Type 1 Diabetes MellitusNCT01483651
Physiologic Response to Glucagon at Varying Insulin Levels
A study testing Glucagon and Insulin in people with Type 1 Diabetes Mellitus, run by Legacy Health System at 1 site in United States.
Trial summary
The purpose of this research study is to test how different levels of insulin block the effect of glucagon. Insulin is a hormone that lowers blood glucose. Glucagon raises blood glucose. Both are natural hormones made by people without diabetes. Read more about this study
- Who is it for?
- Ages 21 to 65 years
- Conditions the study is for
- Type 1 Diabetes Mellitus
- What is being tested?
- Glucagon and Insulin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2011to Mar 2013
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of type 1 diabetes mellitus for at least 1 year
- Male or female subjects 21 to 65 years of age
- Current use of an insulin pump
- Willingness to sign informed consent and HIPAA documents and follow all study procedures
Who cannot join
- Pregnancy or Lactation: For women of childbearing potential: there is a requirement for a negative urine pregnancy test and for agreement to use contraception during the study and for at least 1 month after participating in the study
- Renal insufficiency (serum creatinine of 2.0 mg/dL or greater)
- Liver abnormalities: 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
- Adrenal insufficiency
- Hematocrit of less than or equal to 34%
- A history of cerebrovascular disease or coronary artery disease regardless of the time since occurrence
Show all 23Show fewer
- Congestive heart failure, NYHA class III or IV
- 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
- Any active infection
- Active foot ulceration
- Severe peripheral arterial disease characterized by ischemic rest pain or severe claudication
- 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
- Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic regimen
- Chronic usage of any immunosuppressive medication
- Current 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
- Allergy to glucagon
- Past history of pheochromocytoma or a family history of MEN 2, neurofibromatosis, or von Hippel-Lindau disease
- Insulin resistance requiring more than 200 units per day
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Hepatic Glucose Response to Glucagon at Varying Insulin Levels: Implications for Closed Loop Glycemic Control.
The purpose of this research study is to test how different levels of insulin block the effect of glucagon. Insulin is a hormone that lowers blood glucose. Glucagon raises blood glucose. Both are natural hormones made by people without diabetes. Sensor-based blood glucose control studies have been done by our research group using glucagon in small doses to prevent hypoglycemia (low blood sugar). However, sometimes glucagon does not work to raise blood sugar. The investigators believe this is because of too much insulin in the body. This study will help determine how different levels of insulin in the body affect the ability of glucagon to raise blood sugar.
Read the detailed description
We investigators have been working on the development of a closed loop (artificial endocrine pancreas) insulin and glucagon infusion system since 2005 and are part of the Juvenile Diabetes Research Foundation Artificial Pancreas Consortium. As part of our studies, we give small doses of glucagon to prevent hypoglycemia. As we assessed the success and failure of glucagon administration during these studies, we found the use of glucagon reduced the frequency of hypoglycemia by about 75%. However, the fact that approximately 25% of administrations of glucagon are ineffective remains a concern.
The primary question to be addressed by this study is, in the setting of low dose subcutaneous glucagon administration, how do plasma glucagon and plasma insulin quantitatively interact? In other words, as the rate of insulin administration is increased, how much more glucagon is necessary to overcome the effect of insulin to prevent hypoglycemia? This study is designed to address this question. Subjects will be brought in to a Legacy Hospital for four 10 hour experiments on each of four separate days. On each study day, there will be a continuous infusion of a different rate of IV Regular insulin in order to achieve different steady state free insulin levels. At each insulin level, there will be four subcutaneous glucagon doses given. Octreotide will be infused by IV at a constant rate to suppress endogenous production of glucagon. A stable glucose isotope will also be infused to allow for measurement of hepatic glucose production and glucose turnover. Arterialized venous blood glucose will be measured by the HemoCue Glucose 201 Analyzer.
