEs, regardless of seriousness, severity, or presumed relationship to the trial drug, 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 drug. 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 eCRF within 5 calendar days of the investigator becoming 
aware of the event.  
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All AE information should at a minimum include the following: 
• Date and time of onset 
• Date and time of investigator’s first information about the AE 
• Seriousness 
• Severity 
• Causal relationship with trial product 
• Measures taken due to AE 
• Interruption or discontinuation of treatment with trial product 
• Date and time of resolution and final outcome 
Each AE will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). 
All SAEs, including those spontaneously reported to the investigator within 30 days after the last 
dose of trial drug, must be reported within 24 hours after obtaining knowledge about the event, 
by completing the SAE form in EDC. A separate SAE form should be completed for each SAE.  
All SAEs will be reported in EDC; for each reported event, a system-generated e-mail will be 
sent to the Safety CRO (
), medical monitor, sponsor’s medical director, and trial 
manager. 
Specific information about AESIs will be collected via the SAE form (if qualifying for an SAE), 
as well as via dedicated AESI eCRF page(s). Reporting requirements for serious and non-serious 
AEs as described previously also apply for serious and non-serious AESIs. 
Other important events (Section 11.1.6) will be reported via a dedicated eCRF page. Reporting 
timelines will be within 24 hours if related to an SAE and 5 calendar days for all other events. 
It is the responsibility of 
 to report all SUSARs that occur in this trial to competent 
authorities, the institutional review board (IRB), or independent ethics committee (IEC) in 
accordance with the local requirements in force and ICH guideline for GCP. 
11.2.1. Contact Information 
Pharmacovigilance for this trial is outsourced to 
; refer to Appendix A for contact 
details. 
11.3. Follow-up of Adverse Events 
The investigator must record follow-up information in the eCRF. Follow-up questions to 
investigators regarding serious adverse events are queried directly by 
 to the 
investigator. 
Follow-up information must be reported according to the following: 
• SAEs: All SAEs 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 
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The SAE follow-up information should only include new (e.g., 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 
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 3-4 hours after the event and again approximately 
1-2 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, from the start of trial product administration (i.e., the most severe of the 
applied severity/seriousness categories should be ascribed to the event). Accordingly, for AEs 
with onset after trial product administration, changes in the severity or seriousness of an event 
should not lead to reporting of separate AEs. In contrast, for AEs with onset before trial product 
administration, any worsening of severity/seriousness after trial product administration should be 
recorded as a separate AE, with onset date of the event corresponding to the date of the 
severity/seriousness upgrade.  
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.  
11.4. Pregnancy 
Parent(s)/guardian of female patients who are of childbearing potential must be instructed to 
notify the investigator immediately if their child becomes pregnant or if they suspect she is 
pregnant during the trial. All initial reports of pregnancy in female patients must be reported by 
trial site personnel using the appropriate pregnancy form in EDC within 24 hours of their 
knowledge of the event. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, or ectopic pregnancy) are considered SAEs and must be reported 
using the SAE form. If a patient becomes pregnant during the trial, treatment must be 
discontinued. 
The investigator must follow the pregnancy until its 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. 
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11.5. Precautions 
Normal precautions taken for a clinical trial, including the provision of emergency equipment, 
will be taken during this trial. Qualified and well-trained physicians and medical staff will 
instruct patients’ parents. During a patient’s participation in the trial, the investigator should 
ensure that adequate medical care is provided to patients for any AEs, including clinically 
significant laboratory values related to the trial. The investigator should inform the patient’s 
parents when medical care is needed for intercurrent illnesses of which the investigator becomes 
aware. 
For further information on safety precautions for dasiglucagon, refer to the current version of the 
IB. 
11.6. Safety Committee 
An internal Zealand Safety Committee is constituted to perform ongoing 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 
meets quarterly and additionally on an ad hoc basis as needed. 
11.7. Independent Data Monitoring Committee 
An independent data monitoring committee (DMC) will be established for this trial and follow 
the procedures outlined in the DMC Charter. 
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12. STATISTICS 
12.1. Statistical Hypotheses 
This section details the null hypotheses for this trial, which are presented in the form Hij, where 
i = treatment period (i = 1) and j = hypothesis number (j = 1, 2, 3, 4). 
The hypothesis relating to the primary endpoint is: 
H11: Hypoglycemia event rate dasiglucagon = hypoglycemia event rate SOC only  
The hypotheses relating to the key secondary endpoints are: 
H12: Increase in fasting tolerance dasiglucagon = increase in fasting tolerance SOC only  
H13: CGM percent time in range dasiglucagon = CGM percent time in range SOC only 
H14: Clinically significant hypoglycemia event rate dasiglucagon = clinically significant 
hypoglycemia event rate SOC only 
A fixed-sequence statistical strategy will test the primary (Section 6.2.1) and 3 key secondary 
endpoints of Treatment Period 1 (Section 6.2.2) in a pre-defined order, all at the same 
significance level (α = 0.05 to maintain an overall Type I error rate of at maximum α = 0.05; see 
statistical analysis plan [SAP] for more details), moving to a second endpoint only after a success 
on the previous endpoint. 
The test hierarchy is: 
Treatment Period 1 
H11: Hypoglycemia event rate (measured by SMPG) during Weeks 2-4 of the treatment 
period (primary endpoint) 
H12: Increase in fasting tolerance (i.e., time from meal to PG <70 mg/dL) from baseline to 
Weeks 2-4 of the treatment period (key secondary endpoint) 
H13: CGM percent time in range 70-180 mg/dL (3.9-10.0 mmol/L) during Weeks 2-4 of 
the treatment period (key secondary endpoint) 
H14: Clinically significant hypoglycemia event rates, defined as average weekly number 
of events <54 mg/dL (3.0 mmol/L) (as detected by SMPG) during Weeks 2-4 of the 
treatment period (key secondary endpoint) 
12.2. Sample Size Determination 
Patients will be randomized into the trial if they have at least 3 events of hypoglycemia on 
average per week, as recorded in the diary during the 2 weeks prior to randomization. It is 
assumed that patients continuing on standard of care will maintain a similar level through 
Treatment Period 1, with the number of hypoglycemia events (PG <70 mg/dL or 3.9 mmol/L) 
during Weeks 2-4, as detected by SMPG following a Poisson distribution with a mean of 9. The 
trial is powered to detect a treatment effect of 50%, hence, assuming that the number of 
hypoglycemia events reported for patients in the dasiglucagon group during Weeks 2-4 will 
follow a Poisson distribution with a mean of 4.5. At the final analysis, 32 patients will have 99% 
power testing at a 0.05 significance level. The overall alpha level is strongly controlled in this 
setting, remaining at or below 0.05. 
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12.3. Analysis Populations 
Three analysis populations are defined for this trial: 
• The Safety Set: defined as all patients administered any randomized treatment. This 
population will be used to provide descriptive summaries of safety data. Patients will be 
summarized by treatment period according to treatment received 
• The Full Analysis Set (FAS): defined as all patients in the Safety Set who have a valid 
baseline efficacy assessment. This population will be used to analyze efficacy data. 
Patients will be analyzed by treatment period according to planned treatment 
• The Per Protocol (PP) Analysis Set: defined as all patients in the FAS without any major 
protocol deviations. This population will be used to analyze primary and key secondary 
endpoints as a supportive analysis. Patients will be analyzed according to planned 
treatment for the first treatment period only 
Inclusion in the analysis populations will be determined prior to database lock. 
12.4. Statistical Analyses 
This section presents a summary of the planned statistical analyses. A SAP that describes the 
details of the analyses to be conducted will be finalized prior to database lock.  
Unless otherwise indicated, all testing of statistical significance will be 2-sided with a 
significance level of α = 0.05 to maintain an overall Type I error rate of α = 0.05; see SAP for 
more details. 
For analyses involving trial site, if the number of patients per site is small, sites may be pooled 
for analysis, or omitted from statistical models. The final determination will be made prior to 
database lock. 
Continuous endpoints will be summarized with number (n), mean, SD, median, minimum, and 
maximum. In addition, change from baseline values will be calculated at each time point and 
summarized descriptively. For categorical endpoints, descriptive summaries will include counts 
and percentages. 
Immunogenicity data will be analyzed descriptively. No statistical tests are planned. Baseline 
ADA-positive patients will be calculated as a percentage of the total number of patients whose 
baseline samples were tested for ADA. Overall ADA incidence, the combined results of 
treatment induced, and treatment boosted ADA-positive patients, will be calculated as a 
percentage of the total number of evaluable patients, excluding baseline positive patients without 
any samples available after drug administration. Titers will be reported as median and 
interquartile range. 
Graphical presentations of selected endpoints will be prepared and will be outlined in the SAP. 
12.4.1. Trial Patients and Demographics 
12.4.1.1. Disposition and Withdrawals 
The numbers of patients randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of patients in each 
analysis population will be reported. 
12.4.1.2. Protocol Deviations 
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Protocol deviations will be provided in a listing and summarized if appropriate. 
12.4.1.3. Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, race, ethnicity, weight, and 
length/height) at screening will be summarized using descriptive statistics. No formal statistical 
analyses will be performed.  
Prior and concomitant medications and procedures will be summarized by treatment group and 
the number and percentage of patients taking each medication, classified using World Health 
Organization Drug Dictionary Anatomical Therapeutic Chemical classes and preferred term 
(PT). 
12.4.2. Duration of Exposure and Compliance 
Trial drug administration will be summarized in terms of each patient’s mean, mode, and final 
dose, and in terms of duration of exposure. Descriptive statistics for these quantities, including 
the mean, median, SD, minimum, maximum, and quartiles, will be provided by treatment group.  
12.4.3. Efficacy Analyses 
The efficacy analysis will be separated into 3 categories: 
1. Treatment Period 1, FAS 
2. Treatment Period 1, PP (primary and key secondary endpoints only) 
3. Treatment Period 2, FAS 
12.4.3.1. Primary Analysis 
Primary Endpoint (Treatment Period 1) 
The primary efficacy endpoint is the hypoglycemia event rate during Weeks 2-4 of Treatment 
Period 1. A hypoglycemia event is defined as PG <70 mg/dL or 3.9 mmol/L, as detected by 
SMPG. The analysis will be based on the hypoglycemia events reported in the eCRF. Baseline is 
defined as the average weekly number of hypoglycemic events during the 2-week baseline 
period. Weeks 2-4 of Treatment Period 1 is defined as the average weekly number of 
hypoglycemic events across the last 3 weeks of the treatment period. The hypothesis:  
H11: Hypoglycemia event rate dasiglucagon = hypoglycemia event rate SOC only  
will be analyzed by using negative binomial regression, with treatment group as a fixed effect 
and baseline hypoglycemic rate as a covariate. The log-transformed number of days in Treatment 
Period 1 will be used as an offset variable. The null hypothesis is that there is no difference in the 
incidence of average weekly number of hypoglycemic events between the 2 treatment groups, 
which will be tested at the significance level of α=0.05. 
The primary analysis will estimate the treatment effect based on the de facto (treatment policy) 
estimand. All available data in the form of actual measurements will therefore be included in the 
analysis, irrespective of adherence to treatment or use of subsequent therapy. Missing data will 
be imputed using multiple imputation (MI) methodology as described in Section 12.4.3.4.  
As a sensitivity analysis, the primary endpoint will also be analyzed without imputation of 
missing data; however, this analysis will not be included in the fixed-sequence hierarchical 
testing strategy. Similarly, the primary endpoint may be analyzed excluding post-baseline data 
collected after trial drug discontinuation/completion. 
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12.4.3.2. Key Secondary Analyses 
Treatment Period 1 
The key secondary endpoint of clinically significant hypoglycemia (<54 mg/dL [3.0 mmol/L]) 
event rates will be analyzed using a negative binomial regression, with treatment group as a fixed 
effect and baseline hypoglycemic rate as a covariate. Percent time in range (i.e., the percent time 
between 70 mg/dL [3.9 mmol] and 180 mg/dL [10.0 mmol], inclusive, as measured by CGM, 
where percent time is calculated as [number of minutes in range/total number of minutes patient 
is wearing CGM] * 100%) will be analyzed by using an ANCOVA, with treatment group and 
region as fixed effects and baseline time in range as a covariate. Increase in fasting tolerance 
(i.e., change from baseline in time from meal to PG <70 mg/dL) will be analyzed similarly, using 
an ANCOVA, with treatment group and region as fixed effects and baseline fasting tolerance as 
a covariate. Baseline is defined as the mean weekly value during the 2-week baseline period; 
Weeks 2-4 of Treatment Period 1 is defined as the mean weekly value across the last 3 weeks of 
the treatment period. 
Missing data will be imputed in a similar manner to the primary endpoint. Analyses will be 
repeated without imputation of missing data; as with the primary endpoint, these analyses will 
not be included in the fixed-sequence hierarchical testing strategy. 
12.4.3.3. Secondary and Other Efficacy Analyses 
For the remaining efficacy endpoints, continuous and categorical endpoints will be presented 
using summary statistics or frequencies, respectively; no inference will be performed. Missing 
data will not be imputed. 
The secondary efficacy endpoints related to the use of gastric carbohydrates will be evaluated 
descriptively only in the subgroup of patients with gastrostomy or NG tube at baseline.  
Resource Utilization 
The number and percentage of patients with admissions/emergency department visits for 
glycemia, hospitalizations due to CHI, visits to health care providers (family doctor, specialists, 
etc.) caused by CHI or CHI-related events, and need for home visits by parameters will be 
summarized. Additionally, number and length (in days) of hospitalizations due to CHI, number 
of visits to health care providers (family doctor, specialists, etc.) caused by CHI or CHI-related 
events, and number of home visits by paramedics will be summarized. 
Quality of Life 
Quality of life will be assessed by the PedsQL and a CHI disease-specific questionnaire 
(Appendix B). For each item of the PedsQL instrument (parent), a 5-point response scale is used 
(0 = never, 1 = almost never, 2 = sometimes, 3 = often, 4 = almost always). Items are reverse-
scored and linearly transformed to a 0-100 scale (0 → 100, 1 → 75, 2 → 50, 3 → 25, 4 → 0) so 
that higher scores indicate better health-related QoL (less negative impact). Scale scores are 
computed as the sum of the items divided by the number of items answered (this accounts for 
missing data). If more than 50% of the items in the scale are missing, the scale score is not 
computed. Change from baseline for PedsQL for each of the scales (physical functioning, 
emotional functioning, social functioning, and school functioning) and summary scores (total 
scale score, physical health summary score, and psychosocial health summary score) will be 
summarized. 
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Answers to each question on the CHI disease-specific questionnaire will be summarized using 
frequencies at each relevant visit. 
12.4.3.4. Imputation of Missing Data 
For analysis of primary and key secondary endpoints, a jump-to-control (J2C) MI method, with 
SAS procedures PROC MI and PROC MIANALYZE, will be performed, including 
demographics and baseline characteristics in a first MI analysis. Due to the expectation of rapid 
metabolism and excretion of trial drug, it is expected that efficacy would be similar to the control 
group in cases of premature treatment discontinuation; thus, the J2C method is appropriate to 
handle missing values in this situation (considered missing not at random [MNAR]). Any 
missing values occurring before the patient discontinues/completes treatment will be imputed 
based on the data from the same treatment group (considered missing at random [MAR]).   
The analysis will have 3 broad components: i) the MI process for the SOC only data; ii) the MI 
process for the dasiglucagon + SOC patients’ data; and iii) the analysis model that will be used to 
draw inference regarding the primary causal estimand, along with the method for combining the 
results across the multiply imputed datasets. The seed to be used in the analysis is 12255070. The 
algorithm will use 20 burn-in iterations before each imputation, and 1000 imputed datasets will 
be created for the analysis for each of steps i and ii. 
To accommodate both monotone and non-monotone missingness patterns, imputed values will 
be generated by a pattern mixture imputation model under the MNAR assumption using the fully 
conditional specification (FCS) method. The primary analysis will be performed using a negative 
binomial regression model from which hypoglycemia incidence density ratios (IDR) and 
95% confidence intervals are obtained, along with the model parameter estimates, standard 
errors, and p values; analyses of the key secondary endpoints will be performed using the 
appropriate modeling. The final step in the imputation will involve using PROC MIANALYZE 
to derive valid univariate inference for these parameters. Multivariate inference based on the 
Wald test will be derived to test for the significance of these parameters. 
Complete details for conducting this analysis will be outlined in the SAP. 
12.4.4. Safety and Tolerability Analyses 
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 12.3). Safety assessments will include the evaluation of AEs; clinical laboratory 
assessments (hematology, biochemistry, and ADAs); vital signs, physical examinations; ECGs, 
echocardiography, and local tolerability issues. No formal inferential analyses will be conducted 
for safety variables, unless otherwise noted. 
Baseline is defined as the last non-missing assessment before first dose in each treatment period. 
All safety analyses will be summarized by treatment received within treatment period and by 
trial visit, if applicable. 
12.4.4.1. Adverse Events 
Adverse events will be coded using the latest version of MedDRA.  
A treatment-emergent AE is defined as an AE with an onset at the time of or following the start 
of treatment with the trial drug through the Follow-up Visit or Early Termination Visit, 
whichever occurs first. 
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The number and percentage of patients with AEs will be displayed by system organ class, PT, 
and treatment group. The incidence of AEs will also be presented by severity and by relationship 
to the trial drug. Serious AEs and AEs resulting in discontinuation of trial drug will be 
summarized separately in a similar manner. Patient listings of AEs, SAEs, and AEs causing 
discontinuation of trial drug will be produced. 
12.4.4.2. Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values. 
The number of patients with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory analyte. 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. Any out-of-range values that are identified by the 
investigator as being clinically significant will also be shown in a data listing. 
12.4.4.3. Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure, diastolic blood pressure, 
heart rate, respiratory rate, and SpO2. 
The number of patients with vital signs values categorized as below, within, or above normal 
ranges will be tabulated showing change from baseline (shift tables) for each parameter. 
12.4.4.4. Twelve-lead Electrocardiograms 
The number and percentage of patients with normal and abnormal ECG findings will be 
summarized. Abnormal results will be grouped as Abnormal, Clinically Significant; or 
Abnormal, Not Clinically Significant. 
12.4.4.5. Physical Examination Findings 
The number and percentage of patients with normal and abnormal findings in the complete 
physical examination will be displayed. 
12.4.4.6. Local Tolerability 
The number and percentage of patients with local tolerability findings, collected separately from 
AEs, will be summarized. 
12.4.5. Interim Analysis 
No interim analysis is planned. 
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13. TRIAL CONDUCT 
The accuracy and reliability of data is ensured, among others, by the selection of qualified 
investigators and appropriate trial sites, review of protocol procedures with the investigator and 
associated personnel before the trial, periodic monitoring visits, and meticulous data 
management. 
13.1. Sponsor and Investigator Responsibilities 
13.1.1. Sponsor Responsibilities 
The sponsor is obligated to conduct the trial in accordance with strict ethical principles 
(Section 15). The sponsor reserves the right to terminate participation of a trial site at any time 
(Section 13.7), and/or to discontinue the trial (Section 13.6 for US studies and Section 13.6.2 for 
studies conducted outside of the US). 
The sponsor agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the trial according to the trial protocol. 
13.1.2. Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.2), the investigator indicates that he/she has 
carefully read the protocol, fully understands the requirements, and agrees to conduct the trial in 
accordance with the procedures and requirements described in this protocol. 
The investigator also agrees to conduct this trial in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including the November 2016 ICH Guidance 
for Industry E6(R2) GCP, and in agreement with the 2013 version of the Declaration of Helsinki. 
While delegation of certain aspects of the trial to subinvestigators and trial coordinators is 
appropriate, the investigator will remain personally accountable for closely overseeing the trial 
and for ensuring compliance with the protocol and all applicable regulations and guidelines. The 
investigator is responsible for maintaining a list of all persons that have been delegated trial-
related responsibilities (e.g., subinvestigators and trial coordinators) and their specific trial-
related duties. 
Investigators should ensure that all persons who have been delegated trial-related responsibilities 
are adequately qualified and trained in the protocol, trial drugs handling, and their specific duties 
within the context of the trial. Investigators are responsible for providing the sponsor with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the trial may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all trial documentation by authorized individuals. 
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13.2. Site Initiation 
Trial personnel may not screen or enroll patients into the trial until after receiving notification 
from the sponsor or its designee that the trial can be initiated at the trial site. The trial site will 
not be authorized for trial initiation until: 
1. The trial site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF 
2. All regulatory documents have been submitted to and approved by the sponsor or its 
designee 
3. The trial site has a Clinical Trial Agreement in place 
4. Trial site personnel, including the investigator, have participated in a trial initiation 
meeting 
The regulatory documents must be received from the investigator before the sponsor will 
authorize shipment of trial drug to the trial site, Regulatory Green Light. Copies of the 
investigator’s regulatory documents must be retained at the trial site in a secure location in the 
ISF. Additional documents, including a copy of the protocol and applicable amendment(s), the 
dasiglucagon IB, eCRF completion guidelines, copies of regulatory references, copies of 
IRB/IEC correspondence, and trial drug accountability records should also be retained in the ISF. 
It is the investigator’s responsibility to ensure that copies of all required regulatory documents 
are organized, current, and available for inspection. 
13.3. Screen Failures 
Patients who fail inclusion and/or exclusion criteria may be rescreened for the trial upon 
approval by the sponsor and medical monitor. Patients may only be rescreened once 30 days or 
more after the original Screening Visit. If a patient is eligible to enter the trial after having 
previously failed screening, the patient will be assigned a new patient identification number. 
13.4. Trial Documents 
All documentation and material provided by the sponsor for this trial are to be retained in a 
secure location and treated as confidential material. 
13.4.1. Investigator’s Regulatory Documents 
The regulatory documents will be maintained by the investigator in the ISF. 
13.4.2. Case Report Forms 
By signing the Investigator’s Agreement (Section 17.2), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all patients who sign 
an ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the trial to ensure that the trial information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual patient visits should be completed as soon as 
possible after the visit. All requested information must be entered in the EDC system according 
to the completion guidelines provided by the sponsor or its designee. 
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The eCRF must be signed by the investigator or a subinvestigator when all data are entered and 
cleaned. These signatures serve to attest that the information contained in the eCRF is accurate 
and true. 
13.4.3. Source Documents 
Information recorded in the eCRF should be supported by corresponding source documentation. 
Examples of acceptable source documentation include, but are not limited to, hospital records, 
clinic and office charts, laboratory notes, and recorded data from automated instruments, 
memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be entered into the eCRF at the site. 
The investigator should permit trial-related monitoring, IEC review, regulatory inspections, and 
sponsor audit by providing direct access to source data and documents. 
13.5. Data Quality Control 
The sponsor and its designees will perform quality control checks on this clinical trial. 
13.5.1. Monitoring Procedures 
The sponsor and/or its designee will conduct site visits to monitor the trial and ensure (i) the 
safety and rights of the patients are respected, (ii) compliance with the protocol, GCP, and 
applicable regulations and guidelines and (iii) that accurate, valid, and complete data are 
collected. The assigned CRA(s) will visit the investigator and trial site at periodic intervals and 
maintain periodic communication, this are described in detail in the Monitoring Plan. The 
investigator agrees to allow the CRA(s) and other authorized sponsor personnel access to ISF 
and source data (original documents, data, and records). The CRA(s) will maintain current 
personal knowledge of the trial through observation, review of trial records and source 
documentation, and discussion of the conduct of the trial with the investigator and staff. While 
on site, the CRA(s) will review: 
• regulatory documents 
• entries in the EDC system compared with the source documents 
• consents  
• adherence to the inclusion/exclusion criteria 
• AE records 
• storage and accountability of trial drug and trial materials 
• adherence to the protocol and ICH-GCP 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRFs are described in the Trial Reference Manual. As representatives of the sponsor, 
CRAs are responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.2), the investigator agrees to meet with the 
CRA(s) during trial site visits; to ensure that trial staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all trial documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow the sponsor or designee auditors or inspectors from regulatory agencies to review 
records, and to assist the inspectors in their duties, if requested. 
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13.5.2. Data Management 
The sponsor or designee will be responsible for activities associated with the data management 
of this trial. The standard procedures for handling and processing records will be followed per 
GCP and Premier standard operating procedures. A comprehensive data management plan will 
be developed, including a data management overview, description of database contents, 
annotated eCRF, pre-entry review list, self-evident correction conventions, query contacts, and 
consistency checks. 
Trial site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the trial manual. 
13.5.3. Quality Assurance/Audit 
This trial will be subject to audit by the sponsor/its designee or national/international regulatory 
authorities. Audits may be performed to check compliance with GCP guidelines, and can 
include: 
• site audits 
• trial master file audits 
• database audits 
• document audits (e.g., protocol and/or the clinical trial report [CTR]) 
The sponsor or its designee may conduct additional audits on a selection of trial sites, requiring 
access to patient notes, trial documentation, and facilities or laboratories used for the trial. 
The trial site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB/IEC or regulatory authorities 
according to GCP guidelines. The investigator agrees to cooperate with the auditor during the 
visit and will be available to supply the auditor with eCRFs or other files necessary to conduct 
that audit. Any findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify the sponsor immediately. 
13.6. Trial Termination 
The trial may be terminated at the sponsor’s discretion at any time and for any reason. 
13.6.1. Regular Trial Termination 
The end of this trial is defined as the date of the last visit of the last patient (last patient out or 
last patient last visit) participating in the trial. Within 90 days of the end of the clinical trial, the 
sponsor or its designee and/or site will notify the IRBs and IECs and regulatory authorities on the 
regular termination of the trial as required according to national laws and regulations.  
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13.6.2. Premature Trial Termination 
The trial may be terminated prematurely for any reason and at any time by the sponsor, the 
IRBs/IECs, regulatory authorities, respective steering committees, or the coordinating 
investigator. A decision to terminate the trial prematurely is binding to all investigators at all trial 
sites. 
Within 15 days of premature termination of a clinical trial, the sponsor or its designee and/or site 
will notify the IRBs/IECs and regulatory authorities on the premature termination as required 
according to national laws and regulations. The sponsor or its designee must clearly explain the 
reasons for premature termination. 
If the trial is terminated prematurely, all investigators must inform their patients and take care of 
their appropriate follow-up and further treatment to ensure protection of their interests. Trial sites 
may be asked to have all patients currently participating in the trial complete all of the 
assessments for an Early Termination Visit. 
13.7. Trial Site Closure 
At the end of the trial, all trial sites will be closed. The sponsor may terminate participation of a 
trial site at any time. Examples of conditions that may require premature termination of a trial 
site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate patient enrollment 
13.7.1. Record Retention 
After trial completion at sites in the US, the investigator shall 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 drug has been approved 
or the sponsor has discontinued its research with the trial drug, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
the trial drug 
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 shall notify the sponsor in writing of his or her intent 
to destroy all such material. The sponsor shall have 30 days to respond to the investigator’s 
notice, and the sponsor shall 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 shall 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. 
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The investigator shall 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. 
13.7.2. Sample Retention 
Samples will only be used for purposes related to this trial. 
All blood samples will be destroyed upon completion of the CTR, except for residual ADA 
samples, which will be stored until approval of market authorization because further 
characterization of the antibody response may be requested by the health authorities. Identifiable 
samples can be destroyed at any time at the request of the patient. 
13.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of the sponsor. The protocol amendment must be signed by the 
investigator and approved by the IRB/IEC before it may be implemented. Protocol amendments 
will be filed with the appropriate regulatory agency(s) having jurisdiction over the conduct of the 
trial. 
13.9. Use of Information and Publication 
All information concerning dasiglucagon, the sponsor’s operations, patent applications, 
formulae, manufacturing processes, basic scientific data, and formulation information supplied 
by the sponsor or its designee to the investigator and not previously published, is considered 
confidential and remains the sole property of the sponsor. Case report forms also remain the 
property of the sponsor. The investigator agrees to use this information for purposes of trial 
execution through finalization and will not use it for other purposes without the written consent 
of the sponsor. 
The information developed in this trial will be used by the sponsor in connection with the 
continued development of dasiglucagon and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. 
The information generated by this trial is the property of the sponsor. Publication or other public 
presentation of dasiglucagon data resulting from this trial requires prior review and written 
approval of the sponsor. Abstracts, manuscripts, and presentation materials should be provided to 
the sponsor for review and approval at least 30 days prior to the relevant submission deadline. 
Data from individual trial sites must not be published separately. 
It is agreed that the results of the trial will not be submitted for presentation, abstract, poster 
exhibition or publication by the investigator until the sponsor has reviewed and commented on 
such a presentation or manuscript for publication. 
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14. FINAL CLINICAL TRIAL REPORT 
The sponsor will retain ownership of the data. 
The final CTR will be prepared and reviewed in cooperation with the signatory investigator. The 
coordinating investigator will be appointed by the sponsor to review and sign the CTR on behalf 
of all participating investigators. This report will include a summary of the trial results based on 
a statistical evaluation and clinical assessment of the protocol-defined endpoints. The results 
from the neutralizing antibody assay may be included or reported separately pending availability 
of the results. 
The final CTR may be submitted to the regulatory authorities.  
15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1. Declaration of Helsinki and Good Clinical Practice 
This trial will be conducted in compliance with the November 2016 ICH Guidance for Industry 
E6(R2) GCP (including archiving of essential trial documents), the 2013 version of the 
Declaration of Helsinki, and the applicable regulations of the country(ies) in which the trial is 
conducted. 
See Appendix C for regulation and guidelines. 
15.2. Patient Information and Informed Consent 
According to the Declaration of Helsinki and ICH-GCP, patients’ parent(s)/guardian must 
provide their written informed consent prior to enrollment in a clinical trial and before any 
protocol-specified procedures are performed. Patients’ parent(s)/guardian must declare their 
consent by personally signing and dating the ICF. 
France, Germany, Israel: The consent must correspond to the patient’s presumed will where 
such a will can be ascertained. 
The written ICF will embody the elements of informed consent as described in the Declaration of 
Helsinki and will also comply with local regulations.  
Each patient’s parent(s)/guardian should be made aware by the investigator of the nature of the 
trial (objectives, methods, and potential hazards and benefits) and the procedures involved using 
the information on the ICF. 
France, Germany, Israel: Additionally, the patient will be informed about the nature, 
significance, risks, and implications of the trial with age-appropriate information, and his or her 
assent will be obtained in accordance with local regulations, as applicable. 
Information should be given in both oral and written form whenever possible and deemed 
appropriate by the IRB/IEC. Patients’ relatives, or, if necessary, legal representatives must be 
given ample opportunity to inquire about details of the trial.  
Patient information and the ICF must be in a language fully comprehensible to the prospective 
patient’s parent(s)/guardian. The written information must be provided to the patient’s 
parent(s)/guardian to give him or her sufficient time to understand the information and to prepare 
questions before being asked for his or her consent. The investigator must confirm that the text 
was understood by the patient’s parent(s)/guardian. The patient’s parent(s)/guardian will then 
sign and date the IRB/IEC-approved consent form indicating that he or she has given his or her 
consent for his or her child to participate in the trial. The signature confirms that the consent is 
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based on information that has been understood. The form will also be signed by the investigator 
obtaining the consent and annotated with the trial patient number. Each signed patient 
parent(s)/guardian ICF must be kept on file by the investigator for possible inspection by 
regulatory authorities, the sponsor, and/or its designee. Collection of informed consent has to be 
documented on the eCRF. 
Furthermore, the patient’s parent(s)/guardian will be informed that if he or she wishes to 
withdraw his or her child (see Section 8.3 at any time during the trial, this will not have any 
negative consequences. Patients may be withdrawn by the investigator if any change related to 
safety or ethics precludes further participation in the trial. Patients’ parent(s)/guardian will be 
asked to agree to a final assessment in the event of an early termination of the trial. 
If information becomes available that may be relevant to the patient’s willingness to continue 
participating in the trial, the Investigator must inform the patients’ parent(s)/guardian in a timely 
manner, and a revised written informed consent must be obtained. 
Patients’ parent(s)/guardian will be informed that data from their children’s case may be stored 
in a computer without inclusion of their name and that such data will not be revealed to any 
unauthorized third party. Data will be reviewed by the monitor, an independent auditor, and 
possibly by representatives of regulatory authorities and/or IRBs/IECs. The terms of the local 
data protection legislation will be applied as appropriate. 
15.3. Approval by Institutional Review Board and Independent Ethics Committee 
For Investigational New Drug studies, the minimum standards of conduct and requirements for 
informed consent are defined in the FDA regulations. 
A valid IRB/IEC must review and approve this protocol before trial initiation. Written 
notification of approval is to be provided by the investigator to the sponsor’s monitor and PM 
before shipment of investigational drug supplies, and will include the date of the committee’s 
approval and the chairperson’s signature. This written approval must consist of a completed 
sponsor form, IRB/IEC Approval Form, or written documentation from the IRB/IEC containing 
the same information. 
Until written approval by the IRB/IEC has been received by the investigator, no patient may 
undergo any procedure not part of routine care for the patient’s condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval 
from the IRB/IEC, or a designee, must be received by the sponsor before implementation. This 
written approval will consist of a completed IRB Approval Form or written documentation from 
the IRB/IEC containing the same information. 
15.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the 
investigator and the sponsor. 
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16. REFERENCES 
1. 
Arnoux J-B, Verkarre V, Saint-Martin C, et al. Congenital hyperinsulinism: current trends in 
diagnosis and therapy. Orphanet J Rare Dis. 2011;6:63:1-14. 
2. 
De Leon DD, Stanley CA. Congenital hypoglycemia disorders: New aspects of etiology, 
diagnosis, treatment and outcomes. Pediatr Diabetes. 2016;1-7. 
3. 
Lord K, Radcliffe J, Gallagher PR, et al. High risk of diabetes and neurobehavioral deficits 
in individuals with surgically treated hyperinsulinism. J Clin Endocrinol Metab. 
2015;100(11):4133-4139. 
4. 
Stanley CA. Perspective on the genetics and diagnosis of congenital hyperinsulinism 
disorders. J Clin Endocrinol Metab. 2016;101(3):815-826. 
5. 
Mazor-Aronovitch K, Gillis D, Lobel D, et al. Long-term neurodevelopmental outcome in 
conservatively treated congenital hyperinsulinism. Eur J Endocrinol. 2007;157(4):491-497. 
6. 
Welters A, Lerch C, Kummer S, et al. Long-term medical treatment in congenital 
hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical 
centers. Orphanet J Rare Dis. 2015;10;150:1-10. 
7. 
Arya VB, Senniappan S, Demirbilek H, et al. Pancreatic endocrine and exocrine function in 
children following near-total pancreatectomy for diffuse congenital hyperinsulinism. PLoS 
ONE. 2014;9(5):e98054. https://doi.org/10.1371/journal.pone.0098054. 
8. 
Cederblad F, Ewald U, Gustafsson J. Effect of glucagon on glucose production, lipolysis 
and gluconeogenesis in familial hyperinsulinism. Horm. Res. 1998;50:94-98. 
9. 
Miralles RE, Lodha A, Perlman M, Moore AM. Experience with intravenous glucagon 
infusions as a treatment for resistant neonatal hypoglycemia. Arch Pediatr Adolesc Med. 
2002;156(10):999-1004. 
10. Lord K, Dzato E, Snider KE, Gallagher PR, De Leon DD. Clinical presentation and 
management of children with diffuse and focal hyperinsulinism: a review of 223 cases. 
J Clin Endocrinol Metab. 2013;98(11):E1786-E1789. 
11. Mohnike K, Blankenstein O, Pfuetzner A, et al. Long-term non-surgical therapy of severe 
persistent congenital hyperinsulinism with glucagon. Horm Res. 2008;70:59-64. 
12. Pedersen JS, Dikov D, Flink JL, Jhuler HA, Christiansen G, Otzen DE. The changing face 
of glucagon fibrillation: structural polymorphism and conformational imprinting. 
J Mol Biol. 2006;355(3):501-523. 
13. Rose SR, Chrousos G, Cornblath M, Sidbury J. Management of postoperative 
nesidioblastosis with zinc protamine glucagon and oral starch. J Pediatr. 
1986;108(1):97-100. 
14. Chastain MA. The glucagonoma syndrome: A review of its features and discussion of new 
perspectives. Am J Med Sci. 2001;321(5):306–320. 
15. Zealand Pharma report. Population PK modeling and simulation of dasiglucagon in pediatric 
patients with type I diabetes mellitus. 2017. 
16. European Medicines Agency. ICH Topic E11: Clinical Investigation of Medicinal Products 
in the Paediatric Population. January 2001. 
17. Howie, S. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ 2011; 89:46–53. 
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18. Food and Drug Administration (FDA). Guidance for Industry on Bioanalytical Method
Validation. Food and Drug Administration. 2001.
19. Viswanathan CT, Bansal S, Booth B, et al. Quantitative bioanalytical methods validation
and implementation: best practices for chromatographic and ligand binding assays.
Pharm Res. 2007;24(10):1962-73.
20. Shankar G, Devanarayan V, Amaravadi L, et al. Recommendations for the validation of
immunoassays used for detection of host antibodies against biotechnology products.
J Pharm Biomed Anal. 2008;48(5):1267-81.
21. Food and Drug Administration (FDA). Guidance Industry. E14 Clinical Evaluation of
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs.
Food and Drug Administration. 2005.
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17. ATTACHMENTS
17.1. Schedule of Events 
Table 2 Schedule of Events 
Trial Period 
Screening 
Treatment Period 1 
Treatment Period 2 
Follow-up 
Week 
1b 
Telephone Callc 2 
4 
5d 
Telephone Callc 6 
9 
12 
Day 
1 
8 
22 
29 
36 
57 
85 
Time window (days) 
Day -28 to -14a 
±2 
±2 
±2 
±2 
±2 
±2 
±5 
Visit # 
1 
2 
3 
4 
5 
6 
7e 
8 
General assessments 
Informed consent/assent 
X 
Inclusion/exclusion criteria 
X 
X 
Randomization criteria 
X 
Demography 
X 
Body weight and length/heightf 
X 
X 
X 
X 
X 
Medical history (including current illness) 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessment 
Electrocardiogram 
X 
Xr 
X 
Xr 
X 
X 
X 
Echocardiography 
Xg 
X 
X 
Vital signsh 
X 
Xs 
X 
X 
Xs 
X 
X 
X 
Serum Pregnancy testi 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local tolerability 
X 
X 
X 
X 
X 
X 
Physical examination and neurological 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments 
Clinical laboratory testj 
X 
X 
X 
X 
X 
X 
Antibodiesk 
 Xl 
X 
X 
Xk 
Pharmacokinetics/drug exposure 
X 
X 
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Trial Period 
Screening 
Treatment Period 1 
Treatment Period 2 
Follow-up 
Week 
1b 
Telephone Callc 2 
4 
5d 
Telephone Callc 6 
9 
12 
Day 
1 
8 
22 
29 
36 
57 
85 
Time window (days) 
Day -28 to -14a 
±2 
±2 
±2 
±2 
±2 
±2 
±5 
Visit # 
1 
2 
3 
4 
5 
6 
7e 
8 
Efficacy 
Continuous glucose monitoring 
 X (for at least 
14 days prior to 
randomization) 
Continuousm 
Self-monitored plasma glucose 
 X (for at least 
14 days prior to 
randomization) 
X (at least 3 times daily) 
Fasting tolerance testn 
X (during active 
CGM period) 
Xo 
Trial Materials and reminders 
Randomization 
X 
Dispense patient diary 
Xp 
X 
X 
X 
X 
X 
Diary review 
X 
X 
X 
X 
X 
X 
QoL questionnairesq 
X 
X 
X 
X 
Dispensing of trial product 
X 
X 
X 
X 
X 
Abbreviations: CGM = continuous glucose monitoring; PG = plasma glucose; QoL = quality of life; SMPG = self-monitoring of plasma glucose; SOC = standard of care; 
SpO2 = blood oxygen saturation level; W = week 
Note: An unscheduled visit can occur at any time if the investigator deems it necessary for patient safety. 
a 
Screening must occur within a minimum of 14 days to allow for solid baseline assessment. 
b At the beginning of Treatment Period 1 (Week 1), all patients will be hospitalized for 1-2 days. Patients assigned to SOC plus dasiglucagon treatment will be initiated and 
titrated on dasiglucagon, trained in the use of the infusion pump, and supervised. Patients are assigned to SOC alone will receive a similar degree of supervision alongside the 
training in the use of the infusion pump. This period can be extended for both treatment groups if dasiglucagon titration has not been finalized or if training of the 
family/caregivers has not been completed satisfactorily. 
c 
Patients will be contacted by the investigator by telephone the day after discharge. The investigator will ask the parent(s)/guardian if they have any questions about the trial 
procedures and whether their child has experienced any AEs.  
d In Treatment Period 2, patients who were assigned to SOC treatment only in Treatment Period 1 will be hospitalized for the first 1-2 days of Week 5. 
e 
Visit 7 can be used as the first visit for Trial ZP4207 17106 (long-term extension trial) if the patient is continuing in long-term extension trial. 
f 
Length/height will be measured at Screening only. 
g An echocardiogram performed within 1 month of screening can be used. 
h Vital signs include blood pressure, heart rate, respiratory rate, and SpO2. 
i 
A serum pregnancy test will be performed for girls of childbearing potential. 
j 
Clinical laboratory tests include hematology and biochemistry. 
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k Any anti-dasiglucagon antibody-positive patient (treatment induced or treatment boosted) will be monitored at an additional  ollow-up Visit, preferably 16 weeks after the last 
ADA-positive sample. Patients completing the trial before the ADA screening and confirmatory assays have been approved by the FDA and who do not continue treatment in 
the long-term extension trial will have this additional visit 16 weeks after the End of Trial visit (Visit 8). 
l
The sample for ADAs should be taken prior to dosing of dasiglucagon in Treatment Period 1.
m Continuous glucose monitoring is required during Weeks 2-4 of Treatment Period 1 and Weeks 6-8 of Treatment Period 2.
n The fasting tolerance test will be stopped when PG is ≤60 mg/dL (3.3 mmol/L) and then ketones, insulin, and free fatty acids will be measured.
o
The fasting tolerance test at Visit 5 should take place before initiation of dosing in Treatment Period 2 but while the patient is still on CGM.
p At screening, dispense diary and instruct patients’ parent(s)/guardian in its use. At all other visits, the parent(s)/guardian will return the completed diary and obtain a new one.
q The PedsQL (parent-reported versions) and CHI disease-specific questionnaires should be the first assessments performed at each visit.
r 
ECG should be performed at the start of the visit and at 24 ± 4 hours after initiation of trial drug for patients initiating treatment.
s 
Vital signs should be measured at the start of the visit and at 6 ± 1, 12 ± 2, and 24 ± 4 hours after initiation of the trial drug for patients initiating treatment.
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17.2. Investigator’s Agreement 
PROTOCOL NUMBER: 
ZP4207-17109 
PROTOCOL TITLE: 
A Two-Period, Open-label Trial Evaluating the Efficacy and 
Safety of Dasiglucagon for the Treatment of Children with 
Congenital Hyperinsulinism 
FINAL PROTOCOL: 
Version 13.0, 12-Nov-2020 
The undersigned acknowledges possession of and has read the product information (e.g., IB) on 
the trial drug and have discussed these data with the trial monitor. Having considered fully all the 
available information, the undersigned considers that it is ethically justifiable to give the trial 
drug to selected patients in his or her care, according to the trial protocol. 
•
He or she agrees to use the trial material, including trial drug, only as specified in the
protocol. He or she understands that changes cannot be made to the protocol without prior
written approval of the sponsor
•
He or she understands that any deviation from the protocol may lead to early termination
of the trial
•
He or she agrees to report to the sponsor within time any clinical AE or abnormal
laboratory value that is serious, whether or not considered related to the administration of
trial drug
•
He or she agrees to comply with the sponsor and regulatory requirements for the
monitoring and auditing of this trial
In addition, he or she agrees that the trial will be carried out in accordance with the revised 
Declaration of Helsinki (2013) and the local laws and regulations relevant to the use of new 
therapeutic agents. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the trial. 
Principal Investigator: 
Printed Name: 
Signature: 
Date: 
Investigator’s name and address (stamp) 
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18. APPENDICES 
A. Contact Information 
B. Quality of Life Questionnaires 
C. Regulations and Good Clinical Practice Guidelines 
 
