Sensor-Augmented Insulin Delivery: Insulin Plus Glucagon Versus Insulin Alone

• Sponsor: Legacy Health System (Other)
• Overall Status: Completed
• CT.gov ID: NCT00797823
• Collaborator: Juvenile Diabetes Research Foundation (Other), Oregon Health and Science University (Other)
• Enrollment: 14
• Location: 1
• Arms: 3
• Duration (Months): 10
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This study aims to test an insulin and glucagon delivery algorithm designed to be used in conjunction with a continuous glucose monitoring system. This combined glucose sensing/hormone delivery approach is a step on the way to eventual development of an artificial (or automated) pancreas. The insulin and glucagon delivery algorithm is based on the difference between the current blood glucose and the target glucose (proportional error) and the rate of change in blood glucose (derivative error), both adjusted for the recent glucose history. This algorithm is called the Fading Memory Proportional-Derivative (FMPD) Algorithm. The principal investigator of this study has published previous research regarding the use of this algorithm and found it to be well-suited to control blood glucose in type 1 diabetic animals. The addition of glucagon was helpful; better glycemic control with fewer glucose excursions were observed when small intermittent infusions of subcutaneous glucagon were given during times of impending low blood sugar (Ward et al. 2008).

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes	Drug: Insulin, Asp(B28)-; Drug: Glucagon; Drug: Placebo	Phase 2

Detailed Description

The objective of the current human study is to compare glycemic control in persons with Type 1 Diabetes using the FMPD Insulin plus Glucagon Delivery Algorithm vs. the FMPD Insulin-Alone Algorithm. Subjects will undergo two 28-hour sensor-augmented glycemic control studies. Each subject will be fitted with two short term continuous glucose monitoring systems and two subcutaneous (SC) infusion catheters. These catheters will allow for SC delivery of insulin and glucagon (or insulin plus a glucagon placebo). The accuracy of the wire sensors will be verified every 10 minutes with a venous blood glucose test. For the first 4 hours, the insulin and glucagon delivery will be controlled by venous blood in order to assess and compare the accuracy of the two sensors, after which the more accurate sensor (if it remains accurate) will control the FMPD algorithm. The main outcomes of our study are time spent in the target range (70 - 180 mg/dl) and the percentage of studies requiring intervention due to hypoglycemia (glucose < 70 mg/dl). The accuracy of the sensors over the life of the study will also be evaluated.

The specific system used in this study of frequent blood testing and the use of two separate infusion pumps is not feasible for every day use for individuals with diabetes. However, if the glucose control algorithm (with or without the use of glucagon) provides effective blood glucose management over long time periods the calculation program may be integrated into a continuous blood glucose monitoring system with an insulin and glucagon pump.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: A Comparison of Two Sensor-Augmented Glycemic Control Systems in Persons With Type 1 Diabetes Mellitus: Subcutaneous (SC) Insulin and Glucagon Delivery vs. SC Insulin Only
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Insulin + Placebo Glycemic control of subject participants was managed by the closed-loop system which delivered insulin and normal saline (instead of glucagon) as a placebo, based upon algorithm calculations.	Drug: Insulin, Asp(B28)-; Insulin dosing and frequency calculated by Fading Memory Proportional Derivative algorithm; Other Names: Aspart insulin Novolog ; Drug: Placebo; Saline solution 0.9%; Other Names: Normal saline, NaCl 0.9%
Active Comparator: Insulin + Glucagon Glycemic control of subject participants was managed by the system which delivered insulin and glucagon based upon algorithm calculations.	Drug: Insulin, Asp(B28)-; Insulin dosing and frequency calculated by Fading Memory Proportional Derivative algorithm; Other Names: Aspart insulin Novolog ; Drug: Glucagon; During incipient hypoglycemia, glucagon was given in an attempt to prevent overt hypoglycemia. Dosing and frequency was calculated by the Fading Memory Proportional Derivative algorithm; Other Names: Glucagen
Experimental: Pilot Study Pilot studies designed to assess safety of the system. Includes 6 participants undergoing 7 studies.	Drug: Insulin, Asp(B28)-; Insulin dosing and frequency calculated by Fading Memory Proportional Derivative algorithm; Other Names: Aspart insulin Novolog ; Drug: Glucagon; During incipient hypoglycemia, glucagon was given in an attempt to prevent overt hypoglycemia. Dosing and frequency was calculated by the Fading Memory Proportional Derivative algorithm; Other Names: Glucagen ; Drug: Placebo; Saline solution 0.9%; Other Names: Normal saline, NaCl 0.9%