- Conditions
- Type 1 Diabetes Mellitus
- Being tested
- Glucagon, Insulin
- Keywords
- diabetes, glucagon, insulin, dideuterated glucose
- Medical subject headings
- Diabetes Mellitus, Type 1, Diabetes Mellitus, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GlucagonDrug
Also called GlucaGen
The first dose of glucagon will be delivered approximately one hour after infusion of IV insulin has started. The subsequent three doses will be delivered every two hours. The dosage will depend on the IV insulin infusion (50 units regular insulin in 499.5 mL 0.9% saline): Study 1) insulin 0.01 units/kg/hour and glucagon doses (ug): 10,25,45,70; Study 2) insulin 0.02 units/kg/hr and glucagon doses (ug): 25,45,70,100; Study 3) insulin 0.04 units/kg/hr and glucagon doses (ug): 45,70,100,135; Study 4) insulin 0.08 units/kg/hr and glucagon doses (ug): 70,100,135,175. Insulin levels and glucagon doses will be randomized. Glucagon will be reconstituted with 10 mL of sterile water and administered subcutaneously.
InsulinDrug
Also called Regular insulin
Insulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants.
| Study group | Role | What they receive |
|---|---|---|
| Low, Medium and High insulin infusion | Experimental | All study subjects in this arm were randomized as follows:
First study is regular insulin infused at lowest level with glucagon administration.
Second study is regular insulin infused at medium level with glucagon adminstration.
Third study is regular insulin infused at highest level with glucagon administration. Receives: Drug: Glucagon; Drug: Insulin |
| Low, High and Medium insulin infusion | Experimental | All study subjects in this arm were randomized as follows:
First study is regular insulin infused at lowest level with glucagon administration.
Second study is regular insulin infused at highest level with glucagon adminstration.
Third study is regular insulin infused at medium level with glucagon administration. Receives: Drug: Glucagon; Drug: Insulin |
| Medium, Low and High insulin infusion | Experimental | All study subjects in this arm were randomized as follows:
First study is regular insulin infused at medium level with glucagon administration.
Second study is regular insulin infused at lowest level with glucagon adminstration.
Third study is regular insulin infused at highest level with glucagon administration. Receives: Drug: Glucagon; Drug: Insulin |
| Medium, High and Low insulin infusion | Experimental | All study subjects in this arm were randomized as follows:
First study is regular insulin infused at medium level with glucagon administration.
Second study is regular insulin infused at highest level with glucagon adminstration.
Third study is regular insulin infused at lowest level with glucagon administration. Receives: Drug: Glucagon; Drug: Insulin |
| High, Low and Medium insulin infusion | Experimental | All study subjects in this arm were randomized as follows:
First study is regular insulin infused at highest level with glucagon administration.
Second study is regular insulin infused at lowest level with glucagon adminstration.
Third study is regular insulin infused at medium level with glucagon administration. Receives: Drug: Glucagon; Drug: Insulin |
| High, Medium and Low insulin infusion | Experimental | All study subjects in this arm were randomized as follows:
First study is regular insulin infused at highest level with glucagon administration.
Second study is regular insulin infused at medium level with glucagon adminstration.
Third study is regular insulin infused at lowest level with glucagon administration. Receives: Drug: Glucagon; Drug: Insulin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Area Under the Curve for Glucose Above Baseline
The change in the rate of glucose appearance will be assessed by measuring the stable glucose isotope (dideuterated glucose, D2) using a gas chromatography-mass spectrometry assay. The units of the area under the curve are defined as milligrams per kilogram of glucose, since the dependent variable is a rate of glucose production [mg/kg/min] measured over time [min]. The time variable therefore cancels out. Additionally, this area under the curve is being normalized per microgram of glucagon delivered.