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A. Contact Information 
Pharmacovigilance 
Name: 
 
Address: 
 
 
 
E-mail: 
 
Telephone: 
 
 
Technical Complaints 
Name: 
Zealand Pharma A/S Quality Assurance 
E-mail: 
 
 
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B. Quality of Life Questionnaires 
• Infants 1-12 Months: “PedsQL™ Pediatric Quality of Life Inventory Infant Scales –
Version 1 - Parent Report for Infants (ages 1-12 months)” 
• Infants 13-24 Months: “PedsQL™ Pediatric Quality of Life Inventory Infant Scales –
Version 1 - Parent Report for Infants (ages 13-24 months)” 
• Parent Report for Teens 13-18 Years: “PedsQL™ Pediatric Quality of Life Inventory – 
Version 4 - Parent Report for Teens (ages 13-18 yrs)” 
• Parent Report for Children 8-12 Years: “PedsQL™ Pediatric Quality of Life Inventory – 
Version 4 - Parent Report for Children (ages 8-12 yrs)” 
• Parent Report for Children 5-7 Years: “PedsQL™ Pediatric Quality of Life Inventory – 
Version 4 - Parent Report for Young Children (ages 5-7 yrs)” 
• Parent Report for Toddlers 2-4 Years: “PedsQL™ Pediatric Quality of Life Inventory – 
Version 4 - Parent Report for Toddlers (ages 2-4 yrs)” 
• CHI Disease-Specific Questionnaire Developed by the Patient Association, Congenital 
Hyperinsulinism International, and Taken from the Patient-Reported Registry, the 
HI Global Registry 
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C. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
Refer to the following European Directives and applicable regulations/guidances: 
• European Directive 2001/20/EC and related guidance documents 
• European Directive 2005/28/EC and related guidance documents 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2_G
uideline.pdf 
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PROTOCOL 
PRODUCT NAME/NUMBER: 
Dasiglucagon 
PROTOCOL NUMBER: 
ZP4207-17109 
IND NUMBER: 
135869 
EUDRACT NUMBER: 
2017-004547-21 
DEVELOPMENT PHASE: 
Phase 3 
PROTOCOL TITLE: 
A Two-Period, Open-label Trial Evaluating the Efficacy and 
Safety of Dasiglucagon for the Treatment of Children with 
Congenital Hyperinsulinism 
PROTOCOL DATE: 
Original Protocol Version 1.0, 14-Dec-2017 
Final Version 14.0, 12-Nov-2020 (Germany) 
SPONSORED BY: 
Zealand Pharma A/S 
Sydmarken 11 
2860 Soeborg (Copenhagen) 
Denmark 
Telephone: +45 88 77 36 00 
CONTRACT RESEARCH 
ORGANIZATION: 
Premier Research  
One Park Drive 
Suite 150 
Durham, NC 27709 USA 
This trial will be performed in compliance with Good Clinical Practices (GCP) and applicable 
regulatory requirements, including the archiving of essential documents. Information contained 
in this protocol is confidential in nature, and may not be used, divulged, published, or otherwise 
disclosed to others, except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that this information is confidential and may not be further 
disclosed without the express permission of Zealand Pharma A/S. 
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1. REVISION HISTORY 
PROTOCOL TITLE: 
A Two-Period, Open-label Trial Evaluating the Efficacy and 
Safety of Dasiglucagon for the Treatment of Children with 
Congenital Hyperinsulinism 
PROTOCOL DATE: 
Original Protocol Version 1.0, 14-Dec-2017 
This updated protocol version 12.0 is applicable for Germany 
only, and includes: 
AMENDMENT No. 1 
Final Version 2.0, 22-May-2018 (All countries) 
AMENDMENT No. 2 
Final Version 3.0, 05-Jul-2018 (United Kingdom) 
AMENDMENT No. 3 
Final Version 4.0, 25-Jul-2018 (France, Germany, and Israel) 
AMENDMENT No. 4 
Final Version 5.0, 14-Dec-2018 (All countries) 
AMENDMENT No. 5 
Final Version 6.0, 25-Mar-2019 (Germany) 
AMENDMENT No. 6 
Final Version 7.0, 03-Jun-2019 (All countries except 
Germany) 
AMENDMENT No. 7 
Final Version 8.0, 05-Jul-2019 (Germany) 
AMENDMENT No. 8 
Final Version 9.0, 19-Sep-2019 (All countries except 
Germany) 
AMENDMENT No. 9 
Final Version 10.0, 11-Oct-2019 (Germany) 
AMENDMENT No. 10 
Final Version 11.0, 06-Mar-2020 (All countries except 
Germany) 
AMENDMENT No. 11 
Final Version 12.0, 11-Mar-2020 (Germany) 
AMENDMENT No. 12 
Final Version 13.0, 12-Nov-2020 (All countries except 
Germany) 
AMENDMENT No. 13 
Final Version 14.0, 12-Nov-2020 (Germany) 
 
 
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2. APPROVAL SIGNATURES 
PROTOCOL 
NUMBER: 
ZP4207-17109 
PROTOCOL TITLE: 
A Two-Period, Open-label Trial Evaluating the Efficacy and Safety of 
Dasiglucagon for the Treatment of Children with Congenital 
Hyperinsulinism 
 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the trial. 
 
 
 
 
 
 
Clinical Trial Manager 
Zealand Pharma A/S 
 
Date 
 
 
 
 
 
 
Medical Director 
Zealand Pharma A/S 
 
Date 
 
 
 
 
 
 
Manager Biostatistics 
Premier Research 
 
Date 
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3. SYNOPSIS 
PRODUCT 
NAME/NUMBER 
Dasiglucagon 
PROTOCOL 
NUMBER 
ZP4207-17109 
EUDRACT NUMBER 
2017-004547-21 
DEVELOPMENT 
PHASE 
Phase 3 
PROTOCOL TITLE 
A Two-Period, Open-label Trial Evaluating the Efficacy and Safety of Dasiglucagon for 
the Treatment of Children with Congenital Hyperinsulinism 
INDICATION 
Congenital hyperinsulinism (CHI) 
OBJECTIVES 
Primary: To evaluate the efficacy of dasiglucagon administered as a subcutaneous (SC) 
infusion in reducing hypoglycemia in children with CHI. 
Secondary:  
• 
To evaluate the safety and tolerability of dasiglucagon administered as an SC 
infusion in children with CHI 
• 
To evaluate the efficacy of dasiglucagon in reducing glucose requirements 
• 
To investigate quality of life and resource utilization 
TRIAL DESIGN 
This is a 2-period, open-label trial to evaluate the efficacy and safety of dasiglucagon in 
children between the ages of 3 months and 12 years (both inclusive) with CHI.  
Patients are to experience frequent (≥3 events per week) episodes of hypoglycemia despite 
standard of care (SOC) medications to be eligible for this trial, and are to have previously 
undergone sub-total pancreatectomy for CHI or be treated with a non-surgical approach, 
having been evaluated as not eligible for pancreatic surgery. 
After screening and eligibility assessments (during which a 2-week baseline for plasma 
glucose [PG] will be established), patients will be randomly assigned in a 1:1 ratio to 
continue receiving SOC alone or SOC plus dasiglucagon for 4 weeks. In 
Treatment Period 2, all patients will receive SOC plus dasiglucagon for 4 weeks. 
At the beginning of Treatment Period 1 (Week 1), all patients will be hospitalized for 
1-2 days. Patients assigned to SOC plus dasiglucagon treatment will have dasiglucagon 
infusion initiated and titrated, and will be trained in the use of the infusion pump, 
continuous glucose monitoring (CGM) sensor, and glucose meter, and supervised. Patients 
assigned to SOC alone will receive a similar degree of supervision alongside the training 
in the use of the CGM sensor and glucose meter. This period can be extended for both 
treatment groups if dasiglucagon titration has not been finalized or if training of the 
family/caregivers has not been completed satisfactorily.  
Patients originally assigned to receive SOC alone in Treatment Period 1 will also be 
hospitalized for the first 2 days of Treatment Period 2 (Week 5), and will have 
dasiglucagon infusion initiated and titrated, and will be trained in the use of the infusion 
pump. This period can be extended if dasiglucagon titration or pump training has not been 
completed. Regardless of whether dasiglucagon is initiated during Treatment Period 1 
or Treatment Period 2, SOC CHI medications should subsequently be kept constant 
throughout the trial. Adjustments to gastric and oral feeds are permitted. 
Patients’ parent(s)/guardian will be trained to perform PG assessments. Events of 
hypoglycemia will be documented by self-monitored PG (SMPG) measurements. The 
extent of hypoglycemia (episodes and percent time below the threshold) will be further 
quantified by CGM measurements during the 2 weeks before randomization (baseline), 
Weeks 2-4 in Treatment Period 1, and Weeks 6-8 of Treatment Period 2. The CGM results 
will be masked.  
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Patients completing the trial will (pending investigator confirmation of continued positive 
benefit-risk balance) be offered to enter a long-term extension trial (Trial ZP4207-17106) 
to continue dasiglucagon treatment. Patients who do not continue in the long-term 
extension trial will have a Follow-up visit performed 4 weeks after stopping dasiglucagon 
treatment. 
PLANNED NUMBER 
OF PATIENTS 
A sufficient number of patients will be screened to reach a total maximum of 
32 randomized patients with CHI. Patients who withdraw prematurely will not be 
replaced. 
TRIAL ENTRY 
CRITERIA 
Eligible patients will be male or female between 3 months and 12 years of age (both 
inclusive) at screening with an established and documented diagnosis of CHI and who are 
experiencing ≥3 events of hypoglycemia per week (events of PG <70 mg/dL 
[<3.9 mmol/L]) according to investigator’s evaluation. Patients are to have previously 
undergone sub-total pancreatectomy or being treated with a non-surgical approach, having 
been evaluated as not eligible for pancreatic surgery.  
INVESTIGATIONAL 
PRODUCT 
Dasiglucagon injection 4 mg/mL in a 3 mL vial containing 1 mL. 
REFERENCE 
PRODUCT 
None 
TREATMENT 
REGIMENS 
Dosing of dasiglucagon will approximate continuous infusion by delivering small doses at 
frequent intervals via an infusion pump. 
During the trial, PG assessments will be performed regularly (at least 3 times daily, 
preferably before main meals, and as instructed by the investigator); adjustments to the 
gastric dextrose infusion and/or trial drug will occur at the investigator’s discretion. 
Dasiglucagon treatment will be initiated at 10 µg/hr (t=0). Every 2 hours (t=2, 4, 6, etc.), 
the dose will be increased by an additional 10 µg/hr until either: 
1) 
The patient is weaned off entirely from gastric dextrose infusion and/or 
glucose-fortified feeds, or 
2) 
Plasma glucose during the last 2 hours was consistently above 120 mg/dL 
(6.7 mmol/L), or 
3) 
The maximum trial drug product infusion rate of 70 µg/hr is reached, or 
4) 
Adverse events (AEs) emerge that are considered to be related to dasiglucagon 
(e.g., nausea and vomiting) and limit further dose escalation 
The dose of dasiglucagon should not be escalated beyond the treatment objectives of 
PG in the range of 70 to 120 mg/dL (3.9-6.7 mmol/L) while approaching a normal feeding 
regimen according to age.  
The 2-hour dose-adjustment interval will allow plasma drug levels to approach 
approximately steady-state before the dose is further increased. The maximum cumulative 
dose over the first 24 hours is 1.26 mg.  
After the first 24 hours, the dose of dasiglucagon can still be modified to optimize each 
patient’s treatment and to reduce gastric dextrose infusions. The maximum dose of 
dasiglucagon will be 70 µg/hr, corresponding to a maximum of 1.68 mg per day. 
PLANNED TRIAL 
SITES 
Up to 14 sites in the United States, Europe, and Israel. 
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CRITERIA FOR 
EVALUATION 
Primary efficacy endpoint:  
Treatment Period 1 
• 
Hypoglycemia event rate, defined as average weekly number of hypoglycemic 
events (PG <70 mg/dL or 3.9 mmol/L) during Weeks 2-4, as detected by SMPG. 
Key secondary efficacy endpoints: 
Treatment Period 1 
• 
Increase in fasting tolerance (time from beginning of meal to the beginning of the 
first continuous 15-minute CGM reading <70 mg/dL [3.9 mmol/L]) 
• 
CGM percent time in range 70-180 mg/dL (3.9-10.0 mmol/L) during Weeks 2-4 
• 
Clinically significant hypoglycemia event rates, defined as average weekly number 
of events <54 mg/dL (3.0 mmol/L), as detected by SMPG during Weeks 2-4  
STATISTICAL 
METHODS 
Continuous endpoints will be summarized with number (n), mean, standard deviation 
(SD), median, minimum, and maximum. In addition, change from baseline values will be 
calculated at each time point and summarized descriptively; the exception to this is the 
time of PG within pre-specified ranges, which will not have a baseline value. For 
categorical endpoints, descriptive summaries will include counts and percentages. 
All data will be presented in the data listings. 
Analysis Populations 
Three analysis populations are defined for this trial: 
The Safety Set: defined as all patients administered any randomized treatment. This 
population will be used to provide descriptive summaries of safety data. Patients will be 
summarized by treatment period according to treatment received. 
The Full Analysis Set (FAS): defined as all patients in the Safety Set who have a valid 
baseline efficacy assessment. This population will be used to analyze efficacy data. 
Patients will be analyzed by treatment period according to planned treatment. 
The Per Protocol (PP) Analysis Set: defined as all patients in the FAS without any major 
protocol deviations. This population will be used to analyze primary and key secondary 
endpoints as a supportive analysis. Patients will be analyzed according to planned 
treatment for the first treatment period only. 
The analysis of efficacy will be separated into 3 categories: 
1. Treatment Period 1, FAS 
2. Treatment Period 1, PP (primary and key secondary endpoints only) 
3. Treatment Period 2, FAS 
In Treatment Period 1 (categories 1 and 2), the 2 treatment arms will be compared by a 
testing procedure starting with the primary and subsequently continuing through the 
key secondary endpoints if the hypotheses are rejected. 
In Treatment Period 2 (category 3), only descriptive analyses will performed. 
Graphical presentations of selected analyses in the 2 treatment periods will be prepared, 
and will be discussed in the formal statistical analysis plan (SAP). 
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Efficacy Analyses  
Primary Endpoint (Treatment Period 1) 
The primary efficacy endpoint is the hypoglycemia event rate during Weeks 2-4 of 
Treatment Period 1. A hypoglycemia event is defined as PG <70 mg/dL or 3.9 mmol/L, as 
detected by SMPG. Baseline is defined as the average weekly number of hypoglycemic 
events during the 2-week baseline period. Weeks 2-4 of Treatment Period 1 is defined as 
the average weekly number of hypoglycemic events across the last 3 weeks of the 
treatment period. The hypoglycemic event rate will be analyzed by using negative 
binomial regression, with treatment group as a fixed effect and baseline hypoglycemic rate 
as a covariate. The null hypothesis is that there is no difference in the incidence of average 
weekly number of hypoglycemic events between the 2 treatment groups, which will be 
tested at the significance level of α = 0.05. 
The primary analysis will estimate the treatment effect based on the de facto (treatment 
policy) estimand. All available data in the form of actual measurements will therefore be 
included in the analysis, irrespective of adherence to treatment or use of subsequent 
therapy. 
As a sensitivity analysis, the primary endpoint will also be analyzed without imputation of 
missing data; however, this analysis will not be included in the fixed-sequence hierarchical 
testing strategy. Similarly, the primary endpoint may be analyzed excluding post-baseline 
data collected after trial drug discontinuation/completion. 
Key Secondary Endpoints (Treatment Period 1) 
The key secondary endpoint of clinically significant hypoglycemia (<54 mg/dL 
[3.0 mmol/L]) event rates will be analyzed using a negative binomial regression, with 
treatment group as a fixed effect and baseline hypoglycemic rate as a covariate. Percent 
time in range (i.e., the percent time between 70 mg/dL [3.9 mmol] and 180 mg/dL [10.0 
mmol], inclusive, as measured by CGM, where percent time is calculated as [number of 
minutes in range/total number of minutes patient is wearing CGM] * 100%) will be 
analyzed by using an ANCOVA, with treatment group and region as fixed effects and 
baseline time in range as a covariate. Increase in fasting tolerance (i.e., change from 
baseline in time from meal to PG <70 mg/dL) will be analyzed similarly using an 
ANCOVA, with treatment group and region as fixed effects and baseline fasting tolerance 
as a covariate. 
For the remaining efficacy endpoints, continuous and categorical endpoints will be 
presented using summary statistics or frequencies, respectively; no inference will be 
performed.  
Safety Analyses 
Adverse events will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Adverse events that begin after the first dose of 
dasiglucagon will be defined as treatment emergent. The overall incidence of AEs will be 
displayed by system organ class, preferred term, and treatment. The incidence of AEs will 
also be presented by severity and by relationship to the trial drug. Vital signs, clinical 
laboratory measures (including hematology, biochemistry, incidence of anti-drug 
antibodies [ADAs]), electrocardiograms (ECGs), echocardiography, physical 
examinations, and local tolerability data will be summarized by treatment, where 
applicable. Out-of-range safety endpoints may be categorized as low or high where 
applicable. 
A SAP will be prepared to provide further details on the methods for statistical analysis, 
including rules for handling multiplicity and missing data. 
SAMPLE SIZE 
DETERMINATION 
Patients will be randomized into the trial if they have at least 3 events of hypoglycemia on 
average per week, as recorded in the diary during the 2 weeks prior to randomization. It is 
assumed that patients continuing on standard of care will maintain a similar level through 
Treatment Period 1, with the number of hypoglycemia events (PG <70 mg/dL or 
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3.9 mmol/L) during Weeks 2-4, as detected by SMPG following a Poisson distribution 
with a mean of 9. The trial is powered to detect a treatment effect of 50%, hence, 
assuming that the number of hypoglycemia events reported for patients in the 
dasiglucagon group during Weeks 2-4 will follow a Poisson distribution with a mean of 
4.5. At the final analysis, 32 patients will have 99% power testing at a 0.05 significance 
level. The overall alpha level is strongly controlled in this setting, remaining at or below 
0.05. 
TRIAL AND 
TREATMENT 
DURATION 
The overall trial duration is expected to be 15 months. 
The sequence and maximum duration of the trial periods will be as follows: 
1. Screening: at least 14 days up to 28 days 
2. Treatment Period 1: 4 weeks 
3. Treatment Period 2: 4 weeks 
4. Follow-up Period: 4 weeks 
The maximum trial duration for each patient is approximately 16 weeks. 
The dasiglucagon treatment duration for each patient is 4 or 8 weeks. 
 
