Type 1 Diabetes Mellitus
Conditions
Keywords
Insulin analog, Type 1 diabetes mellitus, Pharmacokinetic, Glucodynamic, Phase 1
Brief summary
The purpose of this study is to determine if recombinant human hyaluronidase PH20 (rHuPH20) will change the exposure and action of approved insulin analogs when given by continuous subcutaneous insulin infusion (CSII) in participants with Type 1 diabetes mellitus (T1DM). This study is divided into Stage 1, 2, and 3. Stage 3 was started chronologically before Stage 2 and, prior to performing Stage 2, the Sponsor made the decision to terminate Stage 2. Stage 2 was not initiated due to a strategic business decision and termination was not based on safety or efficacy concerns. No participants were enrolled in Stage 2.
Interventions
DRUGInsulin aspart
Sponsors
Halozyme Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male or female aged 18 to 65 years, inclusive. Females of child-bearing potential must use a standard and effective means of birth control for the duration of the study. 2. Non-smoking participants with Type 1 diabetes mellitus (T1DM) treated with insulin for greater than or equal to 12 months. Non-smoking means abstinence from cigarettes and cigars for 3 months and negative cotinine screening tests. 3. Body mass index (BMI) 18.0 to 35.0 kilograms per meter squared (kg/m\^2), inclusive. 4. Glycosylated hemoglobin A1c (HbA1c) ≤10 % based on local laboratory results. 5. Fasting C-peptide \<0.6 nanograms per milliliter (ng/mL). 6. Current treatment with insulin \<90 units per day (U/d). 7. Routine use of continuous subcutaneous insulin infusion (CSII) as the primary route of insulin administration. 8. Participant should be in good general health based on medical history and physical examination, without medical conditions that might prevent the completion of study drug infusions and assessments required in this protocol.
Exclusion criteria
1. Known or suspected allergy to any component of any of the study drugs in this trial. 2. Previous enrollment in this trial (Exception: participants in Stage 1 are permitted to participate in Stage 2). 3. Use of drugs that may interfere with the interpretation of trial results or are known to cause clinically relevant interference with insulin action, glucose utilization, or recovery from hypoglycemia. Participants taking maintenance doses of blood thinners (eg, Coumadin or heparin) will be excluded. 4. Use of any long-acting insulin injection within 72 hours of Stage 1 or Stage 3. 5. Recurrent major hypoglycemia or hypoglycemic unawareness, as judged by the Investigator. 6. Current addiction to alcohol or substances of abuse as determined by the Investigator. 7. Blood donation or phlebotomy (\>500 milliliters \[mL\]) within the previous 8 weeks of Screening. This applies both to new participants and to participants who have participated in Stage 1 and who wish to continue in Stage 2. 8. Pregnancy, breast-feeding, the intention of becoming pregnant, or not using adequate contraceptive measures (adequate contraceptive measures consist of sterilization, intra-uterine device \[IUD\], oral or injectable contraceptives, or barrier methods). 9. Symptomatic gastroparesis. 10. Receipt of any investigational drug within 4 weeks of Stage 1 or Stage 2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Insulin Exposure (%AUC[0-60]), Stage 1 | 10 minutes predose up to 60 minutes postdose | Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve \[AUC{0-360}\]) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 120, 150, 180, 240, 300, and 360 minutes postdose during the euglycemic clamp. |
| Early Exposure to Insulin (%AUC[0-60]), Stage 3 | 10 minutes predose up to 60 minutes postdose on Days 2/7, 3/8, and 5/10 | Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve \[AUC{0-360}) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 120, 150, 180, 240, 300, and 360 minutes postdose during the euglycemic clamp. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1 | 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 | Time to first occurrence of maximum glucose infusion rate (tGIRmax) for Stage 1 is presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 | 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 | Time to first occurrence of maximum glucose infusion rate (tGIRmax) for Stage 3 is presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 | 0 up to 360 minutes postdose on day 2/6 and Day 4/8 | Early and late times to 50% maximum glucose infusion rate (tGIR50%max) for Stage 1 are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 | Early and late time to 50% maximum glucose infusion rates (tGIR50%max) for Stage 3 studies are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Time to 50% Total Glucose Infused (50%Gtot), Stage 1 | 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 | Time to 50% total glucose infused (50%Gtot) is presented for Stage 1. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Maximum Glucose Infusion Rate (GIRmax), Stage 1 | 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 | Maximum glucose infusion rates (GIRmax) for Stage1 are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1 | 30 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8 | Area under the glucose concentration curve for 0 to 360 minutes (AUC\[0-360\]) from Stage 1 is presented. Blood samples were collected 30 and 10 minutes prior to insulin bolus and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 | 30 minutes predose up to 360 minutes postdose Days 2/7, 3/8, and 5/10 | Area under the glucose concentration curve from 0 to 360 minutes (AUC\[0-360\]) for Stage 3 studies is presented. Blood samples were collected 30 and 10 minutes prior to insulin bolus and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1 | 10 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8 | Duration of insulin action was calculated by dividing the area under the first moment curve (AUMC\[0-360\]) by the area under the concentration versus time curve (AUC\[0-360\]) for Stage 1. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 | 10 minutes predose up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 | Duration of insulin action was calculated by dividing the area under the first moment curve (AUMC\[0-360\]) by the area under the concentration versus time curve (AUC\[0-360\]) for Stage 3. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Time to 50% Total Glucose Infused (50%Gtot), Stage 3 | 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 | Time to 50% of total glucose infused (50%Gtot) is presented for Stage 3. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
| Maximum Glucose Infusion Rate (GIRmax), Stage 3 | 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 | Maximum glucose infusion rates (GIRmax) for Stage 3 are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20 Participants first received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4.
After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8. | 11 |
| Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart Participants first received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4.
After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart alone as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8. | 9 |
| Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20 Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp.
After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a 1.0-milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to a 6-hr euglycemic clamp. | 13 |
| Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a 1.0-milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the euglycemic clamp .
After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a sham injection was administered 2.5 hr prior to a 6-hr euglycemic clamp. | 12 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 | Physician Decision | 1 | 0 | 0 | 0 |
| Period 1 | Withdrawal by Subject | 1 | 0 | 3 | 2 |
| Period 2 (Crossover) | Adverse Event | 0 | 1 | 0 | 0 |
| Period 2 (Crossover) | Withdrawal by Subject | 1 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart | Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20 | Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20 | Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart |
|---|---|---|---|---|---|
| Age, Continuous | 35.44 Years STANDARD_DEVIATION 9.95 | 32.3 Years STANDARD_DEVIATION 10.29 | 35.5 Years STANDARD_DEVIATION 9.5 | 31.3 Years STANDARD_DEVIATION 6.39 | 44.6 Years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants | 12 Participants | 13 Participants | 10 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 42 Participants | 11 Participants | 11 Participants | 11 Participants | 9 Participants |
| Region of Enrollment United States | 45 Participants | 12 Participants | 13 Participants | 11 Participants | 9 Participants |
| Sex: Female, Male Female | 22 Participants | 6 Participants | 7 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 23 Participants | 6 Participants | 6 Participants | 5 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 20 | 13 / 18 | 14 / 23 | 12 / 22 |
| serious Total, serious adverse events | 0 / 20 | 0 / 18 | 0 / 23 | 0 / 22 |
Outcome results
Primary
Early Exposure to Insulin (%AUC[0-60]), Stage 3
Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve \[AUC{0-360}) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 120, 150, 180, 240, 300, and 360 minutes postdose during the euglycemic clamp.
