Research Study to Look at Fast-acting Insulin Aspart With the Insulin Pump System 'iLet™' in Adults With Type 1 Diabetes

Study Overview
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Brief Summary
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The iLet™ is a new insulin pump that is programmed to work with a Continuous Glucose Monitoring (CGM) device. This is to give participants insulin automatically. The CGM device is already available for sale. The iLet™ is not yet approved for use. Fast-acting insulin aspart is a type of insulin that doctors can already prescribe for use with insulin pens, but not for use in an insulin pump. This study is to test how safe fast acting insulin aspart is when used with different insulin delivery settings in the iLet™ in people with type 1 diabetes. Participants will get fast-acting insulin aspart as participants' insulin and use the iLet™ as participants' insulin pump with a CGM device. Participants' iLet™ will be set to 2 different insulin delivery settings for 7 days on each setting. The setting participants get first is decided by chance. The study will last for about 5 to 9 weeks. Participants will have 4 visits and 1 phone contact with the study or staff.

Official Title
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An Exploratory Trial Investigating the Safety and Efficacy of Fast-acting Insulin Aspart in a Closed-loop Insulin Delivery System (Bionic Pancreas) in Adults With Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Fast-acting insulin aspart
* Device: iLet™


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial Male or female, age more than or equal to 18 years and less than or equal to 75 years at the time of signing informed consent Diagnosed with type 1 diabetes mellitus more than or equal to 1 year prior to the day of screening Treated with continuous subcutaneous insulin infusion more than or equal to 1 year prior to the day of screening Have a mean total daily dose of insulin more than or equal to 20 units Familiar with continuous glucose monitoring as judged by the investigator Has someone over 18 years of age who (i) lives with them, (ii) has access to where they sleep, (iii) is willing to be in the house when the subject is sleeping, and (iv) is willing to receive calls from the study staff and check the welfare of the study subject Body mass index (BMI) less than or equal to 35.0 kg/m^2 at screening Glycated haemoglobin (HbA1c) more than or equal to 6.5% (47 mmol/mol) and less than or equal to 9% (75 mmol/mol) at screening Able and willing to remain in a designated place for the specified duration of the 'in-patient' periods Lives within a 120-minute drive away from the central monitoring location (site) Exclusion Criteria: Known or suspected hypersensitivity to trial product(s) or related products Previous participation in this trial. Participation is defined as signed informed consent Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice) Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days before screening Any disorder, except for conditions associated with diabetes mellitus, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol Anticipated initiation or change in concomitant medications known to affect weight or glucose metabolism during the trial Impaired liver function, defined as Alanine Aminotransferase (ALT) more than or equal to 2.5 times or Bilirubin more than 1.5 times upper normal limit at screening Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR less than 60 ml/min/1.73 m^2 Any episodes of diabetic ketoacidosis within the past 90 days prior to the day of screening Known hypoglycaemic unawareness as indicated by the Investigator according to Clarke's questionnaire question 8 Recurrent severe hypoglycaemic episodes within the last year as judged by the Investigator Any of the following: myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within the past 180 days prior to the day of screening Subjects presently classified as being in New York Heart Association (NYHA) Class IV Planned coronary, carotid or peripheral artery revascularisation known on the day of screening Inadequately treated blood pressure defined as Grade 3 hypertension or higher (systolic more than or equal to 180 mmHg or diastolic more than or equal to 110 mmHg) at screening Unwilling or unable to avoid acetaminophen throughout the trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fast-acting insulin aspart, default tmax setting<br>Participants will receive fast-acting insulin aspart using the iLet™ with default tmax setting (t65 = 65 minutes) in two different treatment periods in a cross-over manner. There will be 3 different cohorts with 2 treatment periods in each cohort. | Drug: Fast-acting insulin aspart<br>* In each cohort, participants will receive fast-acting insulin aspart using the iLet™ in a cross-over manner for 14 days (7days per period). Dose modification will be handled autonomously by the iLet™ based on the CGM sensor readings and the user interaction with the iLet™ e.g. meal announcements.<br>Device: iLet™<br>* The bionic pancreas including pigtail adapters, used in insulin-only configuration<br>|