 
 
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4. TABLE OF CONTENTS 
1. 
REVISION HISTORY .............................................................................................................2 
2. 
APPROVAL SIGNATURES ...................................................................................................3 
3. 
SYNOPSIS ...............................................................................................................................4 
4. 
TABLE OF CONTENTS .........................................................................................................9 
4.1. 
LIST OF TABLES ......................................................................................................13 
4.2. 
LIST OF FIGURES ....................................................................................................13 
5. 
LIST OF ABBREVIATIONS .................................................................................................14 
6. 
INTRODUCTION ..................................................................................................................17 
6.1. 
Background and Rationale ..........................................................................................17 
6.2. 
Current Treatment and Unmet Medical Need .............................................................17 
6.3. 
Dasiglucagon for the Treatment of Congenital Hyperinsulinism ...............................18 
6.3.1. 
Dasiglucagon ...................................................................................................18 
6.3.2. 
Nonclinical Experience ...................................................................................19 
6.3.3. 
Clinical Experience .........................................................................................19 
6.3.4. 
Literature Data ................................................................................................21 
6.3.5. 
Anticipated Medical Benefit of Dasiglucagon in the Treatment of CHI ........22 
6.3.6. 
Anticipated Risks of Dasiglucagon in the Treatment of CHI .........................22 
6.3.7. 
Summary of Potential Benefits and Risks .......................................................23 
7. 
OBJECTIVES AND ENDPOINTS ........................................................................................24 
7.1. 
Objectives....................................................................................................................24 
7.1.1. 
Primary Objective ...........................................................................................24 
7.1.2. 
Secondary Objectives ......................................................................................24 
7.2. 
Endpoints ....................................................................................................................24 
7.2.1. 
Primary Endpoint ............................................................................................24 
7.2.2. 
Key Secondary Efficacy Endpoints ................................................................24 
7.2.3. 
Secondary Efficacy Endpoints ........................................................................24 
7.2.4. 
Other Efficacy Endpoints ................................................................................25 
7.2.5. 
Safety Endpoints .............................................................................................25 
8. 
TRIAL DESIGN .....................................................................................................................26 
8.1. 
Overall Trial Design and Plan .....................................................................................26 
8.2. 
Discussion of Trial Design ..........................................................................................27 
8.3. 
Trial Sites ....................................................................................................................27 
8.4. 
Point of Contact ..........................................................................................................27 
9. 
PATIENT POPULATION ......................................................................................................28 
9.1. 
Selection of Trial Population ......................................................................................28 
9.2. 
Trial Entry Criteria ......................................................................................................28 
9.2.1. 
Inclusion Criteria .............................................................................................28 
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9.2.2. 
Exclusion Criteria ............................................................................................29 
9.2.3. 
Randomization Exclusion Criteria ..................................................................29 
9.3. 
Premature Patient Withdrawal ....................................................................................30 
9.4. 
Treatment Discontinuation ..........................................................................................30 
9.5. 
Patient Replacement Criteria ......................................................................................30 
10. TREATMENTS ......................................................................................................................31 
10.1. Identification of Investigational Product .....................................................................31 
10.1.1. Packaging and Labeling ..................................................................................31 
10.2. Treatments Administered ............................................................................................31 
10.3. Trial Supplies ..............................................................................................................33 
10.4. Dispensing and Storage ...............................................................................................33 
10.5. Method of Assigning Patients to Treatment Groups ...................................................34 
10.6. Blinding and Unblinding Treatment Assignment .......................................................34 
10.7. Selection of Doses in the Trial ....................................................................................34 
10.8. Selection of Timing of Dose for Each Patient ............................................................35 
10.9. Dose Adjustment Criteria............................................................................................35 
10.10. Treatment Compliance ................................................................................................35 
10.11. Permitted and Prohibited Therapies ............................................................................35 
10.11.1. Permitted Therapies ........................................................................................35 
10.11.2. Prohibited Therapies .......................................................................................35 
10.12. Patients May be Discharged for Home Treatment ......................................................36 
10.13. Treatment After End of Trial ......................................................................................36 
11. TRIAL PROCEDURES ..........................................................................................................37 
11.1. Trial Duration ..............................................................................................................37 
11.2. Assessments ................................................................................................................37 
11.2.1. Efficacy ...........................................................................................................37 
11.2.1.1. 
Plasma Glucose Monitoring ................................................................37 
11.2.1.2. 
Continuous Glucose Monitoring .........................................................37 
11.2.1.3. 
Quality of Life .....................................................................................38 
11.2.1.4. 
Other Assessments ..............................................................................39 
11.2.1.5. 
Fasting Tolerance Test/Safety Fast .....................................................39 
11.2.2. Pharmacokinetics/Drug Exposure ...................................................................40 
11.2.3. Safety ...............................................................................................................40 
11.2.3.1. 
Laboratory Safety Assessments ...........................................................40 
11.2.3.2. 
Clinical Examinations .........................................................................42 
11.2.3.3. 
Reporting of Hypoglycemia Events ....................................................43 
11.2.3.4. 
Reporting of Technical Complaints ....................................................43 
11.2.3.5. 
Adverse Events ....................................................................................44 
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12. ADVERSE EVENTS AND PREGNANCIES .......................................................................44 
12.1. Definitions ...................................................................................................................44 
12.1.1. Adverse Events ................................................................................................44 
12.1.2. Severity ...........................................................................................................44 
12.1.3. Causality ..........................................................................................................45 
12.1.4. Outcome ..........................................................................................................45 
12.1.5. Serious Adverse Events ...................................................................................45 
12.1.6. Other Important Events ...................................................................................46 
12.1.7. Non-serious Adverse Events ...........................................................................46 
12.1.8. Adverse Events of Special Interest .................................................................46 
12.1.9. Suspected Unexpected Serious Adverse Reactions ........................................46 
12.1.10. Adverse Events Associated with Devices .......................................................46 
12.1.10.1. Adverse Device Effect .........................................................................46 
12.1.10.2. Serious Adverse Device Effect ............................................................47 
12.1.10.3. Unanticipated Serious Adverse Device Effect ....................................47 
12.1.10.4. Device Deficiency ...............................................................................47 
12.2. Collection, Recording, and Reporting of Adverse Events ..........................................47 
12.2.1. Serious Adverse Event Reporting Process in Germany ..................................48 
12.2.2. Contact Information ........................................................................................48 
12.3. Follow-up of Adverse Events .....................................................................................48 
12.4. Pregnancy ....................................................................................................................49 
12.5. Precautions ..................................................................................................................50 
12.6. Safety Committee ........................................................................................................50 
12.7. Independent Data Monitoring Committee ..................................................................50 
13. STATISTICS ..........................................................................................................................51 
13.1. Statistical Hypotheses .................................................................................................51 
13.2. Sample Size Determination .........................................................................................51 
13.3. Analysis Populations ...................................................................................................52 
13.4. Statistical Analyses .....................................................................................................52 
13.4.1. Trial Patients and Demographics ....................................................................52 
13.4.1.1. 
Disposition and Withdrawals ..............................................................52 
13.4.1.2. 
Protocol Deviations .............................................................................53 
13.4.1.3. 
Demographics and Other Baseline Characteristics .............................53 
13.4.2. Duration of Exposure and Compliance ...........................................................53 
13.4.3. Efficacy Analyses ............................................................................................53 
13.4.3.1. 
Primary Analysis .................................................................................53 
13.4.3.2. 
Key Secondary Analyses .....................................................................54 
13.4.3.3. 
Secondary and Other Efficacy Analyses .............................................54 
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13.4.3.4. 
Imputation of Missing Data .................................................................55 
13.4.4. Safety and Tolerability Analyses ....................................................................55 
13.4.4.1. 
Adverse Events ....................................................................................55 
13.4.4.2. 
Clinical Laboratory Evaluations ..........................................................56 
13.4.4.3. 
Vital Signs ...........................................................................................56 
13.4.4.4. 
Twelve-lead Electrocardiograms .........................................................56 
13.4.4.5. 
Physical Examination Findings ...........................................................56 
13.4.4.6. 
Local Tolerability ................................................................................56 
13.4.4.7. 
Interim Analysis ..................................................................................56 
14. TRIAL CONDUCT ................................................................................................................57 
14.1. Sponsor and Investigator Responsibilities ..................................................................57 
14.1.1. Sponsor Responsibilities .................................................................................57 
14.1.2. Investigator Responsibilities ...........................................................................57 
14.2. Site Initiation ...............................................................................................................58 
14.3. Screen Failures ............................................................................................................58 
14.4. Trial Documents ..........................................................................................................58 
14.4.1. Investigator’s Regulatory Documents .............................................................58 
14.4.2. Case Report Forms ..........................................................................................58 
14.4.3. Source Documents ..........................................................................................59 
14.5. Data Quality Control ...................................................................................................59 
14.5.1. Monitoring Procedures ....................................................................................59 
14.5.2. Data Management ...........................................................................................60 
14.5.3. Quality Assurance/Audit .................................................................................60 
14.6. Trial Termination ........................................................................................................60 
14.6.1. Regular Trial Termination ...............................................................................60 
14.6.2. Premature Trial Termination ...........................................................................61 
14.7. Trial Site Closure ........................................................................................................61 
14.7.1. Record Retention .............................................................................................61 
14.7.2. Sample Retention ............................................................................................62 
14.8. Changes to the Protocol ..............................................................................................62 
14.9. Use of Information and Publication ............................................................................62 
15. FINAL CLINICAL TRIAL REPORT ....................................................................................63 
16. ETHICAL AND LEGAL CONSIDERATIONS ....................................................................63 
16.1. Declaration of Helsinki and Good Clinical Practice ...................................................63 
16.2. Patient Information and Informed Consent .................................................................63 
16.3. Approval by Institutional Review Board and Independent Ethics Committee ...........64 
16.4. Finance and Insurance .................................................................................................64 
17. REFERENCES .......................................................................................................................65 
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18. ATTACHMENTS ...................................................................................................................67 
18.1. Schedule of Events ......................................................................................................67 
18.2. Investigator’s Agreement ............................................................................................70 
19. APPENDICES ........................................................................................................................71 
20. ADDENDUM .........................................................................................................................72 
20.1. Administrative Information.........................................................................................72 
20.2. Device Information .....................................................................................................72 
20.2.1. Planned Devices ..............................................................................................72 
20.2.1.1. 
Pump System Accu-Chek Spirit Combo .............................................72 
20.2.1.2. 
Self-Monitoring Plasma Glucose StatStrip Xpress2 ...........................74 
20.2.1.3. 
Dexcom Platinum Professional G4 Continuous Glucose Monitoring 
System .................................................................................................75 
20.2.1.4. 
Other Medical Devices ........................................................................78 
20.2.1.5. 
Risk Evaluation for Off-label Use of Devices .....................................78 
20.3. Device-related Safety Section .....................................................................................81 
20.3.1. Anticipated Adverse Device Effects ...............................................................81 
20.3.2. Pump system Accu-ChekSpirit Combo ..........................................................81 
20.3.3. Self-monitored Plasma Glucose StatStrip Xpress2 .........................................81 
20.3.4. Continuous Glucose Monitoring Dexcom Platinum Profession G4 ...............81 
20.4. Protocol Clarifications ................................................................................................82 
20.4.1. Informed Consent ............................................................................................82 
20.4.2. Vulnerable Population .....................................................................................82 
20.4.3. Addition to Statistical Section .........................................................................82 
20.4.4. Protocol Deviations .........................................................................................82 
A. 
Contact Information ....................................................................................................84 
B. 
Quality of Life Questionnaires ....................................................................................85 
C. 
Regulations and Good Clinical Practice Guidelines ...................................................86 
1. 
Regulations ......................................................................................................86 
2. 
Good Clinical Practice Guidelines ..................................................................86 
 
4.1. LIST OF TABLES 
Table 1 
Initial 24-hour Maximum Dose of Dasiglucagon ..............................................32 
Table 2 
Schedule of Events ............................................................................................67 
 
4.2. LIST OF FIGURES 
Figure 1 
Trial Design .......................................................................................................27 
 
 
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5. LIST OF ABBREVIATIONS 
ADA 
anti-drug antibodies 
ADE 
adverse device effect 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AOCglucose 
area over the glucose curve up to 70 mg/dL 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-inf 
area under the plasma concentration-time curve from time zero to infinity 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte 
CGM 
continuous glucose monitoring 
CHI 
congenital hyperinsulinism 
Cmax 
maximum observed concentration 
CRA 
clinical research associate 
CRO 
contract research organization 
CTR 
clinical trial report 
DMC 
data monitoring committee  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ER 
emergency room 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
H 
hypothesis 
HbA1c 
glycated hemoglobin 
HIV 
human immunodeficiency virus 
HNF4A-DM 
hepatocyte nuclear factor 4 alpha diabetes mellitus 
HNF4A-IGT 
hepatocyte nuclear factor 4 alpha impaired glucose tolerance 
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IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IFU 
instructions for use 
IM 
intramuscular(ly) 
IRB 
institutional review board 
ISF 
Investigator Site File 
ISPE  
International Society of Pharmaceutical Engineers 
IV 
intravenous(ly) 
J2C 
jump to control 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MNAR 
missing not at random 
NG 
nasogastric 
PD 
pharmacodynamics(s) 
PedsQL™ 
Pediatric Quality of Life Inventory 
PG 
plasma glucose 
PK 
pharmacokinetic(s) 
PP 
Per protocol 
PT 
preferred term 
QoL 
quality of life 
RBC 
red blood cell 
RSI 
Reference Safety Information 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SEM 
standard error of the mean 
SMPG 
self-monitored plasma glucose 
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SpO2 
blood oxygen saturation level 
SOC 
standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
USADE 
unanticipated serious adverse device effect 
Zealand 
Zealand Pharma A/S 
 
