A Study of U-500 Insulin (LY041001) in Participants With Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this two-part study is to measure how much of the study drug gets into the blood stream and how long it takes the body to get rid of it. In Part A, each participant will receive two treatments, a single dose and a single dose with continuous infusion of U-500R insulin, both administered just under the skin. Participants who complete Part A will continue into Part B where they will be assigned to 1 of 2 treatments with U-500R insulin, injected either twice or three times daily under the skin for 5-10 days. This study can last from 7-14 weeks including initial screening and follow up.

Official Title
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Comparative Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin Administered Subcutaneously as a Bolus Via Syringe Versus Continuous Subcutaneous Insulin Infusion and Characterization of TID and BID Dosing at Steady State in High-Dose Insulin-Treated Subjects With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: U-500R


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females with type 2 diabetes mellitus (T2DM) Are current users of U-100, U-200 and/or U-300 insulin/analog as, basal, premixed and/or basal/bolus delivered with any injection device (pens and/or syringe/vial but excluding continuous subcutaneous infusion (CSII)/insulin pump use in the preceding 3 months), taking a total daily dose (TDD) of greater than or equal to (≥) 150 units (U) or at least one dose greater than (>) 100 U as part of a multiple daily injection (MDI) regimen and TDD less than or equal to (≤)3.0 units per kilogram (U/kg) Concomitant antihyperglycemic agent(s) (AHA) therapy may include: metformin (MET), dipeptidyl peptidase 4 inhibitors, pioglitazone (doses ≤30 milligrams per day (mg/day)), glucagon like peptide (GLP)-1 receptor agonists, sodium-glucose co-transporter-2 (SGLT2) inhibitors, except in combination with GLP-1 receptor agonists Participant's antihyperglycemic agent (AHA) therapy must have been stable for ≥3 months (except for weekly GLP-1 receptor agonists which must have been stable for ≥4 months) Have hemoglobin A1c (HbA1c) 7.5-11.5 percent (%) Exclusion Criteria: Have type 1 diabetes mellitus (T1DM), or other types of diabetes mellitus apart from T2DM Have known hypersensitivities or allergies to insulin, excipients contained in insulin products, or related compounds Have used U-500R within 3 months prior to screening Have used rosiglitazone, pramlintide, once weekly or twice daily exenatide, or other injectable or oral antihyperglycemic agent(s) not listed in the inclusion criterion; or are taking oral antidiabetic medications at doses exceeding the respective product labels Have had a blood transfusion or severe blood loss within 3 months prior to screening or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia which may affect reliability of HbA1c measurements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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: Part A: U-500R Single Injection<br>Bolus of U-500R administered via single subcutaneous (SC) injection. | Drug: U-500R<br> <br> * Other names: Humulin;|
| Experimental: Part A: U-500R CSII<br>Bolus of U-500R administered via continuous subcutaneous insulin infusion (CSII). | Drug: U-500R<br> <br> * Other names: Humulin;|
| Experimental: Part B: U-500R TID<br>U-500R administered thrice-daily (TID) via SC injection under steady state conditions for 5 to 10 days | Drug: U-500R<br> <br> * Other names: Humulin;|
| Experimental: Part B: U-500R BID<br>U-500R administered twice-daily (BID) via SC injection under steady state conditions for 5 to 10 days | Drug: U-500R<br> <br> * Other names: Humulin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Pharmacokinetics (PK): Time to Maximum Drug Concentration (Tmax) of U-500R | Part A: Pharmacokinetics (PK): Time to Maximum Drug Concentration (Tmax) of U-500R. | Period 1 and 2: -0.5, 0, 0.5, 1, 2, 3, 4, 6, 7, 8, 12, 16, 24 hours (h) post dose | 
| Part B: Pharmacokinetics: Area Under the Concentration Versus Time Curve From Zero to 24 Hours Postdose (AUC[0-24]) of U-500R | Part B: Pharmacokinetics: Area Under the Concentration Versus Time Curve from Zero to 24 Hours Postdose (AUC[0-24]) of U-500R. | Period 3: -0.5, 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose | 
| Part B: Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of U-500R | Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of U-500R. | Period 3: -0.5, 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose | 
| Part B: Pharmacodynamics: Maximum Glucose Infusion Rate (Rmax) of U-500R | Pharmacodynamics: Maximum Glucose Infusion Rate (Rmax) of U-500R. | Period 3 day 1: 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18h post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Pharmacokinetics: Area Under The Concentration Versus Time Curve From Time Zero to Last Time Point With A Measurable Concentration (AUC[0-tlast]) of U-500R | Part A: Pharmacokinetics: Area Under The Concentration Versus Time Curve From Time Zero to Last Time Point With A Measurable Concentration (AUC[0-tlast]) of U-500R. | Period 1 and 2: -0.5, 0, 0.5, 1, 2, 3, 4, 6, 7, 8, 12, 16, 24h post dose | 
| Part A: Pharmacodynamics (PD): Time to Rmax (tRmax) of U-500R | Part A: Pharmacodynamics (PD): Time to Rmax (tRmax) of U-500R. | Period 1 and 2: 0, 0.5, 1, 2, 3, 4, 6, 7, 8, 12, 16, 24h post dose | 
| Part B: Pharmacokinetics: Time to Maximum Concentration (Tmax) of U-500R | Part B: Pharmacokinetics: Time to Maximum Concentration (Tmax) of U-500R. | Period 3: -0.5, 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose | 
| Part B: Pharmacodynamics: Total Amount of Glucose Infused (Gtot) of U-500R | Pharmacodynamics: Total Amount of Glucose Infused (Gtot) of U-500R. | Period 3: 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose | 
| Part B: Pharmacodynamics: Time to Rmax (tRmax) of U-500R | Part B: Pharmacodynamics: Time to Rmax (tRmax) of U-500R. | Period 3: 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose |