Safety/Efficacy Study of Subcutaneously Injected Prandial Insulins Compared to Insulin Lispro Alone in Patients With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
The purpose of the study was to compare Humalog (insulin lispro)-recombinant human hyaluronidase PH20 (rHuPH20) or Novolog (insulin aspart)-rHuPH20 to insulin lispro for the treatment of Type 2 diabetes mellitus (T2DM) in basal-bolus therapy.

Detailed Description
-----------------
Criteria for randomization into the study included 1) fasting blood glucose and pre-dinner glucose values in the range of 70 to 140 milligrams per deciliter (mg/dL) approximately 60% of the time for 7 days prior to randomization; 2) 90 minute or 2-hour postprandial blood glucose <220 mg/dL approximately 70% of the time for 7 days prior to randomization; and 3) successfully completing 3 days of 10-point glucose monitoring and have at least 4 self-monitored blood glucose values on all non-10-point monitoring days. Participants that did not meet 1 or more of these criteria during a 4- to 6-week Titration Period were not randomized.

Official Title
-----------------
A Phase II, Randomized, Double Blind, 2-Way Crossover Safety and Efficacy Study of Subcutaneously Injected Prandial Insulins: Lispro-PH20 or Aspart-PH20 Compared to Insulin Lispro (Humalog®) in Patients With Type 2 Diabetes

Conditions
-----------------
Diabetes Mellitus, Type II

Intervention / Treatment
-----------------
* Drug: Insulin lispro
* Drug: Insulin aspart
* Drug: Recombinant human hyaluronidase PH20
* Drug: Insulin glulisine
* Drug: Insulin glargine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females ≥18 years Type 2 diabetes mellitus (T2DM) treated with insulin ≥12 months and prandial insulin (at least 2 meals per day) for ≥2 months Body mass index (BMI) of 23.0 to 45.0 kilograms per meter squared (kg/m^2) Glycosylated hemoglobin (HbA1C) level 7.0 to 8.5%, inclusive Fasting C-peptide <0.6 nanograms per milliliter (ng/mL) Willingness to use insulin glargine twice a day as basal insulin for the duration of the study Willingness to avoid use of an insulin infusion pump or unblinded continuous glucose monitoring (CGM) during the study Exclusion Criteria: Known or suspected allergy to any component of any of the study drugs Exclusive use of pre-mixed insulins Use of pramlintide, exenatide, and/or liraglutide within 30 days of screening Use of sulfonylureas within two months of screening Use of drugs (such as corticosteroids or antimetabolites) that could interfere with the interpretation of study results or are known to cause clinically relevant interference with insulin action, glucose utilization, or recovery from hypoglycemia, during the study or within 30 days of screening Recurrent severe hypoglycemia (more than 2 episodes over the last 6 months) or hypoglycemic unawareness, as judged by the investigator