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6. INTRODUCTION 
6.1. Background and Rationale 
Congenital hyperinsulinism (CHI) is a rare and challenging disorder in which β-cells in the 
pancreas secrete insulin irrespective of plasma glucose (PG) concentration, resulting in persistent 
and often severe hypoglycemia.1 Congenital hyperinsulinism affects up to 1 in 50,000 newborns. 
It is typically diagnosed on the basis of signs and symptoms of hypoglycemia during the neonatal 
period or in infancy; however, the diagnosis may be made later in childhood. Mutations in 
several different genes have been described to cause CHI, which can be either focal (only a small 
area of the pancreas is affected) or diffuse (most of the pancreas is affected). The condition can 
persist into adulthood; however, the severity generally decreases with age due to the increased 
insulin requirements and/or increased insulin resistance, and CHI is thus primarily a pediatric 
disease with regard to medical treatment needs. Hypoglycemia that results from CHI is of 
particular concern because it is an important cause of brain injury in neonates, infants, and 
children with this disease, which leads to long-term neurological impairments.1,2 Up to 
approximately 50% of children with CHI experience neurodevelopmental abnormalities caused 
by severe hypoglycemia that results from inadequate treatment and/or delays in diagnosis.1,3 
Severe brain damage is the consequence of severe hypoglycemia, which presents as coma and/or 
long-lasting epileptic seizures in neonates. Major intellectual disability is, therefore, most 
frequent in patients with neonatal onset, whereas hypoglycemia is usually less severe and brain 
damage less frequent in children with CHI diagnosed later in childhood.1 Since symptoms and 
severity of hypoglycemia can vary and pose a diagnostic challenge in neonates, infants and 
children with CHI, prompt recognition and treatment of hypoglycemia is critical to reduce the 
risk of long-term neurological consequences. 
6.2. Current Treatment and Unmet Medical Need 
Medical treatment for CHI is focused on chronic therapies to avoid hypoglycemia, as well as on 
rescue therapy during acute episodes of severe hypoglycemia. Available medical therapies 
(mainly diazoxide, octreotide, or glucagon alone or in combination with glucose infusion) are 
often inadequate and accompanied by inability to control PG, as reflected in a large proportion of 
patients requiring sub-total pancreatectomy.4,5,6 With the exception of surgery for focal CHI, 
which is curative in the vast majority of patients, sub-total pancreatectomy for diffuse CHI has 
substantial inadequacies. A recent trial7 showed that 60% of patients who underwent near-total 
pancreatectomy had persistent hypoglycemia after surgery. Moreover, 96% had developed 
insulin-dependent diabetes within 11 years after surgery, indicating the serious and long-term 
consequences of the procedure. 
First-line medical treatment is diazoxide, which is the only EU- and US-approved drug for 
treatment of hyperinsulinemic hypoglycemia. Diazoxide acts to open KATP channels of the 
pancreatic β-cells, thereby inhibiting insulin secretion. Unfortunately, many patients with CHI 
are resistant to diazoxide because of mutations in the genes encoding the KATP channel of the 
pancreatic β-cells.6 For those who respond to diazoxide treatment, the more common side effects 
comprise hypertrichosis, fluid retention, and gastrointestinal (GI) symptoms; however, side 
effects are usually not severe. In diazoxide non-responders, second-line (and off-label) treatment 
is a somatostatin analog (octreotide or lanreotide [long acting]), which (among other effects) 
inhibits secretion of insulin and glucagon from the pancreas and suppresses GLP-1 secretion. 
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Factors that limit their use comprise tachyphylaxis, as well as possible side effects, including 
necrotizing enterocolitis, gallstones, and hepatitis.6 
Glucagon has been shown to be effective in the treatment of CHI. The glycogenolytic effect of 
glucagon and its ability to increase PG levels has been confirmed in children with CHI or 
neonatal hypoglycemia,8,9 and administration of reconstituted glucagon (via intravenous [IV] 
infusion or as repeated subcutaneous [SC] injection) is often used in the initial phase during the 
establishment of CHI diagnosis and to stabilize patients with CHI before surgery or initiation of 
other medical treatments.10 Furthermore, glucagon is administered as single SC doses to treat 
severe hypoglycemic episodes. While IV administration of glucagon to patients with CHI is used 
short-term in the hospital setting, e.g., before pancreatectomy,2,10,11 long-term glucagon treatment 
is complicated by the fact that currently available glucagon products are unstable and form fibrils 
within hours after reconstitution.12 This fibril formation may lead to infusion set clotting, 
catheter obstruction, and dosing errors that may cause acute severe hypoglycemia. Catheter 
obstruction and occlusion because of glucagon fibril formation and aggregation were observed 
daily to 2 to 3 times weekly in a retrospective review of 9 patients with CHI receiving 
continuous SC infusion of glucagon for weeks or months.11 In another series of patients, 60% of 
the patients treated with SC glucagon experienced catheter occlusion.6 In a home-care setting, 
this fibril formation and associated risk of dosing errors carry the risk of hypoglycemic events, 
which is a major barrier for using currently marketed glucagon products for long-term treatment 
of patients with CHI.  
With respect to long-term glucagon treatment in CHI, there are a few reports on home treatment 
with subcutaneously infused glucagon in children with CHI over extended periods (years) that 
suggest benefit in patient care with a potentially good safety profile as compared to diazoxide 
and octreotide.6,11,13 While this attests to the potential clinical relevance of long-term glucagon 
treatment in CHI, the use of SC infusion of currently marketed glucagon is severely limited by 
the issues with fibril formation and solution instability of recombinant glucagon as described 
previously. 
6.3. Dasiglucagon for the Treatment of Congenital Hyperinsulinism 
6.3.1. 
Dasiglucagon 
Dasiglucagon is a peptide analog of human glucagon that is in development for the treatment and 
prevention of hypoglycemia in patients with diabetes mellitus and CHI via SC or intramuscular 
(IM) administration. Dasiglucagon is a stable analog of glucagon that has been specifically 
designed to overcome the issues with fibril formation and instability in solution observed with 
marketed glucagon products. Compared to native human glucagon, dasiglucagon also comprises 
29 amino acids. As a result of chemical modifications (7 amino acid substitutions compared to 
human glucagon), the pronounced tendency of glucagon to form fibrils and aggregate has been 
effectively prevented in dasiglucagon. In addition, the chemical stability in aqueous media at 
physiological pH has been improved.  
To support the use of dasiglucagon in the pump, compatibility/in-use studies have been 
performed with dasiglucagon 4 mg/mL in the Roche Accu-Chek® Combo pump using the 
Accu-Chek® Spirit 3.15 mL cartridge system and the Accu-Chek® FlexLink infusion set. The 
studies support an in-use time for up to 6 days at 37ºC. 
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Dasiglucagon was granted orphan drug designation by the European Commission on 20 June 
2017 for the ‘treatment of congenital hyperinsulinism.’ Furthermore, the FDA granted an orphan 
drug designation for the ‘treatment of hypoglycemia in patients with congenital hyperinsulinism 
(CHI)’ on 10 August 2017.  
6.3.2. 
Nonclinical Experience 
The completed nonclinical pharmacology program has determined that dasiglucagon is a specific 
glucagon receptor agonist with comparable in vitro potency to glucagon, promoting a rapid onset 
of PG increase in both normal and insulin-induced hypoglycemic animals, similar to that of 
glucagon. The effects of dasiglucagon and glucagon were investigated in an insulin-induced 
hypoglycemic rat model, which is considered particularly relevant to characterize the use of 
dasiglucagon for the treatment of CHI because it mimics the inappropriate insulin to PG levels in 
CHI and resultant hypoglycemia. The onset of PG increase with dasiglucagon was rapid and 
similar to that observed for glucagon, confirming comparable pharmacodynamics. 
Results of the toxicity studies with dasiglucagon are comparable to what has been reported for 
glucagon. Those from chronic toxicity studies with dasiglucagon in rats and dogs are in line with 
the results of short-term toxicity studies, indicating that long-term treatment with dasiglucagon is 
safe and that the pharmacodynamic (PD) effects noted do not adversely affect organ function 
following chronic use. 
6.3.3. 
Clinical Experience 
Dasiglucagon is being developed to manage patients with CHI 1) as an initial short-term therapy 
to stabilize PG levels and reduce glucose infusion needs, and 2) as a long-term treatment to help 
maintain euglycemia. Dasiglucagon has not previously been studied in patients with CHI. 
Clinical experience with dasiglucagon comes from the following studies in healthy subjects and 
type 1 diabetics. 
The safety, tolerability, pharmacokinetic (PK), and PD characteristics of dasiglucagon were 
investigated in 2 phase 1 trials and 3 phase 2 trials.  
ZP4207-14013 was a phase 1 randomized, double-blind, 2-part, single-dose trial designed to 
evaluate the pharmacokinetics, PD, safety, and tolerability of dasiglucagon compared to 
GlucaGen®. Part 1 consisted of SC and intramuscular (IM) administration of single ascending 
doses of dasiglucagon in 64 adult healthy volunteers. Part 2 consisted of 20 adult patients with 
type 1 diabetes using a crossover design with IM administration of 0.7 mg dasiglucagon. 
GlucaGen® 1.0 mg was used as a comparator in both parts of the trial. 
ZP4207-15007 was a phase 1 randomized, placebo-controlled, double-blind, multiple-dose trial 
designed to evaluate the PK, PD, safety, and tolerability of repeated doses of dasiglucagon SC in 
24 healthy adult volunteers. The trial included 3 dose cohorts of 8 healthy volunteers each. In 
each cohort, patients were randomly assigned in a 3:1 ratio to receive 5 repeated daily doses of 
0.1, 0.3, and 1.0 mg dasiglucagon (n=6) or placebo (n=2). 
After the 2 phase 1 trials were completed, the composition of the dasiglucagon formulation was 
optimized with respect to its excipients (buffer, tonicity adjusting agent, and stabilizer). The PK 
and PD properties, safety, and tolerability of the optimized formulation were evaluated in the 
phase 2 trial. 
ZP4207-15126 was a phase 2 randomized, double-blind, single-dose trial designed to evaluate 
the PK, PD, safety, and tolerability of a single SC dose of dasiglucagon in the optimized 
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formulation (0.1, 0.3, 0.6, and 1.0 mg) or GlucaGen® (0.5 and 1.0 mg) in 58 adult patients with 
type 1 diabetes. 
ZP4207-16051 was a phase 2 open-label, randomized, crossover trial designed to evaluate the 
feasibility of using dasiglucagon 1 mg/mL SC in conjunction with insulin in a pump setting 
using an iLet algorithm as part of an automated dual hormone pump delivery system in 
12 patients with type 1 diabetes. The primary objective was to evaluate the safety and tolerability 
of dasiglucagon compared to marketed glucagon (Lilly Glucagon™). The trial also aimed to 
demonstrate the functionality and accuracy of the iPhone-based bionic pancreas in a controlled, 
clinical setting. Patients were randomly assigned to two 1-day treatment arms: dasiglucagon or 
Lilly Glucagon™ in the iPhone-based bionic pancreas. 
ZP4207-16098 was a phase 2 randomized, crossover, double-blind trial designed to evaluate the 
safety, tolerability, PK, and PD of dasiglucagon in 23 patients with type 1 diabetes using a 
4 mg/mL formulation of dasiglucagon compared to an active comparator, Lilly Glucagon™. 
Overall, no safety concerns were observed for dasiglucagon at the doses investigated in these 
clinical trials. The most frequently reported adverse event (AE) in each trial was nausea, which is 
a known side effect after administration of glucagon, and appeared at a similar frequency to 
marketed glucagon, which was used as active comparator in some of the trials. No local 
tolerability issues were reported. Injection site reactions were observed only sporadically after 
administration with dasiglucagon, placebo, or marketed glucagon in trials with SC or IM 
administration, and all events were mild and transient. No treatment-induced or 
treatment-boosted anti-drug antibodies (ADAs) were noted in any of the trials, except for trial 
ZP4207-16098, in which 1 patient tested positive for both anti-dasiglucagon and anti-glucagon 
antibodies. Due to the crossover nature of this trial, the induction of ADAs could not be 
associated with a specific treatment. 
Dose-proportionality for dasiglucagon PK using the 1 mg/mL formulation was confirmed in the 
clinical trials, with doses ranging between 0.1 and 1.0 mg, characterized by a fast absorption 
with a peak plasma concentration obtained after 35 minutes. The median time to maximum 
concentration was later for dasiglucagon compared to marketed glucagon (GlucaGen®) 
(35 vs 20 minutes). In the phase 2 trial, doses of 0.3 mg dasiglucagon and 0.5 mg GlucaGen and 
also 0.6 mg dasiglucagon and 1.0 mg GlucaGen were similar with regard to maximum observed 
concentration (Cmax). The total exposure in terms of area under the concentration-time curve 
(AUC) from time zero to infinity (AUC0-inf) was consistently higher for dasiglucagon compared 
to GlucaGen. This was likely due to a higher bioavailability of dasiglucagon since nonclinical 
data consistently show that the bioavailability of dasiglucagon is higher compared to marketed 
glucagon formulations. For the 4 mg/mL formulation, dose-proportionality of dasiglucagon 
doses between 0.03 and 0.6 mg was indicated for AUC0-240min and AUC0-inf. Pharmacokinetic 
parameters were all similar for dasiglucagon administration under both euglycemic and 
hypoglycemic conditions. An approximately 30 to 40% greater exposure in terms of AUC0-inf 
and Cmax was observed with the 4 mg/mL formulation as compared with the 1 mg/mL 
formulation. 
In the phase 2 trial ZP4207-15126, all patients after insulin-induced hypoglycemia achieved a 
PG level of at least 70 mg/dL (3.9 mmol/L) at all dose levels of dasiglucagon, as well as an 
increase in PG by at least 20 mg/dL (1.1 mmol/L) within 30 minutes postdose. The PD responses 
of 0.3 mg of dasiglucagon and 0.5 mg of marketed glucagon (GlucaGen) were similar in the first 
30 minutes postdose, as were the PD responses of 0.6 mg of dasiglucagon and 1.0 mg of 
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GlucaGen. The PD response over the entire observation time (0-360 minutes) was significantly 
greater after dosing with dasiglucagon than with GlucaGen for all pre-specified dose 
comparisons. This was likely an effect of the higher total drug exposure (AUC0-inf) of 
dasiglucagon mentioned previously. 
No major differences in PD responses were observed between dasiglucagon doses under 
euglycemic or hypoglycemic conditions in phase 2 trial ZP4207-16098. Under euglycemic 
conditions, all patients achieved an increase in PG of at least 20 mg/dL (1.1 mmol/L) within 
30 minutes postdose with 0.08 mg dasiglucagon and above, while this target was reached only 
for 0.2 mg of marketed glucagon (Lilly Glucagon™). Under hypoglycemic conditions, 
dasiglucagon met the target at doses of 0.2 mg and above. The PD response over the entire 
observation time of 240 minutes was significantly higher with dasiglucagon than with Lilly 
Glucagon at the same doses. In the bionic pancreas feasibility trial ZP4207-16051, results 
demonstrated comparable autonomous glycemic control with dasiglucagon compared to Lilly 
Glucagon. This was despite the stressed conditions of the trial in terms of fasted patients being 
on up to twice their basal insulin rate to stimulate glucagon use during the 8-hour test, and 
inclusion of a structured exercise period. With dasiglucagon, patients obtained a glucose value 
within target (70-180 mg/dL [3.9-10.0 mmol/L]) 70.9% of the time vs 65.6% with Lilly 
Glucagon. 
6.3.4. 
Literature Data 
In a retrospective review of 223 cases of diffuse or focal CHI, glucagon was reported to be used 
in 55% of patients with diffuse CHI and in 31% of patients with focal CHI.10 In an observational 
trial of 55 newborns who received glucagon because of hypoglycemia after birth, applied doses 
were mainly in the range of 0.5 to 1.0 mg/day, and results indicated an increase in PG from a 
mean of 36.3 md/dL to a mean of 93.0 mg/dL, observed within 4 hours after the start of glucagon 
infusion.9 The frequency of hypoglycemic episodes was significantly reduced, and no further 
episodes of severe hypoglycemia were observed. 
The long-term use of glucagon in patients with CHI is limited by the instability of marketed 
glucagon after reconstitution. A literature review on the long-term medical treatment of CHI 
revealed that only 1% of 619 patients identified received glucagon as part of their medical 
management.6 A retrospective review of 9 children with CHI who received continuous SC 
infusion of glucagon for weeks or months showed that introduction of glucagon allowed the 
reduction or discontinuation of central glucose infusion in all patients.11 Six of 9 patients were 
discharged with continued glucagon therapy that their parents were able to continue without 
further symptomatic hypoglycemia, convulsions, or unconsciousness. In 3 children, glucagon 
therapy was continued for 1 to 4 years, which led to stable euglycemia.  
The data reported on marketed glucagon use in patients with CHI indicate that continuous SC 
infusion of a glucagon agonist could provide therapeutic benefit to patients by stabilizing PG 
levels and reducing the frequency of hypoglycemic episodes.5,6,9,10,11 
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6.3.5. 
Anticipated Medical Benefit of Dasiglucagon in the Treatment of CHI 
With its physio-chemical stability in liquid formulation, dasiglucagon could provide significant 
added benefit in the treatment of CHI relative to currently marketed glucagon by enabling 
long-term reliable IV infusion to control blood glucose. Long-term subcutaneous infusion of 
dasiglucagon through a pump may be an attractive alternative or addition to diazoxide and 
octreotide, as it may reduce the dependency on intensive nutritional support whilst maintaining 
euglycemia by harnessing physiological mechanisms for combating hypoglycemia. It is 
anticipated that reduced need for frequent tube feedings or continuous gastric infusion of 
nutrients, and increased fasting tolerance will be demonstrated, together with improvements in 
the quality of life of the patients and their families/caregivers. If long-term euglycemia is 
achieved with medical therapy, pancreatectomy for the treatment of diffuse CHI could eventually 
be avoided, or at least postponed beyond the neonatal or very young infant period. In one cohort 
of non-surgically treated children, the mean clinical remission rate was 5 (1.5-12) years for 
diffuse CHI.5 This suggests that a significant proportion of infants with CHI could avoid surgery 
if medical treatment allowed for the effective long-term control of hyperinsulinism. 
6.3.6. 
Anticipated Risks of Dasiglucagon in the Treatment of CHI 
In clinical trials with dasiglucagon conducted up to now, the most frequent treatment-related AEs 
were nausea and vomiting, followed by headache. 
Glucagon exerts positive inotropic and chronotropic effects and may, therefore, cause 
tachycardia and hypertension. Transient increases in heart rate have been observed in clinical 
trials with dasiglucagon, but not hypertension. On the contrary, several episodes of hypotension 
have been noted in the clinical program.  
Accidental overdose may occur due to inappropriate handling of the infusion pump or due to 
pump malfunction. Overdose may result in nausea, vomiting, inhibition of GI tract motility, 
short-term increase in heart rate or blood pressure, and/or hypokalemia. Symptomatic care for 
nausea and vomiting, as well as monitoring of heart rate, blood pressure, and hypokalemia, is 
advised.  
Injection site reactions are observed with many injectable peptides. In the phase 1 and 2 clinical 
trials, injection site reactions occurred with a low frequency in all treatment groups 
(dasiglucagon and marketed glucagons), irrespective of dose.  
Overall, the clinical trial data indicate that dasiglucagon has a low risk for induction of ADAs. 
Out of more than 350 doses of dasiglucagon administered to more than 200 patients, only 
1 low-titer transient ADA incident has been reported to date, in a patient after administration of 
11 SC doses of dasiglucagon or Lilly Glucagon ranging from 0.03 to 0.6 mg, with low binding 
and low in vitro neutralizing capability. No apparent clinical effects on PK, PD, or AEs were 
noted. Due to the crossover trial design, the ADA induction could not be ascribed to a specific 
treatment. Based on the current clinical experience and the product characteristics, the risk of 
dasiglucagon inducing an ADA response is considered low. 
Administration of glucagon or dasiglucagon may be associated with a risk of allergic reactions 
similar to those observed for other therapeutic peptides or proteins.  
Data on the risks of chronic administration of dasiglucagon are not available. From sporadic 
reports of extended SC/IV infusion of marketed glucagon and in glucagonoma patients,14 
sustained exposure to high levels of glucagon may lead to development of skin condition 
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necrolytic migratory erythema (NME), a highly specific migrating, erythematous rash with 
predilection for perioral, perianal, and lower leg distribution.11 
For further information on risks, please refer to the current version of the investigator’s brochure 
(IB). 
6.3.7. 
Summary of Potential Benefits and Risks 
As with all treatment interventions, the anticipated benefits to trial patients should be balanced 
against the potential risks. The accumulated experience from nonclinical studies and clinical 
trials with dasiglucagon supports that dasiglucagon is a specific glucagon receptor agonist and is 
well tolerated. Glucagon and its analogs belong to a well-known drug class with known mode of 
action. The clinical investigators involved in the trial will all have had experience with use of 
glucagon in patients with CHI.  
The investigator will inform the patients/parents of the potential risks of dasiglucagon treatment 
and other trial-related procedures before they enter the trial. The investigator must become familiar 
with all sections of the dasiglucagon IB before the start of the trial. 
In summary, with its marked improvements in stability in solution and solubility in aqueous 
media compared to currently marketed glucagon products, dasiglucagon is expected to have 
significant clinical benefits in the treatment of CHI and to substantially reduce the disease burden 
in these patients. This includes enabling convenient and reliable long-term treatment via a pump 
device in a home setting, which holds the potential to delay and ultimately avoid pancreatectomy 
and its related exo/endocrine complications, particularly the development of insulin-dependent 
diabetes. 
Dasiglucagon may overall provide significant added benefit in the treatment of CHI relative to 
currently marketed glucagon products by enabling long-term reliable SC infusion to control PG. 
The proposed trial population is still experiencing hypoglycemia despite medical treatments 
being escalated to the highest therapeutically permissible or tolerated doses, or despite having 
undergone subtotal pancreatectomy. Therefore, these patients are dependent on continuous or 
very frequent delivery of carbohydrates, often through invasive routes (NG tube or gastrostomy). 
This limits their ability to lead normal lives, including participating in everyday activities, and 
therefore, impacts their development. For this trial population, the major and clinically relevant 
benefit is the expected reduction in number and volume of nutritional interventions while 
avoiding hypoglycemia. The reduced volume of nutritional interventions should limit the risk of 
volume overload, especially in patients treated with significant doses of diazoxide. Achievement 
of euglycemia could lead to reduction of other CHI medication, further limiting the potential for 
adverse events associated with those treatments. In addition, the need for pancreatectomy, or 
re-surgery in those who already underwent pancreatic surgery is reduced and potentially 
eliminated.  
Overall, the benefit to risk ratio for patients entering the ZP4207-17109 trial is considered 
acceptable.  
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7. OBJECTIVES AND ENDPOINTS 
7.1. Objectives 
7.1.1. 
Primary Objective 
To evaluate the efficacy of dasiglucagon administered as subcutaneous (SC) infusion in reducing 
hypoglycemia in children with CHI. 
7.1.2. 
Secondary Objectives 
Secondary objectives are: 
• To evaluate the safety and tolerability of dasiglucagon administered as an SC infusion in 
children with CHI 
• To evaluate the efficacy of dasiglucagon in reducing glucose requirements 
• To investigate quality of life and resource utilization 
7.2. Endpoints 
7.2.1. 
Primary Endpoint 
Treatment Period 1 
• Hypoglycemia event rate, defined as average weekly number of hypoglycemic events 
(PG <70 mg/dL or 3.9 mmol/L) during Weeks 2-4, as detected by self-monitored PG 
(SMPG). 
7.2.2. 
Key Secondary Efficacy Endpoints 
Treatment Period 1 
• Increase in fasting tolerance (time from beginning of meal to the beginning of the first 
continuous 15-minute continuous glucose monitoring [CGM] reading <70 mg/dL 
[3.9 mmol/L]). 
• CGM percent time in range 70-180 mg/dL (3.9-10.0 mmol/L) during Weeks 2-4. 
• Clinically significant hypoglycemia event rates, defined as average weekly number of events 
<54 mg/dL (3.0 mmol/L), as detected by SMPG during Weeks 2-4.  
7.2.3. 
Secondary Efficacy Endpoints 
Treatment Period 1 
• Total amount of gastric carbohydrates administered (via nasogastric [NG] tube or 
gastrostomy) per week to treat hypoglycemia during Weeks 2-4.  
• Rate of gastric carbohydrate administrations (NG tube or gastrostomy) per week to treat 
hypoglycemia during Weeks 2-4.  
• Extent of hypoglycemia (area over the glucose curve [AOCglucose] below 70 mg/dL 
[3.9 mmol/L]) as measured by CGM during Weeks 2-4.  
• Extent of hypoglycemia (area over the glucose curve [AOCglucose] below 54 mg/dL 
[3.0 mmol/L]) as measured by CGM during Weeks 2-4.  
• Amount of nightly (midnight to 6 am) gastric carbohydrates administered (NG tube or 
gastrostomy) per week during Weeks 2-4. 
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• Total amount of gastric carbohydrates administered (NG tube or gastrostomy) per week 
during Weeks 2-4. 
• CGM percent time in hypoglycemia (<70 mg/dL or 3.9 mmol/L) during Weeks 2-4. 
• Rate of hypoglycemic episodes, defined as number of episodes <70 mg/dL (3.9 mmol/L) for 
15 minutes or more per week, as measured by CGM during Weeks 2-4. 
Treatment Period 2 
• 
CGM percent time in hypoglycemia (<70 mg/dL or 3.9 mmol/L) during Weeks 6-8.  
• Rate of weekly number of gastric carbohydrate administrations (NG tube or gastrostomy) per 
week to treat hypoglycemia during Weeks 6-8.  
• Rate of hypoglycemic events, defined as number of episodes (PG <70 mg/dL or 3.9 mmol/L) 
per week during Weeks 6-8, as detected by SMPG. 
• Rate of clinically significant hypoglycemia episodes, defined as number of episodes 
<54 mg/dL (3.0 mmol/L) for 15 minutes or more per week, as measured by CGM during 
Weeks 6-8.  
7.2.4. 
Other Efficacy Endpoints 
• Number of IV glucose infusions to treat hypoglycemia per week during Weeks 2-4 of 
Treatment Period 1. 
• Emergency department visits for hypoglycemia. 
• Number and length of hospitalizations due to CHI or CHI-related events. 
• Number of out-patient visits to health care providers (family doctors, specialist, etc.) caused 
by CHI or CHI-related events. 
• Number of home visits by paramedics due to hypoglycemia. 
• Quality of life endpoints (PedsQL™ [Total Scale Score, Physical Health Summary Score, 
and Psychosocial Health Summary Score] and CHI-specific questionnaire). 
• Rate of SMPG readings per week during Weeks 2-4 of Treatment Period 1. 
7.2.5. 
Safety Endpoints 
• Adverse events 
• Changes in clinical evaluations: 
• 
Vital signs 
• 
Physical examination 
• 
12-lead ECG 
• Changes for clinical laboratory assessments: 
• 
Hematology 
• 
Biochemistry 
• 
ADAs 
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8. TRIAL DESIGN 
8.1. Overall Trial Design and Plan 
This is a 2-period, open-label trial to evaluate the efficacy and safety of dasiglucagon in children 
between the ages of 3 months and 12 years (both inclusive) with CHI. To qualify for 
participation, patients must be experiencing ≥3 events of hypoglycemia per week despite 
standard of care (SOC) medications. The determination of hypoglycemia frequency at trial entry 
is according to investigator’s evaluation. Furthermore, patients are to have previously undergone 
sub-total pancreatectomy for CHI or be treated with a non-surgical approach, having been 
evaluated as not eligible for pancreatic surgery.  
The primary objective of this trial is to evaluate whether dasiglucagon can reduce the number 
and severity of hypoglycemic episodes in the investigated population.  
After screening and eligibility assessments, patients will complete a 2-week CGM period to 
establish plasma glucose baseline. Thereafter, patients will be randomly assigned in a 1:1 ratio to 
continue receiving SOC alone, or SOC plus dasiglucagon for 4 weeks. In Treatment Period 2, all 
patients will receive SOC plus dasiglucagon for 4 weeks (see Figure 1). 
At the beginning of Treatment Period 1 (Week 1), all patients will be hospitalized for 1-2 days. 
Patients assigned to SOC plus dasiglucagon treatment will have dasiglucagon infusion initiated 
and titrated, and will be trained and supervised in the use of the infusion pump, CGM sensor, and 
glucose meter. Patients assigned to SOC alone will receive a similar degree of supervision 
alongside the training in the use of the CGM sensor and glucose meter. This period can be 
extended for both treatment groups if dasiglucagon titration has not been finalized or if training 
of the family/caregivers has not been completed satisfactorily.  
Patients originally assigned to receive SOC alone in Treatment Period 1 will also be hospitalized 
for the first 1 to 2 days of Treatment Period 2 (Week 5), and will have dasiglucagon infusion 
initiated and titrated, and will be trained in the use of the infusion pump. This period can be 
extended if dasiglucagon titration or pump training has not been completed. Regardless of 
whether dasiglucagon is initiated during Treatment Period 1 or 2, SOC CHI medications should 
subsequently be kept constant throughout the trial. Adjustments to gastric and oral feeds are 
permitted. 
Patients’ parent(s)/guardian will be trained to perform PG assessments. Events of hypoglycemia 
will be documented by SMPG measurements. The extent of hypoglycemia (episodes and percent 
time below the threshold) will be further quantified by CGM measurements during the 2 weeks 
before randomization (baseline), Weeks 2-4 in Treatment Period 1, and Weeks 6-8 of Treatment 
Period 2. The CGM results will be masked. During the period where the masked trial CGM is 
used, patients are not allowed to use another un-masked CGM. 
Patients completing the trial will (pending investigator confirmation of continued positive 
benefit-risk balance) be offered to enter a long-term extension trial (Trial ZP4207-17106) to 
continue dasiglucagon treatment. Patients who do not continue in the long-term extension trial 
will have a Follow-up visit performed 4 weeks after stopping dasiglucagon treatment. 
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Figure 1 
Trial Design 
8.2. Discussion of Trial Design 
Several sites across multiple geographical regions will be included to ensure results 
representative of the target CHI population.  
A parallel design was chosen rather than a crossover design to avoid the risk of any carry-over 
effect and to limit the total treatment period for the patients included. 
An open-label trial design was chosen because the added burden of a blinded trial design was not 
considered ethically justified. 
8.3. Trial Sites 
This trial will take place at up to 14 sites in the United States and Europe that are experienced in 
the treatment of CHI. A total of up to 32 patients with CHI will be randomized. 
8.4. Point of Contact 
A point of contact will be identified to provide information to each patient’s parent(s)/guardian 
about where to obtain information on the trial, the patient’s rights, and whom to contact in case 
of trial-related injury. This information will be provided in the patient information and informed 
consent form (ICF). 
Week from first treatment
Period
Screening
Treatment Period 1
Treatment Period 2
Follow-up
-4
0
4
8
12
16 children
16 children
1:1 randomization
Standard of Care
Dasiglucagon +
Standard of Care
Dasiglucagon +
Standard of Care
Dasiglucagon +
Standard of Care
Standard of Care or to
Long-term extension trial
Dasiglucagon + Standard of Care
Standard of Care
Screening or Follow-up
0 
--
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9. PATIENT POPULATION 
9.1. Selection of Trial Population 
A screening log of potential trial candidates must be maintained at each trial site. 
9.2. Trial Entry Criteria 
9.2.1. 
Inclusion Criteria 
A patient will be eligible for trial participation if he or she meets all of the following criteria: 
1. Established and documented diagnosis of CHI based on standard of care. 
2. Male or female between 3 months and 12 years of age (both inclusive) at screening  
3. Has a negative serum pregnancy test at screening/baseline (only for girls of childbearing 
potential) 
4. Sexually active female patients (and their partners) must continue to use acceptable 
contraception or refrain from sexual activity from screening until 30 days after the last dose 
of trial drug. Females must abstain from sexual activity that could result in pregnancy or 
agree to use acceptable methods of contraception. Abstinence can only be accepted if this is 
true abstinence in line with the preferred and usual lifestyle of the patient. 
Acceptable methods of contraception are: 
a) Hormonal contraceptives (e.g., oral contraceptive pill, depot, patch, intramuscular 
implant or injection, sponge, or vaginal ring), stabilized for at least 30 days if first use 
or 
b) Barrier method, e.g., (i) condom (male or female) and (ii) diaphragm with spermicide 
Germany: Only highly effective methods of birth control are accepted (i.e., one that results 
in less than 1% per year failure rate when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, some intrauterine device), or sexual abstinence. 
5. Experiencing ≥3 events of hypoglycemia per week (PG <70 mg/dL [<3.9 mmol/L]) 
according to the investigator’s evaluation 
6. Following receipt of oral and written information about the trial, the patient (depending on 
local IRB/IEC requirements) must provide assent and one or both parents* or guardians of 
the patient must provide signed informed consent before any trial-related activity is carried 
out 
France, Germany, Israel: The consent must correspond to the patient’s presumed will where 
such a will can be ascertained. 
7. Previously undergone near-total pancreatectomy or being treated with a non-surgical 
approach, having been evaluated as not eligible for pancreatic surgery 
8. If somatostatin analogues or sirolimus are used, the therapy should be well established as 
judged by the investigator, especially when considering their biological half-life 
* If required by local regulations, both parents must give their permission unless one parent is 
deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal 
responsibility for the care and custody of the child. 
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9.2.2. 
Exclusion Criteria 
A patient will be excluded from the trial if he or she meets any of the following criteria: 
1. Previous administration of dasiglucagon (previously referred to as ZP4207) 
2. Known or suspected allergy to the trial drug or related products 
3. Previous participation (randomization) in this trial 
4. Circulatory instability requiring supportive medication or presence of pheochromocytoma 
United Kingdom: Presence of hypertension or hypotension, including circulatory instability 
requiring supportive medication or presence of pheochromocytoma 
5. Requires exogenous insulin 
6. Body weight of <4 kg (8.8 lbs.) 
7. Documented HbA1c ≥7% subsequent to near-total pancreatectomy and within 6 months prior 
to screening 
8. Known or suspected presence of significant central nervous system disease/injury such that 
in the investigator’s opinion will affect trial participation 
9. Use of systemic corticosteroids, e.g., hydrocortisone >20 mg/mg/m2 body surface area or 
equivalent in the 5 days before screening 
10. Use of anti-inflammatory biological agents, or other immune-modulating agents in the 
3 months prior to screening 
11. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 X the upper limit 
of normal (ULN), or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 
adjusted by a pediatric formula (e.g., Schwartz formula) 
12. Any clinically significant abnormality identified on echocardiogram that in the opinion of the 
investigator would affect the patient’s ability to participate in the trial 
13. History of laboratory test results obtained before screening that show presence of HIV, 
hepatitis B surface antigen, hepatitis C antibody, or hepatitis A immunoglobulin M 
14. Any recognized clotting or bleeding disorders. 
15. Has participated in an interventional clinical trial (investigational or marketed product) 
within 3 months of screening or 5 half-lives of the drug under investigation (whichever 
comes first), or plans to participate in another clinical trial. 
16. The use of prescription or non-prescription medications known to cause QT prolongation.  
9.2.3. 
Randomization Exclusion Criteria 
1. Use of glucagon within 24 hours before randomization 
2. Significant changes to CHI medications during screening 
3. An average of <3 events per week of hypoglycemia, as recorded in the diary during the 
2 weeks prior to randomization  
The Randomization Visit may be rescheduled if randomization Exclusion Criterion 1 is met. 
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9.3. Premature Patient Withdrawal  
Patients’ parent(s)/guardian will be advised that they are free to withdraw their children from 
participation in this trial at any time, for any reason, and without prejudice. Every reasonable 
attempt should be made by the investigator to keep patients in the trial. However, patients must 
be withdrawn from the trial if their parent(s)/guardian withdraw consent to participate.  
Investigators must attempt to contact patients’ parent(s)/guardian who fail to attend scheduled 
visits by telephone or other means to exclude the possibility of an AE being the cause of 
withdrawal. Attempts to contact the patient must be documented. At least 3 phone calls and 
3 written attempts to contact the patient will be made prior to considering them lost to follow-up. 
Should an AE be the cause of withdrawal, the AE must be documented, reported, and followed 
as described in Section 12.2. 
If a patient/parent(s)/guardian withdraws consent, the reason for withdrawal and the date of 
withdrawal will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion 
of the trial should be performed at the time of premature withdrawal.  
9.4. Treatment Discontinuation 
To prevent missing data, patients should, to the extent possible, be kept in the trial; therefore, 
treatment discontinuation is often the preferred option in case of e.g., substantial noncompliance 
with trial procedures or initiation of prohibited treatment that interferes with the efficacy and 
safety evaluation. If it is an investigator’s decision to discontinue the patient’s treatment, the 
investigator should, whenever possible, discuss the potential discontinuation of the treatment 
with the medical monitor. If the patient is discontinued from trial treatment by the investigator, 
or withdraws consent for trial treatment the reason for treatment discontinuation and the date of 
treatment discontinuation will be recorded on the appropriate page of the eCRF. The patient 
should be asked to continue in the trial by following the planned visit schedule. At a minimum 
the patient will be asked to attend the Follow-up Visit 28 days (± 3 days) after discontinuation of 
trial treatment. 
9.5. Patient Replacement Criteria 
Patients who withdraw from the trial prematurely will not be replaced. If a substantial number of 
patients withdraw prematurely, the sponsor will evaluate the need for developing replacement 
criteria. 
Enrolled patients who subsequently withdraw from the trial may not re-enter. The patient number 
for a withdrawn patient will not be reassigned to another patient. 
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10. TREATMENTS 
10.1. Identification of Investigational Product 
Dasiglucagon injection 4 mg/mL will be supplied by the sponsor in a 3 mL vial containing 1 mL. 
Dasiglucagon will be provided in the form of solution for injection for subcutaneous 
administration through an infusion pump. 
The trial drug product must be transferred from the vial to an Accu-Chek® Spirit Cartridge. The 
amount of test product dosed via the pump will vary among patients. 
Cartridges and infusion sets should be replaced as indicated in the instructions for use. 
10.1.1. Packaging and Labeling 
The trial drug product will be packaged and labeled by the sponsor.  
Dispensing unit configuration: 6 vials containing dasiglucagon, 4 mg/mL, packaged in an outer 
carton. The vial and carton will be packaged and labeled in local language indicating the content 
(open label). 
Detailed information on all labels will be in the local language.  
Storage conditions for the trial drug product will be described on the trial drug product label. The 
labels will supply no information about the patients. Each treatment unit (containing 6 vials) 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) Good 
Clinical Practice (GCP) guidelines, local laws, and regulations. 
10.2. Treatments Administered 
In Treatment Period 1, patients will receive SOC only or SOC plus dasiglucagon for 4 weeks 
based on their treatment assignment. In Treatment Period 2, all patients will receive SOC plus 
dasiglucagon for 4 weeks.  
Dosing of dasiglucagon will approximate continuous infusion by delivering small doses at 
frequent intervals via the infusion pump. 
The pump administers 0.000025 mL/dose ~ 0.1 µg/dose (4 mg/mL formulation): 
• 10 µg/hour ~ 0.5 µg every 3 min 
• 20 µg/hour ~ 1 µg every 3 min 
• 30 µg/hour ~ 1.5 µg every 3 min 
• 40 µg/hour ~ 2 µg every 3 min 
• 50 µg/hour ~ 2.5 µg every 3 min 
• 60 µg/hour ~ 3 µg every 3 min 
• 70 µg/hour ~ 3.5 µg every 3 min 
Plasma glucose assessments will be performed regularly (at least 3 times daily, preferably before 
main meals, and as instructed by the investigator) throughout the trial to guide adjustments to the 
gastric dextrose infusion and/or trial drug product upon the investigator’s discretion.  
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Dasiglucagon treatment will be initiated at 10 µg/hr (t=0). Every 2 hours (t=2, 4, 6, etc.), the 
dose will be increased by an additional 10 µg/hr until either: 
1) The patient is weaned off entirely from gastric dextrose infusion and/or glucose-fortified 
feeds, or 
2) Plasma glucose during the last 2 hours was consistently above 120 mg/dL (6.7 mmol/L), or 
3) The maximum trial drug product infusion rate of 70 µg/hr is reached, or 
4) Adverse events emerge that are considered to be related to dasiglucagon (e.g., nausea and 
vomiting) and limit further dose escalation 
The dose of dasiglucagon should not be escalated beyond reaching the treatment objectives of 
PG in the range of 70-120 mg/dL (3.9-6.7 mmol/L) while approaching a normal feeding regimen 
according to age.  
The 2-hour dose-adjustment interval will allow plasma drug levels to approach approximately 
steady-state before the dose is further increased. The maximum dose of trial drug product that 
can be administered over the first 24 hours is shown in Table 1. The maximum cumulative dose 
over the first 24 hours is 1.26 mg. 
After the first 24 hours, the dose of dasiglucagon can still be modified to optimize each patient’s 
treatment and to reduce gastric dextrose infusions. The maximum dose of dasiglucagon will be 
70 µg/hr, corresponding to a maximum of 1.68 mg per day.  
Details on the administration instructions and guidelines for preparation and handling of the trial 
drug product are in the pharmacy manual. 
Table 1 Initial 24-hour Maximum Dose of Dasiglucagon 
 
