Clinical Trials Register

Summary
EudraCT Number:	2016-002127-28
Sponsor's Protocol Code Number:	16016762
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-05-31
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2016-002127-28

A.3

Full title of the trial

The impact of subcutaneous glucagon
before, during and after exercise. A study in patients with type 1 diabetes mellitus

Virkningen af glukagon før, under og efter træning
Hos personer med type 1 diabetes

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

The impact of a glucagon injection before, during and after exercise. A study in patients with type 1 diabetes mellitus

Virkningen af glukagon før, under og efter træning
Hos personer med type 1 diabetes

A.3.2

Name or abbreviated title of the trial where available

The impact of a glucagon injection before, during and after exercise

A.4.1

Sponsor's protocol code number

16016762

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Hvidovre University Hospital
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Danish Diabetes Association
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Zealand Pharma
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hvidovre University Hospital
B.5.2	Functional name of contact point	Isabelle
B.5.3	Address:
B.5.3.1	Street Address	Kettegård Allé, 30
B.5.3.2	Town/ city	Hvidovre
B.5.3.3	Post code	2650
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4551519085
B.5.6	E-mail	Isabelle.Isa.Kristin.Steineck@regionh.dk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	GlucaGen
D.2.1.1.2	Name of the Marketing Authorisation holder	Novo Nordisk
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	GlucaGen
D.3.2	Product code	SUB02347MIG
D.3.4	Pharmaceutical form	Powder and solution for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate and solvent for solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with type 1 diabetes mellitus

Personer med type 1 diabetes mellitus

E.1.1.1

Medical condition in easily understood language

Metabolic disease in which a person has high blood glucose values due to insufficient insulin production

Metabolisk sjukdom med för höga blodsocker på grund av avsaknad av insulin produktion.

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10012608
E.1.2	Term	Diabetes mellitus insulin-dependent
E.1.2	System Organ Class	100000004861

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To compare the increase in plasma glucose after 200µg glucagon given either after exercise or after resting for 45 minutes.

E.2.2

Secondary objectives of the trial

2. To determine whether a subcutaneous glucagon injection just before exercise has a greater impact on hepatic glucose production and thereby is superior to an injection after exercise in preventing hypoglycemia during and two hours after exercise.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age 18 - 70 years
- T1D ≥ 2 year
- BMI 20-30 kg/m2
- Insulin pump ≥ 1 year.
- HbA1c < 69 mmol/mol (8.5 %)
- Hypoglycemia awareness (reported by Gold et al.)
- Use of carbohydrate counting and the insulin pump bolus calculator for all meals

E.4

Principal exclusion criteria

Allergy or intolerance to lactose or GlucaGen® (Novo Nordisk, Bagsværd, DK)
- Impaired renal function (eGFR < 60 ml/min/1.73m2)
- Liver disease with ALAT > 2.5 times the upper limit of the reference interval
- Use of anti-diabetic medicine (other than insulin), per oral corticosteroids or other drugs affecting glucose metabolism during the study period or within 30 days prior to study start
- Known or suspected alcohol or drug abuse
- Other concomitant medical or psychological condition that according to the investigator's assessment makes the patient unsuitable for study participation
- Females who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods
- Inability to understand the patient information and to give informed consent
- Physical or mental incapacity to perform exercise
-People with vigorous intensity aerobic physical activity such as swimming, jogging, aerobics, football, tennis, gym, workout etc, more than 3 hours or more per week.
- Chronic use or unable to stop acetaminophen (paracetamol) use
-Allergy to the patch of CGM sensors

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is peak plasma glucose achieved within 2 hours after the 200 μg subcutaneous glucagon injection. In the primary analysis, we will compare the peak plasma glucose after exercise and after resting.

E.5.1.1

Timepoint(s) of evaluation of this end point

2 hours after injection of glucagon as mentioned in E.5.1

E.5.2

Secondary end point(s)

1) The time-to-peak value after glucagon injection.
2) Duration of the glucagon effect; equal to the time point from glucagon injection to when plasma glucose is below baseline.
3) The glycaemic effect, calculated as the total area under the curve (tAUC) after each glucagon injection.
4) Changes after each glucagon injection (ketone bodies, lactic acid glucagon, and FFA/TG).
5) Differences of continuously glucose monitoring placed at different sites on the patient during exercise compared to plasma glucose monitoring.
6) Number of events of hypoglycemia (plasma glucose ≤3.9 mmol/l) in the three study groups.
7) Number of re-events of hypoglycemia (plasma glucose ≤3.9 mmol/l) 30 minutes after first event in the three study groups.
8) Number of rebound hyperglycemia (plasma glucose ≥10.0 mmol/l).
9) To test the difference in mean absolute relative difference (MARD) during the study visits between the two sensor sites (CGMarm vs. CGMabdomen) with the YSI 2300 STAT PLUS as the reference value.
10) To test the difference in MARD between the two CGM sites (CGMarm vs. CGMabdomen) during the four days after the study day using the daily 8 prespecified plasma glucose measurements by Bayer Contour Link as the reference value.
11) To test the difference in MARD during the hypoglycemia range (≤3.9 mmol/l) of the study visits between the two sensor sites (CGMarm vs. CGMabdomen) with the YSI 2300 STAT PLUS as the reference value.
12) To test the difference in MARD during the euglycemia range (>3.9 mmol/l and < 10.0 mmol/l) of the study visits between the two sensor sites (CGMarm vs. CGMabdomen) with the YSI 2300 STAT PLUS as the reference.
13) To test the difference in MARD during the hyperglycemia range (≥10.0 mmol/l) of the study visits between the two Dexcom G4 sensor sites (CGMarm vs. CGMabdomen) with the YSI 2300 STAT PLUS as the reference value.
14) To test the difference in MARD between the two sensor sites (CGMarm vs. CGMabdomen) from day 1- 7 with the Bayer Contour Link as the reference value.
15) To compare the rate-of change (ROC) accuracy of the two sensors with the actual rate-of-change (ROC) of PG measured by the YSI 2300 STAT PLUS.
16) To determine the Precision Absolute Relative Difference PARD (=CGM readings of one system will be subtracted from CGM readings of the other system, and this difference will be divided by the average of the CGM readings of the abdominal sensors, i.e. CGMabdomen is used as reference):
a. from day 1- 7 with
b. during the study visits
17) To test the difference of the sensors’ sensitivity and specificity to detect a hypoglycemic event. A hypoglycemic period is defined as three consecutive blood glucose values ≤3.9 mmol/l measured with 5 minutes interval on a YSI or one measurements ≤ 3.9 mmol/l by self-monitoring of blood glucose by finger stick measurements.
18) To evaluate the point accuracy of both sensors with the Clarke error grid analysis
19) To evaluate the pressure induced sensor attenuation (PISA) by using a recent fault detection algorithm that can detect non-physiologic anomalous low sensor readings.
20) To fuse the data from the two sensors in order to have one combined processed CGM signal which is more accurate and has less uncertainty than the readings from the individual sensors. We will use novel data fusion techniques to achieve this goal

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluation is performed during the study days and 4 days after.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The subjects will go back to their normal treatment for type 1 diabetes mellitus.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-07-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-07-07

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