A Trial to Evaluate the Immunogenicity of Dasiglucagon and GlucaGen in Patients With Type 1 Diabetes Mellitus

A Phase 3, Randomized, Double-Blind, Parallel Group Safety Trial to Evaluate the Immunogenicity of Dasiglucagon and GlucaGen® Administered Subcutaneously in Patients With Type 1 Diabetes Mellitus (T1DM)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03216226

Enrollment

112

Registered

2017-07-13

Start date

2017-06-28

Completion date

2018-02-13

Last updated

2021-05-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypoglycemia, Diabetes Mellitus, Type 1

Keywords

Glucagon, Dasiglucagon

Brief summary

The trial's objective is to evaluate the immunogenicity of repeated single doses of dasiglucagon\* and GlucaGen following subcutaneous (SC) administration in patients with type 1 diabetes mellitus (T1DM) and further to evaluate the safety and tolerability of dasiglucagon and GlucaGen. \*dasiglucagon is the proposed International Nonproprietary Name (pINN) for ZP4207

Detailed description

Patients with T1DM were randomly assigned in a 1:1 ratio to receive 3 SC injections of either dasiglucagon (0.6 mg) or GlucaGen (1 mg), with 1 week between doses. Patients were followed for 15 weeks from the day of the first dose to assess the immune response. Patients with previous exogenic glucagon exposure were not excluded from the trial, but the information on previous glucagon administration was recorded to enable subgroup analyses. It was expected that 112 patients in total would be randomly assigned to treatment groups and treated. A total of 90 patients were expected to complete the trial (45 in each treatment arm). To qualify as completed, the patient had to be dosed according to the procedure described in the protocol and to have blood drawn for the antidrug antibody analyses as scheduled.

Interventions

DRUGdasiglucagon

Glucagon Analog

DRUGGlucaGen

Native Glucagon

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Informed consent obtained before any trial-related activities (trial-related activities are any procedure that would not have been performed during normal management of the patient) * Availability for the entire trial period * Age between 18 and 70 years, both inclusive * Male or female patients with T1DM for at least 1 year. Diagnostic criteria as defined by the American Diabetes Association * Hemoglobin A1c (HbA1c) \<10% * Stable anti-diabetic treatment for at least 1 month (e.g. within 10% insulin dose adjustment)

Exclusion criteria

* Previous administration of dasiglucagon (previously referred to as ZP4207) * Known or suspected allergy to trial medication(s) or related products * History of anaphylaxis or symptoms of severe systemic allergy (such as angioedema) * Previous participation (randomization) in this trial * Females who are pregnant according to a positive pregnancy test, actively attempting to get pregnant, or are lactating * Patients on a closed loop artificial pancreas * Receipt of any investigational drug within 3 months prior to screening * Active malignancy within the last 5 years * Congestive heart failure, New York Heart Association class II-IV * Inadequately treated blood pressure as defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥90 mmHg at screening * Current bleeding disorder, including use of anticoagulant treatment * Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma (i.e. insulin-secreting pancreas tumor) * Known or suspected HIV infection * Use of a systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs in the previous 28 days before Day 1 of this trial * Use of systemic corticosteroids, anti-inflammatory biological agents, kinase inhibitors or other immune modulating agents within the last 3 months prior to screening * Donation of blood or plasma in the past month, or in excess of 500 mL within 12 weeks prior to screening * A positive result in the alcohol and/or urine drug screen at the screening visit. Significant history of alcoholism or drug abuse as judged by the investigator or consuming more than 24 g alcohol per day for men, or more than 12 g alcohol per day for women. * Surgery or trauma with significant blood loss within the last 2 months prior to screening * Use of prescription or non-prescription medications known to cause QT prolongation

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Patients With ADA	104 days after the first dose	Percentage of the combined results of treatment-induced ADA-positive patients and treatment-boosted ADA-positive patients out of the total number of evaluable patients. ADA = antidrug antibodies.