Patients who complete this trial will be offered to enter a long-term extension trial 
(Trial ZP4207-17106) to continue dasiglucagon treatment (pending investigator confirmation of 
continued positive benefit-risk balance). Patients who do not continue in the long-term extension 
trial will have a Follow-up visit performed 4 weeks after stopping dasiglucagon treatment. 
Time (hours) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Dose (µg) 
10 
10 
20 
20 
30 
30 
40 
40 
50 
50 
60 
60 
Cumulative 
dose (µg) 
10 
20 
40 
60 
90 
120 
160 
200 
250 
300 
360 
420 
 
 
Time (hours) 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
Dose (µg) 
70 
70 
70 
70 
70 
70 
70 
70 
70 
70 
70 
70 
Cumulative 
dose (µg) 
490 
560 
630 
700 
770 
840 
910 
980 
1050 
1120 
1190 
1260 
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10.3. Trial Supplies 
The device and ancillaries listed in the following table will be supplied by the sponsor 
throughout the trial. Trained trial personnel will train parent(s)/guardians on the use of the 
infusion pump, the PG meter and CGM. 
Instructions for the use of all these supplies will be provided in a separate manual. 
Item 
Name 
Manufacturer 
Pump 
Accu-Chek Spirit Combo 
Hoffman-La Roche AG, Basel, 
Switzerland 
Cartridge 
Accu-Chek Spirit 3.15 mL Cartridge system 
Hoffman-La Roche AG, Basel, 
Switzerland 
Infusion sets 
Accu-Chek FlexLink Infusion set (Accu-Check 
UltraFlex Infusion set in US) 
and 
Accu-Chek Rapid-D Link Infusion set 
Hoffman-La Roche AG, Basel, 
Switzerland 
Infusion set 
inserter 
Accu-Chek LinkAssist Insertion device (can be used 
with FlexLink & UltraFlex) 
Hoffman-La Roche AG, Basel, 
Switzerland 
PG monitoring 
StatStrip Xpress2 
Nova Biomedical, Waltham, MA, 
USA 
CGM 
Dexcom G4 
Dexcom Inc., San Diego, CA, USA 
The infusion pump system is CE marked for the management of diabetes mellitus in persons 
requiring insulin, as prescribed by a physician. In this trial, the pump system is used outside of 
the CE-marked intended use since the pump system will be delivering dasiglucagon to patients 
with CHI. The PG meter is used as intended according to the CE mark, except for the use by a 
lay person in a home care setting. The CGM is used as intended according to the CE mark, 
except for the age group and the disease. 
The pump device will be packaged and labeled for use in investigational trials and will contain a 
unique device number. For more information on the devices please refer to Section 20. 
10.4. Dispensing and Storage 
Trial drug product supplied by the sponsor is to be dispensed exclusively for patients enrolled in 
this clinical trial according to the instructions of this protocol and the pharmacy manual. The 
investigator is responsible for dispensing the trial drug product according to the dosage scheme.  
Trial drug product will be allocated using an interactive web response system (IWRS) that has 
been validated for the intended use under the International Society of Pharmaceutical Engineers 
(ISPE) GAMP guidelines, 21CFR Part 11 (FDA regulation for Electronic Records and Electronic 
Signatures), and the ICH Guidance E6 for Industry on Good Clinical Practice.   
Dasiglucagon injection 4 mg/mL must be stored at 2–8°C in a refrigerator. 
The investigator must ensure the availability of proper storage conditions. All trial drug products 
provided for this trial will be stored at the trial site in a secure area with restricted access.  
The temperature should be monitored by recording the actual, minimum, and maximum 
temperatures using a calibrated thermometer or thermocouple, or by continuous recording using 
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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 (ISF) upon trial termination. 
The investigator must contact the clinical research associate (CRA) in case of temperature 
deviations outside the acceptable range.  
Please refer to the pharmacy manual for additional information on handling of the trial drug. 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the trial drug product including the date, quantity, batch or code number, and 
identification of patients (patient number) who received the trial drug. The investigator will not 
supply the trial drug product to any person except subinvestigators, designated trial personnel, 
and patients in this trial. The trial drug product may not be relabeled or reassigned for use by 
other patients. If any of the trial drug product is not dispensed, is lost, stolen, spilled, unusable, 
or is received in a damaged container, this information must be documented and reported to the 
sponsor and the appropriate regulatory agencies as required. 
10.5. Method of Assigning Patients to Treatment Groups 
In Treatment Period 1, patients will be randomly assigned in a 1:1 ratio to receive either SOC 
only or SOC plus dasiglucagon for 4 weeks using a block randomization scheme stratified by 
region US/non-US). In Treatment Period 2, all patients will receive SOC plus dasiglucagon for 
4 weeks. The stratification by region addresses the difference in practice of treatment for CHI, 
especially the prominent difference in frequency of sub-total pancreatectomy for diffuse CHI 
between US/non-US. 
10.6. Blinding and Unblinding Treatment Assignment 
This is an open-label trial. During parts of Screening, Treatment Period 1, and Treatment 
Period 2, patients will have CGM performed but the results will be masked. 
10.7. Selection of Doses in the Trial 
Both the starting dose and the maximum allowed doses are based on experience with marketed 
glucagon products in this patient population.11  
At present, no pediatric PK data are available for dasiglucagon. However, an approximate 
estimation of expected drug concentration in a 3 kg patient has been made by extrapolation of a 
previously made PK model for pediatric patients with weights between 25 and 45 kg.15  
The predicted plasma concentration is expected to give a low PD response at the lowest dose 
level and be above maximum effect at the highest dose level. The maximum expected plasma 
concentrations of dasiglucagon is in the range of what is achieved following a rescue dose to 
adults. The doses of dasiglucagon will be titrated to meet the needs of the individual patient. The 
titration will stop when no additional PD effects are observed as the infusion rate is increased. 
The infusion rate of dasiglucagon will be monitored and adjusted to meet the needs of the 
individual patient throughout the trial period. 
Since the dasiglucagon dose is titrated individually based on the desired PD response, it does not 
need to be related to any measure of the patient’s size. 
The titration interval of 2 hours was chosen based on the PK data of dasiglucagon showing that 
an approximate steady-state is expected after 2 hours. 
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10.8. Selection of Timing of Dose for Each Patient 
Dosing details are presented in Section 10.2. 
10.9. Dose Adjustment Criteria 
Dose adjustment criteria are presented in Section 10.2. 
10.10. 
Treatment Compliance 
Compliance data will be collected. Infusion details will be recorded in the patient’s eCRF by trial 
personnel and drug accountability will be performed as detailed in the pharmacy manual. 
10.11. 
Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
Caution is advised when beta-blockers, indomethacin, anticholinergic drugs, and warfarin are 
prescribed, due to reports of interaction with marketed glucagon products. 
10.11.1. Permitted Therapies 
Concomitant CHI treatments (e.g., somatostatin analogs) that were initiated prior to trial entry 
are permitted throughout the trial. Somatostatin analogs may also be added throughout the trial at 
the investigator’s discretion if the maximum dose level of dasiglucagon (70 µg/hr) has been 
reached or if further titration is not possible due to undesirable side effects.  
Other CHI-specific treatments either prior to trial initiation or added during the trial need to be 
discussed with the medical monitor. 
10.11.2. Prohibited Therapies 
The following therapies are prohibited during the trial: 
• Systemic corticosteroids, e.g., hydrocortisone >20 mg/mg/m2 body surface area or equivalent 
from 5 days before screening and onwards 
• Anti-inflammatory biological agents, or other immune-modulating agents in the 3 months 
prior to screening (except for sirolimus/mTOR inhibitors, as discussed in Section 10.11.1) 
• Exogenous insulin 
• Use of paracetamol/acetaminophen is strongly discouraged for the duration of trial because it 
interferes with CGM accuracy. Parent(s)/guardians should contact the trial site before dosing 
their child with paracetamol/acetaminophen. Both the site staff and the parent(s)/guardians 
should explore other options for treating fever and mild pain before deciding that 
paracetamol/acetaminophen is needed.  
• Other investigational agent 
• Marketed glucagon products within the last 24 hours prior to randomization and throughout 
the trial unless necessary for rescue therapy in case of severe hypoglycemia, as per local SOC 
• Prescription or non-prescription medications known to cause QT prolongation 
Continuation in the trial after the patient has received excluded therapies will be at the 
investigator’s discretion after consultation with the medical monitor. 
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10.12. 
Patients May be Discharged for Home Treatment 
Before discharge of patients from hospital care, the investigator will ensure: 
• Appropriate training of patient’s parent(s)/guardians in the use of dasiglucagon in the Accu-
Chek Spirit Combo pump based on the training material provided. The first pump infusion 
set change should be performed at the hospital 
• Parent(s)/guardian are trained appropriately on the handling of the CGM device 
• Parent(s)/guardian are trained appropriately on how to perform SMPG measurements and 
how to complete the diary. They will check their child’s SMPG at least 3 times daily 
(preferably before main meals) and in case of suspected hypoglycemia 
• Parent(s)/guardian are instructed not to change the dose of trial drug without prior 
consultation with the investigator  
• Parent(s)/guardian are instructed how to recognize and handle signs of hypoglycemia 
• Parent(s)/guardian are instructed to call the investigator/site staff in case of questions  
Patients who are discharged from the hospital will be contacted by the investigator by telephone 
the day after discharge. The investigator will ask the parent(s)/guardian if they have any 
questions about the trial procedures and if their child has experienced any AEs. 
10.13. 
Treatment After End of Trial 
After completing both treatment periods, patients may be eligible to continue in a long-term 
extension trial (Trial ZP4207-17106) (see Section 10.2). Patients who do not continue in the 
long-term extension trial will not be offered further treatment with dasiglucagon. 
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11. TRIAL PROCEDURES 
Patients’ parents/guardians (according to local law) must provide written informed consent 
before any trial-related procedures are initiated, including the cessation of prohibited 
concomitant therapy. 
France, Germany, Israel: The consent must correspond to the patient’s presumed will where 
such a will can be ascertained. Depending on local IRB/IEC requirements the patient should 
also provide assent before any trial-related procedures are initiated. 
For the timing of assessments and procedures throughout the trial, refer to the Schedule of 
Events (Section 18.1). Throughout the trial, trial personnel should make every reasonable effort 
to follow the timing of assessments and procedures in Section 18.1 for each patient. If a patient 
misses a trial visit for any reason, it should be rescheduled as soon as possible. 
11.1. Trial Duration 
The overall trial duration is expected to be 15 months. 
The sequence and maximum duration of the trial periods will be as follows: 
1. Screening: at least 14 days up to 28 days 
2. Treatment Period 1: 4 weeks 
3. Treatment Period 2: 4 weeks 
4. Follow-up Period: 4 weeks 
The maximum trial duration for each patient is approximately 16 weeks. The dasiglucagon 
treatment duration for each patient is 4 or 8 weeks. 
11.2. Assessments 
Quality of life should be the first assessments performed at each visit according to the Schedule 
of Events (Section 18.1). 
11.2.1. Efficacy 
11.2.1.1. Plasma Glucose Monitoring 
During the trial, SMPG assessments (StatStrip Xpress2) will be performed regularly (at least 
3 times daily, preferably before meals, as instructed by the investigator) to evaluate efficacy.  
At each visit, the investigator will ensure that SMPG data are downloaded from the patient’s 
devices. The investigator will check for patient compliance in number of daily SMPG 
measurements and that hypoglycemic episodes are recorded in the diary. The procedure for 
download of SMPG data will be described in the pharmacy manual.  
11.2.1.2.  Continuous Glucose Monitoring 
Additionally, CGM will be used (Dexcom G4) in a blinded manner to evaluate efficacy in terms 
of hypoglycemic episodes. The CGM will be supplied for use throughout the trial, and 
continuous glucose monitoring is required for the 2 weeks up to randomization, during Week 2-4 
of Treatment Period 1, and during Week 6-8 of Treatment Period 2. Short pauses of 1-3 days due 
to skin irritation or discomfort are allowed after consultation with the investigator. 
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At each visit, the investigator will ensure that CGM data are downloaded from the patient’s 
devices. The procedure for download of CGM data will be described in the pharmacy manual. 
Dexcom G4 CGMs configured and labeled for use in this trial will be provided. Each CGM 
device should be calibrated and used according to the manufacturer’s instructions. 
The contract research organization (CRO) or delegate will handle device sourcing, configuration 
for use in the trial, procedures for blinded data extraction, device service, and return handling. 
11.2.1.3. Quality of Life 
Quality of life (Appendix B) will be assessed using the PedsQL and additional CHI 
disease-specific QoL questions (parent-reported versions) according to the Schedule of Events 
(Section 18.1). 
The PedsQL Measurement Model is a modular approach to measuring health-related quality of 
life in healthy children and adolescents and those with acute and chronic health conditions. The 
PedsQL Measurement Model integrates seamlessly both generic core scales and disease-specific 
modules into one measurement system. 
The 23-item PedsQL Generic Core Scales was designed to measure the core dimensions of 
health as delineated by the World Health Organization, as well as role (school) functioning. The 
4 Multidimensional Scales and 3 Summary Scores are: 
Scales 
Summary Scores 
• 
Physical Functioning (8 items) 
• 
Total Scale Score (23 items) 
• 
Emotional Functioning (5 items) 
• 
Physical Health Summary Score (8 items) 
• 
Social Functioning (5 items) 
• 
Psychosocial Health Summary Score (15 items) 
• 
School Functioning (5 items) 
 
