E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
treatment of severe hypoglycemia |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021005 |
E.1.2 | Term | Hypoglycemia |
E.1.2 | System Organ Class | 100000004861 |
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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 of this study is to demonstrate that G-Pen 1 mg (test) is not inferior to GlucaGen Hypokit 1 mg (reference), in Type 1 diabetic (T1D) subjects in a state of insulin-induced hypoglycemia. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is to evaluate the safety and tolerability of G-Pen 1 mg versus GlucaGen Hypokit 1 mg in the study population. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and females diagnosed with T1D for at least 24 months. Women of childbearing potential require a negative urine pregnancy test and must use medically accepted contraception throughout the study and for 7 days after the last dose of study drug.
Nursing mothers will be allowed to participate in the study. However, breast feeding during the inpatient study visits (Visits 2 and 3) and for 48 hours after each dose of study drug is not allowed.
2. Current usage of daily insulin treatment that includes having an assigned “correction factor” for managing hyperglycemia.
3. Age 18 to 75 years, inclusive.
4. Random serum C-peptide concentration < 0.6 ng/mL.
5. Subjects reporting active marijuana use or testing positive for tetrahydrocannabinol (THC) via rapid urine test will be allowed to participate in the study at the discretion of the Investigator.
6. Willingness to follow all study procedures, including attending all clinic visits.
7. Subject has provided informed consent as evidenced by a signed and dated informed consent form (ICF) completed before any trial-related activities occur.
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E.4 | Principal exclusion criteria |
1. Pregnancy
2. Glycated hemoglobin (HbA1c) > 10% at Screening.
3. Body mass index (BMI) > 40 kg/m2.
4. Renal insufficiency (serum creatinine greater than 3.0 mg/dL) or end-stage renal disease requiring renal replacement therapy.
5. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal to or greater than 3 times the upper limit of normal.
6. Hepatic synthetic insufficiency as defined as a serum albumin of less than 3.0 g/dL.
7. Hematocrit < 30%.
8. Blood pressure (BP) readings at Screening where systolic blood pressure (SBP) < 90 or > 150 mm Hg, and diastolic blood pressure (DBP) < 50 or > 100 mm Hg.
9. Clinically significant ECG abnormalities.
10. Use of total insulin dose per day > 2 U/kg.
11. Inadequate venous access.
12. Congestive heart failure, New York Heart Association (NYHA) class III or IV.
13. History of myocardial infarction, unstable angina, or revascularization within the past 6 months.
14. History of a cerebrovascular accident in the past 6 months or with major neurological deficits.
15. Active malignancy within 5 years from Screening, except basal cell or squamous cell skin cancers. Any history of breast cancer or malignant melanoma will be exclusionary.
16. Major surgical operation within 30 days prior to Screening.
17. History of or current seizure disorder (other than with suspect or documented hypoglycemia).
18. Current bleeding disorder, treatment with warfarin, or platelet count below 50 × 109 per liter.
19. History of pheochromocytoma or disorder with increased risk of pheochromocytoma (multiple endocrine neoplasia type 2 [MEN 2], neurofibromatosis, or Von Hippel-Lindau disease).
20. History of insulinoma.
21. History of allergies to glucagon or glucagon-like products, or any history of significant hypersensitivity to glucagon or any related products or to any of the excipients (dimethyl sulfoxide [DMSO] and trehalose) in the investigational formulation.
22. History of glycogen storage disease.
23. Subject tests positive for human immunodeficiency virus [HIV], hepatitis C virus [HCV], or hepatitis B virus [HBV] infection (hepatitis B surface antigen positive [HBsAg+]) at Screening.
24. Active substance other than THC or alcohol abuse (more than 21 drinks per week for male subjects or 14 drinks per week for female subject).
25. Administration of glucagon within 7 days of Screening.
26. Participation in other studies involving administration of an investigational drug or device within 30 days or 5 half-lives, whichever is longer, before Screening for the current study and during participation in the current study.
27. Any other reason the Investigator deems exclusionary.
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E.5 End points |
E.5.1 | Primary end point(s) |
For the primary endpoint, groups will be compared for rates of achieving a positive plasma glucose response, defined as either a plasma glucose concentration > 70 mg/dL (> 3.88 mmol/L) or an increase in plasma glucose concentration > 20 mg/dL (> 1.11 mmol/L) within 30 minutes of study drug injection. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Rates of achieving a positive plasma glucose response, defined as either a plasma glucose concentration > 70 mg/dL (> 3.88 mmol/L) or an increase in plasma glucose concentration > 20 mg/dL (>1.11 mmol/L) within 30 minutes from injection of study drug.
2. Rates of positive symptomatic response, defined as relief of neuroglycopenic symptoms within 30 minutes from a decision to dose.
3. Rates of positive treatment response, defined as exhibiting either a positive plasma glucose response or a positive symptomatic response.
4. Time to a positive plasma glucose response from injection of study drug.
5. Time to administer study drug from a decision to dose.
6. Pharmacodynamic (PD) characteristics of mean plasma glucose concentration (0 to 90 minutes post-dose), maximum observed concentration (Cmax), time to maximum observed concentration (tmax), area under the concentration versus time curve from time 0 to 90 minutes (AUC(0-90)), and area under the concentration versus time curve from time 0 to 180 minutes (AUC(0 180)).
7. Time to (a) initial relief and (b) complete resolution of autonomic and neuroglycopenic symptoms of hypoglycemia from a decision to dose.
8. Time to resolution of the overall feeling of hypoglycemia from a decision to dose.
9. Safety endpoints, including: adverse event (AE)/serious adverse event (SAE) rates, and changes in vital signs, laboratory variables, and physical exam/electrocardiogram (ECG) findings.
10. Tolerability endpoints, including: Draize scale scores for injection site erythema and edema as assessed by the investigator, and injection site discomfort and duration as assessed by subject questionnaire responses
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 3 |
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 |
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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 | 12 |
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 | 12 |
E.8.9.2 | In all countries concerned by the trial days | 0 |