Time frame: 10 minutes predose up to 60 minutes postdose on Days 2/7, 3/8, and 5/10
Population: Participants who completed all periods of study within a given stage with evaluable %AUC(0-60) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Early Exposure to Insulin (%AUC[0-60]), Stage 3 | Stage 3, Day 3/8 | 22.29 Percentage of AUC(0-360) | Standard Deviation 5.43 |
| Stage 1: Insulin Aspart Alone | Early Exposure to Insulin (%AUC[0-60]), Stage 3 | Stage 3, Day 2/7 | 15.70 Percentage of AUC(0-360) | Standard Deviation 6.38 |
| Stage 1: Insulin Aspart Alone | Early Exposure to Insulin (%AUC[0-60]), Stage 3 | Stage 3, Day 5/10 | 27.31 Percentage of AUC(0-360) | Standard Deviation 10.49 |
| Stage 1: Insulin Aspart-rHuPH20 | Early Exposure to Insulin (%AUC[0-60]), Stage 3 | Stage 3, Day 2/7 | 32.11 Percentage of AUC(0-360) | Standard Deviation 10.91 |
| Stage 1: Insulin Aspart-rHuPH20 | Early Exposure to Insulin (%AUC[0-60]), Stage 3 | Stage 3, Day 3/8 | 36.39 Percentage of AUC(0-360) | Standard Deviation 9.43 |
| Stage 1: Insulin Aspart-rHuPH20 | Early Exposure to Insulin (%AUC[0-60]), Stage 3 | Stage 3, Day 5/10 | 32.64 Percentage of AUC(0-360) | Standard Deviation 11.32 |
Comparison: Comparison at Stage 3, Day 2/7p-value: <0.000190% CI: [11.86, 20.97]Mixed Models Analysis
Comparison: Comparison at Stage 3, Day 3/8p-value: <0.000190% CI: [9.55, 18.65]Mixed Models Analysis
Comparison: Comparison at Stage 3, Day 5/10p-value: 0.055290% CI: [0.77, 9.88]Mixed Models Analysis
Primary
Early Insulin Exposure (%AUC[0-60]), Stage 1
Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve \[AUC{0-360}\]) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 120, 150, 180, 240, 300, and 360 minutes postdose during the euglycemic clamp.
Time frame: 10 minutes predose up to 60 minutes postdose
Population: Participants who completed all study periods within a given stage with evaluable early insulin exposure (%AUC\[0-60\]) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Early Insulin Exposure (%AUC[0-60]), Stage 1 | Stage 1, Day 2/6 | 20.99 Percentage of AUC(0-360) | Standard Deviation 6.37 |
| Stage 1: Insulin Aspart Alone | Early Insulin Exposure (%AUC[0-60]), Stage 1 | Stage 1, Day 4/8 | 32.83 Percentage of AUC(0-360) | Standard Deviation 14.66 |
| Stage 1: Insulin Aspart-rHuPH20 | Early Insulin Exposure (%AUC[0-60]), Stage 1 | Stage 1, Day 4/8 | 50.97 Percentage of AUC(0-360) | Standard Deviation 13.91 |
| Stage 1: Insulin Aspart-rHuPH20 | Early Insulin Exposure (%AUC[0-60]), Stage 1 | Stage 1, Day 2/6 | 34.94 Percentage of AUC(0-360) | Standard Deviation 9.48 |
Comparison: Comparison at Stage 1, Day 2/6p-value: 0.000990% CI: [7.37, 20.54]Mixed Models Analysis
Comparison: Comparison at Stage 1, Day 4/8p-value: <0.000190% CI: [11.55, 24.72]Mixed Models Analysis
Secondary
Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1
Area under the glucose concentration curve for 0 to 360 minutes (AUC\[0-360\]) from Stage 1 is presented. Blood samples were collected 30 and 10 minutes prior to insulin bolus and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 30 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8
Population: Participants who completed all periods of study within a given stage with evaluable AUC(0-360) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1 | Stage 1, Day 2/6 | 1978.08 Picomoles*minutes/liter | Standard Deviation 631.89 |
| Stage 1: Insulin Aspart Alone | Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1 | Stage 1, Day 4/8 | 1598.40 Picomoles*minutes/liter | Standard Deviation 546 |
| Stage 1: Insulin Aspart-rHuPH20 | Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1 | Stage 1, Day 2/6 | 1977.02 Picomoles*minutes/liter | Standard Deviation 795.79 |
| Stage 1: Insulin Aspart-rHuPH20 | Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1 | Stage 1, Day 4/8 | 1324.31 Picomoles*minutes/liter | Standard Deviation 500.04 |
Secondary
Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3
Area under the glucose concentration curve from 0 to 360 minutes (AUC\[0-360\]) for Stage 3 studies is presented. Blood samples were collected 30 and 10 minutes prior to insulin bolus and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 30 minutes predose up to 360 minutes postdose Days 2/7, 3/8, and 5/10
Population: Participants who completed all periods of study within a given stage with evaluable AUC(0-360) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 | Stage 3, Day 2/7 | 1197.60 Picomoles*minutes/liter | Standard Deviation 385.44 |