The CHI disease-specific questions have been developed by the patient association, Congenital 
Hyperinsulinism International, and taken from the patient-reported registry, the HI Global 
Registry. The HI Global Registry questions are grouped mostly under general quality of life; 
however, some questions relate specifically to diet and feeding, surgical management, glucose 
monitoring, and child development. The HI Global Registry is governed by a Global Steering 
Committee, including key global clinical experts.  
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11.2.1.4. Other Assessments 
Resource Utilization 
• Emergency department visits for hypoglycemia 
• Number and length of hospitalizations due to CHI or CHI-related events 
• Number of outpatient visits to health care providers (family doctors, specialist, etc.) caused 
by CHI or CHI-related events 
• Number of home visits by paramedics due to hypoglycemia 
Diary 
The patient’s parent(s)/guardian will be provided with a paper diary at all visits except at Visit 7 
and the Follow-up Visit. The investigator will instruct the patient’s parent(s)/guardian on how to 
complete the diary. The diary should be completed throughout the trial until the end of treatment 
visit (Visit 7). The following information should be recorded in the diary: 
• Type and volume of fluid administered through NG tube/gastrostomy (if applicable)  
• Hypoglycemic events, including related SMPG measurements 
• Concomitant medications 
• AEs 
• Hospitalizations, visits to health care providers or ER, and visit by paramedics 
• Data regarding suspicion of NME and neurological findings 
Diary entries should be reviewed at each visit and the review documented in the diary. Data 
from the diary should be transcribed to the eCRF on an ongoing basis. 
11.2.1.5. Fasting Tolerance Test/Safety Fast 
During the screening period and at the end of Treatment Period 1, all patients will undergo a 
fasting tolerance test. This test must be performed when the CGM is active, and not the first day 
of CGM sensor, e.g., the day before randomization. This fasting tolerance test will be initiated 
according to the site’s normal clinical practice and the anticipated duration of the test will be at 
investigator’s discretion.  
The test will commence after the patient’s normal meal (t=0 will be the beginning of the meal). 
The meals have to be the same for both tests for the same individual. The frequency of 
PG sampling using the PG meter will be conducted according to site’s normal practice and the 
individual patient’s needs. This test is planned to last for 12 hours but will be stopped when 
PG is ≤60 mg/dL (3.3 mmol/L) and then ketones, insulin, and free fatty acids will be measured. 
The child will then be fed. If this value has not been reached at 12 hours, the test should be 
extended until it is reached.  
The investigator will record the type and size of the meal, the date, start time, all PG 
measurements obtained, ketone measurement, and the end time of the test in a dedicated eCRF 
page.  
The duration of fasting tolerance will be measured from the beginning of the normal meal until 
the beginning of the first continuous 15-minute CGM reading of <70 mg/dL (3.9 mmol/L). 
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11.2.2. Pharmacokinetics/Drug Exposure 
Blood samples will be collected twice during the trial to measure for dasiglucagon levels at 
steady-state (Schedule of Events; Section 18.1). 
Details on sampling/collection, shipment, and analysis will be provided in the laboratory manual. 
11.2.3. Safety 
Safety assessments will include the evaluation of AEs, clinical laboratory assessments 
(hematology, biochemistry, and ADAs), vital signs, physical examinations; electrocardiograms 
(ECGs), echocardiography, and local tolerability issues. 
11.2.3.1. Laboratory Safety Assessments 
Trial procedures require a maximum total of 12 mL blood in a 30-day period. Where this 
exceeds the 2.5 mL/kg maximum,16,17 safety laboratory tests (2 mL per sampling) will be 
prioritized over immunogenicity (1 mL) and drug exposure (0.4 mL) samples. 
All measurements described in this section are recognized standard methods. 
Laboratory Tests to be Performed 
Samples for hematology and chemistry will be collected at the time points specified in the 
Schedule of Events (Section 18.1). 
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular volume, mean corpuscular 
hemoglobin concentration, platelet count (or estimate), white blood cell 
count, including differential 
Biochemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea 
nitrogen, creatinine, sodium, potassium, chloride, eGFR, urea, insulin, 
ketones (measured at the local laboratory or with the PG meter), free 
fatty acids 
Standard of care blood samples can be used as screening samples if they were collected within 
1 week of screening.  
Laboratory specimens will be analyzed at local laboratories. 
Immunogenicity 
Blood samples will be collected to test for antibodies against dasiglucagon at Visit 2 (Day 1, 
prior to dosing ), Visit 5 (Week 5, prior to dosing), Visit 7 (Week 9) and at the Follow-up Visit 
(Visit 8, Week 12) (Section 18.1) and processed and shipped according to instructions provided 
in the laboratory manual. The samples will be stored until the ADA screening and confirmatory 
assays have been approved by the FDA.  
Patients completing the trial before the ADA screening and confirmatory assays have been 
approved by the FDA and who do not continue treatment in the long-term extension trial will 
have an additional ADA Follow-up Visit (not included in the Schedule of Events) approximately 
16 weeks after the End of Trial visit (Visit 8). 
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Upon ADA assay approval, the ADA samples will be analyzed in batches during the trial. The 
ADA samples will be analyzed at a special laboratory. 
The clinical ADA assays for dasiglucagon have been validated in accordance with existing 
guidelines and recommendations.18,19,20 
Samples will be measured in anti-dasiglucagon antibody screening and confirmatory assays. Due 
to the limited sample volume in the CHI pediatric patients, the ADA characterization of 
confirmed positive samples will be conducted according to the following priority: 
• Cross-reactivity against endogenous glucagon (cross-reactivity Yes/No) 
• Establishment of anti-dasiglucagon binding titer. 
• Dasiglucagon in-vitro neutralizing potential of the antibodies. 
• Glucagon in-vitro neutralizing potential of the antibodies (only if positive for cross-
reactivity). 
• Neutralizing antibody titers, in case of a positive result in the in-vitro neutralizing antibody 
assays. 
The in-vitro neutralizing effects of antibodies will be measured using an assay based on glucagon 
receptor-transfected human embryonic kidney cells. The assays were also validated for both 
dasiglucagon and recombinant glucagon neutralizing antibodies. The cell-based neutralizing 
antibody analyses will be performed by a special laboratory.  
Anti-dasiglucagon antibody-positive patients (treatment induced or treatment boosted [titer 
increase above 4 fold]) will be monitored until the ADA level returns to pre-dose level.  
Any residual serum samples will be stored until approval of market authorization by health 
authorities. 
In addition to the above, the neutralizing potential in samples from ADA-positive patients will be 
evaluated in relation to PK/PD data. 
Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all trial personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of patient samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and 
shipping of infectious samples are outlined in the laboratory manual. The investigator is 
responsible for ensuring that all trial samples that are to be transported to another location are 
packed and shipped appropriately according to the applicable regulations.  
Evaluation of Laboratory Values 
The normal ranges of values for the laboratory assessments in this trial will be provided by the 
responsible laboratory and submitted to the sponsor before the beginning of the trial. They will 
be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, the investigator must evaluate if the value is 
clinically significant and record his or her assessment in the appropriate eCRF. 
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All laboratory values that in the investigator’s opinion are clinically significant during or after 
termination of the treatment have to be reported as AEs and followed, as described in 
Section 12.3. 
11.2.3.2. Clinical Examinations 
Vital Signs 
Vital signs, including blood pressure, heart rate, respiratory rate, and SpO2 will be measured 
according to the Schedule of Events (Section 18.1). 
Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed while the child is in a sleeping or calm state 
according to the time points specified in the Schedule of Events (Section 18.1). If it is not 
practical or possible, then a 2-lead may be used.21 If arrhythmia is detected on a 2-lead ECG, this 
should be followed by a 12-lead ECG. All ECG recordings will be identified with the patient 
number, date, and time of the recording and will be attached to his or her medical record. 
The ECG parameters (heart rate, PQ, QRS, QT, and QTcF) and any abnormality will be recorded 
and described in the eCRF, including the investigator’s assessment of clinical significance 
(Abnormal, Clinically Significant; or Abnormal, or Not Clinically Significant). At subsequent 
visits, any clinically significant deterioration of a pre-existing condition, as well as any new 
clinically significant findings, will be recorded as AEs. 
Echocardiogram 
An echocardiogram will be performed according to the time points specified in the Schedule of 
Events (Section 18.1).  
Physical Examination and Neurological Examination 
A complete physical examination of body systems (excluding breast and genitourinary 
examinations) according to standard of care and a neurological examination (including cranial 
nerves, muscle strength and tone, reflexes, coordination, sensory function, and gait, all as 
applicable for the patient’s age) will be performed according to the Schedule of Events 
(Section 18.1). 
Local Tolerability 
Local tolerability data will be collected separately from AEs. Within the eCRF, data will be 
collected on the nature of any reaction (erythema, pain, swelling, etc.), the severity (mild, 
moderate, or severe), and any action take (e.g., no action, interruption of infusion). The likely 
cause of the reaction will also be collected (e.g., insertion site, drug, or adhesive dressing). 
Other skin findings will be collected along other AEs. If clinical suspicion of NME is made, data 
describing the lesion(s) will be collected as an AE of special interest (AESI) (see Section 12.1.8), 
together with a photograph or series of photographs of the lesion(s) uploaded to a central 
repository. 
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11.2.3.3. Reporting of Hypoglycemia Events 
All hypoglycemic episodes are to be reported via the dedicated hypoglycemia eCRF form. 
Hypoglycemic episodes that fulfill the definition of an SAE should furthermore be recorded as 
an SAE. The following information should be collected: 
• Date, start time 
• PG start value 
• Selected symptoms (e.g., unconsciousness, seizures) 
• Intervention, type, and amount of food; route of administration (oral vs. 
NG tube/gastrostomy); and use of marketed glucagon as rescue therapy 
• Subsequent PG measurements 
• End time (time when PG exceeded a threshold of 70 mg/dL [3.9 mmol/L] or 60 minutes after 
the start of the event) and PG value, if available  
• Contact to trial doctor or emergency services, paramedic visit, ER admission, hospitalization, 
if applicable 
A single hypoglycemia episode is defined as up until 60 minutes from the start of the episode 
even if normoglycemia (>70 mg/dL) is not reached within this time. A new episode of 
hypoglycemia is to be reported when the next PG value below 70 mg/dL (3.9 mmol/L) is 
measured. 
11.2.3.4. Reporting of Technical Complaints 
Technical complaints should be reported to the sponsor on any of the following products if 
technical issues occur between their first and last use: 
• Dasiglucagon 4 mg/mL vial containing 1 mL 
• Accu-Chek Spirit pump 
• Accu-Chek Spirit 3.15 mL Cartridge system, Accu-Chek Flex-link Infusion set (Accu-Check 
UltraFlex Infusion set in the US), and Accu-Check Rapid-D Link infusion set 
• Accu-Chek Link-Assist Insertion device 
• SMPG meter, StatStrip Xpress2 
• Dexcom G4 system 
The investigator must report whether the technical complaint is associated with any AEs or 
SAEs. Any AE/SAE associated with a technical complaint must be reported in accordance with 
Section 12.2; the relationship between the technical complaint and the AE/SAE must be assessed 
by the investigator. 
Technical complaints must be reported on a dedicated technical complaint form.  
The investigator must complete the technical complaint form in the eCRF according to the 
following timelines, starting from the time the trial site becomes aware of the technical 
complaint: 
• Technical complaint assessed as related to an SAE within 24 hours 
• Technical complaint which could have led to serious medical occurrence if either 
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• Suitable action had not been taken, if intervention had not been made, or if circumstances 
had been less fortunate within 24 hours 
• All other technical complaints within 5 calendar days 
Use the paper technical complaint form when reporting a technical complaint for an item that is 
not yet allocated to a patient. The form should be sent by e-mail to sponsor QA, refer to 
Appendix A for contact details. 
Collection, Storage, and Shipment of Technical Complaint Item(s) 
The investigator must collect and store the item(s) that is the subject of the technical complaint 
and notify the CRA (including photo documentation) within 5 calendar days of obtaining the 
item at the trial site. Upon request, the CRA must coordinate the shipment as per instruction from 
the sponsor. 
11.2.3.5. Adverse Events 
The definitions and management of and special considerations for AEs are provided in 
Section 12. 
12. ADVERSE EVENTS AND PREGNANCIES 
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. 
12.1. Definitions 
12.1.1. Adverse Events 
An AE is any untoward medical occurrence in a clinical trial patient administered a medicinal 
(investigational or non-investigational) product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a product, whether or not related to the product or medical device. 
AEs include: 
• A clinically significant worsening of a concomitant illness 
• A clinical laboratory AE: a clinical abnormality which 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, 
e.g., change of dose or more frequent follow-up due to the abnormality. 
The following should not be considered as AEs: 
• Pre-existing conditions, including those found as a result of screening procedures 
(pre-existing conditions should be reported as medical history or concomitant illness). 
• 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. 
12.1.2. Severity 
When assessing the severity of an AE, the following definitions are used: 
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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 find 
unacceptable. A severe reaction does not necessarily deem the AE as serious (SAE), and an SAE 
is not always severe in nature. 
12.1.3. Causality 
When assessing the cause of an AE, the following definitions are used: 
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 product 
Not related: No relationship to product. 
Causality will take into consideration whether the cause of the AE was related to the trial drug, 
device, or procedures. 
12.1.4. Outcome 
When assessing the outcome of an AE, the following definitions are used: 
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 ICF. 
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 or has died from 
another AE 
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, or the outcome is not known 
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. 
12.1.5. Serious Adverse Events 
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 
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• is otherwise medically important and may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when (based on appropriate medical judgement) it 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of an SAE. Examples could be emergency room or home 
treatment of allergic bronchospasm or convulsion 
12.1.6. Other Important Events 
The following events must always be reported in the electronic data capture (EDC) system on a 
dedicated form, regardless of whether it is related to an AE:  
• suspicion of transmission of infectious agents via the trial product 
• overdose of the trial product 
• medication error involving the trial product 
• inadvertent or accidental exposure to the trial product 
12.1.7. Non-serious Adverse Events 
A non-serious AE is any AE that does not fulfill the definition of an SAE. 
12.1.8. Adverse Events of Special Interest 
For this trial, the following events are to be regarded as AEs of special interest (AESI events or 
AESIs), with data collected under a specific eCRF form:  
• Suspicion of NME 
• Risk of liver injury defined as ALT or AST >3 x UNL AND total bilirubin >2 x UNL, where 
no alternative etiology exists (Hy’s law). 
• Loss of consciousness, partial and generalized seizures 
• Clinically significant changes in blood pressure or heart rate  
12.1.9. 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 (RSI). For 
dasiglucagon, the expectedness of an AE will be determined by whether or not it is listed in the 
RSI section of the investigator’s brochure. 
12.1.10.  Adverse Events Associated with Devices 
Adverse events associated with devices must be reported to the ethics committee and competent 
authority according to local requirements. Such events include the following: 
12.1.10.1.  Adverse Device Effect 
An adverse device effect (ADE) is an AE related to the use of an investigational medical device. 
This definition includes AEs resulting from insufficient or inadequate instructions for use, 
deployment, installation, operation, or any malfunction of the investigational medical device. 
This definition also includes any event resulting from use error or from intentional misuse of the 
investigational device.  
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12.1.10.2. Serious Adverse Device Effect 
A serious ADE (SADE) is an ADE that has resulted in any of the consequence characteristics of 
an SAE, meaning that the SAE is related to one of the investigational devices.  
12.1.10.3. Unanticipated Serious Adverse Device Effect 
An unanticipated SADE (USADE) is an SADE which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis report. 
12.1.10.4. Device Deficiency 
A device deficiency is the inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance. It also includes malfunctions, use errors, and 
inadequate labelling. In this clinical trial, these are covered by the term technical complaint (see 
reporting requirements in Section 11.2.3.4). Reporting of technical complaints is synonymous 
with device deficiency. The device deficiencies will be monitored and managed by the sponsor 
throughout the trial.  
12.2. Collection, Recording, and Reporting of Adverse Events 
All AEs, whether serious or non-serious, will be reported from the time a signed and dated ICF is 
obtained until the end of the posttreatment follow-up period (which may include contacts for 
follow-up of safety) or inclusion in the ZP4207-17106 trial. Parent(s)/guardian will be asked 
about their child’s condition by open questioning, such as “How has your child been feeling 
since you were last asked?” at each contact with the trial site (visit or telephone). 
Parent(s)/guardian will also be encouraged to spontaneously report AEs occurring at any other 
time during the trial. In addition, patients will be observed for any signs or symptoms. 
All AEs, regardless of seriousness, severity, or presumed relationship to the trial drug, 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 drug. 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 eCRF within 5 calendar days of the investigator becoming 
aware of the event.  
All AE information should at a minimum include the following: 
• Date and time of onset 
• Date and time of investigator’s first information about the AE 
• Seriousness 
• Severity 
• Causal relationship with trial product 
• Measures taken due to AE 
• Interruption or discontinuation of treatment with trial product 
• Date and time of resolution and final outcome 
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Each AE will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). 
All SAEs, including those spontaneously reported to the investigator within 30 days after the last 
dose of trial drug, must be reported within 24 hours after obtaining knowledge about the event, 
by completing the SAE form in EDC. A separate SAE form should be completed for each SAE.  
All SAEs will be reported in EDC; for each reported event, a system-generated e-mail will be 
sent to the Safety CRO (
 medical monitor, sponsor’s medical director, and trial 
manager. 
Specific information about AESIs will be collected via the SAE form (if qualifying for an SAE), 
as well as via dedicated AESI eCRF page(s). Reporting requirements for serious and non-serious 
AEs as described previously also apply for serious and non-serious AESIs. 
Other important events (Section 12.1.6) will be reported via a dedicated eCRF page. Reporting 
timelines will be within 24 hours if related to an SAE and 5 calendar days for all other events. 
It is the responsibility of 
 to report all SUSARs that occur in this trial to competent 
authorities, the institutional review board (IRB), or independent ethics committee (IEC) in 
accordance with the local requirements in force and ICH guideline for GCP. 
All SAEs, SADEs, and USADEs must be reported to the ethics committee and competent 
authority according to local requirements. 
12.2.1.  Serious Adverse Event Reporting Process in Germany 
The Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) is to be informed about 
events as defined per Medical Device Directive 93/42/EEC, and the Ordinance on Medical 
Device Vigilance Section 3, Sub-section 6. 
The Principal Investigator must report all SAEs and events with SADE potential to the Sponsor 
within 24 hours via the eCRF. Device- and/or procedure-related SAEs and events with SADE 
potential occurring in Germany will be reported individually by the Sponsor to the BfArM 
immediately by using the SAE Form available on the BfArM website. Device- or procedure-
related SAEs and events with SADE potential occurring in all other countries in this trial will be 
reported by the Sponsor to the BfArM immediately using the European Medical Device 
Vigilance System (MEDDEV) 2.7/3 SAE Reporting Form. Serious adverse events deemed 
unrelated to the device and the procedure, occurring both in Germany and in all other countries, 
will be reported by the Sponsor to BfArM quarterly by using the MEDDEV 2.7/3 SAE Reporting 
Form next to the procedure laid out in the protocol. 
12.2.2. Contact Information 
Pharmacovigilance for this trial is outsourced to 
; refer to Appendix A for contact 
details. 
12.3. Follow-up of Adverse Events 
The investigator must record follow-up information in the eCRF. Follow-up questions to 
investigators regarding serious adverse events are queried directly by 
 to the 
investigator. 
Follow-up information must be reported according to the following: 
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• SAEs: All SAEs 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 follow-up information should only include new (e.g., 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.  
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 3-4 hours after the event and again approximately 
1-2 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, from the start of trial product administration (i.e., the most severe of the 
applied severity/seriousness categories should be ascribed to the event). Accordingly, for AEs 
with onset after trial product administration, changes in the severity or seriousness of an event 
should not lead to reporting of separate AEs. In contrast, for AEs with onset before trial product 
administration, any worsening of severity/seriousness after trial product administration should be 
recorded as a separate AE, with onset date of the event corresponding to the date of the 
severity/seriousness upgrade.  
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.  
12.4. Pregnancy 
Parent(s)/guardian of female patients who are of childbearing potential must be instructed to 
notify the investigator immediately if their child becomes pregnant or if they suspect she is 
pregnant during the trial. All initial reports of pregnancy in female patients must be reported by 
trial site personnel using the appropriate pregnancy form in EDC within 24 hours of their 
knowledge of the event. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, or ectopic pregnancy) are considered SAEs and must be reported 
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using the SAE form. If a patient becomes pregnant during the trial, treatment must be 
discontinued. 
The investigator must follow the pregnancy until its 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. 
12.5. Precautions 
Normal precautions taken for a clinical trial, including the provision of emergency equipment, 
will be taken during this trial. Qualified and well-trained physicians and medical staff will 
instruct patients’ parents. During a patient’s participation in the trial, the investigator should 
ensure that adequate medical care is provided to patients for any AEs, including clinically 
significant laboratory values related to the trial. The investigator should inform the patient’s 
parents when medical care is needed for intercurrent illnesses of which the investigator becomes 
aware. 
For further information on safety precautions for dasiglucagon, refer to the current version of the 
IB. 
12.6. Safety Committee 
An internal Zealand Safety Committee is constituted to perform ongoing 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 
meets quarterly and additionally on an ad hoc basis as needed. 
12.7. Independent Data Monitoring Committee 
An independent data monitoring committee (DMC) will be established for this trial and follow 
the procedures outlined in the DMC Charter. 
 
 
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13. STATISTICS 
13.1. Statistical Hypotheses 
This section details the null hypotheses for this trial, which are presented in the form Hij, where 
i = treatment period (i = 1) and j = hypothesis number (j = 1, 2, 3, 4). 
The hypothesis relating to the primary endpoint is: 
H11:  Hypoglycemia event rate dasiglucagon = hypoglycemia event rate SOC only  
The hypotheses relating to the key secondary endpoints are: 
H12:  Increase in fasting tolerance dasiglucagon = increase in fasting tolerance SOC only  
H13:  CGM percent time in range dasiglucagon = CGM percent time in range SOC only 
H14:  Clinically significant hypoglycemia event rate dasiglucagon = clinically significant 
hypoglycemia event rate SOC only 
A fixed-sequence statistical strategy will test the primary (Section 7.2.1) and 3 key secondary 
endpoints of Treatment Period 1 (Section 7.2.2) in a pre-defined order, all at the same 
significance level (α = 0.05 for the final analysis to maintain an overall Type I error rate of at 
maximum α = 0.05; see statistical analysis plan [SAP] for more details), moving to a second 
endpoint only after a success on the previous endpoint. 
The test hierarchy is: 
Treatment Period 1 
H11:  Hypoglycemia event rate (measured by SMPG) during Weeks 2-4 of the treatment 
period (primary endpoint) 
H12:  Increase in fasting tolerance (i.e., time from meal to PG <70 mg/dL) from baseline 
to Weeks 2-4 of the treatment period (key secondary endpoint) 
H13:  CGM percent time in range 70-180 mg/dL (3.9-10.0 mmol/L) during Weeks 2-4 of 
the treatment period (key secondary endpoint) 
H14:  Clinically significant hypoglycemia event rates, defined as average weekly number 
of events <54 mg/dL (3.0 mmol/L) (as detected by SMPG) during Weeks 2-4 of the 
treatment period (key secondary endpoint) 
13.2. Sample Size Determination 
Patients will be randomized into the trial if they have at least 3 events of hypoglycemia on 
average per week, as recorded in the diary during the 2 weeks prior to randomization. It is 
assumed that patients continuing on standard of care will maintain a similar level through 
Treatment Period 1, with the number of hypoglycemia events (PG <70 mg/dL or 3.9 mmol/L) 
during Weeks 2-4, as detected by SMPG following a Poisson distribution with a mean of 9. The 
trial is powered to detect a treatment effect of 50%, hence, assuming that the number of 
hypoglycemia events reported for patients in the dasiglucagon group during Weeks 2-4 will 
follow a Poisson distribution with a mean of 4.5. At the final analysis, 32 patients will have 99% 
power testing at a 0.05 significance level. The overall alpha level is strongly controlled in this 
setting, remaining at or below 0.05. 
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13.3. Analysis Populations 
Three analysis populations are defined for this trial: 
• The Safety Set: defined as all patients administered any randomized treatment. This 
population will be used to provide descriptive summaries of safety data. Patients will be 
summarized by treatment period according to treatment received. 
• The Full Analysis Set (FAS): defined as all patients in the Safety Set who have a valid 
baseline efficacy assessment. This population will be used to analyze efficacy data. Patients 
will be analyzed by treatment period according to planned treatment. 
• The Per Protocol (PP) Analysis Set: defined as all patients in the FAS without any major 
protocol deviations. This population will be used to analyze primary and key secondary 
endpoints as a supportive analysis. Patients will be analyzed according to planned treatment 
for the first treatment period only. 
Inclusion in the analysis populations will be determined prior to database lock. 
13.4. Statistical Analyses 
This section presents a summary of the planned statistical analyses. A SAP that describes the 
details of the analyses to be conducted will be finalized prior to database lock.  
Unless otherwise indicated, all testing of statistical significance will be 2-sided with a 
significance level of α = 0.05 to maintain an overall Type I error rate of α = 0.05; see SAP for 
more details. 
For analyses involving trial site, if the number of patients per site is small, sites may be pooled 
for analysis, or omitted from statistical models. The final determination will be made prior to 
database lock. 
Continuous endpoints will be summarized with number (n), mean, SD, median, minimum, and 
maximum. In addition, change from baseline values will be calculated at each time point and 
summarized descriptively. For categorical endpoints, descriptive summaries will include counts 
and percentages. 
Immunogenicity data will be analyzed descriptively. No statistical tests are planned. Baseline 
ADA-positive patients will be calculated as a percentage of the total number of patients whose 
baseline samples were tested for ADA. Overall ADA incidence, the combined results of 
treatment induced, and treatment boosted ADA-positive patients, will be calculated as a 
percentage of the total number of evaluable patients, excluding baseline positive patients without 
any samples available after drug administration. Titers will be reported as median and 
interquartile range. 
Graphical presentations of selected endpoints will be prepared and will be outlined in the SAP. 
13.4.1. Trial Patients and Demographics 
13.4.1.1. Disposition and Withdrawals 
The numbers of patients randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of patients in each 
analysis population will be reported. 
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13.4.1.2. Protocol Deviations 
Protocol deviations will be provided in a listing and summarized if appropriate. 
13.4.1.3. Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, race, ethnicity, weight, and 
length/height) at screening will be summarized using descriptive statistics. No formal statistical 
analyses will be performed.  
Prior and concomitant medications and procedures will be summarized by treatment group and 
the number and percentage of patients taking each medication, classified using World Health 
Organization Drug Dictionary Anatomical Therapeutic Chemical classes and preferred term 
(PT). 
13.4.2. Duration of Exposure and Compliance 
Trial drug administration will be summarized in terms of each patient’s mean, mode, and final 
dose, and in terms of duration of exposure. Descriptive statistics for these quantities, including 
the mean, median, SD, minimum, maximum, and quartiles, will be provided by treatment group.  
13.4.3. Efficacy Analyses 
The efficacy analysis will be separated into 3 categories: 
1. Treatment Period 1, FAS 
2. Treatment Period 1, PP (primary and key secondary endpoints only) 
3. Treatment Period 2, FAS 
13.4.3.1. Primary Analysis 
Primary Endpoint (Treatment Period 1) 
The primary efficacy endpoint is the hypoglycemia event rate during Weeks 2-4 of Treatment 
Period 1. A hypoglycemia event is defined as PG <70 mg/dL or 3.9 mmol/L, as detected by 
SMPG. The analysis will be based on the hypoglycemia events reported in the eCRF. Baseline is 
defined as the average weekly number of hypoglycemic events during the 2-week baseline 
period. Weeks 2-4 of Treatment Period 1 is defined as the average weekly number of 
hypoglycemic events across the last 3 weeks of the treatment period. The hypothesis:  
H11: Hypoglycemia event rate dasiglucagon = hypoglycemia event rate SOC only  
will be analyzed by using negative binomial regression, with treatment group as a fixed effect 
and baseline hypoglycemic rate as a covariate. The log-transformed number of days in Treatment 
Period 1 will be used as an offset variable. The null hypothesis is that there is no difference in the 
incidence of average weekly number of hypoglycemic events between the 2 treatment groups, 
which will be tested at the significance level of α=0.05. 
The primary analysis will estimate the treatment effect based on the de facto (treatment policy) 
estimand. All available data in the form of actual measurements will therefore be included in the 
analysis, irrespective of adherence to treatment or use of subsequent therapy. Missing data will 
be imputed using multiple imputation (MI) methodology as described in Section 13.4.3.4.  
As a sensitivity analysis, the primary endpoint will also be analyzed without imputation of 
missing data; however, this analysis will not be included in the fixed-sequence hierarchical 
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testing strategy. Similarly, the primary endpoint may be analyzed excluding post-baseline data 
collected after trial drug discontinuation/completion. 
13.4.3.2. Key Secondary Analyses 
Treatment Period 1 
The key secondary endpoint of clinically significant hypoglycemia (<54 mg/dL [3.0 mmol/L]) 
event rates will be analyzed using a negative binomial regression, with treatment group as a fixed 
effect and baseline hypoglycemic rate as a covariate. Percent time in range (i.e., the percent time 
between 70 mg/dL [3.9 mmol] and 180 mg/dL [10.0 mmol], inclusive, as measured by CGM, 
where percent time is calculated as [number of minutes in range/total number of minutes patient 
is wearing CGM] * 100%) will be analyzed by using an ANCOVA, with treatment group and 
region as fixed effects and baseline time in range as a covariate. Increase in fasting tolerance 
(i.e., change from baseline in time from meal to PG <70 mg/dL) will be analyzed similarly, using 
an ANCOVA, with treatment group and region as fixed effects and baseline fasting tolerance as 
a covariate. Baseline is defined as the mean weekly value during the 2-week baseline period; 
Weeks 2-4 of Treatment Period 1 is defined as the mean weekly value across the last 3 weeks of 
the treatment period. 
Missing data will be imputed in a similar manner to the primary endpoint. Analyses will be 
repeated without imputation of missing data; as with the primary endpoint, these analyses will 
not be included in the fixed-sequence hierarchical testing strategy. 
13.4.3.3. Secondary and Other Efficacy Analyses 
For the remaining efficacy endpoints, continuous and categorical endpoints will be presented 
using summary statistics or frequencies, respectively; no inference will be performed. Missing 
data will not be imputed. 
The secondary efficacy endpoints related to the use of gastric carbohydrates will be evaluated 
descriptively only in the subgroup of patients with gastrostomy or NG tube at baseline. 
Resource Utilization 
The number and percentage of patients with admissions/emergency department visits for 
glycemia, hospitalizations due to CHI, visits to health care providers (family doctor, specialists, 
etc.) caused by CHI or CHI-related events, and need for home visits by parameters will be 
summarized. Additionally, number and length (in days) of hospitalizations due to CHI, number 
of visits to health care providers (family doctor, specialists, etc.) caused by CHI or CHI-related 
events, and number of home visits by paramedics will be summarized. 
Quality of Life 
Quality of life will be assessed by the PedsQL and a CHI disease-specific questionnaire 
(Appendix B). For each item of the PedsQL instrument (parent), a 5-point response scale is used 
(0 = never, 1 = almost never, 2 = sometimes, 3 = often, 4 = almost always). Items are reverse-
scored and linearly transformed to a 0-100 scale (0 → 100, 1 → 75, 2 → 50, 3 → 25, 4 → 0) so 
that higher scores indicate better health-related QoL (less negative impact). Scale scores are 
computed as the sum of the items divided by the number of items answered (this accounts for 
missing data). If more than 50% of the items in the scale are missing, the scale score is not 
computed. Change from baseline for PedsQL for each of the scales (physical functioning, 
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emotional functioning, social functioning, and school functioning) and summary scores (total 
scale score, physical health summary score, and psychosocial health summary score) will be 
summarized. 
Answers to each question on the CHI disease-specific questionnaire will be summarized using 
frequencies at each relevant visit. 
13.4.3.4. Imputation of Missing Data 
For analysis of primary and key secondary endpoints, a jump-to-control (J2C) MI method, with 
SAS procedures PROC MI and PROC MIANALYZE, will be performed, including 
demographics and baseline characteristics in a first MI analysis. Due to the expectation of rapid 
metabolism and excretion of trial drug, it is expected that efficacy would be similar to the control 
group in cases of premature treatment discontinuation; thus, the J2C method is appropriate to 
handle missing values in this situation (considered missing not at random [MNAR]). Any 
missing values occurring before the patient discontinues/completes treatment will be imputed 
based on the data from the same treatment group (considered missing at random [MAR]).   
The analysis will have 3 broad components:  i) the MI process for the SOC-only data; ii) the MI 
process for the dasiglucagon + SOC patients’ data; and iii) the analysis model that will be used to 
draw inference regarding the primary causal estimand, along with the method for combining the 
results across the multiply imputed datasets. The seed to be used in the analysis is 12255070. The 
algorithm will use 20 burn-in iterations before each imputation, and 1000 imputed datasets will 
be created for the analysis for each of steps i and ii. 
To accommodate both monotone and non-monotone missingness patterns, imputed values will 
be generated by a pattern mixture imputation model under the MNAR assumption using the fully 
conditional specification (FCS) method. The primary analysis will be performed using a negative 
binomial regression model from which hypoglycemia incidence density ratios (IDR) and 
95% confidence intervals are obtained, along with the model parameter estimates, standard 
errors, and p values; analyses of the key secondary endpoints will be performed using the 
appropriate modeling. The final step in the imputation will involve using PROC MIANALYZE 
to derive valid univariate inference for these parameters. Multivariate inference based on the 
Wald test will be derived to test for the significance of these parameters. 
Complete details for conducting this analysis will be outlined in the SAP. 
13.4.4. Safety and Tolerability Analyses 
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 13.3). Safety assessments will include the evaluation of AEs; clinical laboratory 
assessments (hematology, biochemistry, and ADAs); vital signs, physical examinations; ECGs, 
echocardiography, and local tolerability issues. No formal inferential analyses will be conducted 
for safety variables, unless otherwise noted. 
Baseline is defined as the last non-missing assessment before first dose in each treatment period. 
All safety analyses will be summarized by treatment received within treatment period and by 
trial visit, if applicable. 
13.4.4.1. Adverse Events 
Adverse events will be coded using the latest version of MedDRA.  
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A treatment-emergent AE is defined as an AE with an onset at the time of or following the start 
of treatment with the trial drug through the Follow-up visit or Early Termination visit, whichever 
occurs first. 
The number and percentage of patients with AEs will be displayed by system organ class, PT, 
and treatment group. The incidence of AEs will also be presented by severity and by relationship 
to the trial drug. Serious AEs and AEs resulting in discontinuation of trial drug will be 
summarized separately in a similar manner. Patient listings of AEs, SAEs, and AEs causing 
discontinuation of trial drug will be produced. 
13.4.4.2. Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values. 
The number of patients with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory analyte. 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. Any out-of-range values that are identified by the 
investigator as being clinically significant will also be shown in a data listing. 
13.4.4.3. Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure, diastolic blood pressure, 
heart rate, respiratory rate, and SpO2. 
The number of patients with vital signs values categorized as below, within, or above normal 
ranges will be tabulated showing change from baseline (shift tables) for each parameter. 
13.4.4.4. Twelve-lead Electrocardiograms 
The number and percentage of patients with normal and abnormal ECG findings will be 
summarized. Abnormal results will be grouped as Abnormal, Clinically Significant; or 
Abnormal, Not Clinically Significant. 
13.4.4.5. Physical Examination Findings 
The number and percentage of patients with normal and abnormal findings in the complete 
physical examination will be displayed. 
13.4.4.6. Local Tolerability 
The number and percentage of patients with local tolerability findings, collected separately from 
AEs, will be summarized. 
13.4.4.7. Interim Analysis 
No interim analysis is planned. 
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14. TRIAL CONDUCT 
The accuracy and reliability of data is ensured, among others, by the selection of qualified 
investigators and appropriate trial sites, review of protocol procedures with the investigator and 
associated personnel before the trial, periodic monitoring visits, and meticulous data 
management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1. Sponsor Responsibilities 
The sponsor is obligated to conduct the trial in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to terminate participation of a trial site at any time 
(Section 14.7), and/or to discontinue the trial (Section 14.6 for US studies and Section 14.6.2 for 
studies conducted outside of the US). 
The sponsor agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the trial according to the trial protocol. 
14.1.2. Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 18.2), the investigator indicates that he/she has 
carefully read the protocol, fully understands the requirements, and agrees to conduct the trial in 
accordance with the procedures and requirements described in this protocol. 
The investigator also agrees to conduct this trial in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including the November 2016 ICH Guidance 
for Industry E6(R2) GCP, and in agreement with the 2013 version of the Declaration of Helsinki. 
While delegation of certain aspects of the trial to subinvestigators and trial coordinators is 
appropriate, the investigator will remain personally accountable for closely overseeing the trial 
and for ensuring compliance with the protocol and all applicable regulations and guidelines. The 
investigator is responsible for maintaining a list of all persons that have been delegated trial-
related responsibilities (e.g., subinvestigators and trial coordinators) and their specific trial-
related duties. 
Investigators should ensure that all persons who have been delegated trial-related responsibilities 
are adequately qualified and trained in the protocol, trial drugs handling, and their specific duties 
within the context of the trial. Investigators are responsible for providing the sponsor with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the trial may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all trial documentation by authorized individuals. 
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14.2. Site Initiation 
Trial personnel may not screen or enroll patients into the trial until after receiving notification 
from the sponsor or its designee that the trial can be initiated at the trial site. The trial site will 
not be authorized for trial initiation until: 
1. The trial site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
2. All regulatory documents have been submitted to and approved by the sponsor or its 
designee. 
3. The trial site has a Clinical Trial Agreement in place. 
4. Trial site personnel, including the investigator, have participated in a trial initiation meeting. 
The regulatory documents must be received from the investigator before the sponsor will 
authorize shipment of trial drug to the trial site, Regulatory Green Light. Copies of the 
investigator’s regulatory documents must be retained at the trial site in a secure location in the 
ISF. Additional documents, including a copy of the protocol and applicable amendment(s), the 
dasiglucagon IB, eCRF completion guidelines, copies of regulatory references, copies of 
IRB/IEC correspondence, and trial drug accountability records should also be retained in the ISF. 
It is the investigator’s responsibility to ensure that copies of all required regulatory documents 
are organized, current, and available for inspection. 
14.3. Screen Failures 
Patients who fail inclusion and/or exclusion criteria may be rescreened for the trial upon 
approval by the sponsor and medical monitor. Patients may only be rescreened once 30 days or 
more after the original Screening Visit. If a patient is eligible to enter the trial after having 
previously failed screening, the patient will be assigned a new patient identification number. 
14.4. Trial Documents 
All documentation and material provided by the sponsor for this trial are to be retained in a 
secure location and treated as confidential material. 
14.4.1. Investigator’s Regulatory Documents 
The regulatory documents will be maintained by the investigator in the ISF. 
14.4.2. Case Report Forms 
By signing the Investigator’s Agreement (Section 18.2), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all patients who sign 
an ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the trial to ensure that the trial information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual patient visits should be completed as soon as 
possible after the visit. All requested information must be entered in the EDC system according 
to the completion guidelines provided by the sponsor or its designee. 
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The eCRF must be signed by the investigator or a subinvestigator when all data are entered and 
cleaned. These signatures serve to attest that the information contained in the eCRF is accurate 
and true. 
14.4.3. Source Documents 
Information recorded in the eCRF should be supported by corresponding source documentation. 
Examples of acceptable source documentation include, but are not limited to, hospital records, 
clinic and office charts, laboratory notes, and recorded data from automated instruments, 
memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be entered into the eCRF at the site. 
The investigator should permit trial-related monitoring, IEC review, regulatory inspections, and 
sponsor audit by providing direct access to source data and documents. 
14.5. Data Quality Control 
The sponsor and its designees will perform quality control checks on this clinical trial. 
14.5.1. Monitoring Procedures 
The sponsor and/or its designee will conduct site visits to monitor the trial and ensure (i) the 
safety and rights of the patients are respected, (ii) compliance with the protocol, GCP, and 
applicable regulations and guidelines and (iii) that accurate, valid, and complete data are 
collected. The assigned CRA(s) will visit the investigator and trial site at periodic intervals and 
maintain periodic communication, this are described in detail in the Monitoring Plan. The 
investigator agrees to allow the CRA(s) and other authorized sponsor personnel access to ISF 
and source data (original documents, data, and records). The CRA(s) will maintain current 
personal knowledge of the trial through observation, review of trial records and source 
documentation, and discussion of the conduct of the trial with the investigator and staff. While 
on site, the CRA(s) will review: 
• regulatory documents 
• entries in the EDC system compared with the source documents 
• consents  
• adherence to the inclusion/exclusion criteria 
• AE records 
• storage and accountability of trial drug and trial materials 
• adherence to the protocol and ICH-GCP 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRFs are described in the Trial Reference Manual. As representatives of the sponsor, 
CRAs are responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 18.2), the investigator agrees to meet with the 
CRA(s) during trial site visits; to ensure that trial staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all trial documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow the sponsor or designee auditors or inspectors from regulatory agencies to review 
records, and to assist the inspectors in their duties, if requested. 
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14.5.2. Data Management 
The sponsor or designee will be responsible for activities associated with the data management 
of this trial. The standard procedures for handling and processing records will be followed per 
GCP and Premier standard operating procedures. A comprehensive data management plan will 
be developed, including a data management overview, description of database contents, 
annotated eCRF, pre-entry review list, self-evident correction conventions, query contacts, and 
consistency checks. 
Trial site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the trial manual. 
14.5.3. Quality Assurance/Audit 
This trial will be subject to audit by the sponsor/its designee or national/international regulatory 
authorities. Audits may be performed to check compliance with GCP guidelines, and can 
include: 
• site audits 
• trial master file audits 
• database audits 
• document audits (e.g., protocol and/or the clinical trial report [CTR]) 
The sponsor or its designee may conduct additional audits on a selection of trial sites, requiring 
access to patient notes, trial documentation, and facilities or laboratories used for the trial. 
The trial site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB/IEC or regulatory authorities 
according to GCP guidelines. The investigator agrees to cooperate with the auditor during the 
visit and will be available to supply the auditor with eCRFs or other files necessary to conduct 
that audit. Any findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify the sponsor immediately. 
14.6. Trial Termination 
The trial may be terminated at the sponsor’s discretion at any time and for any reason. 
14.6.1. Regular Trial Termination 
The end of this trial is defined as the date of the last visit of the last patient (last patient out or 
last patient last visit) participating in the trial. Within 90 days of the end of the clinical trial, the 
sponsor or its designee and/or site will notify the IRBs and IECs and regulatory authorities on the 
regular termination of the trial as required according to national laws and regulations.  
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14.6.2. Premature Trial Termination 
The trial may be terminated prematurely for any reason and at any time by the sponsor, the 
IRBs/IECs, regulatory authorities, respective steering committees, or the coordinating 
investigator. A decision to terminate the trial prematurely is binding to all investigators at all trial 
sites. 
Within 15 days of premature termination of a clinical trial, the sponsor or its designee and/or site 
will notify the IRBs/IECs and regulatory authorities on the premature termination as required 
according to national laws and regulations. The sponsor or its designee must clearly explain the 
reasons for premature termination. 
If the trial is terminated prematurely, all investigators must inform their patients and take care of 
their appropriate follow-up and further treatment to ensure protection of their interests. Trial sites 
may be asked to have all patients currently participating in the trial complete all of the 
assessments for an Early Termination Visit. 
14.7. Trial Site Closure 
At the end of the trial, all trial sites will be closed. The sponsor may terminate participation of a 
trial site at any time. Examples of conditions that may require premature termination of a trial 
site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate patient enrollment 
14.7.1. Record Retention 
After trial completion at sites in the US, the investigator shall 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 drug has been approved or 
the sponsor has discontinued its research with the trial drug, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of the 
trial drug 
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 shall notify the sponsor in writing of his or her intent 
to destroy all such material. The sponsor shall have 30 days to respond to the investigator’s 
notice, and the sponsor shall 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 shall 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 
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need to be retained for a longer period of time if required by applicable regulatory authorities or 
by agreement with the sponsor. 
The investigator shall 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. 
14.7.2. Sample Retention 
Samples will only be used for purposes related to this trial. 
All blood samples will be destroyed upon completion of the CTR, except for residual ADA 
samples, which will be stored until approval of market authorization because further 
characterization of the antibody response may be requested by the health authorities. Identifiable 
samples can be destroyed at any time at the request of the patient. 
14.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of the sponsor. The protocol amendment must be signed by the 
investigator and approved by the IRB/IEC before it may be implemented. Protocol amendments 
will be filed with the appropriate regulatory agency(s) having jurisdiction over the conduct of the 
trial. 
14.9. Use of Information and Publication 
All information concerning dasiglucagon, the sponsor’s operations, patent applications, 
formulae, manufacturing processes, basic scientific data, and formulation information supplied 
by the sponsor or its designee to the investigator and not previously published, is considered 
confidential and remains the sole property of the sponsor. Case report forms also remain the 
property of the sponsor. The investigator agrees to use this information for purposes of trial 
execution through finalization and will not use it for other purposes without the written consent 
of the sponsor. 
The information developed in this trial will be used by the sponsor in connection with the 
continued development of dasiglucagon and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. 
The information generated by this trial is the property of the sponsor. Publication or other public 
presentation of dasiglucagon data resulting from this trial requires prior review and written 
approval of the sponsor. Abstracts, manuscripts, and presentation materials should be provided to 
the sponsor for review and approval at least 30 days prior to the relevant submission deadline. 
Data from individual trial sites must not be published separately. 
It is agreed that the results of the trial will not be submitted for presentation, abstract, poster 
exhibition or publication by the investigator until the sponsor has reviewed and commented on 
such a presentation or manuscript for publication. 
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15. FINAL CLINICAL TRIAL REPORT 
The sponsor will retain ownership of the data. 
The final CTR will be prepared and reviewed in cooperation with the signatory investigator. The 
coordinating investigator will be appointed by the sponsor to review and sign the CTR on behalf 
of all participating investigators. This report will include a summary of the trial results based on 
a statistical evaluation and clinical assessment of the protocol-defined endpoints. The results 
from the neutralizing antibody assay may be included or reported separately pending availability 
of the results. 
The final CTR may be submitted to the regulatory authorities.  
16. ETHICAL AND LEGAL CONSIDERATIONS 
16.1. Declaration of Helsinki and Good Clinical Practice 
This trial will be conducted in compliance with the November 2016 ICH Guidance for Industry 
E6(R2) GCP (including archiving of essential trial documents), the 2013 version of the 
Declaration of Helsinki, and the applicable regulations of the country(ies) in which the trial is 
conducted. 
See Appendix C for regulation and guidelines. 
16.2. Patient Information and Informed Consent 
According to the Declaration of Helsinki and ICH GCP, patients’ parent(s)/guardian must 
provide their written informed consent prior to enrollment in a clinical trial and before any 
protocol-specified procedures are performed. Patients’ parent(s)/guardian must declare their 
consent by personally signing and dating the ICF. 
France, Germany, Israel: The consent must correspond to the patient’s presumed will where 
such a will can be ascertained. 
The written ICF will embody the elements of informed consent as described in the Declaration of 
Helsinki and will also comply with local regulations.  
Each patient’s parent(s)/guardian should be made aware by the investigator of the nature of the 
trial (objectives, methods, and potential hazards and benefits) and the procedures involved using 
the information on the ICF. 
France, Germany, Israel: Additionally, the patient will be informed about the nature, 
significance, risks, and implications of the trial with age-appropriate information, and his or her 
assent will be obtained in accordance with local regulations, as applicable. 
Information should be given in both oral and written form whenever possible and deemed 
appropriate by the IRB/IEC. Patients’ relatives, or, if necessary, legal representatives must be 
given ample opportunity to inquire about details of the trial.  
Patient information and the ICF must be in a language fully comprehensible to the prospective 
patient’s parent(s)/guardian. The written information must be provided to the patient’s 
parent(s)/guardian to give him or her sufficient time to understand the information and to prepare 
questions before being asked for his or her consent. The investigator must confirm that the text 
was understood by the patient’s parent(s)/guardian. The patient’s parent(s)/guardian will then 
sign and date the IRB/IEC-approved consent form indicating that he or she has given his or her 
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consent for his or her child to participate in the trial. The signature confirms that the consent is 
based on information that has been understood. The form will also be signed by the investigator 
obtaining the consent and annotated with the trial patient number. Each signed patient 
parent(s)/guardian ICF must be kept on file by the investigator for possible inspection by 
regulatory authorities, the sponsor, and/or its designee. Collection of informed consent has to be 
documented on the eCRF. 
Furthermore, the patient’s parent(s)/guardian will be informed that if he or she wishes to 
withdraw his or her child (see Section 9.3 at any time during the trial, this will not have any 
negative consequences. Patients may be withdrawn by the investigator if any change related to 
safety or ethics precludes further participation in the trial. Patients’ parent(s)/guardian will be 
asked to agree to a final assessment in the event of an early termination of the trial. 
If information becomes available that may be relevant to the patient’s willingness to continue 
participating in the trial, the Investigator must inform the patients’ parent(s)/guardian in a timely 
manner, and a revised written informed consent must be obtained. 
Patients’ parent(s)/guardian will be informed that data from their children’s case may be stored 
in a computer without inclusion of their name and that such data will not be revealed to any 
unauthorized third party. Data will be reviewed by the monitor, an independent auditor, and 
possibly by representatives of regulatory authorities and/or IRBs/IECs. The terms of the local 
data protection legislation will be applied as appropriate. 
16.3. Approval by Institutional Review Board and Independent Ethics Committee 
For Investigational New Drug studies, the minimum standards of conduct and requirements for 
informed consent are defined in the FDA regulations. 
A valid IRB/IEC must review and approve this protocol before trial initiation. Written 
notification of approval is to be provided by the investigator to the sponsor’s monitor and PM 
before shipment of investigational drug supplies, and will include the date of the committee’s 
approval and the chairperson’s signature. This written approval must consist of a completed 
sponsor form, IRB/IEC Approval Form, or written documentation from the IRB/IEC containing 
the same information. 
Until written approval by the IRB/IEC has been received by the investigator, no patient may 
undergo any procedure not part of routine care for the patient’s condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval 
from the IRB/IEC, or a designee, must be received by the sponsor before implementation. This 
written approval will consist of a completed IRB Approval Form or written documentation from 
the IRB/IEC containing the same information. 
16.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the 
investigator and the sponsor. 
 
