Safety Study of Repeated Doses of Glucagon on Animal Starch in the Liver

• Sponsor: Legacy Health System (Other)
• Overall Status: Completed
• CT.gov ID: NCT01986231
• Collaborator: Juvenile Diabetes Research Foundation (Other), Oregon Health and Science University (Other)
• Enrollment: 12
• Location: 1
• Arm: 1
• Duration (Months): 23
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to learn if giving multiple doses of a hormone called glucagon can cause a major decrease in liver glycogen (animal starch). Glucagon is currently approved by the Food and Drug Administration to be given as a large dose to treat severe low blood sugar. Our group is studying whether glucagon can be given in repeated small doses to prevent hypoglycemia.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: Glucagon	N/A

Detailed Description

Hypoglycemia remains a barrier to optimal glucose control, which is necessary to prevent diabetes-related complications including eye, kidney, and nerve diseases. Despite treatment advances such as insulin pump therapy and continuous glucose monitoring, hypoglycemia remains a concern, even when insulin is given in a closed-loop system. A closed-loop system consists of a glucose-measuring device, from which data are collected and entered into an algorithm, which in turn controls insulin delivery. The difficulty of delivering regular or analog insulin in such a manner is related to its slow onset and prolonged effect when delivered subcutaneously. Until a more rapidly-acting insulin preparation is available, discontinuation of subcutaneous insulin during impending hypoglycemia, with any algorithm, may be insufficient to prevent hypoglycemia.

Glucagon, a hormone secreted from the alpha cells of the normal endocrine pancreas, rapidly raises circulating glucose levels within minutes via glycogenolysis, even when given subcu-taneously. Glucagon is approved for use as a parenteral injection for treatment of severe hypoglycemia. Our group has successfully completed studies in humans using a closed-loop system that delivers insulin (in a nearly continuous fashion) to prevent and treat hyperglycemia as well as glucagon (intermittently) to prevent and treat hypoglycemia.

However, it is unknown whether or not repeated doses lead to hepatic glycogen depletion, which would increase the risk of a severe hypoglycemic episode. 13C MRS (magnetic resonance spectroscopy) has been successfully used to quantify hepatic glycogen in a non-invasive fashion. We are proposing to use 13C MRS to compare glycogen stores in subjects with type 1 diabetes after a period without glucagon vs after a period of repeated glucagon dosing. The comparisons will be made when glycogen stores should be replete (after a lunch meal) and when glycogen stores should be lower (after an overnight fast). If repeated doses of glucagon do cause glycogen depletion, then we would revise our dosing strategy in the closed-loop system and/or consider alternative methods for preventing hypoglycemia.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: The Effect of Repeated Doses of Subcutaneous Glucagon on Hepatic Glycogen Stores in Persons With Type 1 Diabetes
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Open-Label Glucagon Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg.

Drug: Glucagon; Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35.; Other Names: GlucaGen

Outcome Measures

Primary Outcome Measures

1. Assess Difference in Hepatic Glycogen Measured in the Fasting State Before vs. After Repeated Glucagon Administration [Baseline and 41 hours]

   The mean difference in estimated hepatic glycogen will be assessed using Carbon 13 Magnetic Resonance Spectroscopy before vs. after glucagon administration in the fasting state.

Secondary Outcome Measures

1. Assess Difference in Hepatic Glycogen Measured in the Fed State Before vs. After Repeated Glucagon Administration [Baseline and 41 hours]

   The mean difference in estimated hepatic glycogen will be assessed using Carbon 13 Magnetic Resonance Spectroscopy before vs. after glucagon administration in the fed state.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 1 diabetes mellitus diagnosed for at least 6 months

• Current usage of subcutaneous insulin pump treatment

• Age 18-65 years

• HbA1c of 5.5 - 7.7% at screening visit

• BMI 18-35 kg/m2

• Willingness to follow all study procedures, including attending all clinic visits

• Willingness to sign informed consent and HIPAA documents

Exclusion Criteria:

• Pregnancy or Lactation: For women of childbearing potential: there is a requirement for a negative urine pregnancy test.

• Renal insufficiency (serum creatinine of 2.0 mg/dL or greater).

• Serum ALT or AST equal to or greater than 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as a serum albumin of less than 3.3 g/dL; or serum bilirubin of over 2.