Outcome Measures

Primary Outcome Measures

1. Effectiveness of Closed Loop Diabetes Control [1 year]

   Effectiveness of closed loop diabetes control will be measured by mean glucose.

Secondary Outcome Measures

1. Percent of Time Venous Blood Glucose <70 mg/dl [1 year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 21-65, history of Type 1 Diabetes Mellitus for > 3 months.

• Women:

• For women of childbearing potential, a negative urine pregnancy test is required on the first day of the study prior to sensor insertion AND the subject must agree to use contraception prior to and during the study.

• For menopausal women or those who have undergone surgical sterilization, no pregnancy test or contraception will be required.

• Willingness to attend all clinic visits and participate in two 28-hour studies or one 9-hour study.

• Hemoglobin A1C of 5.0-10%. (Values below 5.0 suggest a severe tendency towards hypoglycemia, and values above 10% suggest severely uncontrolled diabetes with risk for ketoacidosis.)

• Body mass index of 19-35.

Exclusion Criteria:

• Pregnancy, lactation or refusal to use contraception.

• Use of any investigational drug during the 30 days prior to screening.

• Enrollment or participation in any other research studies 30 days prior to and during the entirety of sensor insertion.

• Current alcohol abuse, substance abuse, or severe mental illness (as judged by the Principal Investigator (PI)).

• Any prior cerebrovascular accident or major permanent neurological damage such as aphasia, hemiparesis, or dementia.

• A history of cerebrovascular disease or cardiovascular disease regardless of the time since occurrence.

• Coronary artery disease (symptomatic or asymptomatic) as manifested by unstable angina, acute coronary syndrome, myocardial infarction or therapeutic coronary procedure (e.g., Percutaneous Transluminal Coronary Angioplasty (PTCA), stent placement, Coronary Artery By-pass Grafting (CABG)) within the prior 6 months.

• Any degree of heart failure (as defined by New York Heart Association)..

• Renal insufficiency (serum creatinine of > 2.5).

• Current foot or leg ulceration.

• Peripheral arterial disease with uncontrolled claudication.

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

• Concurrent illness, other than diabetic mellitus, that is not controlled by a stable therapeutic regimen.

• Hemoglobin A1C of less than 5.0 or greater than 10%.

• A total bilirubin level above 1.5 mg/dl.

• Medications: Oral or parenteral corticosteroids (glucocorticoid therapy) are exclusions; topical corticosteroids are not.

• Any chronic immunosuppressive medication (such as cyclosporine, azathioprine, sirolimus, or tacrolimus).

• Visual impairment that would prevent reading the display of the Medtronic Guardian® Receiver.

• Physical impairment that would prevent using the buttons of the Medtronic Guardian® Receiver.

• Serum Alanine Transaminase (ALT) or Aspartate Transaminase (AST) ≥3x the upper limit of normal.

• Serum albumin level of < 3.2 g/dl.

• Severe anemia as defined by a hematocrit of < 28%.

• Severe serum electrolyte abnormality (sodium, potassium, carbon dioxide, chloride).

• Cardiac rhythm disturbance characterized by: 2nd or 3rd degree heart block, bradycardia of less than 50 bpm (exception of bradycardia in an aerobic athlete), tachycardia of greater than 100 bpm, or any arrhythmia judged by the investigator to be exclusionary.

• A history of Human Immunodeficiency Virus (HIV) infection.

• An active hepatitis infection.

