Study of Human Regular U-500 Insulin in Adult Participants With Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to compare the effectiveness of Human Regular U-500 Insulin three times a day versus twice a day.

Official Title
-----------------
Two Treatment Approaches for Human Regular U-500 Insulin (Thrice-Daily Versus Twice-Daily) in Subjects With Type 2 Diabetes Mellitus Not Achieving Adequate Glycemic Control on High-Dose U-100 Insulin Therapy With or Without Oral Agents: A Randomized, Open-Label, Parallel Clinical Trial

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

Intervention / Treatment
-----------------
* Drug: Human Regular U-500 Insulin


Participation Criteria
=================
Eligibility Criteria
-----------------
Major Inclusion Criteria: Have type 2 diabetes mellitus (World Health Organization [WHO] Classification of Diabetes) Have a body mass index (BMI) ≥25 kilogram per square meter (kg/m^2) Have Glycated Hemoglobin A1c (HbA1c) ≥7.5% and ≤12.0%, as measured by the central laboratory at entry Current U-100 insulin/analogue users on >200 and ≤600 units per day for ≥3 months at study entry and reconfirmed at randomization Have a history of stable body weight for at least 3 months prior to study entry Concomitant medications may include metformin (MET), dipeptidyl peptidase-4 (DPP-4) inhibitors approved for use with insulin at time of study entry (for example, sitagliptin, saxagliptin, and linagliptin), pioglitazone, and/or sulfonylureas (SUs)/glinides (repaglinide or nateglinide). Participant's oral antihyperglycemic drug (OAD) dose(s) must have been stable for ≥3 months Major Exclusion Criteria: Have type 1 diabetes mellitus or other types of diabetes mellitus apart from type 2 diabetes mellitus Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine aminotransferase or aspartate aminotransferase levels ≥3 times the upper limit of the reference range 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 study entry Have received insulin by continuous subcutaneous insulin infusion in the 3 months prior to study entry Have received U-500R in the 3 months prior to study entry Have had a blood transfusion or severe blood loss within 3 months prior to study entry or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia Are taking chronic systemic glucocorticoid therapy or have received such therapy within the 4 weeks immediately prior to study entry Have an irregular sleep/wake cycle Have used rosiglitazone, once- or twice-daily glucagon-like peptide-1 (GLP-1) receptor agents, pramlintide, or other injectable or oral antihyperglycemic therapy not listed in the inclusion criteria in the 3 months prior to study entry. Participants may not have used once-weekly GLP-1 receptor agents in the 4 months prior to study entry Have used any weight loss drugs in the 3 months prior to study entry Have a history of bariatric surgery Have a history of malignancy other than basal cell or squamous cell skin cancer Have New York Heart Association (NYHA) Class III or IV per NYHA Cardiac Disease Functional Classification Are breastfeeding or pregnant, or intend to become pregnant during the course of the study, or are sexually active women of childbearing potential not actively practicing birth control by a method determined by the investigator to be medically acceptable