| Experimental: Fast-acting insulin aspart, non-default tmax setting<br>Participants will receive fast-acting insulin aspart using the iLet™ with non-default tmax setting (t50 = 50 minutes, t40 = 40 minutes or t30 = 30 minutes) in two different treatment periods in a cross-over manner. There will be 3 different cohorts with 2 treatment periods in each cohort. | Drug: Fast-acting insulin aspart<br>* In each cohort, participants will receive fast-acting insulin aspart using the iLet™ in a cross-over manner for 14 days (7days per period). Dose modification will be handled autonomously by the iLet™ based on the CGM sensor readings and the user interaction with the iLet™ e.g. meal announcements.<br>Device: iLet™<br>* The bionic pancreas including pigtail adapters, used in insulin-only configuration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time in Low Interstitial Glucose (Defined as Below 54 mg/dL [3 mmol/L]) From Initiation of Treatment (Day 1) to End of Treatment (Day 7) (Percentage) | Interstitial glucose: glucose measured in interstitial fluid. Time in low interstitial glucose (defined as below 54 mg/dL [3 mmol/L]) from initiation of treatment (day 1) to end of treatment (day 7). Time spent in low interstitial glucose is calculated as the percentage of available interstitial glucose values below the threshold. | Day 1 to day 7 | 
| Time in Low Interstitial Glucose (Defined as Below 54 mg/dL [3 mmol/L]) From Initiation of Treatment (Day 1) to End of Treatment (Day 7) (Percentage) - Median | Interstitial glucose: glucose measured in interstitial fluid. Time in low interstitial glucose (defined as below 54 mg/dL [3 mmol/L]) from initiation of treatment (day 1) to end of treatment (day 7). Time spent in low interstitial glucose is calculated as the percentage of available interstitial glucose values below the threshold. | Day 1 to day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment Emergent Severe Hypoglycaemic Episodes | Number of treatment emergent severe hypoglycaemic episodes from initiation of treatment (day 1) to end of treatment (day 7). Treatment emergent is defined as an episode that has onset in the period from initiation of treatment to end of treatment. Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions. Plasma glucose (PG) concentrations may not be available during an event, but neurological recovery following the return of PG to normal is considered sufficient evidence that the event was induced by a low PG concentration. | Day 1 to day 7 | 
| Number of Self-manageable (Able to Self-treat) Treatment Emergent Hypoglycaemic Episodes That Require Oral Carbohydrate Intervention Per Day | Mean number of self-manageable (able to self-treat) treatment emergent hypoglycaemic episodes that require oral carbohydrate intervention per day. Self-manageable (able to self-treat) hypoglycaemic episodes that require oral carbohydrate intervention per day is calculated as the sum of all hypoglycaemic episodes where the subject is able to self-treat and that require oral carbohydrate intervention divided by the actual duration of the treatment period in days. Treatment emergent is defined as an episode that has onset in the period from initiation of treatment to end of treatment. | Day 1 to day 7 | 
| Number of Treatment Emergent Overall Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | ADA classification of hypoglycaemia: Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions. Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L (70 mg/dL). Documented symptomatic hypoglycaemia: An episode during which typical symptoms of hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL). Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 mg/dL) but approaching that level. Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia are not accompanied by a PG determination but that was presumably caused by a PG concentration ≤ 3.9 mmol/L (70 mg/dL). | Day 1 to day 7 | 
