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Glucagon Counterregulation in Type 1 Diabetes

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ClinicalTrials.gov Identifier: NCT03547427
Recruitment Status : Recruiting
First Posted : June 6, 2018
Last Update Posted : June 6, 2018
Sponsor:
Information provided by (Responsible Party):
Leon Farhi, PhD, University of Virginia

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.


Condition or disease Intervention/treatment Phase
Type 1 Diabetes Mellitus Other: Basal insulin alone Other: Basal pramlintide and reduced basal insulin Other: CGM Other: Acetaminophen test Other: Insulin-induced hypoglycemia Other: Exercise-induced hypoglycemia Not Applicable

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Enhancement of Glucagon Counterregulation in Type 1 Diabetes by Basal Amylin Replacement
Actual Study Start Date : May 20, 2018
Estimated Primary Completion Date : October 31, 2018
Estimated Study Completion Date : November 30, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Glucagon

Arm Intervention/treatment
Experimental: Insulin hypoglycemia + pramlintide
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.
Other: Basal pramlintide and reduced basal insulin
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.

Other: CGM
Subjects will be instructed to initiate a Continuous Glucose Monitor (CGM) session 2-3 days prior to both the experimental and control CRU admissions.

Other: Acetaminophen test
Consumption of a standardized meal mixed with added 1.5 g liquid acetaminophen

Other: Insulin-induced hypoglycemia
During insulin-induced hypoglycemia admission, subjects will receive an insulin bolus(s) dosed to reach blood sugar of less than 55 mg/dL.

Active Comparator: Insulin hypoglycemia
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.
Other: Basal insulin alone
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.

Other: CGM
Subjects will be instructed to initiate a Continuous Glucose Monitor (CGM) session 2-3 days prior to both the experimental and control CRU admissions.

Other: Acetaminophen test
Consumption of a standardized meal mixed with added 1.5 g liquid acetaminophen

Other: Insulin-induced hypoglycemia
During insulin-induced hypoglycemia admission, subjects will receive an insulin bolus(s) dosed to reach blood sugar of less than 55 mg/dL.

Experimental: Exercise hypoglycemia + pramlintide
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.
Other: Basal pramlintide and reduced basal insulin
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.

Other: CGM
Subjects will be instructed to initiate a Continuous Glucose Monitor (CGM) session 2-3 days prior to both the experimental and control CRU admissions.

Other: Acetaminophen test
Consumption of a standardized meal mixed with added 1.5 g liquid acetaminophen

Other: Exercise-induced hypoglycemia
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.

Active Comparator: Exercise hypoglycemia
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.
Other: Basal insulin alone
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.

Other: CGM
Subjects will be instructed to initiate a Continuous Glucose Monitor (CGM) session 2-3 days prior to both the experimental and control CRU admissions.

Other: Acetaminophen test
Consumption of a standardized meal mixed with added 1.5 g liquid acetaminophen

Other: Exercise-induced hypoglycemia
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 Measures :
  1. Relative glucagon counterregulation (GCR) response [ Time Frame: about 19 hours ]
    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 :
  1. Maximal glucagon counterregulation (GCR) response [ Time Frame: about 19 hours ]
    The maximal glucagon concentration achieved during the response to hypoglycemia

  2. Rate of gastric emptying [ Time Frame: about 4 hours ]
    The time to reaching ½ maximal acetaminophen concentration in the bloodstream after ingesting a meal mixed with 1.5 g of liquid acetaminophen.



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03547427


Contacts
Contact: Leon S. Farhy, PhD 434-924-2496 lsf8n@virginia.edu
Contact: Jennifer Pinnata, RN 434-982-0631 JP3TE@virginia.edu

Locations
United States, Virginia
University of Virginia Center for Diabetes Technology Recruiting
Charlottesville, Virginia, United States, 22903
Contact: Leon S. Farhy, PhD    434-924-2496    lsf8n@virginia.edu   
Sub-Investigator: Stacey M. Anderson, MD         
Sub-Investigator: Andy Basu, MD         
Sub-Investigator: Marc D. Breton, PhD         
Sponsors and Collaborators
University of Virginia
Investigators
Principal Investigator: Leon S. Farhy, PhD University of Virginia

Responsible Party: Leon Farhi, PhD, Principal Investigator, University of Virginia
ClinicalTrials.gov Identifier: NCT03547427     History of Changes
Other Study ID Numbers: 20364
First Posted: June 6, 2018    Key Record Dates
Last Update Posted: June 6, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: To be determined
Time Frame: To be determined
Access Criteria: To be determined

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Leon Farhi, PhD, University of Virginia:
Type 1 Diabetes Mellitus
Pramlintide
Lispro Insulin
Continuous Glucose Monitor (CGM)
Acetaminophen
Hypoglycemia
Exercise

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Hypoglycemic Agents
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Insulin, Globin Zinc
Pramlintide
Insulin
Insulin Lispro
Islet Amyloid Polypeptide
Acetaminophen
Glucagon
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antipyretics
Gastrointestinal Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Appetite Depressants
Anti-Obesity Agents
Amylin Receptor Agonists
Molecular Mechanisms of Pharmacological Action