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Effectiveness and Safety of Intranasal Glucagon for Treatment of Hypoglycemia in Adults

Information source: T1D Exchange Clinic Network Coordinating Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2

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

Phase: 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

Summary

The primary objective of this study is to assess the effectiveness and safety of 3 mg glucagon (AMG504-1) administered as a puff into the nose compared with commercially-available glucagon given by injection.

Clinical Details

Official title: Efficacy and Safety of Intranasal Glucagon for Treatment of Insulin Induced Hypoglycemia in Adults With Diabetes

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

Primary outcome: Increase in plasma glucose level to >=70mg/dL or an increase of >=20mg/dL

Secondary outcome:

Nasal and non-nasal effects/symptoms

Recovery from symptoms of hypoglycemia

Time from glucagon administration to return of plasma glucose to >/=70 mg/dL

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

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

Maximum concentration (Cmax) of glucose

Time to maximum concentration (Tmax) of glucose

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. The procedure to evaluate the efficacy of AMG504-1 consists essentially of inducing hypoglycemia by an intravenous (IV) infusion of regular insulin diluted in normal saline. The insulin infusion will be used to decrease the glucose to a target <50 mg/dL. The insulin infusion will be stopped once the plasma glucose is <60 mg/dL. Five minutes after stopping the insulin infusion, participants will be treated with either a 3 mg glucagon dose intranasally or 1 mg of glucagon administered by intramuscular (IM) injection in the deltoid muscle of the non-dominant arm. During the 5-minute period after the insulin infusion has stopped, the glucose level is expected to continue to decrease an additional 15-20 mg/dL. It is believed that a nadir of <50 mg/dL will be low enough to generate clinical symptoms in most participants yet high enough to avoid impairment of consciousness. 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 will return to the clinic and the procedure repeated with each participant crossed over to the other treatment. As such, each participant will undergo two episodes of insulin-induced hypoglycemia in random order and receive AMG504-1 during one episode and commercially available glucagon (GlucaGen, Novo Nordisk) by IM injection during the other episode.

Eligibility

Minimum age: 18 Years. Maximum age: 64 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: To be eligible, the following inclusion criteria must be met: 1. Clinical diagnosis of either type 1 diabetes receiving daily insulin since the time of diagnosis for at least 2 years or type 2 diabetes receiving multiple daily insulin doses for at least 2 years. 2. At least 18. 0 years of age and less than 65. 0 years. 3. Body mass index (BMI) greater than or equal to 20. 0 and below or equal to 35. 0 kg/m2 4. Weighs at least 50 kg (110 lbs) 5. 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 is in a menopausal state (at least 1 year without menses). 6. 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. 7. Willingness to adhere to the protocol requirements Exclusion Criteria: An individual is not eligible if any of the following exclusion criteria are present: 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. Regularly consumes 3 or more alcoholic beverages per day. 9. Use of an Investigational Product in another clinical trial within the past 30 days 10. Donated 225 mL or more of blood in the previous 8 weeks before the first glucagon dosing visit.

Locations and Contacts

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

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

University of Minnesota, Minneapolis, Minnesota 55454, United States

UPA Buffalo, Buffalo, New York 14222, United States

Oregon Health and Science University, Portland, Oregon 97239, United States

University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States

Additional Information

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.

Mehr S, Robinson M, Tang M. Doctor--how do I use my EpiPen? Pediatr Allergy Immunol. 2007 Aug;18(5):448-52.

Sicherer SH, Forman JA, Noone SA. Use assessment of self-administered epinephrine among food-allergic children and pediatricians. Pediatrics. 2000 Feb;105(2):359-62.

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

Harris, G., et al., Glucagon administration - underevaluated and undertaught. Practical Diabetes International, 2001. 18(1): p. 22-25

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

Page last updated: August 23, 2015

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