Assessment of Intranasal Glucagon in Children and Adolescents With Type 1 Diabetes

Condition(s) targeted: Diabetes Mellitus, Type 1

Intervention: Intranasal Glucagon (Drug); Glucagon (Drug)

Phase: Phase 2/Phase 3

Status: Completed

Sponsored by: T1D Exchange Clinic Network Coordinating Center

Official(s) and/or principal investigator(s):
Katrina J Ruedy, MSPH, Principal Investigator, Affiliation: Jaeb Center for Health Research

The purpose of this study is to assess how glucagon administered as a puff into the nose (AMG504-1) works in children and adolescents compared with commercially-available glucagon given by injection. In addition, the safety and tolerability of glucagon given as a puff into the nose will be evaluated.

Official title: Assessment of Intranasal Glucagon in Children and Adolescents With Type 1 Diabetes

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Area under the curve from time zero to the last quantifiable concentration (AUC0-t) of glucagon

Maximum observed concentration (Cmax) of glucagon

Time to maximum concentration (tmax) of glucagon

Secondary outcome:

Nasal and non-nasal effects/symptoms

Maximum concentration (Cmax) of glucose

Time to maximum concentration (Tmax) of glucose

Area under the effect concentration time curve (AUEC0-1.5) of glucose from time zero up to 90 minutes

The proportion and 99% confidence interval of the proportion of participants achieving at least a 25 mg/dl rise in blood glucose above basal level

Time to achieving ≥25 mg/dl rise in plasma glucose above basal level

Detailed description: Glucagon, the treatment of choice for severe hypoglycemia outside of the hospital setting, is currently available only as a powder that must be mixed with a diluent immediately prior to administration by injection. Although this is a very simple procedure for insulin-using individuals, subjects experiencing severe hypoglycemia cannot inject themselves with glucagon because of the disabling effects of severe neuroglycopenia. For any non-medical person who is confronted with an emergency situation in which a patient with diabetes is in a hypoglycemic coma or suffering hypoglycemia-related convulsions, reconstitution and injection of the current injectable glucagon is a complex and daunting procedure. When used at the recommended dose of 1 mg by injection, glucagon often causes a substantial, although transient, hyperglycemia that is often accompanied by nausea and vomiting. The data generated to date with AMG504-1 suggest the resulting glucagon pharmacokinetics (PK), although less than that observed with injected glucagon, results in a therapeutic blood glucose increment with a very low incidence of gastrointestinal adverse effects. Caregivers of children and adolescents with type 1 diabetes are called upon to treat episodes of severe hypoglycemia and may want to use AMG504-1. This study is being conducted to permit determination of appropriate dose level(s) for pediatric use based on the safety observations and results of glucagon and glucose assays. Each participant 12. 0 to less than 17. 0 years of age will undergo two visits in random order and receive AMG504-1 during one visit and commercially available glucagon (GlucaGen, Novo Nordisk) by IM injection during the other visit. Participants 4. 0 to less than 12. 0 years are randomly assigned to have either 1 visit with commercially available glucagon (GlucaGen, Novo Nordisk) by IM injection OR to have 2 visits with a 2. 0 mg dose of AMG504-1 administered during one visit and a 3. 0 mg dose of AMG504-1 administered during the other visit. For those randomized to complete two research dosing visits, the dose of intranasal glucagon given during each visit will be masked to the participant and study personnel. Each dosing visit consists of reducing the plasma glucose level to about 80 mg/dL by increasing the basal insulin infusion rate on the insulin pump or by an intravenous (IV) infusion of regular insulin diluted in normal saline. The insulin infusion will be stopped once the plasma glucose is <80 mg/dL. Five minutes after stopping the insulin infusion, participants will be treated with either glucagon given intranasally (either 2. 0 mg or 3. 0 mg for participants 4. 0 to less than 12. 0 years of age or 3. 0 mg for those 12. 0 to less than 17. 0 years of age) or by intramuscular (IM) injection (1 mg constituted in 1 mL of diluting solution for those 55 lbs or more and 0. 5 mg constituted in 1 mL of diluting solution for those who weigh less than 55 lbs) in the quadriceps muscle of the leg. Blood glucose levels and adverse events will be carefully monitored for 90 minutes post-dosing. After a wash-out period of 7 days or more, participants 12. 0 to less than 17. 0 years of age will return to the clinic and the procedure repeated with each participant crossed over to the other treatment. Participants 4. 0 to less than 12. 0 years assigned to have 2 dosing visits will also return to clinic and repeat the procedure with a different dose of intranasal glucagon given. Participants 4. 0 to less than 12. 0 years assigned to a single dosing visit do not return for a second dosing visit.

