An Administration Method Study of Human Regular U-500 Insulin (LY041001) in Participants With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to evaluate the efficacy and safety of the study drug known as human regular U-500 insulin (U-500R) administered by continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI) in participants with type 2 diabetes mellitus.

Official Title
-----------------
Safety and Efficacy of Human Regular U-500 Insulin Administered by Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections in Subjects With Type 2 Diabetes Mellitus: A Randomized, Open-Label, Parallel Clinical Trial

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Human regular U-500 insulin (CSII)
* Drug: Human regular U-500 insulin (MDI)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosed with type 2 diabetes mellitus (T2DM). Current TDD >200 but ≤600 units of non U-500R insulin (MDI or CSII) and/or U-500R by MDI with syringe and vial for ≥3 months at entry. If TDD of U-500R and other insulins are combined, then insulin other than U-500R not to exceed 25% of TDD. HbA1c ≥7.5% and ≤12.0%. Body mass index ≥25 but ≤50 kilograms per meter squared. Have a history of stable body weight. Concomitant antihyperglycemic agent (AHA) therapy may include metformin (MET), dipeptidyl peptidase-4 inhibitors and/or pioglitazone. Approximately 64 to 96 subjects using glucagon-like peptide-1 (GLP-1) receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors will be enrolled in Study Group B. Exclusion Criteria: Diagnosed with type 1 diabetes mellitus (T1DM) or other types of diabetes apart from T2DM. Have obvious clinical or radiographic signs or symptoms of liver disease (except nonalcoholic fatty liver disease), cirrhosis, acute or chronic hepatitis, or alanine aminotransferase (ALT/SGPT) and/or aspartate aminotransferase (AST/SGOT) levels ≥2.5X upper limit of normal (ULN), alkaline phosphatase ≥2X ULN or total bilirubin ≥2X ULN. Have chronic kidney disease Stage 4 and higher or history of renal transplantation. Have history of more than 1 episode of severe hypoglycemia within the 6 months prior to screening. Have received U-500R insulin by CSII in the 3 months prior to screening. 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. Are taking chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy. Have an irregular sleep/wake cycle. Have used any weight loss drugs in the 3 months prior to screening. Have a history of bariatric surgery including Roux-en-Y gastric bypass surgery, gastric banding, and/or gastric sleeve. Have a history of an active or untreated malignancy, or in remission from a clinically significant malignancy during the last 5 years before screening. Significant hearing loss and/or vision impairment deemed by the investigator to interfere with the safe use of OmniPod U-500 system. Have cardiac disease with functional status that is New York Heart Association (NYHA) Class III or IV per New York Heart Association Cardiac Disease Functional Classification or have congestive heart failure requiring pharmacologic treatment. Are women breastfeeding or pregnant, or intend to become pregnant during the course of the study; are men who intend to impregnate their partners; or are sexually active of procreation potential not actively practicing birth control by a method determined by the investigator to be medically acceptable. Are investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Human regular U-500 insulin administered by CSII<br>Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in. | Drug: Human regular U-500 insulin (CSII)<br>* Administered SC<br>* Other names: LY041001;|
| Active Comparator: Human regular U-500 insulin administered by MDI<br>Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks. | Drug: Human regular U-500 insulin (MDI)<br>* Administered SC<br>* Other names: LY041001;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (HbA1c) | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline of response, glucagon-like peptide-1 (GLP-1) or sodium-glucose cotransporter 2 (SGLT2) use, U-500R at entry, treatment, time and treatment by time interaction. | Baseline, 26 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Fasting plasma glucose (FPG) is a test to determine how much glucose (sugar) is in a plasma sample after an overnight fast. Least Squares (LS) means was determined by MMRM methodology with baseline of response, glucagon-like peptide-1 (GLP-1) or sodium-glucose cotransporter 2 (SGLT2) use, U-500R at entry, treatment, time and treatment by time interaction. | Baseline, 26 Weeks | 
| Percentage of Participants With HbA1c <7.0% | Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Longitudinal logistic regression was used to model the likelihood of having hbA1c<7.0% at Week 26 with baseline of response, glucagon-like peptide-1 (GLP-1) or sodium-glucose cotransporter 2 (SGLT2) use, U-500R at entry, treatment, time and treatment by time interaction. | 26 Weeks | 
| Percentage of Participants With HbA1c <7.5% | Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Longitudinal logistic regression was used to model the likelihood of having hbA1c<7.5% at Week 26 with baseline of response, glucagon-like peptide-1 (GLP-1) or sodium-glucose cotransporter 2 (SGLT2) use, U-500R at entry, treatment, time and treatment by time interaction. | 26 Weeks | 
| Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values | Seven-point SMBG are completed at the following timepoints: Before Morning Meal, 2 Hours After Morning Meal, Before Mid-Day Meal, 2 Hours After Mid-Day Meal, Before Evening Meal, Bed Time and 03:00 AM hours. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, GLP-1 or SGLT2 use, U-500R at entry, baseline HbA1C group, treatment, time and treatment by time interaction. | Baseline, 26 Weeks | 
| Change From Baseline in Total Daily Dose (TDD) | Baseline TDD was defined as the last prestudy insulin TDD prior to randomization to receiving the first dose of U-500 insulin post randomization. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, GLP-1 or SGLT2 use, U-500R at entry, baseline HbA1C group, treatment, time and treatment by time interaction. | Baseline, 26 Weeks | 
| Percentage of Participants With Hypoglycemic Episodes (Documented Hypoglycemia With Blood Glucose <= 70 mg/dL) | The percentage of participants with hypoglycemic episodes (documented hypoglycemia) was calculated by dividing the number of participants with at least 1 hypoglycemic episode (documented hypoglycemia) over the 26-week treatment period by the total number of participants analyzed, multiplied by 100%. Logistic regression was used to estimate the odds ratio between the two treatments of at least 1 hypoglycemic episode (documented hypoglycemia) over 26 week treatment period adjusted for baseline documented hypoglycemia rate, GLP-1 or SGLT2 use, U-500R at entry, baseline HbA1C group, treatment, time and treatment by time interaction. | 26 Weeks | 
| Rate of Hypoglycemic Episodes (Documented Hypoglycemia With Blood Glucose <= 70 mg/dL) | Documented Hypoglycemic episodes with blood glucose<=70mg/dL was used in this outcome measure. Hypoglycemia rate (documented hypoglycemia) per 30 days was summarized at each visit by treatment group. The rate of hypoglycemia (documented hypoglycemia) was analyzed using a generalized estimation equations model with a negative binomial distribution and a Log link. LS mean was determined by MMRM methodology with baseline documented hypoglycemia rate, GLP-1 or SGLT2 use, U-500R at entry, baseline HbA1C group, with log of exposure in days divided by 30 as the offset, treatment, visit, and visit by treatment interaction. | Baseline to 26 Weeks | 
| Change From Baseline in Body Weight | Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, GLP-1 or SGLT2 use, U-500R at entry, baseline HbA1C group, treatment, treatment by time interaction. | Baseline, 26 Weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
insulin pumps, concentrated insulin, OmniPod