A Fully Automated Insulin and Pramlintide Delivery System for Adults With Type 1 Diabetes

Study Overview
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Brief Summary
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The aim of this clinical trial is to investigate whether a fully automated insulin-and-pramlintide delivery system improves glycemic outcomes in adults with type 1 diabetes. The main question we aim to answer is whether an insulin-pramlintide fully closed loop system improves time in range compared to a hybrid closed loop system with carbohydrate counting. We also aim to find the optimal insulin to pramlintide ratio for glycemic control in the fully automated system. In this cross-over study, patients will undergo the following three interventions in a random order: (i) fully automated rapid insulin-and-pramlintide (8 μg/u) (ii) fully automated rapid insulin-and-pramlintide (10 μg/u) (iii) rapid automated insulin-and-placebo with carbohydrate-matched boluses For all interventions, participants will be required to wear two Ypsomed pumps programmed by our developed EuGlide system.

Detailed Description
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The aim of this study is to conduct an outpatient, randomized, crossover clinical trial to compare the glycemic outcomes of a fully automated insulin-pramlintide delivery system to a hybrid automated insulin-placebo delivery system with carbohydrate counting in 26 adults with type 1 diabetes. Design- All participants will undergo three interventions in a random order: (i) Fully automated rapid insulin-pramlintide delivery system. Ratio of 1 unit of inulin for 8μg of pramlintide. (ii) Fully automated rapid insulin-pramlintide delivery system. Ratio of 1 unit of insulin for 10μg of pramlintide. (iii) Hybrid automated rapid insulin-placebo delivery system with carbohydrate-matched boluses. Study drugs- Insulin lispro and aspart are Health Canada approved drugs used to treat type 1 diabetes. Participants who do not currently use insulin lispro or aspart will be switched for the duration of the study. Pramlintide is an FDA-approved drug used in the treatment of type 1 diabetes. It contributes to regulating glucose levels by delaying gastric emptying, suppressing nutrient-stimulated glucagon secretion and increasing satiety. It is not approved for commercial use by Health Canada, but has been approved for the purpose of the study. Study Devices- For the duration of the study, participants will use a Dexcom G6 Continuous Glucose Monitor (GCM), two YpsoPumps (for insulin and pramlintide) as well as a study smartphone with the Euglide application installed. The automated insulin delivery (AID) system will integrate these sets of devices to automate insulin (and pramlintide) delivery in response to an individual's glucose levels. Treatment Period- Each intervention will last three weeks and be preceded by a 5-day at-home run-in period. After both the second and third interventions, there will be a 14-45 day washout period. Participants will be followed-up with remotely on days 2 (+/-1) and 5 of each run-in and on days 2(+/-1), 3(+/-1) and 7(+/-2) of each intervention. Remote contact can be performed via phone, email, text message or another reasonable communication channel. After each intervention, participants will be interviewed and asked to complete questionnaires assessing diabetes control and quality of life. Participants will need approximately 15-30 weeks to complete the study. The study will enroll up to 4 pilot participants, as well as 26 main study participants who meet the eligibility criteria.

Official Title
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A Randomized, Controlled, Crossover Trial to Assess a Fully Automated, Dual-hormone (Insulin-and-pramlintide) Delivery System Without Carbohydrate Counting in Regulating Glucose Levels in Adults With Type 1 Diabetes.

Conditions
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type1diabetes, Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Pramlintide
* Drug: Insulin Lispro
* Drug: Insulin aspart
* Device: Automated Insulin Delivery (AID) system