• Known allergy to any type of insulin

• Insulin resistance requiring more than 200 units of insulin per day

• Known bleeding disorders or chronic usage of warfarin.

• Any known seizure disorder.

• Past history of pheochromocytoma or a family history of Multiple Endocrine Neoplasia (MEN) 2A, MEN 2B, neurofibromatosis, or von Hippel-Lindau disease.

• Hypoglycemic unawareness or chronic hypoglycemia.

• A severe hypoglycemic event which required hospitalization within the past two years.

• Adrenal insufficiency.

• Insulinoma.

• Use of both acetaminophen and ascorbic acid.

• Impaired mentation or psychiatric diagnoses

• Uncontrolled candidiasis.

• Any known allergy to glucagon.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Legacy Research	Portland	Oregon	United States	97232

Sponsors and Collaborators

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

Investigators

• Principal Investigator: William K. 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: NCT00797823
• Other Study ID Numbers: IRB4311
• First Posted: Nov 25, 2008
• Last Update Posted: Oct 7, 2011
• Last Verified: Aug 1, 2009

• Keywords provided by W. Kenneth Ward, Senior Scientist, Legacy Health System: diabetes; pancreas; beta cell; glucagon; insulin; hypoglycemia
• Additional relevant MeSH terms: Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc; Glucagon

Study Results

Participant Flow

Recruitment Details	Patients were recruited from the Oregon Health and Science University (OHSU) outpatient clinics in Portland, Oregon.
Pre-assignment Detail	A total of 22 studies in 14 subjects were performed. 6 subjects participated in 7 9-hour pilot studies, 6 with insulin and glucagon and 1 with insulin + placebo to assess the safety of the protocol. 8 subjects then underwent 2 interventional studies each for a total of 16 studies, one with insulin and placebo and one with insulin and glucagon.

Arm/Group Title	Insulin + Glucagon -> Insulin + Placebo)	Insulin + Placebo -> Insulin + Glucagon	Pilot
Arm/Group Description	This group consists of x participants initially randomized to the insulin plus glucagon (latter to prevent hypoglycemia) intervention for glycemic control of type 1 diabetes during the first period, then insulin plus placebo in the second period. The control system was comprised of glucose sensors, a computer algorithm, and actuator pumps in a circuit meant to automatically adjust insulin and glucagon infusion rates based on glucose values delivered to the algorithm (a closed-loop system, as it is meant to exclude human intervention).	This group consists of x participants initially randomized to the insulin plus placebo intervention for glycemic control of type 1 diabetes during the first period, then insulin plus glucagon (latter to prevent hypoglycemia) in the second period. The control system was comprised of glucose sensors, a computer algorithm, and actuator pumps in a circuit meant to automatically adjust insulin and glucagon infusion rates based on glucose values delivered to the algorithm (a closed-loop system, as it is meant to exclude human intervention).	Pilot studies included 6 participants, one of whom underwent an insulin + glucagon and an insulin + placebo study, while 5 underwent only one insulin + glucagon study.
Period Title: Pilot Studies
STARTED	0	0	6
COMPLETED	0	0	6
NOT COMPLETED	0	0	0
Period Title: Pilot Studies
STARTED	4	4	0
COMPLETED	3	4	0
NOT COMPLETED	1	0	0
Period Title: Pilot Studies
STARTED	3	4	0
COMPLETED	3	4	0
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Insulin + Glucagon -> Insulin + Placebo)	Insulin + Placebo -> Insulin + Glucagon	Pilot	Total
Arm/Group Description	This group consists of x participants initially randomized to the insulin plus glucagon (latter to prevent hypoglycemia) intervention for glycemic control of type 1 diabetes during the first period, then insulin plus placebo in the second period. The control system was comprised of glucose sensors, a computer algorithm, and actuator pumps in a circuit meant to automatically adjust insulin and glucagon infusion rates based on glucose values delivered to the algorithm (a closed-loop system, as it is meant to exclude human intervention).	This group consists of x participants initially randomized to the insulin plus placebo intervention for glycemic control of type 1 diabetes during the first period, then insulin plus glucagon (latter to prevent hypoglycemia) in the second period. The control system was comprised of glucose sensors, a computer algorithm, and actuator pumps in a circuit meant to automatically adjust insulin and glucagon infusion rates based on glucose values delivered to the algorithm (a closed-loop system, as it is meant to exclude human intervention).	Pilot studies included 6 participants, one of whom underwent an insulin + glucagon and an insulin + placebo study, while 5 underwent only one insulin + glucagon study.	Total of all reporting groups
Overall Participants	4	4	6	14
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	4 100%	4 100%	6 100%	14 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.3 (10.5)	39.8 (10.7)	35.1 (17.4)	36.7 (13.7)
Sex: Female, Male (Count of Participants)
Female	2 50%	2 50%	3 50%	7 50%
Male	2 50%	2 50%	3 50%	7 50%
Region of Enrollment (participants) [Number]
United States	4 100%	4 100%	6 100%	14 100%

