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Triple-hormone (Insulin-pramlintide-glucagon) Closed-loop Strategy to Regulate Glucose Levels Without Carbohydrate Counting (Triple)

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ClinicalTrials.gov Identifier: NCT03800875
Recruitment Status : Recruiting
First Posted : January 11, 2019
Last Update Posted : February 8, 2019
Sponsor:
Collaborator:
Diabetes Canada
Information provided by (Responsible Party):
McGill University

Brief Summary:
Closed-loop system systems that are shown to alleviate the burden of carbohydrate counting without degrading glucose control are still lacking. In this proposal, the investigators aim to develop a novel, fully-automated, triple-hormone, closed-loop system that delivers insulin, pramlintide, and glucagon that controls postprandial glucose levels without any input from the user.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Drug: 27-hour inpatient intervention Phase 2

Detailed Description:

Meal carbohydrate content is the main determinant of prandial insulin needs, and consequently, accurate carbohydrate counting is recommended for type 1 diabetes. Advances in glucose sensors have motivated the development of the closed-loop system to automatically regulate glucose levels in individuals with type 1 diabetes. In the closed-loop system, a dosing algorithm adjusts the pump insulin infusion rate based on continuous glucose sensor readings.

Closed-loop system systems that are shown to alleviate the burden of carbohydrate counting without degrading glucose control are still lacking. In this proposal, the investigators aim to develop a novel, fully-automated, triple-hormone, closed-loop system that delivers insulin, pramlintide, and glucagon that controls postprandial glucose levels without any input from the user. Thus, the three hormones' role in the postprandial state will be as follows:

  1. Insulin: to reduce plasma glucose levels. Insulin delivery needs to be aggressive to counter-act fast increase in post-meal glucose levels.
  2. Glucagon: to reduce the risk late postprandial hypoglycemia to the aggressive insulin delivery.
  3. Pramlintide: to slow gastric emptying and aim insulin in efficiently controlling postprandial glucose levels.

The aim of this study is to assess a fully automated, triple-hormone, closed-loop system that delivers insulin, pramlintide, and glucagon to control glucose levels without degrading overall glycemic control compared to an insulin-alone closed-loop system with carbohydrate-matched boluses.

The investigators hypothesize that the triple-hormone closed-loop system will alleviate carbohydrate-counting burden (fully reactive system) without degrading glucose control compared to the insulin-alone closed-loop system.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Controlled, Crossover Trial to Assess a Triple-hormone (Insulin-pramlintide-glucagon) Closed-loop Delivery Without Carbohydrate Counting in Regulating Glucose Levels in Adults With Type 1 Diabetes
Actual Study Start Date : November 10, 2018
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Triple-Hormone Closed-Loop Strategy
Fast-acting insulin, glucaon, and pramlintide will be delivered using three separate infusion pumps. The pumps' infusion rates will then be changed manually based on the computer-generated recommendation. The computer-generated recommendations are based on a dosing algorithm. With no-meal announcement or carbohydrate counting, the triple-hormone closed-loop system will be fully reactive, and insulin, pramlintide and glucagon dosages will be based solely on sensor readings
Drug: 27-hour inpatient intervention
Subjects will be admitted at the research facility at 19:00. Each 27-hour intervention visit includes 3 standardized meals (8:00, 12:00, and 17:00), an evening snack (22:00) and an overnight stay. The glucose level as measured by the real time sensor will be entered manually into the computer every 10 minutes. The infusion rate of either insulin alone or insulin, pramlintide and glucagon will be changed manually based on the computer generated recommendation. The computer generated recommendations are based on a predictive algorithm.

Active Comparator: Insulin-alone Closed Loop Strategy

Fast-acting insulin will be delivered by a subcutaneous insulin infusion pump based on an algorithm that automatically adjusts insulin rates based on a dosing algorithm. The carbohydrate content for every ingested meal will be entered into the algorithm to calculate the insulin prandial bolus based on each participant's insulin-to-carbohydrate ratio. The carbohydrate content will be entered at the onset of the meal.

Drug(s): Insulin (FiAsp)

Drug: 27-hour inpatient intervention
Subjects will be admitted at the research facility at 19:00. Each 27-hour intervention visit includes 3 standardized meals (8:00, 12:00, and 17:00), an evening snack (22:00) and an overnight stay. The glucose level as measured by the real time sensor will be entered manually into the computer every 10 minutes. The infusion rate of either insulin alone or insulin, pramlintide and glucagon will be changed manually based on the computer generated recommendation. The computer generated recommendations are based on a predictive algorithm.