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17. REFERENCES 
1. 
Arnoux J-B, Verkarre V, Saint-Martin C, et al. Congenital hyperinsulinism: current trends in 
diagnosis and therapy. Orphanet J Rare Dis. 2011;6:63:1-14. 
2. 
De Leon DD, Stanley CA. Congenital hypoglycemia disorders: New aspects of etiology, 
diagnosis, treatment and outcomes. Pediatr Diabetes. 2016;1-7. 
3. 
Lord K, Radcliffe J, Gallagher PR, et al. High risk of diabetes and neurobehavioral deficits 
in individuals with surgically treated hyperinsulinism. J Clin Endocrinol Metab. 
2015;100(11):4133-4139. 
4. 
Stanley CA. Perspective on the genetics and diagnosis of congenital hyperinsulinism 
disorders. J Clin Endocrinol Metab. 2016;101(3):815-826. 
5. 
Mazor-Aronovitch K, Gillis D, Lobel D, et al. Long-term neurodevelopmental outcome in 
conservatively treated congenital hyperinsulinism. Eur J Endocrinol. 2007;157(4):491-497. 
6. 
Welters A, Lerch C, Kummer S, et al. Long-term medical treatment in congenital 
hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical 
centers. Orphanet J Rare Dis. 2015;10;150:1-10. 
7. 
Arya VB, Senniappan S, Demirbilek H, et al. Pancreatic endocrine and exocrine function in 
children following near-total pancreatectomy for diffuse congenital hyperinsulinism. PLoS 
ONE. 2014;9(5):e98054. https://doi.org/10.1371/journal.pone.0098054. 
8. 
Cederblad F, Ewald U, Gustafsson J. Effect of glucagon on glucose production, lipolysis 
and gluconeogenesis in familial hyperinsulinism. Horm. Res. 1998;50:94-98. 
9. 
Miralles RE, Lodha A, Perlman M, Moore AM. Experience with intravenous glucagon 
infusions as a treatment for resistant neonatal hypoglycemia. Arch Pediatr Adolesc Med. 
2002;156(10):999-1004. 
10. Lord K, Dzato E, Snider KE, Gallagher PR, De Leon DD. Clinical presentation and 
management of children with diffuse and focal hyperinsulinism: a review of 223 cases. 
J Clin Endocrinol Metab. 2013;98(11):E1786-E1789. 
11. Mohnike K, Blankenstein O, Pfuetzner A, et al. Long-term non-surgical therapy of severe 
persistent congenital hyperinsulinism with glucagon. Horm Res. 2008;70:59-64. 
12. Pedersen JS, Dikov D, Flink JL, Jhuler HA, Christiansen G, Otzen DE. The changing face 
of glucagon fibrillation: structural polymorphism and conformational imprinting. 
J Mol Biol. 2006;355(3):501-523. 
13. Rose SR, Chrousos G, Cornblath M, Sidbury J. Management of postoperative 
nesidioblastosis with zinc protamine glucagon and oral starch. J Pediatr. 
1986;108(1):97-100. 
14. Chastain MA. The glucagonoma syndrome: A review of its features and discussion of new 
perspectives. Am J Med Sci. 2001;321(5):306–320. 
15. Zealand Pharma report. Population PK modeling and simulation of dasiglucagon in pediatric 
patients with type I diabetes mellitus. 2017. 
16. European Medicines Agency. ICH Topic E11: Clinical Investigation of Medicinal Products 
in the Paediatric Population. January 2001. 
17. Howie, S. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ 2011; 89:46–53. 
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18. Food and Drug Administration (FDA). Guidance for Industry on Bioanalytical Method
Validation. Food and Drug Administration. 2001.
19. Viswanathan CT, Bansal S, Booth B, et al. Quantitative bioanalytical methods validation
and implementation: best practices for chromatographic and ligand binding assays.
Pharm Res. 2007;24(10):1962-73.
20. Shankar G, Devanarayan V, Amaravadi L, et al. Recommendations for the validation of
immunoassays used for detection of host antibodies against biotechnology products.
J Pharm Biomed Anal. 2008;48(5):1267-81.
21. Food and Drug Administration (FDA). Guidance Industry. E14 Clinical Evaluation of
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs.
Food and Drug Administration. 2005.
22. McKinlay CJD, Chase JG, Dickson J, et al. Continuous glucose monitoring in neonates: a
review. Matern Health Neonatol Perinatol. 2017;3:18.
23. Rabbone I, Barbetti F, Marigliano M, et al. Successful treatment of young infants presenting
neonatal diabetes mellitus with continuous subcutaneous insulin infusion before genetic
diagnosis. Acta Diabetol. 2016 Aug;53(4):559-65.
24. Beardsall K, Vanhaesebrouck S, Ogilvy-Staurt AK, et al. Validation of the continuous
glucose monitoring sensor in preterm infants. Arch Dis Child Fetal Neonatal Ed.
2013;98(2):F136-40.
25. Baumeister FA, et al. Glucose monitoring with long-term subcutaneous microdialysis in
neonates. Pediatrics. 2001;108:1187-1192.
26. Kerr D, Hoogma RP, Buhr A, et al. Multicenter User Evaluation of ACCU-Chek® Combo,
an Integrated System for Continuous Subcutaneous Insulin Infusion. J Diabetes Sci Technol.
2010;4(6):1400-7.
27. Heinemann L, Fleming GA, Petrie JR, et al. Insulin pump risks and benefits: a clinical
appraisal of pump safety standards, adverse event reporting, and research needs: a joint
statement of the European Association for the Study of Diabetes and the American Diabetes
Association Diabetes Technology Working Group. Diabetes Care. 2015;38(4):716-22.
28. Summary of Safety And Effectiveness Data (SSED). Continuous Glucose Monitoring
System-FDA PMA 05OCT2012.
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18. ATTACHMENTS
18.1. Schedule of Events 
Table 2 Schedule of Events 
Trial Period 
Screening 
Treatment Period 1 
Treatment Period 2 
Follow-up 
Week 
1b 
Telephone Callc 2 
4 
5d 
Telephone Callc 6 
9 
12 
Day 
1 
8 
22 
29 
36 
57 
85 
Time window (days) 
Day -28 to -14a 
±2 
±2 
±2 
±2 
±2 
±2 
±5 
Visit # 
1 
2 
3 
4 
5 
6 
7e 
8 
General assessments 
Informed consent/assent 
X 
Inclusion/exclusion criteria 
X 
X 
Randomization criteria 
X 
Demography 
X 
Body weight and length/heightf 
X 
X 
X 
X 
X 
Medical history (including current illness) 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessment 
Electrocardiogram 
X 
Xr 
X 
Xr 
X 
X 
X 
Echocardiography 
Xg 
X 
X 
Vital signsh 
X 
Xs 
X 
X 
Xs 
X 
X 
X 
Serum Pregnancy testi 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local tolerability 
X 
X 
X 
X 
X 
X 
Physical examination and neurological 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
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Trial Period 
Screening 
Treatment Period 1 
Treatment Period 2 
Follow-up 
Week 
1b 
Telephone Callc 2 
4 
5d 
Telephone Callc 6 
9 
12 
Day 
1 
8 
22 
29 
36 
57 
85 
Time window (days) 
Day -28 to -14a 
±2 
±2 
±2 
±2 
±2 
±2 
±5 
Visit # 
1 
2 
3 
4 
5 
6 
7e 
8 
Laboratory Assessments 
Clinical laboratory testj 
X 
X 
X 
X 
X 
X 
Antibodiesk 
 Xl 
X 
X 
Xk 
Pharmacokinetics/drug exposure 
X 
X 
Efficacy 
Continuous glucose monitoring 
 X (for at least 
14 days prior to 
randomization) 
Continuousm 
Self-monitored plasma glucose 
 X (for at least 
14 days prior to 
randomization) 
X (at least 3 times daily) 
Fasting tolerance testn 
X (during active 
CGM period) 
Xo 
Trial Materials and reminders 
Randomization 
X 
Dispense patient diary 
Xp 
X 
X 
X 
X 
X 
Diary review 
X 
X 
X 
X 
X 
X 
QoL questionnairesq 
X 
X 
X 
X 
Dispensing of trial product 
X 
X 
X 
X 
X 
Abbreviations: CGM = continuous glucose monitoring; PG = plasma glucose; QoL = quality of life; SMPG = self-monitoring of plasma glucose; SOC = standard of care; 
SpO2 = blood oxygen saturation level; W = week 
Note: An unscheduled visit can occur at any time if the investigator deems it necessary for patient safety. 
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a 
Screening must occur within a minimum of 14 days to allow for solid baseline assessment. 
b At the beginning of Treatment Period 1 (Week 1), all patients will be hospitalized for 1-2 days. Patients assigned to SOC plus dasiglucagon treatment will be initiated and 
titrated on dasiglucagon, trained in the use of the infusion pump, and supervised. Patients are assigned to SOC alone will receive a similar degree of supervision alongside the 
training in the use of the infusion pump. This period can be extended for both treatment groups if dasiglucagon titration has not been finalized or if training of the 
family/caregivers has not been completed satisfactorily. 
c 
Patients will be contacted by the investigator by telephone the day after discharge. The investigator will ask the parent(s)/guardian if they have any questions about the trial 
procedures and whether their child has experienced any AEs. 
d In Treatment Period 2, patients who were assigned to SOC treatment only in Treatment Period 1 will be hospitalized for the first 1-2 days of Week 5. 
e 
Visit 7 can be used as the first visit for Trial ZP4207 17106 (long-term extension trial) if the patient is continuing in long-term extension trial. 
f 
Length/height will be measured at Screening only. 
g An echocardiogram performed within 1 month of screening can be used. 
h Vital signs include blood pressure, heart rate, respiratory rate, and SpO2. 
i 
A serum pregnancy test will be performed for girls of childbearing potential. 
j 
Clinical laboratory tests include hematology and biochemistry. 
k Any anti-dasiglucagon antibody-positive patient (treatment induced or treatment boosted) will be monitored at an additional follow-up visit, preferably 16 weeks after the last 
ADA-positive sample. Patients completing the trial before the ADA screening and confirmatory assays have been approved by the FDA and who do not continue treatment in 
the long-term extension trial will have this additional visit 16 weeks after the end of trial visit (Visit 8). 
l
The sample for ADAs should be taken prior to dosing of dasiglucagon in Treatment Period 1.
m Continuous glucose monitoring is required during Weeks 2-4 of Treatment Period 1 and Weeks 6-8 of Treatment Period 2. 
n The fasting tolerance test will be stopped when PG is ≤60 mg/dL (3.3 mmol/L) and then ketones, insulin, and free fatty acids will be measured. 
o
The fasting tolerance test at Visit 5 should take place before initiation of dosing in Treatment Period 2 but while the patient is still on CGM.
p At screening, dispense diary and instruct patients’ parent(s)/guardian in its use. At all other visits, the parent(s)/guardian will return the completed diary and obtain a new one. 
q The PedsQL (parent-reported versions) and CHI disease-specific questionnaires should be the first assessments performed at each visit. 
r 
ECG should be performed at the start of the visit and at 24 ± 4 hours after initiation of trial drug for patients initiating treatment. 
s 
Vital signs should be measured at the start of the visit and at 6 ± 1, 12 ± 2, and 24 ± 4 hours after initiation of the trial drug for patients initiating treatment.  
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18.2. Investigator’s Agreement 
PROTOCOL NUMBER: 
ZP4207-17109 
PROTOCOL TITLE: 
A Two-Period, Open-label Trial Evaluating the Efficacy and 
Safety of Dasiglucagon for the Treatment of Children with 
Congenital Hyperinsulinism 
FINAL PROTOCOL: 
Version 14.0 (Germany), 12-Nov-2020 
The undersigned acknowledges possession of and has read the product information (e.g., IB) on 
the trial drug and have discussed these data with the trial monitor. Having considered fully all the 
available information, the undersigned considers that it is ethically justifiable to give the trial 
drug to selected patients in his or her care, according to the trial protocol. 
• He or she agrees to use the trial material, including trial drug, only as specified in the 
protocol. He or she understands that changes cannot be made to the protocol without prior 
written approval of the sponsor. 
• He or she understands that any deviation from the protocol may lead to early termination of 
the trial. 
• He or she agrees to report to the sponsor within time any clinical AE or abnormal laboratory 
value that is serious, whether or not considered related to the administration of trial drug. 
• He or she agrees to comply with the sponsor and regulatory requirements for the monitoring 
and auditing of this trial. 
In addition, he or she agrees that the trial will be carried out in accordance with the revised 
Declaration of Helsinki (2013) and the local laws and regulations relevant to the use of new 
therapeutic agents. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the trial. 
Principal Investigator: 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
Investigator’s name and address (stamp) 
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19. APPENDICES 
A. Contact Information 
B. Quality of Life Questionnaires 
C. Regulations and Good Clinical Practice Guidelines 
 
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20. ADDENDUM  
20.1. Administrative Information 
The Coordinating Investigator for Germany is: 
 
 
 
 
 
 
 
 
 
