| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067584 |
| E.1.2 | Term | Type 1 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to demonstrate that dasiglucagon is superior to placebo following a single injection of 0.6 mg of dasiglucagon in treating hypoglycemia in children with type 1 diabetes mellitus (T1DM). |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives are:
- To confirm that a single dose of dasiglucagon [0.6 mg] is comparable to a single dose of GlucaGen® [1 mg/mL] in treating hypoglycemia in children with T1DM, (in accordance with the label, children below 25 kg body weight will be administered 0.5 mg GlucaGen®),
- To assess safety profile of dasiglucagon in children with T1DM,
- To assess pharmacokinetic (PK) profile of dasiglucagon in children with T1DM. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be included in the trial, patients have to fulfill all of the following criteria:
1. Following receipt of verbal and written information about the trial, patient, parent(s) or guardian(s) of the patient must provide signed informed consent before any trial-related activity is carried out*
2. Female or male patients with T1DM for at least 1 year, diagnostic criteria as defined by the American Diabetes Association, and receiving daily insulin and in good and stable medical condition
3. At least 6.0 years of age (inclusive) and less than 18.0 years.
Germany only: A “staggered approach” will be applied, whereby a positive safety assessment needs to be available for at least 10 patients who have completed the dosing visit in the overall trial before younger patients (6 to 11 years of age) may be enrolled.
4. Body weight ≥20 kg
5. Female patients must meet one of the following criteria:
a. Participant is of childbearing potential and agrees to use one of the accepted contraceptive regimens throughout the entire duration of the trial from screening until last follow-up visit. An acceptable method of contraception includes at least one of the following:
i. Abstinence from heterosexual intercourse
ii. Systemic contraceptives (birth control pills, injectable/implant/ insertable hormonal birth control products, transdermal patch); if the participant is using systemic contraceptives, she must use an additional form of acceptable contraception (iii or iv, below)
iii. Intrauterine device (with and without hormones)
iv. Condom with spermicide
or
b. Participant is of non-childbearing potential due to pre-puberty status or a medical condition confirmed by the investigator
6. Male patients must meet the following criteria: If sexually active, uses condom and partner practices contraception during the trial from screening and until last follow-up visit
7. Willingness to adhere to the protocol requirements
* Informed consent signatures must be obtained according to local regulations. |
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| E.4 | Principal exclusion criteria |
Exclusion criteria:
Patients meeting any of the following criteria during screening evaluations will be excluded from trial participation:
1. Females who are pregnant according to a positive urine pregnancy test, actively attempting to get pregnant, or are lactating
2. Known or suspected allergy to trial product(s) or related products
3. History of anaphylaxis or symptoms of severe systemic allergy (such as angioedema)
4. Previous randomization in this trial
5. History of an episode of severe hypoglycemia that required a third party assistance within a month prior to screening visit
6. History of hypoglycemic events associated with seizures or hypoglycemia unawareness in the last year prior to screening
7. History of epilepsy or seizure disorder
8. Receipt of any investigational drug within 3 months prior to screening
9. Active malignancy within the last 5 years
10. Congestive heart failure, New York Heart Association class II-IV
11. Current bleeding disorder, including anti-coagulant treatment
12. Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma (i.e. insulin secreting pancreas tumor)
13. Use of a daily systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs in the previous 28 days before Day 1 of this trial
14. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limit of the normal range (ULN), bilirubin >1.5 × ULN, estimated glomerular filtration rate <30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease study definition, or altered electrolyte values of clinical relevance for cardiac conduction, as judged by the investigator
15. Clinically significant abnormal electrocardiogram (ECG) at screening as judged by the investigator
16. Clinically significant illness within 4 weeks before screening as judged by the investigator
17. Surgery or trauma with significant blood loss within the last 2 months prior to screening
18. Patients with mental incapacity or language barriers which preclude adequate understanding or cooperation, who are unwilling to participate in the trial, or who in the opinion of the investigator should not participate in the trial
19. Any condition interfering with trial participation or evaluation or that could be hazardous to the patient
20. The use of prescription or non-prescription medications known to cause QT prolongation.
In addition, the following exclusion criteria at clinic admission on Visit 2, day 0 apply at the time of admission to the clinic, which is the day before clamp procedure:
Patients who meet one or more of the following exclusion criteria at the time of admission to the clinic will be excluded from the dosing visit, however, the visit can be rescheduled 1-7 days later. The dosing visit can only be rescheduled once.
1. Atypically strenuous exercise within 4 days prior to dosing, as judged by the investigator. Exercise during the trial should follow patient’s typical routine, and should not exceed a near maximum intensity for more than 20 minutes per day, or moderate intensity for more than 90 minutes per day
2. Clinically significant illness within 4 weeks before dosing, as judged by the investigator
3. Consumption of alcohol within 24 hours prior to dosing visit, determined by positive results from an alcohol breath test
4. Not fasting from 22:00 hours the evening prior to dosing, apart from water.
5. The use of any non-prescribed systemic or topical medication, except routine vitamins and occasional use (as judged by the investigator) of acetylsalicylic acid and paracetamol within 2 weeks prior to dosing. Treatment with insulin, including analogs, is allowed
6. Use of insulin degludec or insulin glargine U300 within 72 hours prior to dosing; or use of other long-acting insulins (e.g. insulin glargine U100 or insulin detemir) within 48 hours prior to dosing; or use of neutral protamine Hagedorn insulin NPH within 22 hours prior to dosing
7. Use of any short acting (bolus) insulin within 12 hours prior to dosing, except insulin glulisine (Apidra®)
8. Changes in medical history or concomitant medication resulting in fulfillment of clinical exclusion criteria, as judged by the investigatorPlasma glucose value <50 mg/dL (2.8 mmol/L) within the last 24 hours or plasma glucose value <60 mg/dL (3.3 mmol/L) within the last 5 hours prior to admission to the clinic. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Time to plasma glucose recovery.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Plasma glucose recovery is defined as first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline during the hypoglycemic clamp procedure without administration of rescue intravenous (IV) glucose. |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
- Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 minutes, and within 10 minutes after trial product injection without administration of IV glucose
- Plasma glucose changes from baseline within 30 minutes, within 20 minutes, within 15 minutes, and within 10 minutes after trial product injection or at the time of rescue IV glucose. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Secondary 1-4: Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 minutes, and within 10 minutes after study drug injection without administration of rescue IV glucose.
- Secondary 5-8: Plasma glucose changes from baseline within 30 minutes, within 20 minutes, within 15 minutes, and within 10 minutes after study drug injection or at the time of rescue. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| placebo- and active-controlled |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| Slovenia |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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