| Number of Treatment Emergent Overall Hypoglycaemic Episodes Classified According to the Novo Nordisk Classification | Overall hypoglycaemia count according to Novo Nordisk classification. Novo Nordisk classification of hypoglycaemia: Severe hypoglycaemia according to the ADA classification. Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value <3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia. BG confirmed hypoglycaemia: The union of 2. and 3. Severe or BG confirmed symptomatic hypoglycaemia: The union of 1. and 2. Severe or BG confirmed hypoglycaemia: The union of 1., 2. and 3. | Day 1 to day 7 | 
| Number of Treatment Emergent Daytime Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | ADA classification of hypoglycaemia: Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions. Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L (70 mg/dL). Documented symptomatic hypoglycaemia: An episode during which typical symptoms of hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL). Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 mg/dL) but approaching that level. Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia are not accompanied by a PG determination but that was presumably caused by a PG concentration ≤ 3.9 mmol/L (70 mg/dL). | Day 1 to day 7 (in both the treatment periods) | 
| Number of Treatment Emergent Daytime Hypoglycaemic Episodes Classified According to the Novo Nordisk Classification | Number of daytime hypoglycaemic episodes according to Novo Nordisk classification. Novo Nordisk classification of hypoglycaemia: Severe hypoglycaemia according to the ADA classification. Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value <3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia. BG confirmed hypoglycaemia: The union of 2. and 3. Severe or BG confirmed symptomatic hypoglycaemia: The union of 1. and 2. Severe or BG confirmed hypoglycaemia: The union of 1., 2. and 3. | Day 1 to day 7 | 
| Number of Treatment Emergent Nocturnal Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | ADA classification of hypoglycaemia: Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions. Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L (70 mg/dL). Documented symptomatic hypoglycaemia: An episode during which typical symptoms of hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL). Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 mg/dL) but approaching that level. Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia are not accompanied by a PG determination but that was presumably caused by a PG concentration ≤ 3.9 mmol/L (70 mg/dL). | Day 1 to day 7 | 
| Number of Treatment Emergent Nocturnal Hypoglycaemic Episodes Classified According to the Novo Nordisk Classification | Number of nocturnal (from time 00:01-05:59 both inclusive) hypoglycaemic episodes according to Novo Nordisk classification. Novo Nordisk classification of hypoglycaemia: Severe hypoglycaemia according to the ADA classification. Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value <3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia. BG confirmed hypoglycaemia: The union of 2. and 3. Severe or BG confirmed symptomatic hypoglycaemia: The union of 1. and 2. Severe or BG confirmed hypoglycaemia: The union of 1., 2. and 3. | Day 1 to day 7 (in both the treatment periods) | 
| Time in Interstitial Glucose Range Was Defined as 70-180 mg/dL (3.9-10 mmol/L) From Initiation of Treatment (Day 1) to End of Treatment (Day 7) (Percentages) | Time in interstitial glucose range defined as 70-180 mg/dL (3.9-10 mmol/L) from initiation of treatment (day 1) to end of treatment (day 7). Time spent in interstitial glucose range is calculated as the percentage of available interstitial glucose values above or equal to the low threshold and below or equal to the high threshold. | Day 1 to day 7 | 
| Mean Interstitial-glucose Level | Mean interstitial glucose level is calculated as the average of the available interstitial glucose values. | Day 1 to day 7 | 
| Number of Treatment Emergent Adverse Events | Number of treatment emergent adverse events from initiation of treatment (day 1) to end of treatment (day 7). Treatment emergent is defined as an event that has onset in the period from initiation of treatment to end of treatment. | Day 1 to day 7 | 
| Number of Treatment Emergent Infusion Site Reactions | Number of treatment-emergent infusion site reactions from initiation of treatment (day 1) to end of treatment (day 7). Treatment emergent is defined as an event that has onset in the period from initiation of treatment to end of treatment. | Day 1 to day 7 | 
| Total Insulin Dose Per Day | Total insulin dose (U/kg) per day from initiation of treatment (day 1) to end of treatment (day 7). Total daily insulin dose is calculated as the sum of all insulin doses delivered by the iLet™ divided by the actual duration of the treatment period in days. | Day 1 to day 7 |