Minimum age: 4 Years. Maximum age: 16 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: To be eligible, the following inclusion criteria must be met: 1. History of type 1 diabetes and receiving daily insulin therapy from the time of diagnosis for at least 12 months. 2. At least 4. 0 years of age and less than 17. 0 years. 3. Weighs at least:

- 13 kg (28. 6 lbs) for centers that are allowed to reinfuse blood and

Institutional Review Board (IRB) guidelines allow for 3. 5 ml/kg of blood to be collected

- 15. 1 kg (33. 2 lbs) for centers that are allowed to reinfuse blood and IRB

guidelines allow for 3. 0 ml/kg of blood to be collected

- 19 kg (41. 8 lbs) for centers that are not allowed to reinfuse blood and IRB

guidelines allow for 3. 5 ml/kg of blood to be collected

- 22. 1 kg (48. 6 lbs) for centers that are not allowed to reinfuse blood and IRB

guidelines allow for 3. 0 ml/kg of blood to be collected 4. Females must meet one of the following criteria: 1. Of childbearing potential but agrees to use an accepted contraceptive regimen as described in the study procedure manual throughout the entire duration of the study (from the screening visit until study completion). or 2. Of non-childbearing potential, defined as a female who has had a hysterectomy or tubal ligation, is clinically considered infertile or has not yet reached menarche. 5. In good general health with no conditions that could influence the outcome of the trial, and in the judgment of the Investigator is a good candidate for the study based on review of available medical history, physical examination and clinical laboratory evaluations. 6. Willingness to adhere to the protocol requirements Exclusion Criteria: An individual is not eligible if any of the following exclusion criteria are present: 1. 1. Females who are pregnant according to a positive urine pregnancy test, actively attempting to get pregnant, or are lactating. 2. History of hypersensitivity to glucagon or any related products or severe hypersensitivity reactions (such as angioedema) to any drugs. 3. Presence of cardiovascular, gastrointestinal, liver or kidney disease, or any other conditions which in the judgment of the investigator could interfere with the absorption, distribution, metabolism or excretion of drugs or could potentiate or predispose to undesired effects. 4. History of pheochromocytoma (i. e. adrenal gland tumor) or insulinoma. 5. History of an episode of severe hypoglycemia (as defined by an episode that required third party assistance for treatment) in the 1 month prior to enrolling in the study. 6. Use of daily systemic beta-blocker, indomethacin, warfarin or anticholinergic drugs. 7. History of epilepsy or seizure disorder. 8. Use of an Investigational Product in another clinical trial within the past 30 days 9. Blood donation in 3 months prior to first glucagon dosing visit.

Barbara Davis Center for Diabetes, Aurora, Colorado 80045, United States

Yale University, New Haven, Connecticut 06520, United States

University of Florida, Gainesville, Florida 32605, United States

Nemours Children's Clinic, Jacksonville, Florida 32207, United States

Riley Hospital for Children Indiana University Health, Indianapolis, Indiana 46202, United States

University of Massachusettes, Worcester, Massachusetts 01655, United States

University of Minnesota, Minneapolis, Minnesota 55454, United States

UPA Buffalo, Buffalo, New York 14222, United States

Related publications:

CARSON MJ, KOCH R. Clinical studies with glucagon in children. J Pediatr. 1955 Aug;47(2):161-70.

Miller RE, Chernish SM, Skucas J, Rosenak BD, Rodda BE. Hypotonic roentgenography with glucagon. Am J Roentgenol Radium Ther Nucl Med. 1974 Jun;121(2):264-74.

Pontiroli AE, Alberetto M, Pozza G. Intranasal glucagon raises blood glucose concentrations in healthy volunteers. Br Med J (Clin Res Ed). 1983 Aug 13;287(6390):462-3.

Stenninger E, Aman J. Intranasal glucagon treatment relieves hypoglycaemia in children with type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1993 Oct;36(10):931-5.

Glucagon for Injection® (rDNA origin) [Label] (02/24/2004). September 13, 2012]; Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda.

Lee, E.W., L.J. Wei, and D. Amato, in Cox-Type Regression Analysis for Large Numbers of Small Groups of Correlated Failure Time Observations. 1992, Kluwer Academic: Netherlands. p. 237-247.

Starting date: November 2013
Last updated: April 14, 2015