Measured: 60 minutes after each glucagon administration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Dec 2011 (estimated)
- Study startNov 2011
- Primary completionMar 2013
- Study completionMar 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Type 1 Diabetes MellitusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- Legacy Health System
- Sponsor type
- University, hospital or other
- Collaborators
- Juvenile Diabetes Research Foundation, Oregon Health and Science University
- Responsible party
- Principal investigator, W. Kenneth Ward, Legacy Health System
- Investigators
- W Kenneth Ward, MD, Principal investigator, Legacy Health System
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01483651
- Sponsor's protocol ID
- kw02
- Status last verified
- Mar 2016
- First submitted
- 29 Nov 2011
- Last updated
- 29 Mar 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 29 Mar 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Hepatic Glucose Response to Glucagon at Varying Insulin Levels: Implications for Closed Loop Glycemic Control.
- ClinicalTrials.gov ID
- NCT01483651
- Acronym / sponsor ID
- kw02
- Conditions
- Type 1 Diabetes Mellitus
- Keywords
- diabetes, glucagon, insulin, dideuterated glucose
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- Legacy Health SystemUniversity, hospital or other
- Collaborators
- Juvenile Diabetes Research Foundation, Oregon Health and Science University
- Study start
- Nov 2011
- Primary completion
- Mar 2013 (actual)
- Study completion
- Mar 2013 (actual)
- First posted
- 1 Dec 2011 (estimated)
- Results
- Posted 22 Sep 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this research study is to test how different levels of insulin block the effect of glucagon. Insulin is a hormone that lowers blood glucose. Glucagon raises blood glucose. Both are natural hormones made by people without diabetes. Sensor-based blood glucose control studies have been done by our research group using glucagon in small doses to prevent hypoglycemia (low blood sugar). However, sometimes glucagon does not work to raise blood sugar. The investigators believe this is because of too much insulin in the body. This study will help determine how different levels of insulin in the body affect the ability of glucagon to raise blood sugar.
Detailed description
We investigators have been working on the development of a closed loop (artificial endocrine pancreas) insulin and glucagon infusion system since 2005 and are part of the Juvenile Diabetes Research Foundation Artificial Pancreas Consortium. As part of our studies, we give small doses of glucagon to prevent hypoglycemia. As we assessed the success and failure of glucagon administration during these studies, we found the use of glucagon reduced the frequency of hypoglycemia by about 75%. However, the fact that approximately 25% of administrations of glucagon are ineffective remains a concern.
The primary question to be addressed by this study is, in the setting of low dose subcutaneous glucagon administration, how do plasma glucagon and plasma insulin quantitatively interact? In other words, as the rate of insulin administration is increased, how much more glucagon is necessary to overcome the effect of insulin to prevent hypoglycemia? This study is designed to address this question. Subjects will be brought in to a Legacy Hospital for four 10 hour experiments on each of four separate days. On each study day, there will be a continuous infusion of a different rate of IV Regular insulin in order to achieve different steady state free insulin levels. At each insulin level, there will be four subcutaneous glucagon doses given. Octreotide will be infused by IV at a constant rate to suppress endogenous production of glucagon. A stable glucose isotope will also be infused to allow for measurement of hepatic glucose production and glucose turnover. Arterialized venous blood glucose will be measured by the HemoCue Glucose 201 Analyzer.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Low, Medium and High insulin infusion | Experimental | Drug: Glucagon, Drug: InsulinAll study subjects in this arm were randomized as follows: First study is regular insulin infused at lowest level with glucagon administration. Second study is regular insulin infused at medium level with glucagon adminstration. Third study is regular insulin infused at highest level with glucagon administration. |
| Low, High and Medium insulin infusion | Experimental | Drug: Glucagon, Drug: InsulinAll study subjects in this arm were randomized as follows: First study is regular insulin infused at lowest level with glucagon administration. Second study is regular insulin infused at highest level with glucagon adminstration. Third study is regular insulin infused at medium level with glucagon administration. |