 
A list of all participating investigational sites, including name, address, and professional position 
of the Principal Investigator for each site is maintained in the trial master file.  
20.2. Device Information 
This clinical trial is being conducted solely to investigate the safety and efficacy of dasiglucagon 
usage in children with CHI. More information can be found in Section 6.2. 
This clinical trial is not being conducted to verify claims and new intended performance of the 
medical devices. No risks and device effects will be formally assessed, but only collected and, if 
appropriate, reported to the applicable bodies. The planned devices are only being used for the 
administration of dasiglucagon and to measure glucose levels since no other approved devices 
are available as an alternative for this rare disease. The protocol will be submitted to competent 
authorities and ethics committees for approval. If additional requirements are imposed by these 
bodies, those recommendations will be followed. 
20.2.1. Planned Devices 
20.2.1.1. Pump System Accu-Chek Spirit Combo  
The planned drug delivery pump Accu-Chek Spirit Combo System with its components as 
described in Section 10.3 will be used to administer the investigational drug dasiglucagon. The 
Accu-Chek Spirit Combo Pump is a portable, battery-operated pump indicated for subcutaneous 
or intraperitoneal continuous delivery of insulin for the management of diabetes mellitus in 
persons requiring insulin as prescribed by a physician. It is a CE-marketed Class IIb product 
under the EC directive 92/42/EEC and is also in conformity with the EU directive 1999/5/EC on 
radio and telecommunications terminal equipment. The manufacturer is Roche Diabetes Care 
GmbH, Sandhofer Str. 116, 68305 Mannheim - Germany.  
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The pump system consists of the following components: 
• Programmable Accu-Chek Spirit Combo pump with a display screen 
• Adapter that connects the cartridge to the infusion set 
• Batteries and battery key 
• Sterile disposables: 
• 
Accu-Chek Spirit 3.15-mL cartridge with luer-lock connection 
• 
Infusion sets:  
▪ Accu-Chek FlexLink Infusion set  
▪ Accu-Chek Ultraflex 
▪ Accu-Chek LinkAssist insertion tool 
▪ Accu-Chek Rapid-D Link Infusion set cannula 
▪ Accu-Chek Rapid-D Transfer Set 
The single-use disposable infusion sets and sterile cartridges are packed in sealed pouches and 
are sterilized with ethylene oxide. Pictures of the pump and system components are provided in 
the ZP4207-17109 Trial Materials Manual for further information. Additional available 
accessories for the Accu-Check Spirit Combo System are an alcantara pouch in black and a 
neoprene pouch in white with a belly belt. 
The trial sites will be supplied with the pumps and their components and will be asked to 
document receipt of this equipment. Each pump will be identified by a serial number that will be 
used for accountability and traceability; the device will be labelled “for investigational use only.” 
The trial sites must store the devices in a secure area with restricted access and at the storage 
conditions indicated in the user manual (+5ºC – 45°C). After a patient is enrolled into the trial, 
one (1) pump device will be allocated exclusively to this patient; disposables are not accounted 
for. Upon completion of the trial and if the patient is not continuing in the ZP4207-17106 trial, 
the pump must be returned to the site. The site will ship all returned pumps (with the exception 
of those continuing in 17106 trial) back to the sponsor upon completion of the trial. 
The Roche pump is CE-marked and marketed in Germany, and it can administer very low doses. 
The pump is designed to deliver 0.05 to 25.0 units of U l00 insulin per hour in basal rates, which 
corresponds to 2 to 1000 μg dasiglucagon per hour. This dosing accuracy allows reliable dosing 
of dasiglucagon between 10 and 70 μg per hour in the clinical trial. Further, this pump has been 
used in pediatric diabetes treatment in the EU since 2010. However, the Accu-Chek Spirit 
Combo pump system will not be used within its approved indication. The pump will be used for 
the administration of the investigational glucagon analogue dasiglucagon for the indication of 
CHI. Additional compatibility testing and assessments were performed to ensure that the Accu-
Check Spirit Combo pump system and its components are not adversely affected by using 
dasiglucagon instead of insulin. Also, testing was performed to ensure that dasiglucagon is stable 
and effective when administered via this pump system. The general management of the device, 
as well as the duration of contact of the pump material and infusion sets with human tissue, will 
be based on the approved intended use of the device. The complete infusion set will be changed 
every 2 days (48 hours) for the Accu-Chek Rapid-D link infusion set, and every 3 days (72 
hours) as a maximum for the Accu-Chek FlexLink infusion set. Only the application and dosage 
of dasiglucagon via the Accu-Chek pump system requires an off-label change in practice 
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compared to the procedure described in the general instruction for use for Accu-Chek Spirit 
Combo pump system. The pump is programmed to reflect doses of insulin in units (U), whilst 
dasiglucagon requires weight-based dose administration (μg). The site staff and the patient’s 
parent(s)/guardian(s) will be instructed on the procedures for filling the content of the trial drug 
vials into the cartridge to be used in the infusion pump and how to convert dasiglucagon (μg) 
into units (U) as shown on the pump display. For this purpose an extensive, trial-specific 
instruction for use was developed to accommodate the training of site staff and the patient’s 
parent(s)/guardian(s) as described in Section 10.12.  
20.2.1.2. Self-Monitoring Plasma Glucose StatStrip Xpress2 
To assess plasma glucose levels and events of hypoglycemia, SMPG measurements will be 
taken. The plasma glucose level will be assessed at least 3 times daily and in cases of suspected 
hypoglycemia throughout the trial.  
The hand-held StatStrip Xpress2 meter GLU/KET from Nova Biomedical is to be used to 
measure glucose and ketone levels in the design of the trial. The ketone measurement will only 
be performed by trial staff when the patient is in the clinic.  
The SMPG meter manufactured by Nova Biomedical is a small (size of 98.0 x 64.0 x 22.9 mm 
and a weight of 78.5g) battery-powered meter. Blood sample strips are inserted and glucose (in 
mg/dl or mmol/L) and ketone values (in mmol/l) will be displayed on the screen. Function and 
data selection are done by choosing 1 of 3 buttons. Up to 400 measurements can be stored in the 
device memory. 
The test strip is designed with an electrode that measures glucose levels. Glucose in the blood 
sample mixes with reagent on the test strip, which produces an electric current. The amount of 
current that is produced depends on the amount of glucose in the blood. The electrical current is 
detected by the monitor and displayed as the glucose value. The test strip is designed such that 
when a drop of blood touches the end of the strip, the blood is drawn into the reaction space via 
capillary action. Test strips are available in cartons of 100 strips: 50 strips/vial. Additionally a 
QC control glucose/ketone solution is provided to test device functionality. 
The manufacturer Nova Biomedical Corporation, 200 Prospect Street, Waltham, MA 
02454-9141 – USA (European Authorized Representative Nova Biomedical U.K.; Innovation 
House Aston Lane South, Runcorn, Cheshire WA7 3FY, UK) have self-declared conformity 
with the EU Directive 98/79/EC In Vitro Diagnostic Medical Device Directive. This SMPG 
device is marketed as an In Vitro Diagnostic Device. The SMPG device is intended for in-vitro 
diagnostic use by health care professionals and for point-of-care usage in the quantitative 
measurement of glucose in fresh capillary, venous, arterial, and neonate whole blood; it can also 
be used for quantitative determination of beta-hydroxybutyrate-ketone in fresh capillary and 
venous blood samples. It is not intended for diagnosing or screening for diabetes. 
The SMPG device is reusable with single-use test strips. The SMPG device is not sterile; 
however, the strips themselves are in sterile packaging. Once the vial containing the strips is 
opened, the single strips may be used for 180 days or until the expiration date printed on the 
label has been reached, whichever comes first. The patient’s blood will be drawn via single-use 
lancing devices and a drop is applied to the strip. The strip is then inserted into the device and the 
glucose level is displayed.  
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The rationale for selecting this device for the clinical trial is that this blood glucose meter is the 
only one approved for use in neonates in an intensive care unit setting, based on its accuracy and 
extensive testing for possible concomitant medication interference. No BG meter for use by lay 
person in the home care setting is approved for the age group <1 year. To ensure consistency of 
data between the hospitalized and home-care periods in the trial, it was deemed preferable to 
continue with the same BG meter, rather than change to ones approved for use by lay persons in 
home-care settings, but that were not approved for this specific age group. 
The trial sites will be supplied with the StatStrip Glucose Xpress2 meter and the StatStrip 
Glucose and ketone test strips by the sponsor, and are asked to document the receipt of the 
material. Each SMPG is identified by a serial number that will be used for accountability and 
traceability and the device is labelled as “for investigational use only.” The trial sites are asked to 
store the devices in a secure area with restricted access at the storage conditions indicated in the 
user manual (+1ºC – 30ºC); the QC Control GLU/KET solution must be stored between +15-
30ºC. After a patient is enrolled into the trial, 1 SMPG device is exclusively allocated to that 
patient; disposable accessories are not accounted for. Upon completion of the trial and if the 
patient is not continuing in the ZP4207-17106 trial, the SMPG device has to be returned to the 
site. The site will ship all returned SMPG devices back to the sponsor upon completion of the 
trial. 
The same SMPG StatStrip Glucose Xpress2 meter will be used for each enrolled patient during 
the hospital stay and at home. The home assessments will be performed by the 
parent(s)/guardian(s); however, the use of the device by a lay-person is outside the intended 
purpose. The risk resulting from this deviation from the intended purpose will be minimized by 
offering extensive training of the parent(s)/guardian(s) by the site staff, before independent 
measurements are performed.  
Upon return to the site, the SMPG data will be uploaded to a tablet provided to the site 
personnel. The trial tablet is loaded with the applicable software for sending the SMPG data to 
the Vitalograph Web Portal.  
20.2.1.3. Dexcom Platinum Professional G4 Continuous Glucose Monitoring System 
In this trial, the Dexcom Platinum Professional Continuous Glucose Monitoring system G4 from 
Dexcom will be used. The Dexcom G4 is indicated for detecting trends and tracking patterns in 
patients (aged 2 and older) with diabetes. The system is intended for single-patient use in the 
home setting and also in healthcare facilities. It is indicated for use as an adjunct device to 
complement, not replace, information obtained from standard home glucose-monitoring devices. 
The G4 Platinum system aids in the detection of episodes of hyperglycemia and hypoglycemia, 
facilitating both acute and long-term therapy adjustments, which may minimize their excursions. 
Interpretation of CGM G4 results should be based on the trends and patterns noted in several 
sequential readings over time.  
The system components include the following:  
• Sensor (Disposable) – comprises a sensor applicator, an adhesive pad, transmitter mount, 
and the sensor probe. The sensor can be worn for up to 7 days. The sensor is a sterile device 
inserted by the user into the abdominal subcutaneous tissue using the applicator for that 
purpose. The applicator is attached to the surface of the skin with a standard medical grade 
adhesive pad. The applicator is a 26-gauge introducer needle that contains the sensor probe. 
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The needle is not exposed, or even visible, to the user during the insertion process. After 
deployment of the introducer needle, the needle is retracted back into the applicator. The 
sensor probe remains beneath the surface of the skin and uses the enzyme glucose oxidase to 
convert the glucose in the interstitial fluid around the sensor into an electrical current 
proportional to the ambient glucose concentration. The applicator is detached and discarded 
by the user, exposing a transmitter mount ready for placement of the transmitted current and 
signal. 
• Transmitter – The G4 Platinum transmitter component is a miniature radio transmitter 
operating at an internationally accepted radiofrequency. After sensor insertion and removal 
of the applicator, the user manually places the transmitter into the transmitter mount on the 
adhesive pad already attached to the skin. The transmitter contains all the electrical circuitry 
necessary for the operation of the electrochemical sensor and all the radiofrequency circuitry 
necessary to transmit the sensor signal to the receiver. The transmitter collects the small 
electrical current from the sensor and transmits the sensor signal wirelessly to the receiver at 
regular 5-minute intervals. The transmitter is reusable and can be used for repeated 7-day 
sessions by a single user over the lifetime of the battery encased in the device. 
• Receiver – The G4 receiver is a small hand-held device that contains an antenna and the 
associated electrical circuitry to receive the wireless sensor signal from the transmitter. The 
receiver contains a rechargeable battery. In typical use, the receiver may last for up to 3 days 
before requiring recharging. The user must maintain the receiver within 6 meters or less of 
the transmitter, which is attached to the sensor on the body. The receiver also contains 
calibration and signal processing algorithms required to convert the sensor electrical signal to 
glucose values. Calibrations are performed twice daily by the patient’s parent(s) /guardian(s) 
using measurements from a standard blood glucose meter device and manually entered into 
the receiver. In this trial the StatStrip Xpress2 meter GLU/KET from Nova Biomedical will 
be used to calibrate the CGM. 
Other accessories include the following: 
• Receiver USB charging / download cable 
• Alternating current (AC) power adapter - MT21255 
• User’s guide 
• Site training checklist 
• Receiver shield pack containing receiver shield, square seals, triangle seal, and acoustic 
spacer 
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The manufacturer is Dexcom, Inc. located at 6340 Sequence Drive – San Diego, CA 92121 
United States of America. The European Authorized Representative is MediTech Strategic 
Consultants B.V., Maastrichterlaan 127-129, 6291 EN Vaals, the Netherlands. The following 
device classifications and rules were applied to demonstrate compliance with the Medical Device 
Directives: 
• Sensor: Class IIb: Rule 8 according to Annex IX of the MDD 93/42/EEC & 2007/47/EC 
• Transmitter/SBT and Receiver: Class IIa, Rule 10 according to Annex IX of the 
MDD 93/42/EEC and 2007/47/EC 
• Dexcom G4 Platinum System: Class IIb, Rule 8 according to Annex IX of the 
MDD 93/42/EEC and 2007/47/EC 
The associate notified body is the British Standards Institution. The device has been marketed 
since October 2012. 
The system components (applicator, transmitter housing, insertion needle and sensor are 
sterilized via electron beam radiation using the (VD)max22 method. Transmitters and receivers are 
not sterile products. 
The trial sites will be supplied with the Dexcom Platinum CGM system G4 by the sponsor and 
are asked to document the receipt of the material. Each CGM is identified by a serial number 
which will be used for accountability and traceability and the device is labelled as “for 
investigational use only.” The trial sites are asked to store the devices in a secure area with 
restricted access at the storage conditions indicated in the user manual: 
• Sensors (+2°C- 25°C) 
• Transmitter and receiver (0°C – 45°C)  
After the patient is enrolled into the trial, a CGM device is allocated exclusively to this patient; 
disposable materials are not accounted for. Upon completion of the trial, the CGM must be 
returned to the site. The site will ship all returned CGMs back to the sponsor upon completion of 
this trial. 
Congenital hyperinsulinism is characterized by frequent, often severe episodes of hypoglycemia 
due to over-secretion of insulin regardless of blood glucose. Therefore, CHI closely mimics the 
exogenous insulin overdose occurring in insulin-dependent diabetes management. The 
CGM device is being used in this clinical trial to confirm potential treatment effects on a 
continuous basis.  
The rationale for selecting the Dexcom G4 CGM device for this clinical trial is that it can be 
used in a blinded mode. By using the blinded mode, the patient’s parent(s)/guardian(s) and the 
investigator will not be able to make any treatment decisions or change behavior based on the 
CGM readings. 
The same Dexcom Platinum G4 system will be used by the patient during the hospital stay, as 
well as at home. For the purpose of this trial the device will be used outside the intended purpose 
in regard to the age of the patients (3 months or older instead of 2 years and older) and in regard 
to the indication (CHI instead of Diabetes). No mechanical or design changes have been made to 
the device. The CGM device is used as intended according to the CE mark, except for the age 
group and the disease. The essential requirements testing performed for CE marking is assessed 
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applicable for proposed use. Additionally, literature shows that CGMs have been successfully 
used in infants and neonates.23 The risk resulting from this deviation from the intended purpose, 
in terms of age, will be minimized by offering extensive training to parent(s)/guardian(s) by the 
site staff, before the device and its components are used independently. 
The results of the CGM assessments are blinded for review by patient(s)/parent(s)/guardians and 
trial staff. The display with be visible and the menu functions available for the user, but the 
display will not show any measurements nor will any alarm go off based on the measurements. 
The device will still indicate when calibration is needed (as if the device was in unblinded 
mode). At every patient’s onsite visit, the site staff will transfer data of the CGM device via the 
CENDUIT Data Agent, after the device has been initially registered within the CENDUIT IRT 
system. Full instructions on data transfer are available in the CENDUIT user manual. 
20.2.1.4. Other Medical Devices 
The following medical devices will be used within their intended purpose during this trial: 
• BD Lancet – BD Microtainer® CAL – contact-activated lancet 
• Disinfecting wipes (alcohol pads) 
• Disinfecting wipes – Diabete ezy 
The provided devices are disposable; they will be provided to the patient but not accounted for. 
20.2.1.5. Risk Evaluation for Off-label Use of Devices 
20.2.1.5.1. Anticipated Clinical Benefit of Planned Devices 
The main aim of this clinical trial is to assess the safety and efficacy of the investigational drug 
dasiglucagon. To achieve this, the Accu-Chek Spirit Combo Pump system, the Self-Monitoring 
Plasma Glucose StatStrip Xpress2 and Dexcom G4 devices are utilized in this trial outside their 
intended use. There is no direct clinical benefit anticipated by using the Accu-Chek  Spirit 
Combo Pump except the administration of dasiglucagon and therefore, only an indirect benefit 
can be anticipated, resulting from the drug administration as referenced in section 5.3.5. The 
clinical benefit of the SMPG is to help to assess if patients undergo hyper/hypoglycemic events 
requiring adjustments to gastric and oral feeds or dose. For the usage of the CGM, there is no 
direct clinical benefit anticipated for the patients, but the CGM data will help to confirm 
treatment effects independent from parents’/guardians’ ability to suspect hypoglycemia.  
20.2.1.5.2. Risks Associated with the Planned Devices and their Control 
A risk analysis according to EN ISO 14971:2012 was performed specifically for risks related to 
the off-label use of the planned devices, to identify and mitigate potential risks due to the off-
label use of the devices. The analysis rated risks based on their probability of occurrence and the 
severity of their consequence. Unacceptable risk levels were defined and risks, meeting this 
definition were mitigated as far as possible to get to an acceptable level. Results of the risk 
analysis were entered into a risk management report. The identified risks were evaluated and risk 
mitigation measures were and will be implemented throughout this trial. The main task to 
mitigate the risks is to educate site staff, parents and guardians on the proper use of the devices 
to minimize the risks associated with the off-label use. 
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The following residual risks were identified, which will be specifically addressed in the planned 
training of the users and thereby risks will be mitigated: 
Accu-Chek® Spirit Combo Pump System and Self-Monitoring Plasma Glucose (SMPG) 
meter (Nova Biomedical / Xpress2 GLU/KET) 
Training will cover the following aspects: 
• Recognition of hypo- and hyperglycemia in the patient 
• Response to hypo- and hyperglycemia 
• Usage of the devices according to the instructions for use in the trial 
• Communication between patients/parents/guardians and the medical professionals of the trial 
team. 
Dexcom G4 Continuous Glucose Monitoring (CGM) device 
The training will cover the following aspects: 
• Avoid to cover the sensor by the diaper in babies  
• Avoid that the transmitter is grabbed by baby by covering it with bandage or clothes 
• Avoid that the transmitter is misplaced under diaper area or child pollutes around diaper area 
Additionally, the assessment identified other risks caused by potential Accu-Chek® Spirit Combo 
pump system/drug interaction e.g. unintentional misappropriation of drug delivery or hazards 
caused by direct drug/device interactions. These potential risks were assessed by additional 
compatibility and in-use stability testing and no unacceptable risk was noticed. Flow-rate 
assessments were performed and a conversion table for the use of dasiglucagon in the Accu-
Chek® Spirit Combo pump system was developed and tested in a Human Factor trial. This 
conversion table was included with further instructions in a trial specific “Instruction for Use”  
for the combination of dasiglucagon with the pump system. By this measure the risk of 
misappropriation of drug delivery was reduced to an acceptable level. 
20.2.1.5.3. Possible Interactions with Concomitant Medical Treatment 
The use of the planned devices is not expected to interfere with other concomitant medical 
treatments, except those treatments referenced in Section 10.11.2. 
20.2.1.5.4. Risk/Benefit Assessment 
At the present time there are no known CE Marked devices intended for the delivery of 
dasiglucagon for the treatment of CHI. Additionally, there are no known devices intended to 
monitor glycemic control in children with CHI. Since there are no devices currently approved to 
treat this condition, off-label use of the Accu-Chek Combo Insulin pump system, Dexcom G4 
CGM and Nova Biomedical / Xpress2 GLU/KET for the purpose of delivering dasiglucagon and 
monitoring glucose levels potentially presents a beneficial alternative to the standard clinical 
practices of current treatment options, continuous gastric infusion and pancreatectomy for 
controlling CHI. 
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The most relevant risks resulting from the off-label use in terms of their potential to cause harm 
in relationship to their probability are the following: 
• Lay persons using devices which are not used according to their intended use e.g. perform 
and interpret blood glucose measurements 
• Lay person applying devices which require invasive procedures at home for very young 
children in skin areas which might be contaminated due to the expectable uncleanliness of 
babies and the fact that they might carry diapers. 
To evaluate the risks and the benefits of the clinical trial, the duration of the trial and the effect of 
the foreseeable risks during the trial period are compared to the current standard of care 
treatment for CHI. This comparison is done without taking the possible positive results of the 
trial into account. A positive trial outcome would most likely result in a change in the treatment 
of CHI towards a continuous delivery of dasiglucagon with devices that are proven to be save in 
use by children. 
In general, the current standard of care (SoC) treatment for patients with CHI bears higher risks 
than risks associated with the clinical trial participation. The current risks associated with the 
SoC treatment result from: 
• Continuous application of glucose rich liquids via intravenous infusion (infection, skin 
injury, thrombi, contamination, dosage and content errors, risk of volume overload) 
• Frequent tube feedings or gastric infusions 
• For patients on diazoxide treatment, the more common side effects comprise hypertrichosis, 
fluid retention, and gastrointestinal symptoms 
• For patients on somatostatin analog (octreotide or lanreotide [long acting]) possible side 
effects include necrotizing enterocolitis, gallstones, and hepatitis 
• Pancreatectomy (and its related exo/endocrine complications, particularly the development of 
insulin-dependent diabetes) 
• Local wound infection  
Irrespective if the patient participates in the planned clinical trial or is treated by SoC, 
parent(s)/guardian(s) need to be able to detect and respond to hypoglycemic events, therefore the 
risk of not noticing such a situation is not increased by participating in the trial. The blood 
glucose measurements are performed by SMPGs, where the general functionality of the device 
can be considered as being equivalent to the proposed Nova Biomedical SMPG. It can be 
concluded, that there will be no additional risks for the clinical trial participants by using the 
Nova Biomedical SMPG compared to patients who do not take part in the clinical trial, provided 
the users are adequately trained.  
The clinical trial aims to determine practicable procedures for treating CHI with dasiglucagon 
that can eliminate, minimize or postpone the need for continuous application of glucose via 
intravenous infusions, frequent tube feedings or continuous gastric infusions and finally, 
pancreatectomy in the treatment of children with CHI. This will significantly reduce the risks for 
the patient’s health. The nature of the residual risks introduced by the off-label use of the devices 
selected for the clinical trial is similar to the risks which already exist in the treatment of these 
patients and their severity is only minor. The most relevant risks result from the usage of the 
CGM, which is not intended to be used directly for the patient care in the trial. However, the 
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duration of the trial will be shorter than the duration of the disease or of its long-term side-effects 
(either of the disease or the treatment). Thus, the potential benefit of a positive trial outcome is 
estimated higher than the risks introduced, especially when taking into account the risks which 
are present by the current standard of care treatment of CHI. 
20.3. Device-related Safety Section 
20.3.1. Anticipated Adverse Device Effects 
The following anticipated ADEs may be associated with the use of these medical devices, 
together with those associated with the application of dasiglucagon. All AEs and ADEs will be 
assessed if they meet the requirements for competent authority reporting.  
The following device-related possible complications/AEs are anticipated: 
20.3.2. Pump system Accu-ChekSpirit Combo  
• Ketoacidosis, hypo- or hyperglycemic events resulting from incorrect pump usage, a 
damaged pump, or infusion set blockage24,25 
• At infusion site: 
• 
Local infection 
• 
Irritation 
• 
Local pain 
• 
Redness  
• 
Swelling 
• 
Lumps 
• 
Heat 
• Strangulation if tubing becomes wrapped around the neck 
20.3.3. Self-monitored Plasma Glucose StatStrip Xpress2 
Since the StatStrip Xpress 2 Blood Glucose Monitoring System is intended for use outside the 
body, only the following limited ADEs are expected: 
• Hypo- or hyperglycemic events due to incorrect usage or damaged meter or strips 
• Indirectly related to SMPG: Local infections caused by the single-use lancing devices to 
obtain blood 
20.3.4. Continuous Glucose Monitoring Dexcom Platinum Profession G4 
The following events are possible ADEs of inserting a sensor or wearing the adhesive patch: 
• Local infection 
• Inflammation 
• Pain or discomfort 
• Bleeding at the glucose sensor inserting site 
• Bruising 
• Itching 
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• Scarring or skin discoloration 
• Hematoma 
• Tape irritation 
• Sensor or needle fracture during insertion, wear of removal 
The following risks are inherent to the device, but not anticipated for the trial since the device 
will be used in a blinded manner and no treatment decisions will be based on the CGM results. 
However, there are potential risks due to missed alerts, false alerts, false-negative hypoglycemia, 
hyperglycemic readings, false-positive hypoglycemia, and hyperglycemia readings by the device. 
There are additional possible risks if the system inaccurately calculates the rate of change of 
glucose.26 
20.4. Protocol Clarifications 
20.4.1. Informed Consent 
A patient is considered enrolled in the trial as soon as the patients’ parent(s)/guardian(s) 
(according to local law) have signed the EC-approved ICF.  
20.4.2. Vulnerable Population 
As discussed in Section 8.1 children between the ages of 3 months and 12 years (both inclusive) 
with CHI will be enrolled in this clinical trial. The informed consent process is referenced in 
Section 9.2.1, Inclusion Criteria, Section 11, Trial Procedures, and Section 16.2, Patient 
Information and Informed Consent. No vulnerable patients other than children are planned to be 
enrolled in this trial and no enrollment under an emergency situation is allowed. 
20.4.3. Addition to Statistical Section 
• Drop-out rate: With the planned sample size, the overall alpha level is strongly controlled, 
remaining at or below 0.05. Due to the short period of trial conduct, 4 weeks for Treatment 
Period 1 and another 4 weeks for Treatment Period 2, no formal drop-out rate was 
anticipated. 
• Pass/fail criteria: No pass/fail criteria were defined since no trial endpoints are device 
related 
• Criteria for termination of trial on statistical grounds: Please refer to Section 13.4.4.7 
Interim Analysis. 
• Procedures for reporting deviation from statistical plan: Since no medical device data 
will be evaluated statistically, no reporting of deviations from statistical plan are anticipated 
in regard to the devices. 
• Enrollment rate per investigational site: Anticipated enrollment for the German clinical 
trial sites is 0-5 patients per German site. For analysis involving trial site, if the number of 
patients per site is small, sites may be pooled for analysis, or omitted from statistical models. 
The final determination will be made prior to database lock. 
20.4.4. Protocol Deviations 
A protocol deviation is defined as an event where the investigator or site personnel did not 
conduct the trial according to the protocol. Investigators are not allowed to deviate from the 
protocol unless it is necessary to protect the life or physical well-being of a patient in an 
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emergency situation. Those emergency situations or other unforeseen circumstances that are 
beyond the investigator’s control, e.g., the patient did not attend scheduled visits or blood 
samples were lost by the laboratory, are still considered deviations. Deviations will be reported 
to the sponsor, regardless of whether or not they are medically justifiable or done to protect the 
patient in an emergency. All deviations will be reported in a timely manner on a protocol 
deviation form.  
In addition, the investigator is required to adhere to the ethics committee procedures for 
reporting protocol deviations. International regulatory body regulations require that investigators 
maintain accurate, complete, and current records, including documents showing the dates of and 
reasons for each deviation from the trial protocol. The site will receive a list of all site-specific 
deviations upon completion of the trial. 
Deviations include, but are not limited to the following list: 
• Failure to obtain informed consent prior to conducting trial-specific activities 
• Incorrect version of patient information and/or ICF used 
• Patient did not attend a visit or the visit was outside the required time frame 
• Assessments as detailed in the Schedule of Events (Table 2) were not conducted or were 
performed incorrectly 
• Adverse events and deficiency with SADE potential not reported by investigators 
within the required timeframe as specified in the protocol 
• Source data were permanently lost 
As addressed in Section 14.5.1 of the protocol, the CRA will review the site compliance with 
regard to deviations at each monitoring visit. The monitor will discuss any deviations directly 
with the investigator and will summarize the findings in a follow-up letter to the site.  
If a trial site deviates from the protocol, those deviations will be analyzed and re-training on the 
particular topic(s) will be initiated as appropriate, e.g., training on the informed consent process, 
training on visit window adherence, and planned assessments, etc. Such trainings will be 
documented on the training logs for the applicable roles. If despite all training efforts an 
investigational site continues to deviate from the trial protocol, a site can be discontinued from 
the trial as agreed upon by the Principal Investigator according to his or her signature on the 
Investigator’s Agreement in Section 18.2. 
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A. Contact Information 
Pharmacovigilance 
Name: 
 
Address: 
 
 
 
E-mail: 
 
Telephone: 
 
Technical Complaints 
Name: 
Zealand Pharma A/S Quality Assurance 
Email: 
 
 
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B. Quality of Life Questionnaires 
• Infants 1-12 Months: “PedsQL™ Pediatric Quality of Life Inventory Infant Scales –
Version 1 - Parent Report for Infants (ages 1-12 months)” 
• Infants 13-24 Months: “PedsQL™ Pediatric Quality of Life Inventory Infant Scales –
Version 1 - Parent Report for Infants (ages 13-24 months)” 
• Parent Report for Teens 13-18 Years: “PedsQL™ Pediatric Quality of Life Inventory – 
Version 4 - Parent Report for Teens (ages 13-18 yrs)” 
• Parent Report for Children 8-12 Years: “PedsQL™ Pediatric Quality of Life Inventory – 
Version 4 - Parent Report for Children (ages 8-12 yrs)” 
• Parent Report for Children 5-7 Years: “PedsQL™ Pediatric Quality of Life Inventory – 
Version 4 - Parent Report for Young Children (ages 5-7 yrs)” 
• Parent Report for Toddlers 2-4 Years: “PedsQL™ Pediatric Quality of Life Inventory – 
Version 4 - Parent Report for Toddlers (ages 2-4 yrs)” 
• CHI Disease-Specific Questionnaire Developed by the Patient Association, Congenital 
Hyperinsulinism International, and Taken from the Patient-Reported Registry, the HI Global 
Registry 
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C. Regulations and Good Clinical Practice Guidelines 
1. 
Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
Refer to the following European Directives and applicable regulations/guidances: 
• European Directive 2001/20/EC and related guidance documents 
• European Directive 2005/28/EC and related guidance documents 
 
2. 
Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2_G
uideline.pdf 
 
 
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