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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 TID<br>Human Regular U-500 Insulin (U-500R) titrated based on blood glucose readings, administered subcutaneously (SC), three times a day (TID) for 24 weeks. | Drug: Human Regular U-500 Insulin<br> <br> * Other names: U-500R;|
| Experimental: Human Regular U-500 Insulin BID<br>U-500R Insulin titrated based on blood glucose readings, administered SC, two times a day (BID) for 24 weeks. | Drug: Human Regular U-500 Insulin<br> <br> * Other names: U-500R;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in Glycated Hemoglobin A1c (HbA1c) | Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with investigator, baseline total daily dose (TDD; ≤300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline HbA1c as a covariate. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving HbA1c of ≤6.5%, <7.0%, <7.5%, and <8.0% at Week 24 | The percentage of participants achieving an HbA1c of ≤6.5%, <7.0%, <7.5%, and <8.0% at Week 24 was calculated by the dividing the number of participants meeting the criteria by the total number of participants analyzed, multiplied by 100. | Week 24 | 
| 30-Day Adjusted Rate of Hypoglycemic Events | Hypoglycemic events (HE) were classified as severe (an event requiring assistance from another person [accompanied by neurologic/cognitive impairment]), documented symptomatic (an event which is associated with signs/symptoms of hypoglycemia and plasma glucose [PG] ≤70 milligrams per deciliter [mg/dL]), documented symptomatic nocturnal (any documented symptomatic HE that occurred between bedtime and waking), or asymptomatic (any measured PG ≤70 mg/dL not accompanied by hypoglycemic signs/symptoms). The 30-day adjusted rate of HE is summarized cumulatively at 24 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through Week 24 | 
| Change From Baseline to Week 24 in Body Weight | LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (≤8% or >8%), baseline TDD (≤300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline body weight as a covariate. | Baseline, Week 24 | 
| Change From Baseline to Week 24 in Total Daily Dose (TDD; Units) of Insulin | Baseline TDD was defined as the last U-100 insulin TDD prior to receiving the first dose of U-500R insulin. LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (≤8% or >8%), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline TDD as a covariate. | Baseline, Week 24 | 
| Change From Baseline to Week 24 in Total Daily Dose (TDD; Units/kg) of Insulin | Baseline TDD was defined as the last U-100 insulin TDD prior to receiving the first dose of U-500R insulin. LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (≤8% or >8%), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline TDD as a covariate. | Baseline, Week 24 | 
| Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) Levels | LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (≤8% or >8%), baseline TDD (≤300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline FPG as a covariate. | Baseline, Week 24 | 
| Time to Reach HbA1c Target Values | The cumulative number of participants achieving an HbA1c of ≤6.5%, <7.0%, <7.5%, and <8.0% is summarized at Weeks 6, 12, 18, and 24. The number of participants at risk (n) is also provided for each target value and timepoint. | Baseline through 6, 12, 18, and 24 weeks. | 
| Percentage of Participants With Hypoglycemic Events | Hypoglycemic events (HE) were classified as severe (an event requiring assistance from another person [accompanied by neurologic/cognitive impairment]), documented symptomatic (an event which is associated with signs/symptoms of hypoglycemia and plasma glucose [PG] ≤70 milligrams per deciliter [mg/dL]), documented symptomatic nocturnal (any documented symptomatic HE that occurred between bedtime and waking), or asymptomatic (any measured PG ≤70 mg/dL not accompanied by hypoglycemic signs/symptoms). The percentage of participants with HE at 24 weeks was calculated by the dividing the number of participants meeting the criteria by the total number of participants analyzed, multiplied by 100. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through Week 24 | 
| Change From Baseline to Week 24 in Number of Insulin Injections | The number of insulin injections per day at baseline (Week 0) and at Week 24 are presented. | Baseline, Week 24 | 
| Mean Change From Baseline to Week 24 in 7-Point Self-Monitored Blood Glucose (SMBG) | The 7-point SMBG is a participant self-administered blood glucose test which utilizes measurements at specific time points over a 24-hour period, including pre-morning meal (fasting), 2 hours after morning meal, pre-midday meal, 2 hours after midday meal, pre-evening meal, 2 hours after evening meal, and 3 AM. LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (≤8% or >8%), baseline TDD (≤300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline SMBG as a covariate. | Baseline, Week 24 | 
| Change From Baseline to Week 24 in HbA1c Based on Baseline TDD Insulin ≤2.0 Units/kg and >2.0 Units/kg | Participants were stratified by their baseline TDD insulin (≤2.0 units/kg or >2.0 units/kg). LS means of change from baseline were calculated using MMRM with investigator, baseline TDD (≤300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline HbA1c as a covariate. | Baseline, Week 24 | 
| Change From Baseline to Week 24 in 30-Day Adjusted Rate of Hypoglycemic Events Based on Baseline TDD Insulin ≤2.0 Units/kg and >2.0 Units/kg | Participants were stratified by their baseline TDD insulin (≤2.0 units/kg or >2.0 units/kg). Hypoglycemic events (HE) were classified as severe (an event requiring assistance from another person [accompanied by neurologic/cognitive impairment]), documented symptomatic (DS; an event which is associated with signs/symptoms of hypoglycemia and plasma glucose [PG] ≤70 milligrams per deciliter [mg/dL]), or nocturnal (Noc; any documented symptomatic HE that occurred between bedtime and waking). The 30-day adjusted rate of HE is summarized cumulatively at 24 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline, Week 24 | 
| Change From Baseline to Week 24 in Percentage of Participants With Hypoglycemic Events Based on Baseline TDD Insulin ≥2.0 Units/kg and <2.0 Units/kg | Participants were stratified by their baseline TDD insulin (≤2.0 units (U)/kg or >2.0 U/kg). The percentage of participants at risk of developing hypoglycemia (including documented symptomatic, asymptomatic, probable symptomatic, unspecified, or severe hypoglycemia) is presented at Baseline and at Week 24 and was calculated using MMRM fit with options of the binomial distribution and log link function including treatment, TDD (>300 units or ≤300 units), pioglitazone use (yes or no), visit, and treatment-by-visit interaction as fixed effects, and baseline HbA1c value as a covariate. | Baseline, Week 24 | 
| Change From Baseline to Week 24 in Body Weight Based on Baseline TDD Insulin ≥2.0 Units/kg and <2.0 Units/kg | Participants were stratified by their baseline TDD insulin (≤2.0 units/kg or >2.0 units/kg). LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (≤8% or >8%), baseline TDD (≤300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline body weight as a covariate. | Baseline, Week 24 |