| Medium, Low and High insulin infusion | Experimental | Drug: Glucagon, Drug: InsulinAll study subjects in this arm were randomized as follows: First study is regular insulin infused at medium level with glucagon administration. Second study is regular insulin infused at lowest level with glucagon adminstration. Third study is regular insulin infused at highest level with glucagon administration. |
| Medium, High and Low insulin infusion | Experimental | Drug: Glucagon, Drug: InsulinAll study subjects in this arm were randomized as follows: First study is regular insulin infused at medium level with glucagon administration. Second study is regular insulin infused at highest level with glucagon adminstration. Third study is regular insulin infused at lowest level with glucagon administration. |
| High, Low and Medium insulin infusion | Experimental | Drug: Glucagon, Drug: InsulinAll study subjects in this arm were randomized as follows: First study is regular insulin infused at highest level with glucagon administration. Second study is regular insulin infused at lowest level with glucagon adminstration. Third study is regular insulin infused at medium level with glucagon administration. |
| High, Medium and Low insulin infusion | Experimental | Drug: Glucagon, Drug: InsulinAll study subjects in this arm were randomized as follows: First study is regular insulin infused at highest level with glucagon administration. Second study is regular insulin infused at medium level with glucagon adminstration. Third study is regular insulin infused at lowest level with glucagon administration. |
Who may qualify
- Ages
- 21 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Diagnosis of type 1 diabetes mellitus for at least 1 year
- Male or female subjects 21 to 65 years of age
- Current use of an insulin pump
- Willingness to sign informed consent and HIPAA documents and follow all study procedures
Key exclusion criteria (23 listed)
- Pregnancy or Lactation: For women of childbearing potential: there is a requirement for a negative urine pregnancy test and for agreement to use contraception during the study and for at least 1 month after participating in the study
- Renal insufficiency (serum creatinine of 2.0 mg/dL or greater)
- Liver abnormalities: 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
- Adrenal insufficiency
- Hematocrit of less than or equal to 34%
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GlucagonAlso: GlucaGenThe first dose of glucagon will be delivered approximately one hour after infusion of IV insulin has started. The subsequent three doses will be delivered every two hours. The dosage will depend on the IV insulin infusion (50 units regular insulin in 499.5 mL 0.9% saline): Study 1) insulin 0.01 units/kg/hour and glucagon doses (ug): 10,25,45,70; Study 2) insulin 0.02 units/kg/hr and glucagon doses (ug): 25,45,70,100; Study 3) insulin 0.04 units/kg/hr and glucagon doses (ug): 45,70,100,135; Study 4) insulin 0.08 units/kg/hr and glucagon doses (ug): 70,100,135,175. Insulin levels and glucagon doses will be randomized. Glucagon will be reconstituted with 10 mL of sterile water and administered subcutaneously. | Drug | High, Low and Medium insulin infusion, High, Medium and Low insulin infusion, Low, High and Medium insulin infusion, Low, Medium and High insulin infusion, Medium, High and Low insulin infusion, Medium, Low and High insulin infusion |
| InsulinAlso: Regular insulinInsulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants. | Drug | High, Low and Medium insulin infusion, High, Medium and Low insulin infusion, Low, High and Medium insulin infusion, Low, Medium and High insulin infusion, Medium, High and Low insulin infusion, Medium, Low and High insulin infusion |
Primary outcome
Area Under the Curve for Glucose Above Baseline
Time frame: 60 minutes after each glucagon administration
The change in the rate of glucose appearance will be assessed by measuring the stable glucose isotope (dideuterated glucose, D2) using a gas chromatography-mass spectrometry assay. The units of the area under the curve are defined as milligrams per kilogram of glucose, since the dependent variable is a rate of glucose production [mg/kg/min] measured over time [min]. The time variable therefore cancels out. Additionally, this area under the curve is being normalized per microgram of glucagon delivered.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Mar 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
W Kenneth Ward, MD principal investigator
Legacy Health System
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Glucagon and Insulin in people with Type 1 Diabetes Mellitus, run by Legacy Health System at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Sep 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Area Under the Curve for Glucose Above Baseline (time frame: 60 minutes after each glucagon administration). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Mar 2016.