| Stage 1: Insulin Aspart Alone | Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 | Stage 3, Day 3/8 | 1368.81 Picomoles*minutes/liter | Standard Deviation 424.16 |
| Stage 1: Insulin Aspart Alone | Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 | Stage 3, Day 5/10 | 1289.22 Picomoles*minutes/liter | Standard Deviation 486.03 |
| Stage 1: Insulin Aspart-rHuPH20 | Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 | Stage 3, Day 2/7 | 1509.38 Picomoles*minutes/liter | Standard Deviation 541.45 |
| Stage 1: Insulin Aspart-rHuPH20 | Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 | Stage 3, Day 3/8 | 1405.75 Picomoles*minutes/liter | Standard Deviation 516.85 |
| Stage 1: Insulin Aspart-rHuPH20 | Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 | Stage 3, Day 5/10 | 1369.97 Picomoles*minutes/liter | Standard Deviation 462.78 |
Secondary
Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1
Duration of insulin action was calculated by dividing the area under the first moment curve (AUMC\[0-360\]) by the area under the concentration versus time curve (AUC\[0-360\]) for Stage 1. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 10 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8
Population: Participants who completed all periods of study within a given stage with evaluable AUMC(0-360)/AUC(0-360) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1 | Stage 1, Day 2/6 | 163.63 Ratio | Standard Deviation 14.7 |
| Stage 1: Insulin Aspart Alone | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1 | Stage 1, Day 4/8 | 147.50 Ratio | Standard Deviation 23.86 |
| Stage 1: Insulin Aspart-rHuPH20 | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1 | Stage 1, Day 4/8 | 132.60 Ratio | Standard Deviation 15.55 |
| Stage 1: Insulin Aspart-rHuPH20 | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1 | Stage 1, Day 2/6 | 146.51 Ratio | Standard Deviation 16.3 |
Secondary
Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3
Duration of insulin action was calculated by dividing the area under the first moment curve (AUMC\[0-360\]) by the area under the concentration versus time curve (AUC\[0-360\]) for Stage 3. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 10 minutes predose up to 360 minutes postdose on Days 2/7, 3/8, and 5/10
Population: Participants who completed all periods of study within a given stage with evaluable AUMC(0-360)/AUC(0-360) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 | Stage 3, Day 2/7 | 180.39 ratio | Standard Deviation 18.72 |
| Stage 1: Insulin Aspart Alone | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 | Stage 3, Day 5/10 | 156.14 ratio | Standard Deviation 26.38 |
| Stage 1: Insulin Aspart Alone | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 | Stage 3, Day 3/8 | 164.65 ratio | Standard Deviation 19.97 |
| Stage 1: Insulin Aspart-rHuPH20 | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 | Stage 3, Day 2/7 | 138.59 ratio | Standard Deviation 18.41 |
| Stage 1: Insulin Aspart-rHuPH20 | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 | Stage 3, Day 3/8 | 135.71 ratio | Standard Deviation 17.3 |
| Stage 1: Insulin Aspart-rHuPH20 | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 | Stage 3, Day 5/10 | 145.81 ratio | Standard Deviation 16.42 |
Secondary
Maximum Glucose Infusion Rate (GIRmax), Stage 1
Maximum glucose infusion rates (GIRmax) for Stage1 are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8
Population: Participants who completed all periods of study within a given stage with evaluable GIRmax data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Maximum Glucose Infusion Rate (GIRmax), Stage 1 | Stage 1, Day 2/6 | 13.37 Milligrams/kilogram/minute | Standard Deviation 4.23 |
| Stage 1: Insulin Aspart Alone | Maximum Glucose Infusion Rate (GIRmax), Stage 1 | Stage 1, Day 4/8 | 11.88 Milligrams/kilogram/minute | Standard Deviation 3.64 |
| Stage 1: Insulin Aspart-rHuPH20 | Maximum Glucose Infusion Rate (GIRmax), Stage 1 | Stage 1, Day 2/6 | 12.51 Milligrams/kilogram/minute | Standard Deviation 3.19 |
| Stage 1: Insulin Aspart-rHuPH20 | Maximum Glucose Infusion Rate (GIRmax), Stage 1 | Stage 1, Day 4/8 | 11.52 Milligrams/kilogram/minute | Standard Deviation 3.67 |
Secondary
Maximum Glucose Infusion Rate (GIRmax), Stage 3
Maximum glucose infusion rates (GIRmax) for Stage 3 are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10