• Hematocrit of less than or equal to 34%.

• Congestive heart failure, NYHA class II, III or IV.

• Coronary artery or cerebrovascular disease.

• Active foot ulceration.

• Active alcohol abuse, substance abuse, or severe mental illness (as judged by the principal investigator).

• Active malignancy, except basal cell or squamous cell skin cancers.

• Major surgical operation within 30 days prior to screening.

• Seizure disorder (epilepsy).

• Contraindication to an MRI scan, including having metallic splinters in the eye, a cardiac pacemaker, defibrillator, or any other ferromagnetic or electronically charged implanted device, or ferromagnetic clip(s) in the central nervous system.

• Currently administration of oral or parenteral corticosteroids.

• Use of an investigational drug within 30 days prior to screening.

• Bleeding disorder, treatment with warfarin, or platelet count below 50,000.

• History weight loss of ≥ 5 lbs over the prior month.

• Weight ≥ 300 lbs.

• Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic regimen.

• Any reason the principal investigator deems exclusionary.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oregon Health and Science University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• Legacy Health System
• Juvenile Diabetes Research Foundation
• Oregon Health and Science University

Investigators

• Principal Investigator: W Kenneth Ward, MD, Legacy Health System

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: W. Kenneth Ward, Senior Scientist, Legacy Health System
• ClinicalTrials.gov Identifier: NCT01986231
• Other Study ID Numbers: IRB00006947
• First Posted: Nov 18, 2013
• Last Update Posted: May 4, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by W. Kenneth Ward, Senior Scientist, Legacy Health System: diabetes; insulin; glucagon; glycogen; MRS
• Additional relevant MeSH terms: Diabetes Mellitus, Type 1; Glucagon

Study Results

Participant Flow

Arm/Group Title	Open-Label Glucagon
Arm/Group Description	Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35. Glucagon: Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35.
Period Title: Overall Study
STARTED	12
COMPLETED	11
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Open-Label Glucagon
Arm/Group Description	Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35. Glucagon: Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35.
Overall Participants	11
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	8 72.7%
Male	3 27.3%

Outcome Measures

1. Primary Outcome

Title	Assess Difference in Hepatic Glycogen Measured in the Fasting State Before vs. After Repeated Glucagon Administration
Description	The mean difference in estimated hepatic glycogen will be assessed using Carbon 13 Magnetic Resonance Spectroscopy before vs. after glucagon administration in the fasting state.
Time Frame	Baseline and 41 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open-Label Glucagon
Arm/Group Description	Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35. Glucagon: Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35.
Measure Participants	11
Mean (Standard Deviation) [g/L]	6.5 (4.5)

2. Secondary Outcome

Title	Assess Difference in Hepatic Glycogen Measured in the Fed State Before vs. After Repeated Glucagon Administration
Description	The mean difference in estimated hepatic glycogen will be assessed using Carbon 13 Magnetic Resonance Spectroscopy before vs. after glucagon administration in the fed state.
Time Frame	Baseline and 41 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open-Label Glucagon
Arm/Group Description	Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35. Glucagon: Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35.
Measure Participants	11
Mean (Standard Deviation) [g/L]	10.6 (7.7)

Adverse Events

Arm/Group Title	Open-Label Glucagon
Arm/Group Description	Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35. Glucagon: Subjects will receive 8 doses of glucagon, each dose will be 2.0 mcg per kg. Glucagon will be reconstituted immediately prior to administration and each dose will be administered subcutaneously via syringe/needle. The first glucagon dose is at hour 17, second at hour 22, third at hour 24, fourth at hour 27, fifth at hour 29, sixth at hour 31, seventh at hour 33, eighth at hour 35.
All Cause Mortality
	Open-Label Glucagon
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Open-Label Glucagon
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Other (Not Including Serious) Adverse Events
	Open-Label Glucagon
	Affected / at Risk (%)	# Events
Total	3/12 (25%)
Cardiac disorders
lightheadedness	1/12 (8.3%)	1
Gastrointestinal disorders
Vomiting	1/12 (8.3%)	1
Nausea	1/12 (8.3%)	1
Diarrhea	1/12 (8.3%)	1
Nervous system disorders
headache	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.