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals ≥ 18 years of age. A clinical diagnosis of type 1 diabetes for at least 12 months. The diagnosis of type 1 diabetes relies on the investigator's judgment; C peptide level and antibody determinations are unnecessary. Using insulin pump therapy for at least three months. Individuals of childbearing potential using an effective birth-control method. An individual of childbearing potential must agree to use a highly effective method of birth control. Exclusion Criteria: Current or recent use of antihyperglycemic agents other than insulin (≤ 2-week use of sodium-glucose cotransporter-2 inhibitor (SGLT2I), Metformin, etc.; ≤ 1-month for glucagon-like peptide-1 receptor agonists (GLP1-RA)). Current use of glucocorticoid medication (except low, stable doses and inhaled steroids). Individuals with confirmed gastroparesis. Use of medication that alters gastrointestinal motility (ex: domperidone). Use of hydroxyurea. Planned or ongoing pregnancy. Breastfeeding individuals. Severe hypoglycemia requiring hospitalization in the past month. Severe hypoglycemia is defined as requiring the assistance of another person, due to altered consciousness, to administer carbohydrates, glucagon, or other resuscitative actions. Diabetic ketoacidosis episode in the past month. Clinically significant nephropathy, neuropathy, or retinopathy as judged by the investigator. Recent (< 6 months) acute macrovascular event, e.g., acute coronary syndrome. Other serious medical illnesses which are likely to interfere with study participation or the ability to complete the trial by the investigator's judgment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fully automated rapid insulin-and-pramlintide delivery system (8 μg/u)<br>Insulin aspart/ insulin lispro and pramlintide fully automated delivery system with no meal announcement. Ratio of 1 unit of insulin for 8 μg of pramlintide. | Drug: Pramlintide<br>* Pramlintide delivered in a basal-bolus manner.<br>Drug: Insulin Lispro<br>* Insulin Lispro delivered in a basal-bolus manner.<br>Drug: Insulin aspart<br>* Insulin Aspart delivered in a basal-bolus manner.<br>Device: Automated Insulin Delivery (AID) system<br>* The AID system consists of a set of devices that work inter-connectedly to automate insulin (and pramlintide) delivery in response to an individual's glucose levels. It consists of a (i) Dexcom G6 glucose sensor, (ii) a smartphone-based algorithm, (iii) an insulin YpsoPump, and (iv) a pramlintide/placebo YpsoPump in a dual hormone configuration.<br>|
| Experimental: Fully automated rapid insulin-and-pramlintide delivery system (10 μg/u)<br>Insulin aspart/ insulin lispro and pramlintide fully automated delivery system with no meal announcement. Ratio of 1 unit of insulin for 10 μg of pramlintide. | Drug: Pramlintide<br>* Pramlintide delivered in a basal-bolus manner.<br>Drug: Insulin Lispro<br>* Insulin Lispro delivered in a basal-bolus manner.<br>Drug: Insulin aspart<br>* Insulin Aspart delivered in a basal-bolus manner.<br>Device: Automated Insulin Delivery (AID) system<br>* The AID system consists of a set of devices that work inter-connectedly to automate insulin (and pramlintide) delivery in response to an individual's glucose levels. It consists of a (i) Dexcom G6 glucose sensor, (ii) a smartphone-based algorithm, (iii) an insulin YpsoPump, and (iv) a pramlintide/placebo YpsoPump in a dual hormone configuration.<br>|
| Active Comparator: Rapid automated insulin-and-placebo delivery system with carbohydrate-matched boluses<br>Insulin aspart/ insulin lispro and saline placebo hybrid automated delivery system with meal announcement. Participants must input the carbohydrate content of their meals to inform the insulin bolus doses based on their pre-programmed insulin-to-carbohydrate ratios. | Drug: Insulin Lispro<br>* Insulin Lispro delivered in a basal-bolus manner.<br>Drug: Insulin aspart<br>* Insulin Aspart delivered in a basal-bolus manner.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time of glucose levels spent in the target range (3.9-10.0 mmol/L). |  | 18 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time of glucose levels spent between 3.9-7.8 mmol/L. |  | 18 days | 
| Percentage of time of glucose levels spent between 3.0-3.9 mmol/L. |  | 18 days | 
| Percentage of time of glucose levels spent between 10.0-13.9 mmol/L. |  | 18 days | 
| Mean glucose levels. |  | 18 days | 
| Standard deviation of glucose levels. |  | 18 days | 
| Coefficient of variance of glucose levels. |  | 18 days | 
| Total pramlintide delivery (overall, basal, and bolus). |  | 18 days | 
| Total insulin delivery (overall, basal, and bolus). |  | 18 days | 
| Mean score on the Type 1 Diabetes Distress Scale (T1DDS) excluding the physician subscale. | A scale from 1-6 indicating overall diabetes distress. Higher scores indicate higher levels of diabetes distress. Any total subscale score of >2.0 is considered clinically significant. | 18 days | 
| Mean score on the Hypoglycemia Fear Survey - II (Worry Subscale) (HSF2). | A scale from 1-5 with higher scores indicating a greater fear of hypoglycemia. | 18 days | 
| Mean score on the INSPIRE questionnaire for adults (INSPIRE). | A scale from 1-5 with higher scores reflecting more favorable opinions about using Automated Insulin Delivery (AID). | 18 days | 
| Mean score on selected items from The Diabetes Bowel Symptoms Questionnaire (DBSQ). | A 1-5 scale with higher values reflecting a greater quantity and severity of diabetes bowel symptoms. | 18 days | 
| Mean score on a Treatment Satisfaction Questionnaire (TSQ) taken from Marrero et al. | A 1-6 scale with higher values indicating more satisfaction with treatment. | 18 days | 
| Thematic interview analysis | Semi-structured interviews will be carried out after every intervention. We will analyze their qualitative content. | 18 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pramlintide, fully closed loop, fully automated delivery system, artificial pancreas, Insulin, Aspart, Lispro