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Glucagon Counterregulation in Type 1 Diabetes

Primary Purpose

Type 1 Diabetes Mellitus

Status
Terminated
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Basal insulin alone
Basal pramlintide and reduced basal insulin
CGM
Acetaminophen test
Insulin-induced hypoglycemia
Exercise-induced hypoglycemia
Sponsored by
University of Virginia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Type 1 Diabetes Mellitus focused on measuring Type 1 Diabetes Mellitus, Pramlintide, Lispro Insulin, Continuous Glucose Monitor (CGM), Acetaminophen, Hypoglycemia, Exercise

Eligibility Criteria

21 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least 5 years and using insulin for at least 5 years
  • Use of an insulin pump for at least 6 months with established parameters for basal rate(s), carbohydrate ratio(s) and insulin sensitivity factor(s) for at least 3 months.
  • HbA1c level <10.5% at screening
  • Demonstration of proper mental status and cognition for the study
  • Investigator has confidence that the subject can successfully operate all study devices and is capable of adhering to the protocol

Exclusion Criteria:

  • Admission for diabetic ketoacidosis in the 6 months prior to enrollment.
  • Severe hypoglycemia resulting in seizure or loss of consciousness in the 3 months prior to enrollment.
  • Hematocrit less that the lower limit of normal for the assay.
  • Pregnancy, breast-feeding, or intention of becoming pregnant over time of study procedures
  • A known medical condition, which in the opinion of the investigator or designee, would put the participant or study at risk
  • A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol
  • Current use of some drugs and supplements
  • Participation in another pharmaceutical or device trial at the time of enrollment or during the study
  • Basal insulin rates less than 0.01 units per hour
  • Diagnosed food allergies that would prohibit the consumption of a standardized meal
  • Any reason the study MD considers that the subject is not appropriate for the trial

Sites / Locations

  • University of Virginia Center for Diabetes Technology

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Experimental

Active Comparator

Arm Label

Insulin hypoglycemia + pramlintide

Insulin hypoglycemia

Exercise hypoglycemia + pramlintide

Exercise hypoglycemia

Arm Description

Subjects will have a 25% reduction in their standard basal insulin therapy with concurrent basal pramlintide infusion ('Basal pramlintide and reduced basal insulin'). They will receive a Lispro bolus to induce hypoglycemia of ≤55mg/dL ('Insulin-induced hypoglycemia'). After induction of hypoglycemia is completed subjects will have an acetaminophen test. Subjects will be instructed to initiate a CGM session 2-3 days prior to both the admissions. Blood samples will be collected during the hypoglycemic induction and acetaminophen test.

Subjects will have their standard basal insulin treatment ('Basal insulin alone') and receive a Lispro bolus to induce hypoglycemia of ≤55mg/dL ('Insulin-induced hypoglycemia'). After induction of hypoglycemia is completed subjects will have an acetaminophen test. Subjects will be instructed to initiate a CGM session 2-3 days prior to both the admissions. Blood samples will be collected during the hypoglycemic induction and acetaminophen test.

Subjects will have a 25% reduction in their standard basal insulin therapy with concurrent basal pramlintide infusion ('Basal pramlintide and reduced basal insulin'). They will have three bouts of exercise to induce hypoglycemia of ≤55mg/dL ('Exercise-induced hypoglycemia'). After induction of hypoglycemia is completed subjects will have an acetaminophen test. Subjects will be instructed to initiate a CGM session 2-3 days prior to both the admissions. Blood samples will be collected during the hypoglycemic induction and acetaminophen test.

Subjects will have their standard basal insulin treatment ('Basal insulin alone'). They will have three bouts of exercise to induce hypoglycemia of ≤55mg/dL ('Exercise-induced hypoglycemia' ). After induction of hypoglycemia is completed subjects will have an acetaminophen test. Subjects will be instructed to initiate a CGM session 2-3 days prior to both the admissions. Blood samples will be collected during the hypoglycemic induction and acetaminophen test.

Outcomes

Primary Outcome Measures

Relative glucagon counterregulation (GCR) response
The primary outcome is the relative glucagon counterregulation (GCR) response, computed as the ratio between average glucagon concentration in response to insulin-induced hypoglycemia, and the pre-hypoglycemic baseline value. The baseline glucagon level is defined as the average concentration of glucagon when the falling plasma glucose is below 100mg/dl but above the hypoglycemic threshold of 60mg/dl. The response to hypoglycemia is the average concentration of glucagon between the hypoglycemic threshold crossing point and the time of the meal ingestion.