Outcome Measures

1. Primary Outcome

Title	Effectiveness of Closed Loop Diabetes Control
Description	Effectiveness of closed loop diabetes control will be measured by mean glucose.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The number of participants for analysis was determined was per protocol.

Arm/Group Title	Placebo Comparator: Insulin Alone	Active Comparator: Insulin Plus Glucagon
Arm/Group Description	No glucagon given during closed loop control-insulin only	Insulin plus glucagon given (latter to prevent hypoglycemia) for closed loop control.
Measure Participants	8	13
Mean (Standard Error) [mg/dl]	136.9 (5.0)	149.5 (5.5)

2. Secondary Outcome

Title	Percent of Time Venous Blood Glucose <70 mg/dl
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo Comparator: Insulin Alone	Active Comparator: Insulin Plus Glucagon
Arm/Group Description	No glucagon given during closed loop control-insulin only	Insulin plus glucagon given (latter to prevent hypoglycemia) for closed loop control.
Measure Participants	8	13
Mean (Standard Error) [percent of time]	2.8 (0.67)	1.15 (0.41)

Adverse Events

Time Frame	Over 1 year for entire research period, and over the study period for each individual study.
Arm/Group Title	Insulin + Glucagon -> Insulin + Placebo)		Insulin + Placebo -> Insulin + Glucagon		Pilot
Arm/Group Description	This group consists of x participants initially randomized to the insulin plus glucagon (latter to prevent hypoglycemia) intervention for glycemic control of type 1 diabetes during the first period, then insulin plus placebo in the second period. The control system was comprised of glucose sensors, a computer algorithm, and actuator pumps in a circuit meant to automatically adjust insulin and glucagon infusion rates based on glucose values delivered to the algorithm (a closed-loop system, as it is meant to exclude human intervention).		This group consists of x participants initially randomized to the insulin plus placebo intervention for glycemic control of type 1 diabetes during the first period, then insulin plus glucagon (latter to prevent hypoglycemia) in the second period. The control system was comprised of glucose sensors, a computer algorithm, and actuator pumps in a circuit meant to automatically adjust insulin and glucagon infusion rates based on glucose values delivered to the algorithm (a closed-loop system, as it is meant to exclude human intervention).		Pilot studies included 6 participants, one of whom underwent an insulin + glucagon and an insulin + placebo study, while 5 underwent only one insulin + glucagon study.
All Cause Mortality
	Insulin + Glucagon -> Insulin + Placebo)		Insulin + Placebo -> Insulin + Glucagon		Pilot
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Insulin + Glucagon -> Insulin + Placebo)		Insulin + Placebo -> Insulin + Glucagon		Pilot
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/4 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Insulin + Glucagon -> Insulin + Placebo)		Insulin + Placebo -> Insulin + Glucagon		Pilot
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		4/4 (100%)		1/6 (16.7%)
Endocrine disorders
Severe Hypoglycemia	4/4 (100%)	55	4/4 (100%)	67	1/6 (16.7%)	1
Gastrointestinal disorders
Nausea and vomiting	1/4 (25%)	1	0/4 (0%)	0	0/6 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.