Diabetes Mellitus, Type 1
Conditions
Keywords
Type 1 diabetes
Brief summary
The purpose of the study is to compare Humalog (Insulin lispro)-recombinant human hyaluronidase (rHuPH20) or Novolog (Insulin aspart)-rHuPH20 to Humalog (Insulin lispro) for the treatment of Type 1 Diabetes Mellitus (T1DM) in basal-bolus therapy.
Detailed description
Criteria for randomization into the study included 1) fasting blood glucose and predinner 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 completed 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 aged ≥18 years * Type 1 Diabetes Mellitus (T1DM) treated with insulin for ≥12 months * Body mass index (BMI) 18.0 to 40.0 kilograms per square meter (kg/m\^2). * Hemoglobin A1C (HbA1C) level 6.7% to 8.2%, inclusive * Fasting C-peptide \<0.6 nanograms per milliliter (ng/mL) * Willingness to use twice daily (BID) insulin glargine 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 * Use of pramlintide within 30 days of Screening * Use of drugs during the study or within 30 days of Screening (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 * 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 | Glycosylated hemoglobin A1C (HBA1c) levels were measured at baseline (Week 0) and at the end of each treatment period (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 cohorts). Least Squares (LS) means were calculated from mixed effects linear models with treatment (Lispro, Aspart), recombinant human hyaluronidase PH20 (rHuPH20; 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 | Week 10 and Week 22 | Prandial insulin doses were recorded during 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). The mean daily insulin dose over the 3 days during each treatment period is presented. Data is 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 | 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 during non-10-point glucose monitoring days was recorded. The percentage was calculated by dividing 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 | Overall rates of hypoglycemia (blood glucose ≤70 milligrams per deciliter \[mg/dL\] and \<56 mg/dL) were calculated based on 4 weeks of observation for each treatment period. Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts). 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 | Body weight was measured at baseline (Week 0) and at the end of each treatment period (Week 12 and Week 24). Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts). |
| Mean Daily Postprandial Glucose (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 postprandial plasma glucose (PPG) excursions (referring to the change in blood glucose levels from before to after a meal) during 10-point glucose monitoring for breakfast, lunch, and dinner are presented. Data were collected 1 and 2 hours (hr) after each meal for 3 days and the means of each excursion are presented. |
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 |
|---|---|
| Non-randomized Participants Participants underwent a titration period of 4-6 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. Participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.
Participants did not complete the titration period or did not meet one or more randomization criteria and, therefore, were not randomized. | 18 |
| Lispro-PH20 First, Then Insulin Lispro Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment A for the first 3-month treatment cycle, followed by Treatment B for the second 3-month treatment cycle.
Lispro-PH20 (Treatment A): 100 units per milliliter (U/mL) insulin lispro with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (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. | 29 |
| Insulin Lispro First, Then Lispro-PH20 Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment B for the first 3-month treatment cycle, followed by Treatment A for the second 3-month treatment cycle.
Insulin Lispro (Treatment B): 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually
Lispro-PH20 (Treatment A): 100 U/mL insulin lispro with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, 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. | 28 |
| Aspart-PH20 First, Then Insulin Lispro Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment A for the first 3-month treatment cycle, followed by Treatment B for the second 3-month treatment cycle.
Aspart-PH20 (Treatment A): 100 units per milliliter (U/mL) insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (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. | 30 |
| Insulin Lispro First, Then Aspart-PH20 Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment B for the first 3-month treatment cycle, followed by Treatment A for the second 3-month treatment cycle.