Secondary Outcome Measures

Maximal glucagon counterregulation (GCR) response
The maximal glucagon concentration achieved during the response to hypoglycemia
Rate of gastric emptying
The time to reaching ½ maximal acetaminophen concentration in the bloodstream after ingesting a meal mixed with 1.5 g of liquid acetaminophen.

Full Information

First Posted
May 24, 2018
Last Updated
March 10, 2022
Sponsor
University of Virginia
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1. Study Identification

Unique Protocol Identification Number
NCT03547427
Brief Title
Glucagon Counterregulation in Type 1 Diabetes
Official Title
Enhancement of Glucagon Counterregulation in Type 1 Diabetes by Basal Amylin Replacement
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Terminated
Why Stopped
Clinical staffing issues and COVID-19 pandemic
Study Start Date
May 20, 2018 (Actual)
Primary Completion Date
March 11, 2019 (Actual)
Study Completion Date
March 11, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Virginia

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to find out whether the combination of insulin and pramlintide is better than insulin alone at helping the pancreas release glucagon in response to a low blood sugar episode. A secondary goal is to assess whether basal pramlintide will delay gastric emptying.
Detailed Description
Participation in this study will require three (3) study visits over 12 weeks: one screening visit lasting 2-3 hours, and two overnight study visits at the university's Clinical Research Unit (CRU). The two overnight visits will last about 22 hours. During the CRU admission, all subjects will wear a Continuous Glucose Monitor (CGM) starting 2-3 days prior to the CRU admission and after having a CGM training. Eligible subjects will be randomized to either insulin- or exercise-induced hypoglycemia group. Each subject will have two overnight CRU admissions in randomized order: Experimental (basal pramlintide + 25% reduction of basal insulin) or Control (standard basal insulin therapy) admissions. During these two admissions, the study team will deliberately induce hypoglycemia as follows: Subjects randomized to insulin-induced hypoglycemia admission will receive an insulin bolus(s) dosed to reach blood sugar of less than 55 mg/dL. Subjects randomized to exercise-induced hypoglycemia will participate in three 15 minute exercise bouts (45 minutes total) to lower blood sugar to less than 55 mg/dL. After hypoglycemia induction, all subjects will receive one and the same standard meal (lunch) mixed with 1.5 g liquid acetaminophen to measure how quickly acetaminophen is absorbed to estimate the rate of gastric emptying. The study team will collect blood samples during the hypoglycemic induction and the gastric emptying monitoring which will be analysed for levels of various substances used to address the study goals.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes Mellitus
Keywords
Type 1 Diabetes Mellitus, Pramlintide, Lispro Insulin, Continuous Glucose Monitor (CGM), Acetaminophen, Hypoglycemia, Exercise

