Diabetes Mellitus, Type II
Conditions
Keywords
Type 2 diabetes
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.
Interventions
DRUGInsulin lispro
DRUGInsulin aspart
DRUGInsulin glulisine
DRUGInsulin glargine
Sponsors
Halozyme Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin A1C (HbA1C) at the End of Each Treatment Period | Baseline, Week 12 and Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Daily Insulin Dose as Recorded During 10-Point Glucose Monitoring | Week 10 and Week 22 | 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). |
| Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | Baseline through Week 24, excluding 10-point glucose monitoring days | 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). |
| Rates of Hypoglycemia at the End of Each Treatment Period | Week 12 and Week 24 | 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. |
| Change From Baseline in Body Weight at the End of Each Treatment Period | Baseline, Week 12 and Week 24 | 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). |
| Mean Daily PPG Excursions | Week 10 and Week 22 | 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). |
Countries
United States
Participant flow
Pre-assignment details
The study included an open-label titration period of at least 4 weeks and up to 6 weeks prior to randomization at Week 0.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All participants in the study, including those who were enrolled but were not randomized. | 132 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Period 1 (12 Weeks) | Death | 0 | 0 | 0 | 0 | 1 |
| Period 2 (12 Weeks) | Adverse Event | 0 | 1 | 0 | 0 | 0 |
| Period 2 (12 Weeks) | Lost to Follow-up | 0 | 0 | 0 | 0 | 2 |
| Period 2 (12 Weeks) | Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 |
| Titration Period | Lost to Follow-up | 2 | 0 | 0 | 0 | 0 |
| Titration Period | Titration failure | 3 | 0 | 0 | 0 | 0 |
| Titration Period | Withdrawal by Subject | 6 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 9.85 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 113 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 115 Participants |
| Region of Enrollment United States | 132 participants |
| Sex: Female, Male Female | 53 Participants |
| Sex: Female, Male Male | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 34 / 132 | 19 / 59 | 29 / 59 | 32 / 60 | 35 / 62 |
| serious Total, serious adverse events | 2 / 132 | 0 / 59 | 0 / 59 | 1 / 60 | 4 / 62 |
Outcome results
Primary
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.
Time frame: Baseline, Week 12 and Week 24
Population: All participants who completed both Treatment Period 1 and Treatment Period 2 with evaluable HbA1C data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Analog-PH20 | Change From Baseline in Glycosylated Hemoglobin A1C (HbA1C) at the End of Each Treatment Period | -0.48 percentage of HbA1C | Standard Deviation 0.59 |
| Insulin Lispro | Change From Baseline in Glycosylated Hemoglobin A1C (HbA1C) at the End of Each Treatment Period | -0.46 percentage of HbA1C | Standard Deviation 0.571 |
Comparison: Approximately 110 participants were planned to be enrolled to allow approximately 88 participants to complete both treatment periods. Assuming a dropout rate of ≤20%, an intra-participant correlation of 0.80, a standard deviation of 1.2, and a true difference of 0, the study would have \>90% power to show that either Lispro-PH20 or Aspart-PH20 (each tested separately) was non-inferior to insulin lispro alone with respect to the change from baseline in A1C at the end of each treatment period.p-value: 0.387695% CI: [-0.12, 0.05]Mixed Models Analysis
Secondary
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).
Time frame: Baseline, Week 12 and Week 24
Population: All participants who completed both Period 1 and Period 2 with evaluable body weight data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Analog-PH20 | Change From Baseline in Body Weight at the End of Each Treatment Period | 3.35 pounds | Standard Deviation 5.466 |
| Insulin Lispro | Change From Baseline in Body Weight at the End of Each Treatment Period | 3.44 pounds | Standard Deviation 5.852 |
Secondary
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).
Time frame: Week 10 and Week 22
Population: All participants who completed both Treatment Period 1 and Treatment Period 2 with evaluable insulin dosing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Analog-PH20 | Mean Daily Insulin Dose as Recorded During 10-Point Glucose Monitoring | 122.99 units of Insulin | Standard Deviation 67.15 |
| Insulin Lispro | Mean Daily Insulin Dose as Recorded During 10-Point Glucose Monitoring | 127.47 units of Insulin | Standard Deviation 69.483 |
Secondary
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).