Insulin Lispro (Treatment B): 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually
Aspart-PH20 (Treatment A): 100 U/mL insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, 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. | 30 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Titration Period (4 to 6 Weeks) | Did Not Meet Randomization Criteria | 7 | 0 | 0 | 0 | 0 |
| Titration Period (4 to 6 Weeks) | Physician Decision | 3 | 0 | 0 | 0 | 0 |
| Titration Period (4 to 6 Weeks) | Titration Failure | 3 | 0 | 0 | 0 | 0 |
| Titration Period (4 to 6 Weeks) | Withdrawal by Subject | 5 | 0 | 0 | 0 | 0 |
| Treatment Period 1 (Weeks 0 to 12) | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| Treatment Period 1 (Weeks 0 to 12) | Withdrawal by Subject | 0 | 0 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Insulin Lispro First, Then Aspart-PH20 | Aspart-PH20 First, Then Insulin Lispro | Non-randomized Participants | Insulin Lispro First, Then Lispro-PH20 | Lispro-PH20 First, Then Insulin Lispro |
|---|---|---|---|---|---|---|
| Age, Continuous | 42.6 years STANDARD_DEVIATION 14.41 | 42.5 years STANDARD_DEVIATION 14.7 | 42.8 years STANDARD_DEVIATION 14.13 | 34.8 years STANDARD_DEVIATION 11.71 | 45.7 years STANDARD_DEVIATION 14.94 | 44.6 years STANDARD_DEVIATION 14.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 1 Participants | 2 Participants | 4 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 125 Participants | 29 Participants | 28 Participants | 14 Participants | 26 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 129 Participants | 28 Participants | 30 Participants | 17 Participants | 27 Participants | 27 Participants |
| Region of Enrollment United States | 135 participants | 30 participants | 30 participants | 18 participants | 28 participants | 29 participants |
| Sex: Female, Male Female | 61 Participants | 15 Participants | 14 Participants | 6 Participants | 13 Participants | 13 Participants |
| Sex: Female, Male Male | 74 Participants | 15 Participants | 16 Participants | 12 Participants | 15 Participants | 16 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 | 48 / 135 | 34 / 56 | 29 / 57 | 27 / 58 | 30 / 59 |
| serious Total, serious adverse events | 2 / 135 | 0 / 56 | 1 / 57 | 0 / 58 | 1 / 59 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin A1C (HbA1c) at the End of Each Treatment Period
Glycosylated hemoglobin A1C (HBA1c) levels were measured at baseline (Week 0) and at the end of each treatment period (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 cohorts). Least Squares (LS) means were calculated from mixed effects linear models with treatment (Lispro, Aspart), recombinant human hyaluronidase PH20 (rHuPH20; 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: Participants who completed both Treatment Period 1 and Treatment Period 2 and had evaluable hemoglobin A1C data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Analog-PH20 | Change From Baseline in Glycosylated Hemoglobin A1C (HbA1c) at the End of Each Treatment Period | -0.14 percentage of hemoglobin A1C | Standard Deviation 0.415 |
| Insulin Lispro | Change From Baseline in Glycosylated Hemoglobin A1C (HbA1c) at the End of Each Treatment Period | -0.19 percentage of hemoglobin A1C | Standard Deviation 0.44 |
Comparison: Approximately 110 participants were to be enrolled, allowing approximately 88 participants to complete both treatment periods (44 for each investigational drug). Assuming a dropout rate of no more than 20%, intra-participant correlation of 0.80, standard deviation of 1.2, and a true difference of 0, the study would have a greater than 90% power to show that Analog-PH20 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: 0.287895% CI: [-0.05, 0.15]Mixed Models Analysis
Secondary
Change From Baseline in Body Weight at the End of Each Treatment Period
Body weight was measured at baseline (Week 0) and at the end of each treatment period (Week 12 and Week 24). 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, Week 12 and Week 24
Population: Participants who completed both Treatment Period 1 and Treatment Period 2 and had evaluable body weight data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Analog-PH20 | Change From Baseline in Body Weight at the End of Each Treatment Period | -0.25 pounds (lbs) | Standard Deviation 5.702 |
| Insulin Lispro | Change From Baseline in Body Weight at the End of Each Treatment Period | 0.10 pounds (lbs) | Standard Deviation 4.601 |
Secondary
Mean Daily Insulin Dose
Prandial insulin doses were recorded during 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). The mean daily insulin dose over the 3 days during each treatment period is presented. Data is 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: Participants who completed both Treatment Period 1 and Treatment Period 2 and had evaluable insulin dose data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Analog-PH20 | Mean Daily Insulin Dose | 54.28 units (U) | Standard Deviation 27.071 |
| Insulin Lispro | Mean Daily Insulin Dose | 56.05 units (U) | Standard Deviation 27.243 |
Secondary
Mean Daily Postprandial Glucose (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 postprandial plasma glucose (PPG) excursions (referring to the change in blood glucose levels from before to after a meal) during 10-point glucose monitoring for breakfast, lunch, and dinner are presented. Data were collected 1 and 2 hours (hr) after each meal for 3 days and the means of each excursion are presented.
