Ultrarapid Insulin Administered by a Bihormonal Closed Loop System in Patients With Type 1 Diabetes

Study Overview
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Brief Summary
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The main objective is to determine the efficacy of Lyumjev (insulin) in a bi-hormonal reactive closed loop system for automated glucose regulation (artificial pancreas; AP®) in patients with diabetes mellitus type 1. In addition, safety parameters, pharmacodynamics and AP-related parameters will be acquired. This study is a multicenter, open-label, randomized, cross-over trial in 12 subjects. The subjects will be randomized to receive either Lyumjev or Humalog® for a 30-day study period and will then switch to the alternate insulin treatment after a wash-out period.

Detailed Description
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Background of the study: Inreda Diabetic B.V. (Goor, The Netherlands) developed a bi-hormonal reactive closed loop system to automate glucose regulation (artificial pancreas; AP) in patients with diabetes mellitus type 1. In the current CE-marked AP, Humalog® (Eli Lilly) is used as rapid-acting insulin. Currently, the ultra rapid-acting insulin Lyumjev (Eli Lilly) is available but has not yet been tested in combination with the AP of Inreda. Both are insulin lispro, but additions to the insulin lispro allow the insulin to act faster with a shorter duration. The hypothesis is that the combination of Lyumjev and the reactive AP system can decrease the time that glucose values are above range which can have a positive effect on glucose regulation. Objectives of the study: The main objective is to determine the efficacy of Lyumjev in the Inreda AP system. Secondary objectives are to assess safety parameters, differences in pharmacodynamics and AP-related outcomes comparing Lyumjev to Humalog®. Study design: This study is a multicenter, open-label, randomized, cross-over trial which will be performed in a free-living environment. Study population: The study population will comprise 12 subjects with diabetes type 1 using the AP system. Inclusion criteria are subjects from 18 to 75 years and treated with the Inreda AP system for at least 1 month. Intervention: The intervention includes the administration of Lyumjev by the Inreda AP system. The subject will be randomized to receive either Lyumjev or Humalog® during the first 30 days. After a wash-out period of 8 days using the standard insulin Humalog®, the subject will switch to the alternate treatment, again for a 30-day period. During the study periods, subjects have to keep a Wi-Fi access point with them. Primary study parameters/outcome of the study: Main parameter to express efficacy is the time above range (>10.0 mmol/l), which will be compared between Lyumjev and Humalog®. Secondary study parameters/outcome of the study: Safety will be expressed as the side effects of Lyumjev. Pharmacodynamics will be expressed in proportions of time spent in eu-/hypo-/hyperglycemia (%), median glucose value (mmol/l) and glycemic variability (% and interquartile range). These parameters will all be compared between Lyumjev and reference Humalog®. AP-related outcomes will be expressed in daily administered dosage of insulin and glucagon (units), and the percentage of time that the closed loop algorithm is active (%).

Official Title
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Fully Automated Glycemic Control With Ultrarapid Insulin in a Bihormonal Closed Loop System in Patients With Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Insulin Lispro Cartridge [Lyumjev]
* Drug: Insulin Lispro Cartridge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with diabetes mellitus type 1; Treated with the Inreda AP system for a minimum of 1 month; Age between 18 and 75 years; Willing and able to sign informed consent. Since subjects are treated with the Inreda AP, the following inclusion criteria will be met: Treated with sensor augmented pump (SAP) or CSII for a minimum of 6 months; HbA1c < 97 mmol/mol; BMI < 35 kg/m^2; No use of acetaminophen, as this may influence the sensor glucose measurements. Exclusion Criteria: Impaired awareness of hypoglycemia (score ≥ 4) according to Gold and/or Clarke questionnaire; Pregnancy and/or breastfeeding; Use of oral antidiabetic agents; Insulinoma; Hypersensitivity reactions to Lyumjev or any of the excipients.

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
Interventional Model Description: Allocation by randomization: Study period 1 (Humalog or Lyumjev) Wash-out period (Humalog: standard therapy) Study period 2 (other type of insulin than in Study period 1 (Humalog or Lyumjev))
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lyumjev (insulin lispro)<br>Administration of Lyumjev for a 30-day study period (dosage and frequency is patient-dependent) | Drug: Insulin Lispro Cartridge [Lyumjev]<br>* Administration of Lyumjev in combination with the AP system<br>* Other names: Lyumjev;|
| Active Comparator: Humalog (insulin lispro)<br>Administration of standard used Humalog for a 30-day study period and 8-day wash-out period located between the two study periods (dosage and frequency is patient-dependent) | Drug: Insulin Lispro Cartridge<br>* Administration of Humalog in combination with the AP system (standard therapy)<br>* Other names: Humalog;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time the glucose level is above 10 mmol/l for the study participants | Time the glucose level is above range (>10 mmol/l) expressed as a percentage (%) | 68 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety parameters | Side effects of Lyumjev | 30 days | 
| Pharmacodynamic parameters: euglycemia | Percentage of time the glucose level is between 3.9 and 10 mmol/l (%) | 68 days | 
| Pharmacodynamic parameters: hypoglycemia | Percentage of time the glucose level is below 3.9 mmol/l (%) | 68 days | 
| Pharmacodynamic parameters: median glucose value | Median of the glucose values (mmol/l) | 68 days | 
| Pharmacodynamic parameters: standard deviation of glucose value | Standard deviation of the glucose values (parameter required to determine the coefficient of variation) | 68 days | 
| Pharmacodynamic parameters: mean glucose value | Mean of the glucose values (parameter required to determine the coefficient of variation) | 68 days | 
| Pharmacodynamic parameters: glycemic variability (CoV) | Glycemic variability expressed as the coefficient of variation (CoV): standard deviation divided by the mean of the glucose values (%) | 68 days | 
| Pharmacodynamic parameters: glycemic variability (IQR) | Glycemic variability expressed as the interquartile range (IQR) (mmol/l) | 68 days | 
| AP-related parameters: insulin usage | Daily usage of insulin (units) | 68 days | 
| AP-related parameters: glucagon usage | Daily usage of glucagon (units) | 68 days | 
| AP-related parameters: algorithm activity | Percentage of time the algorithm is active (%) | 68 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ultra rapid-acting insulin, Lyumjev, Humalog®, Artificial pancreas (AP®), Bihormonal reactive closed loop system, Automated glucose regulation, Time above range