Primary Outcome Measures :
  1. Mean blood glucose level of a participant [ Time Frame: 24 hours ]

Secondary Outcome Measures :
  1. Total percentage of time (22:00-22:00) that the glucose concentration remained within specified ranges. [ Time Frame: 24 hours ]
    a. between 3.9 and 7.8 mmol/L; b. between 3.9 and 10 mmol/L; c. below 3.9 mmol/L; d. below 3.3 mmol/L; e. below 2.8 mmol/L; f. above 7.8 mmol/L; g. above 10 mmol/L; h. above 13.9 mmol/L; i. above 16.7 mmol/L.

  2. Percentage of overnight time (24:00-8:00) that the glucose concentration remained within specified ranges. [ Time Frame: 8 hours ]
    a. between 3.9 and 7.8 mmol/L; b. between 3.9 and 10 mmol/L; c. below 3.9 mmol/L; d. below 3.3 mmol/L; e. below 2.8 mmol/L; f. above 7.8 mmol/L; g. above 10 mmol/L; h. above 13.9 mmol/L; i. above 16.7 mmol/L.

  3. Total amount of insulin delivered to the participant [ Time Frame: 24 hours ]
  4. Mean sensor glucose concentration during the overnight stay [ Time Frame: 8 hours ]
  5. Number of participants experiencing hypoglycemia requiring oral treatment during: a. the overall study period; b. the night; c. the day [ Time Frame: 27 hours ]
  6. The number and severity of gastrointestinal sysmptoms experienced by a participant [ Time Frame: 27 hours ]
    GI symptoms include: nausea, vomiting, bloating and heartburn

  7. Mean daytime insulin concentration [ Time Frame: 14 hours ]
  8. Mean daytime concentration of glucagon [ Time Frame: 14 hours ]
  9. Mean daytime concentration of amylin [ Time Frame: 14 hours ]
  10. Total amount of glucagon delivered to the participant [ Time Frame: 24 hours ]
  11. Total amount of pramlintide delivered to the participant [ Time Frame: 24 hours ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males and females ≥ 18 years of age.
  2. Clinical diagnosis of type 1 diabetes for at least 12 months. The diagnosis of type 1 diabetes is based on the investigator's judgment; C peptide level and antibody determinations are not needed.
  3. Insulin pump therapy for at least 6 months.
  4. HbA1c ≤ 12% in the last 6 months.

Exclusion Criteria:

  1. Current or ≤ 1 month use of other antihyperglycemic agents (SGLT2, GLP-1, Metformin, Acarbose, etc.…).
  2. Severe hypoglycemic episode within one month of admission.
  3. Severe diabetic ketoacidosis episode within one month of admission.
  4. Pregnancy.
  5. Known or suspected allergy to the study drugs.
  6. Gastroparesis.
  7. Use of prokinetic drugs that stimulate gastric emptying (domperidone, cisapride, metoclopramide).
  8. Clinically significant nephropathy, neuropathy or retinopathy as judged by the investigator.
  9. Recent (< 6 months) acute macrovascular event e.g. acute coronary syndrome or cardiac surgery.
  10. Current use of glucocorticoid medication.
  11. Other serious medical illness likely to interfere with study participation or with the ability to complete the trial by the judgment of the investigator.
  12. Failure to comply with team's recommendations (e.g. not willing to eat meals/snacks, not willing to change pump parameters, etc.).

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): NCT03800875


Contacts
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Contact: Dorsa Majdpour (514) 553-5500 ext 3238 dorsa.majdpour@mail.mcgill.ca

Locations
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Canada, Quebec
McGill University Health Centre Recruiting
Montréal, Quebec, Canada, H4A 3J1
Contact: Jennifer Rene       jennifer.rene@mcgill.ca   
Sub-Investigator: Ahmad Haidar, Eng., PhD         
Principal Investigator: Michael Tsoukas, MD         
Sub-Investigator: Laurent Legault, MD         
Sub-Investigator: Jean- François Yale, MD         
Sponsors and Collaborators
McGill University
Diabetes Canada
Investigators
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Principal Investigator: Michael Tsoukas McGill University Health Center

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Responsible Party: McGill University
ClinicalTrials.gov Identifier: NCT03800875     History of Changes
Other Study ID Numbers: Triple Hormone
First Posted: January 11, 2019    Key Record Dates
Last Update Posted: February 8, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by McGill University:
Diabetes Mellitus, Type 1
Pramlintide
Glucagon
Insulin
Triple-Hormone
Closed-Loop
Artificial Pancreas

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