Time frame: Week 10 and Week 22
Population: All participants who completed both Period 1 and Period 2 with evaluable PPG excursion data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Analog-PH20 | Mean Daily PPG Excursions | 2 hr after lunch excursion (n=104, n=106) | 20.76 mg/dL | Standard Deviation 38.939 |
| Analog-PH20 | Mean Daily PPG Excursions | 1 hr after breakfast excursion (n=105, n=107) | 33.67 mg/dL | Standard Deviation 34.48 |
| Analog-PH20 | Mean Daily PPG Excursions | 1 hr after dinner excursion (n=104, n=107) | 21.24 mg/dL | Standard Deviation 32.807 |
| Analog-PH20 | Mean Daily PPG Excursions | 1 hr after lunch excursion (n=105, n=106) | 18.47 mg/dL | Standard Deviation 35.419 |
| Analog-PH20 | Mean Daily PPG Excursions | 2 hr after dinner excursion (n=104, n=107) | 12.72 mg/dL | Standard Deviation 35.917 |
| Analog-PH20 | Mean Daily PPG Excursions | 2 hr after breakfast excursion (n=105, n=107) | 16.64 mg/dL | Standard Deviation 40.463 |
| Insulin Lispro | Mean Daily PPG Excursions | 2 hr after dinner excursion (n=104, n=107) | 15.75 mg/dL | Standard Deviation 36.104 |
| Insulin Lispro | Mean Daily PPG Excursions | 2 hr after breakfast excursion (n=105, n=107) | 22.94 mg/dL | Standard Deviation 33.514 |
| Insulin Lispro | Mean Daily PPG Excursions | 1 hr after lunch excursion (n=105, n=106) | 27.28 mg/dL | Standard Deviation 30.075 |
| Insulin Lispro | Mean Daily PPG Excursions | 2 hr after lunch excursion (n=104, n=106) | 25.27 mg/dL | Standard Deviation 34.288 |
| Insulin Lispro | Mean Daily PPG Excursions | 1 hr after dinner excursion (n=104, n=107) | 18.09 mg/dL | Standard Deviation 28.869 |
| Insulin Lispro | Mean Daily PPG Excursions | 1 hr after breakfast excursion (n=105, n=107) | 40.38 mg/dL | Standard Deviation 30.213 |
Secondary
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).
Time frame: Baseline through Week 24, excluding 10-point glucose monitoring days
Population: Participants in Treatment Period 1 or Treatment Period 2 who received at least 1 dose of study drug and had evaluable postprandial blood glucose data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | Overall 90-minute PPG <140 mg/dL | 13.9 Percentage of participants |
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <140 mg/dL for breakfast | 24.3 Percentage of participants |
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <140 mg/dL for lunch | 28.7 Percentage of participants |
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <140 mg/dL for dinner | 13.0 Percentage of participants |
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | Overall 90 minute PPG <180 mg/dL | 71.3 Percentage of participants |
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <180 mg/dL for breakfast | 70.4 Percentage of participants |
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <180 mg/dL for lunch | 83.5 Percentage of participants |
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <180 mg/dL for dinner | 67.0 Percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <180 mg/dL for dinner | 70.4 Percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | Overall 90-minute PPG <140 mg/dL | 14.8 Percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | Overall 90 minute PPG <180 mg/dL | 74.8 Percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <140 mg/dL for breakfast | 17.4 Percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <180 mg/dL for lunch | 80.0 Percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <140 mg/dL for lunch | 26.1 Percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <180 mg/dL for breakfast | 65.2 Percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time | PPG <140 mg/dL for dinner | 15.7 Percentage of participants |
Secondary
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.
Time frame: Week 12 and Week 24
Population: All participants who completed both Treatment Period 1 and Treatment Period 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Analog-PH20 | Rates of Hypoglycemia at the End of Each Treatment Period | Blood glucose <70 mg/dL (n=111, n=113) | 7.92 Events per participant per month |
| Analog-PH20 | Rates of Hypoglycemia at the End of Each Treatment Period | Blood glucose <56 mg/dL (n=91, n=86) | 1.99 Events per participant per month |
| Insulin Lispro | Rates of Hypoglycemia at the End of Each Treatment Period | Blood glucose <70 mg/dL (n=111, n=113) | 7.66 Events per participant per month |
| Insulin Lispro | Rates of Hypoglycemia at the End of Each Treatment Period | Blood glucose <56 mg/dL (n=91, n=86) | 1.78 Events per participant per month |