Population: Participants who completed all periods of study within a given stage with evaluable GIRmax data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Maximum Glucose Infusion Rate (GIRmax), Stage 3 | Stage 3, Day 3/8 | 10.07 Milligrams/kilogram/minute | Standard Deviation 3.36 |
| Stage 1: Insulin Aspart Alone | Maximum Glucose Infusion Rate (GIRmax), Stage 3 | Stage 3, Day 2/7 | 9.58 Milligrams/kilogram/minute | Standard Deviation 2.28 |
| Stage 1: Insulin Aspart Alone | Maximum Glucose Infusion Rate (GIRmax), Stage 3 | Stage 3, Day 5/10 | 9.97 Milligrams/kilogram/minute | Standard Deviation 3.53 |
| Stage 1: Insulin Aspart-rHuPH20 | Maximum Glucose Infusion Rate (GIRmax), Stage 3 | Stage 3, Day 2/7 | 12.63 Milligrams/kilogram/minute | Standard Deviation 3.88 |
| Stage 1: Insulin Aspart-rHuPH20 | Maximum Glucose Infusion Rate (GIRmax), Stage 3 | Stage 3, Day 3/8 | 12.4 Milligrams/kilogram/minute | Standard Deviation 3.39 |
| Stage 1: Insulin Aspart-rHuPH20 | Maximum Glucose Infusion Rate (GIRmax), Stage 3 | Stage 3, Day 5/10 | 10.76 Milligrams/kilogram/minute | Standard Deviation 3.35 |
Secondary
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1
Early and late times to 50% maximum glucose infusion rate (tGIR50%max) for Stage 1 are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 0 up to 360 minutes postdose on day 2/6 and Day 4/8
Population: Participants who completed all periods of study within a given stage with evaluable early or late tGIR50%max data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 | Early tGIR50%max, Stage 1, Day 2/6 | 46.50 Minutes | Standard Deviation 18.08 |
| Stage 1: Insulin Aspart Alone | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 | Late tGIR50%max, Stage 1, Day 2/6 | 162.19 Minutes | Standard Deviation 56.78 |
| Stage 1: Insulin Aspart Alone | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 | Early tGIR50%max, Stage 1, Day 4/8 | 35.19 Minutes | Standard Deviation 28.54 |
| Stage 1: Insulin Aspart Alone | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 | Late tGIR50%max, Stage 1, Day 4/8 | 132.63 Minutes | Standard Deviation 47.37 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 | Late tGIR50%max, Stage 1, Day 4/8 | 114.19 Minutes | Standard Deviation 29.05 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 | Early tGIR50%max, Stage 1, Day 2/6 | 34.88 Minutes | Standard Deviation 17.92 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 | Early tGIR50%max, Stage 1, Day 4/8 | 39.75 Minutes | Standard Deviation 18.71 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 | Late tGIR50%max, Stage 1, Day 2/6 | 158.06 Minutes | Standard Deviation 52.58 |
Secondary
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3
Early and late time to 50% maximum glucose infusion rates (tGIR50%max) for Stage 3 studies are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10
Population: Participants who completed all periods of study within a given stage with evaluable early and late tGIR50%max data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Early tGIR50%max, Stage 3, Day 2/7 | 58.47 Minutes | Standard Deviation 17.53 |
| Stage 1: Insulin Aspart Alone | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Late tGIR50%max, Stage 3, Day 3/8 | 153.41 Minutes | Standard Deviation 65.35 |
| Stage 1: Insulin Aspart Alone | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Early tGIR50%max, Stage 3, Day 5/10 | 27.29 Minutes | Standard Deviation 18.4 |
| Stage 1: Insulin Aspart Alone | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Late tGIR50%max, Stage 3, Day 2/7 | 144.18 Minutes | Standard Deviation 61.44 |
| Stage 1: Insulin Aspart Alone | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Late tGIR50%max, Stage 3, Day 5/10 | 136.88 Minutes | Standard Deviation 73.39 |
| Stage 1: Insulin Aspart Alone | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Early tGIR50%max, Stage 3, Day 3/8 | 32.59 Minutes | Standard Deviation 22.88 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Late tGIR50%max, Stage 3, Day 5/10 | 110.59 Minutes | Standard Deviation 55.1 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Early tGIR50%max, Stage 3, Day 3/8 | 31.53 Minutes | Standard Deviation 21.27 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Early tGIR50%max, Stage 3, Day 2/7 | 31.06 Minutes | Standard Deviation 20.73 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Late tGIR50%max, Stage 3, Day 2/7 | 98.71 Minutes | Standard Deviation 39.87 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Late tGIR50%max, Stage 3, Day 3/8 | 102.88 Minutes | Standard Deviation 44.57 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Early tGIR50%max, Stage 3, Day 5/10 | 28.88 Minutes | Standard Deviation 21.97 |