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Insulin hypoglycemia + pramlintide
Arm Type
Experimental
Arm Description
Subjects will have a 25% reduction in their standard basal insulin therapy with concurrent basal pramlintide infusion ('Basal pramlintide and reduced basal insulin'). They will receive a Lispro bolus to induce hypoglycemia of ≤55mg/dL ('Insulin-induced hypoglycemia'). After induction of hypoglycemia is completed subjects will have an acetaminophen test. Subjects will be instructed to initiate a CGM session 2-3 days prior to both the admissions. Blood samples will be collected during the hypoglycemic induction and acetaminophen test.
Arm Title
Insulin hypoglycemia
Arm Type
Active Comparator
Arm Description
Subjects will have their standard basal insulin treatment ('Basal insulin alone') and receive a Lispro bolus to induce hypoglycemia of ≤55mg/dL ('Insulin-induced hypoglycemia'). After induction of hypoglycemia is completed subjects will have an acetaminophen test. Subjects will be instructed to initiate a CGM session 2-3 days prior to both the admissions. Blood samples will be collected during the hypoglycemic induction and acetaminophen test.
Arm Title
Exercise hypoglycemia + pramlintide
Arm Type
Experimental
Arm Description
Subjects will have a 25% reduction in their standard basal insulin therapy with concurrent basal pramlintide infusion ('Basal pramlintide and reduced basal insulin'). They will have three bouts of exercise to induce hypoglycemia of ≤55mg/dL ('Exercise-induced hypoglycemia'). After induction of hypoglycemia is completed subjects will have an acetaminophen test. Subjects will be instructed to initiate a CGM session 2-3 days prior to both the admissions. Blood samples will be collected during the hypoglycemic induction and acetaminophen test.
Arm Title
Exercise hypoglycemia
Arm Type
Active Comparator
Arm Description
Subjects will have their standard basal insulin treatment ('Basal insulin alone'). They will have three bouts of exercise to induce hypoglycemia of ≤55mg/dL ('Exercise-induced hypoglycemia' ). After induction of hypoglycemia is completed subjects will have an acetaminophen test. Subjects will be instructed to initiate a CGM session 2-3 days prior to both the admissions. Blood samples will be collected during the hypoglycemic induction and acetaminophen test.
Intervention Type
Other
Intervention Name(s)
Basal insulin alone
Intervention Description
A study insulin pump containing lispro insulin will be programmed to deliver basal lispro insulin at according to the subject's normal basal profile. The carbohydrate ratio(s) and insulin sensitivity factor(s) will be programmed per the subject's usual home parameters.
Intervention Type
Other
Intervention Name(s)
Basal pramlintide and reduced basal insulin
Intervention Description
A study insulin pump containing pramlintide will be programmed to deliver pramlintide at 6:1 pramlintide:insulin ratio. Simultaneously, a study insulin pump containing lispro insulin will be programmed to deliver basal lispro insulin at ~25% reduced rate from the subject's normal basal profile. The carbohydrate ratio(s) and insulin sensitivity factor(s) will be programmed per the subject's usual home parameters.
Intervention Type
Other
Intervention Name(s)
CGM
Intervention Description
Subjects will be instructed to initiate a Continuous Glucose Monitor (CGM) session 2-3 days prior to both the experimental and control CRU admissions.
Intervention Type
Other
Intervention Name(s)
Acetaminophen test
Intervention Description
Consumption of a standardized meal mixed with added 1.5 g liquid acetaminophen
Intervention Type
Other
Intervention Name(s)
Insulin-induced hypoglycemia
Intervention Description
During insulin-induced hypoglycemia admission, subjects will receive an insulin bolus(s) dosed to reach blood sugar of less than 55 mg/dL.
Intervention Type
Other
Intervention Name(s)
Exercise-induced hypoglycemia
Intervention Description
During exercise-induced hypoglycemia admission, subjects participate in three 15 minute exercise bouts (45 minutes total) to lower blood sugar to less than 55 mg/dL.
Primary Outcome Measure Information:
Title
Relative glucagon counterregulation (GCR) response
Description
The primary outcome is the relative glucagon counterregulation (GCR) response, computed as the ratio between average glucagon concentration in response to insulin-induced hypoglycemia, and the pre-hypoglycemic baseline value. The baseline glucagon level is defined as the average concentration of glucagon when the falling plasma glucose is below 100mg/dl but above the hypoglycemic threshold of 60mg/dl. The response to hypoglycemia is the average concentration of glucagon between the hypoglycemic threshold crossing point and the time of the meal ingestion.
Time Frame
about 19 hours
Secondary Outcome Measure Information:
Title
Maximal glucagon counterregulation (GCR) response
Description
The maximal glucagon concentration achieved during the response to hypoglycemia
Time Frame
about 19 hours
Title
Rate of gastric emptying
Description
The time to reaching ½ maximal acetaminophen concentration in the bloodstream after ingesting a meal mixed with 1.5 g of liquid acetaminophen.
Time Frame
about 4 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least 5 years and using insulin for at least 5 years Use of an insulin pump for at least 6 months with established parameters for basal rate(s), carbohydrate ratio(s) and insulin sensitivity factor(s) for at least 3 months. HbA1c level <10.5% at screening Demonstration of proper mental status and cognition for the study Investigator has confidence that the subject can successfully operate all study devices and is capable of adhering to the protocol Exclusion Criteria: Admission for diabetic ketoacidosis in the 6 months prior to enrollment. Severe hypoglycemia resulting in seizure or loss of consciousness in the 3 months prior to enrollment. Hematocrit less that the lower limit of normal for the assay. Pregnancy, breast-feeding, or intention of becoming pregnant over time of study procedures A known medical condition, which in the opinion of the investigator or designee, would put the participant or study at risk A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol Current use of some drugs and supplements Participation in another pharmaceutical or device trial at the time of enrollment or during the study Basal insulin rates less than 0.01 units per hour Diagnosed food allergies that would prohibit the consumption of a standardized meal Any reason the study MD considers that the subject is not appropriate for the trial
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Leon S. Farhy, PhD
Organizational Affiliation
University of Virginia
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Virginia Center for Diabetes Technology
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22903
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
To be determined
IPD Sharing Time Frame
To be determined
IPD Sharing Access Criteria
To be determined

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Glucagon Counterregulation in Type 1 Diabetes

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