A Study to Compare and Measure the Effects of Insulin Peglispro (LY2605541) and Glargine on Meal Time Insulin Requirements

Study Overview
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Brief Summary
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This study will look into how a base dose of insulin peglispro and insulin glargine will affect the meal time dose and efficacy of insulin lispro in type 1 diabetics.

Official Title
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The Effect of Treatment With Basal Insulin Peglispro or Insulin Glargine on the Dose Response Effect of Prandial Insulin Lispro in Patients With Type 1 Diabetes Mellitus.

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Insulin Peglispro
* Drug: Insulin Lispro
* Drug: Insulin Glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a stable (within 0.5 percent (%) from last measure) glycated hemoglobin (HbA1c) <9.0% Have a stable (within 30%) basal insulin dose of 0.2 to 1.0 units per kilogram per day (U/kg/day) and a total daily insulin dose (basal + prandial/bolus) <1.5 units per kilogram (U/kg) Have C-peptide <0.3 nanomoles per liter (nmol/L) Are able and willing to eat the protocol specified standard breakfast and other meals as required Exclusion Criteria: Have corrected QT interval (QTc) prolongation >500 milliseconds (ms) or have any other abnormality in the 12 lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study Have an abnormal blood pressure as determined by the investigator Have a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine (apart from Type 1 Diabetes Mellitus [T1DM]), hematological, or neurological disorders Have fasting triglycerides (TGs) >400 milligrams per deciliter (mg/dL) (4.52 micromoles per liter [mmol/L]) Have used systemic corticosteroids within 4 weeks prior to randomization Currently receive insulin pump or insulin degludec Have poorly controlled diabetes or are known to have poor awareness of hypoglycemia Have history of gastroparesis or gastrointestinal malabsorption Require treatment with any drug other than insulin to treat diabetes Have a previous history of proliferative retinopathy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin peglispro (LY2605541, with Insulin Lispro)<br>Insulin peglispro (LY2605541) once daily subcutaneous (SC) injection at bedtime. Insulin lispro given SC prandially or as bolus as required | Drug: Insulin Peglispro<br>* Administered SC<br>* Other names: LY2605541;Drug: Insulin Lispro<br>* Administered SC<br>|
| Active Comparator: Insulin Glargine (with Insulin Lispro)<br>Insulin glargine once daily SC injection at bedtime. Insulin lispro given SC prandially or as a bolus as required | Drug: Insulin Lispro<br>* Administered SC<br>Drug: Insulin Glargine<br>* Administered SC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics (PD): Plasma Glucose Area Under the Concentration Curve Zero Through 5 Hours (AUC 0-5h), Above Pre Meal Baseline for Insulin Lispro | To quantitate the pharmacodynamic (PD) effect of a range of prandial insulin lispro doses after treatment with insulin peglispro (LY2605541) compared to insulin glargine during a meal tolerance test (MTT), with sequenced doses of insulin lispro ranging from 25% to 150% of each participant's normal dose. Data presented as hours times milligrams per deciliter (mg*h/dL) | Day 30, 31, 32, 33, 34, pre-breakfast and10,20,30,40,50,60,90,120,150,180,210,240,270, 300 minutes (5 hours) post-breakfast | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Under the Concentration Curve Zero Through 5 Hours (AUC 0-5h) for Prandial Insulin Lispro | Abbreviation for hours times picomol per liter (pmol*h/L) | Day 29: Pre-breakfast, and 15, 30, 45, 60, 90, 120, 150,180,210,270, and 300 minutes (5 hours) post-breakfast | 
| Pharmacodynamics (PD): Average Glucose Infusion Rate From Euglycemic 2-step Hyperinsulinemic Clamp (M-value) | Abbreviation for micro mole per kilogram per minute (µmol/kg/min). Both arms received insulin lispro in addition to their respective study drug. During the euglycemic 2-step hyperinsulinemic clamp, both low and high insulin was infused sequentially during the same procedure. The 2-step clamp procedure allowed insulin sensitivity to be measured in participants and uses a lower dose of insulin of which the effect is largely on the liver and a high dose of insulin at which the effect has reached 100% on liver and effects are largely on glucose uptake in peripheral tissues. Measurements for average glucose infusion rate are collected for both steps (low and high) of the clamp procedure. | Day 35, last 60 minutes of euglycemic 2-step hyperinsulinemic clamp | 
| Pharmacokinetics (PK): Area Under the Concentration Curve From Time Zero to Last Time (AUC [0 Tlast]) for Paracetamol |  | Day 29: Pre-breakfast, and 15, 30, 45, 60, 90, 120, 150,180,210,270, and 300 minutes (5 hours) post-breakfast | 
| Appetite and Satiety Ratings, as Measured Using Visual Analog Scale (VAS) on Day 29 | VAS was scored from 0 - 100 millimeters (mm) as a perception of appetite and satiety (Flint et al. 2000), 0 being not hungry at all or nothing at all and 100 being extremely hungry and extremely large amount. The questions are abbreviated in table from: How hungry do you feel right now? to Hunger and How much food do you think you could eat right now? to Food amount. Day 29 and cumulative insulin lispro doses of 25%, 50%, 75%, 100% and 150 % of normal insulin lispro dose included.Scores were averaged will be presented and calculated by a sum of the scores dividing by the total by the number of scores reported for timepoints and reported in millimeters. | Day 29:Upon waking, pre-breakfast, 1 hour (hr), 2 hr, 3 hr, 4 hr and 5 hr post breakfast | 
| Pharmacodynamics (PD): Area Under the Concentration Zero Through 5 Hours (AUC 0-5h) for Triglycerides |  | Day 29, predose and 15, 30, 45, 60, 90, 120, 150,180,210,270, and 300 minutes (5 hours) post-breakfast | 
| Pharmacokinetics (PK): Area Under the Concentration Curve (AUC) for Insulin Lispro During Clamp | During the euglycemic 2-step hyperinsulinemic clamp, both low and high insulin was infused sequentially during the same procedure. The 2-step clamp procedure allowed insulin sensitivity to be measured in participants and uses a lower dose of insulin (Low) of which the effect is largely on the liver and a high dose of insulin (high) at which the effect has reached 100% on liver and effects are largely on glucose uptake in peripheral tissues. AUC is taking during infusion for this outcome measure. | Day 35, insulin clearance during lispro infusion (dosing=infusion) |