Secondary

Measure	Time frame	Description
Percentage of Patients With Treatment-induced ADA	104 days after the first dose	Percentage of the total number of evaluable patients that were ADA negative at baseline and ADA positive after drug administration out of the total number of evaluable patients. ADA = antidrug antibodies
Percentage of Patients With Treatment-boosted ADA	104 days after the first dose	Percentage of baseline ADA-positive patients with significant increases (≥5-fold) in ADA titre after drug administration out of the total number of evaluable patients. ADA = antidrug antibodies
Characterization of ADA Response - Neutralizing Activity	104 days after the first dose	Percentage of ADA positive patients with ADA neutralizing activity. ADA = antidrug antibodies.
Characterization of ADA Response - Titer of Neutralizing Activity	104 days after the first dose	Titre of neutralizing activity of ADA positive patients. ADA = antidrug antibodies.
Characterization of ADA Response - Cross-reactivity	104 days after the first dose	Percentage of ADA positive patients with cross-reactivity towards endogenous glucagon. ADA = antidrug antibodies.
Characterization of ADA Response - Timing	104 days after the first dose	The timing of detected ADA response. ADA = antidrug antibodies.
Characterization of ADA Response - Duration	104 days after the first dose	The Duration of detected ADA response. ADA = antidrug antibodies.
Pharmacokinetics - Area Under the Plasma Concentration Curve	0-30 minutes	Area under the plasma concentration curve (AUC) 0-30 minutes at visit 2 and 4 (days 0 and 14). Plasma PK concentrations were measured before dosing and at 5, 10 and 30 minutes after dosing.
Pharmacokinetics - Maximum Plasma Concentration	90 minutes	Maximum plasma concentration (Cmax) at visit 2 and 4 (days 0 and 14). Plasma PK concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing.
Pharmacokinetics - Time to Maximum Plasma Concentration	90 minutes	Time to maximum plasma concentration (Tmax) at visit 2 and 4 (days 0 and 14). Plasma PK concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing.
Pharmacodynamics - Area Under the Effect Curve	0-30 minutes	Plasma glucose profiles, area under the effect curve (AUE) 0-30 minutes at visit 2 and 4 (days 0 and 14). Plasma glucose concentrations were measured before dosing and at 5, 10 and 30 minutes after dosing.
Pharmacodynamics - Change From Baseline Plasma Glucose	90 minutes	Change from baseline plasma glucose to maximum plasma glucose (CEmax) at visit 2 and 4 (days 0 and 14). Plasma glucose concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing.
Pharmacodynamics - Time to Maximum Plasma Glucose Concentration	90 minutes	Time to maximum plasma glucose concentration (Tmax) at visit 2 and 4 (days 0 and 14). Plasma glucose concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing.
Pharmacodynamics - An Increase in the Plasma Glucose Concentration of ≥20 mg/dL Within 30 Minutes After Treatment	30 minutes	An increase in the plasma glucose concentration of ≥20 mg/dL within 30 minutes after treatment at visit 2 and visit 4. Plasma glucose concentrations were measured before dosing and at 5, 10, 30, 60 and 90 minutes after dosing.

Countries

Austria, Canada, Germany, United States

Participant flow

Participants by arm

Arm	Count
Dasiglucagon (ZP4207) 3 repeated doses (s.c.injection) of 0.6 mg dasiglucagon, with 1 week between each dose. dasiglucagon: Glucagon Analog	57
GlucaGen 3 repeated doses (s.c.injection) of 1.0 mg GlucaGen, with 1 week between each dose. GlucaGen: Native Glucagon	54
Total	111

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	3	0
Overall Study	Deviation from protocol window during visit as patient had to leave for work	0	1
Overall Study	Patient unable to take time off work to come in for the third injection	1	0
Overall Study	Patient withdrawn prior to treatment. Patient veins unsuitable for blood draws	0	1
Overall Study	Protocol Violation	1	3

Baseline characteristics

Characteristic	Dasiglucagon (ZP4207)	GlucaGen	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	2 Participants	2 Participants	4 Participants
Age, Categorical Between 18 and 65 years	55 Participants	52 Participants	107 Participants
Age, Continuous	45.3 years STANDARD_DEVIATION 12.21	38.8 years STANDARD_DEVIATION 13.65	42.1 years STANDARD_DEVIATION 13.29
Body mass index	27.2 kg/m^2 STANDARD_DEVIATION 4.88	27.4 kg/m^2 STANDARD_DEVIATION 4.7	27.3 kg/m^2 STANDARD_DEVIATION 4.77
Body weight	82.9 kg STANDARD_DEVIATION 18.44	82.7 kg STANDARD_DEVIATION 16.25	82.8 kg STANDARD_DEVIATION 17.33
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	4 Participants	2 Participants	6 Participants
Race (NIH/OMB) Black or African American	2 Participants	0 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	50 Participants	52 Participants	102 Participants
Region of Enrollment Austria	15 Participants	15 Participants	30 Participants
Region of Enrollment Canada	28 Participants	26 Participants	54 Participants
Region of Enrollment Germany	9 Participants	8 Participants	17 Participants
Region of Enrollment United States	5 Participants	5 Participants	10 Participants
Sex: Female, Male Female	16 Participants	22 Participants	38 Participants
Sex: Female, Male Male	41 Participants	32 Participants	73 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 57	0 / 54
other Total, other adverse events	42 / 57	43 / 54
serious Total, serious adverse events	1 / 57	0 / 54

Outcome results

Primary

Percentage of Patients With ADA

Percentage of the combined results of treatment-induced ADA-positive patients and treatment-boosted ADA-positive patients out of the total number of evaluable patients. ADA = antidrug antibodies.