Time frame: Week 10 and Week 22
Population: Participants who completed both Treatment Period 1 and Treatment Period 2 and had evaluable postprandial glucose (PPG) excursion data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Analog-PH20 | Mean Daily Postprandial Glucose (PPG) Excursions | 1-hr breakfast excursion | 18.85 milligrams per deciliter (mg/dL) | Standard Deviation 48.348 |
| Analog-PH20 | Mean Daily Postprandial Glucose (PPG) Excursions | 2-hr breakfast excursion | -5.63 milligrams per deciliter (mg/dL) | Standard Deviation 52.657 |
| Analog-PH20 | Mean Daily Postprandial Glucose (PPG) Excursions | 1-hr lunch excursion | 16.26 milligrams per deciliter (mg/dL) | Standard Deviation 46.524 |
| Analog-PH20 | Mean Daily Postprandial Glucose (PPG) Excursions | 2-hr lunch excursion | 10.68 milligrams per deciliter (mg/dL) | Standard Deviation 53.787 |
| Analog-PH20 | Mean Daily Postprandial Glucose (PPG) Excursions | 1-hr dinner excursion | -0.31 milligrams per deciliter (mg/dL) | Standard Deviation 41.368 |
| Analog-PH20 | Mean Daily Postprandial Glucose (PPG) Excursions | 2-hr dinner excursion | -5.13 milligrams per deciliter (mg/dL) | Standard Deviation 46.956 |
| Insulin Lispro | Mean Daily Postprandial Glucose (PPG) Excursions | 1-hr dinner excursion | 4.47 milligrams per deciliter (mg/dL) | Standard Deviation 52.986 |
| Insulin Lispro | Mean Daily Postprandial Glucose (PPG) Excursions | 1-hr breakfast excursion | 27.46 milligrams per deciliter (mg/dL) | Standard Deviation 43.938 |
| Insulin Lispro | Mean Daily Postprandial Glucose (PPG) Excursions | 2-hr lunch excursion | 20.77 milligrams per deciliter (mg/dL) | Standard Deviation 47.005 |
| Insulin Lispro | Mean Daily Postprandial Glucose (PPG) Excursions | 2-hr breakfast excursion | 7.08 milligrams per deciliter (mg/dL) | Standard Deviation 56.997 |
| Insulin Lispro | Mean Daily Postprandial Glucose (PPG) Excursions | 2-hr dinner excursion | -5.16 milligrams per deciliter (mg/dL) | Standard Deviation 54.309 |
| Insulin Lispro | Mean Daily Postprandial Glucose (PPG) Excursions | 1-hr lunch excursion | 26.25 milligrams per deciliter (mg/dL) | Standard Deviation 39.07 |
Secondary
Percentage of Participants Meeting Glucose Targets
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 during non-10-point glucose monitoring days was recorded. The percentage was calculated by dividing 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 who completed both Treatment Period 1 and Treatment Period 2 and had evaluable postprandial glucose data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets | PPG <140 mg/dL for all meals | 15.0 percentage of participants |
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets | PPG <140 mg/dL for breakfast | 21.4 percentage of participants |
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets | PPG <180 mg/dL for all meals | 69.9 percentage of participants |
| Analog-PH20 | Percentage of Participants Meeting Glucose Targets | PPG <180 mg/dL for breakfast | 70.5 percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets | PPG <180 mg/dL for breakfast | 54.0 percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets | PPG <140 mg/dL for all meals | 8.8 percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets | PPG <180 mg/dL for all meals | 59.3 percentage of participants |
| Insulin Lispro | Percentage of Participants Meeting Glucose Targets | PPG <140 mg/dL for breakfast | 10.6 percentage of participants |
Secondary
Rates of Hypoglycemia at the End of Each Treatment Period
Overall rates of hypoglycemia (blood glucose ≤70 milligrams per deciliter \[mg/dL\] and \<56 mg/dL) were calculated based on 4 weeks of observation for each treatment period. Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts). 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: 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 | ≤70 mg/dL | 18.96 events per participant per month |
| Analog-PH20 | Rates of Hypoglycemia at the End of Each Treatment Period | <56 mg/dL | 7.50 events per participant per month |
| Insulin Lispro | Rates of Hypoglycemia at the End of Each Treatment Period | ≤70 mg/dL | 19.91 events per participant per month |
| Insulin Lispro | Rates of Hypoglycemia at the End of Each Treatment Period | <56 mg/dL | 8.05 events per participant per month |