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lispro-PH20/Insulin lispro<br>All enrolled participants underwent a titration period of 4 to 6 weeks in which they received 100 units per milliliter (U/mL) insulin glulisine, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually. Next, participants were randomly assigned to 1 of 2 study treatments (Treatment A or B) for the first of two, 3-month treatment cycles. Each participant then received the second treatment for the second cycle. Lispro-PH20 (Treatment A): 100 U/mL insulin lispro with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (combined: Lispro-PH20), injected SC, pre-meals, with doses titrated to each participant individually. Insulin Lispro (Treatment B): 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually. Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine. | Drug: Insulin lispro<br> <br> * Other names: Humalog;Drug: Recombinant human hyaluronidase PH20<br> <br> * Other names: Hylenex;Drug: Insulin glulisine<br> <br> * Other names: Apidra;Drug: Insulin glargine<br> <br> * Other names: Lantus;|
| Experimental: Aspart-PH20/Insulin Lispro<br>All enrolled participants underwent a titration period of 4 to 6 weeks in which they received 100 U/mL insulin glulisine, injected SC, pre-meals, with doses titrated to each participant individually. Next participants were randomly assigned to 1 of 2 study treatments (Treatment A or B) for the first of two, 3-month treatment cycles. Each participant then received the second treatment for the second cycle. Aspart-PH20 (Treatment A): 100 U/mL insulin aspart with 5.0 µg/mL rHuPH20 (combined: Aspart-PH20), injected SC, pre-meals, with doses titrated to each participant individually. Insulin lispro (Treatment B): 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually. Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine. | Drug: Insulin lispro<br> <br> * Other names: Humalog;Drug: Insulin aspart<br> <br> * Other names: Novolog;Drug: Recombinant human hyaluronidase PH20<br> <br> * Other names: Hylenex;Drug: Insulin glulisine<br> <br> * Other names: Apidra;Drug: Insulin glargine<br> <br> * Other names: Lantus;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin A1C (HbA1C) at the End of Each Treatment Period | Change in glycosylated hemoglobin A1C (HbA1C) from baseline (Week 0) to end of treatment period (Week 12 and Week 24) is presented. Data are presented by combined treatment group (Lispro-recombinant human hyaluronidase PH20 (PH20) + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin lispro from both groups). Least squares (LS) means were calculated from linear contrasts of mixed effects linear models with treatment (Lispro, Aspart), PH20 (yes, no), and treatment sequence as fixed effects and participant within treatment sequence as a random effect. | Baseline, Week 12 and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Daily Insulin Dose as Recorded During 10-Point Glucose Monitoring | Mean daily insulin dose as recorded during 10-point glucose monitoring is reported. Blood glucose values were obtained during a total of 3 days during each treatment period (3 days during Week 10 of Treatment Period 1 and 3 days during Week 22 of Treatment Period 2) at the following timepoints: immediately prior to breakfast (fasting), 1 hour (hr) after breakfast, 2 hr after breakfast, immediately prior to lunch, 1 hr after lunch, 2 hr after lunch, immediately prior to dinner, 1 hr after dinner, 2 hr after dinner, and at 03:00. A minimum of 7 determinations were required for each day during the 3 days of 10-point glucose profiles. Prandial insulin doses were also recorded during the 10-point glucose monitoring and the mean daily insulin dose over the 3 days was calculated. Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts). | Week 10 and Week 22 | 
| Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | Participants were instructed to monitor their blood glucose levels a minimum of 4 times per day on all non-10-point glucose monitoring days. The number of participants meeting 90-minute postprandial plasma glucose (PPG) targets of <140 and <180 milligrams per deciliter (mg/dL) for at least 2/3 of values was recorded during non-10-point glucose monitoring was recorded. The number of participants was recorded, and the percentage of participants meeting glucose targets was calculated by the number of participants with values meeting the specified target at least 2/3 of the time by the total number of participants analyzed, multiplied by 100. Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts). | Baseline through Week 24, excluding 10-point glucose monitoring days | 
| Rates of Hypoglycemia at the End of Each Treatment Period | The rate of hypoglycemia, defined as blood glucose levels ≤70 mg/dL and <56 mg/dL, was calculated based on 4 weeks of observation prior to the end of treatment period (that is, Week 12 and Week 24). Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin lispro from both groups). A summary of serious and other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. | Week 12 and Week 24 | 
| Change From Baseline in Body Weight at the End of Each Treatment Period | Change from baseline in body weight at the end of each treatment period (Week 12 and Week 24) is presented. Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin lispro from both cohorts). | Baseline, Week 12 and Week 24 | 
| Mean Daily PPG Excursions | Participants performed 10-point glucose monitoring for a total of 3 days during each treatment period (3 days during Week 10 of Treatment Period 1 and 3 days during Week 22 of Treatment Period 2). Mean daily PPG excursions during 10-point glucose monitoring for breakfast, lunch, and dinner from Treatment Period 1 or Treatment Period 2 are presented. PPG refers to the change in glucose concentration before to after a meal. Data were collected 1 and 2 hours (hr) after each meal. Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (insulin lispro from both cohorts). | Week 10 and Week 22 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Type 2 diabetes