Secondary
Time to 50% Total Glucose Infused (50%Gtot), Stage 1
Time to 50% total glucose infused (50%Gtot) is presented for Stage 1. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8
Population: Participants who completed all periods of study within a given stage with evaluable 50%Gtot data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Time to 50% Total Glucose Infused (50%Gtot), Stage 1 | Stage 1, Day 4/8 | 137.38 Minutes | Standard Deviation 22.21 |
| Stage 1: Insulin Aspart Alone | Time to 50% Total Glucose Infused (50%Gtot), Stage 1 | Stage 1, Day 2/6 | 156.13 Minutes | Standard Deviation 18.7 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Total Glucose Infused (50%Gtot), Stage 1 | Stage 1, Day 2/6 | 134.94 Minutes | Standard Deviation 18.28 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Total Glucose Infused (50%Gtot), Stage 1 | Stage 1, Day 4/8 | 115.25 Minutes | Standard Deviation 14.5 |
Secondary
Time to 50% Total Glucose Infused (50%Gtot), Stage 3
Time to 50% of total glucose infused (50%Gtot) is presented for Stage 3. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10
Population: Participants who completed all periods of study within a given stage with evaluable 50%Gtot data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Time to 50% Total Glucose Infused (50%Gtot), Stage 3 | Stage 3, Day 2/7 | 174.59 Minutes | Standard Deviation 25.86 |
| Stage 1: Insulin Aspart Alone | Time to 50% Total Glucose Infused (50%Gtot), Stage 3 | Stage 3, Day 3/8 | 154.06 Minutes | Standard Deviation 24.02 |
| Stage 1: Insulin Aspart Alone | Time to 50% Total Glucose Infused (50%Gtot), Stage 3 | Stage 3, Day 5/10 | 146.59 Minutes | Standard Deviation 28.63 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Total Glucose Infused (50%Gtot), Stage 3 | Stage 3, Day 2/7 | 124.18 Minutes | Standard Deviation 22.03 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Total Glucose Infused (50%Gtot), Stage 3 | Stage 3, Day 3/8 | 120.00 Minutes | Standard Deviation 17.12 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to 50% Total Glucose Infused (50%Gtot), Stage 3 | Stage 3, Day 5/10 | 130.18 Minutes | Standard Deviation 23.54 |
Secondary
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1
Time to first occurrence of maximum glucose infusion rate (tGIRmax) for Stage 1 is presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8
Population: Participants who completed all periods of study within a given stage with evaluable tGIRmax data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1 | Stage 1, Day 4/8 | 92.50 Minutes | Standard Deviation 24.71 |
| Stage 1: Insulin Aspart Alone | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1 | Stage 1, Day 2/6 | 115.38 Minutes | Standard Deviation 59.21 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1 | Stage 1, Day 2/6 | 102.38 Minutes | Standard Deviation 38.28 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1 | Stage 1, Day 4/8 | 84.31 Minutes | Standard Deviation 25.89 |
Secondary
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3
Time to first occurrence of maximum glucose infusion rate (tGIRmax) for Stage 3 is presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10
Population: Participants who completed all periods of study within a given stage with evaluable tGIRmax data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Insulin Aspart Alone | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 | Stage 3, Day 2/7 | 127.65 Minutes | Standard Deviation 60.02 |
| Stage 1: Insulin Aspart Alone | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 | Stage 3, Day 3/8 | 135.24 Minutes | Standard Deviation 73 |
| Stage 1: Insulin Aspart Alone | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 | Stage 3, Day 5/10 | 117.76 Minutes | Standard Deviation 75.2 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 | Stage 3, Day 2/7 | 78.53 Minutes | Standard Deviation 27.04 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 | Stage 3, Day 3/8 | 79.47 Minutes | Standard Deviation 42.57 |
| Stage 1: Insulin Aspart-rHuPH20 | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 | Stage 3, Day 5/10 | 79.53 Minutes | Standard Deviation 42.99 |