Diabetes Mellitus
Conditions
Keywords
rHuPH20, Hyaluronidase, Insulin
Brief summary
The purpose of the study is to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of Humalog (insulin lispro) or Humulin-R (recombinant human insulin) when administered as a single subcutaneous (SC) injection of 20 units (U) with or without coadministration of recombinant human hyaluronidase PH20 (rHuPH20). The study hypothesizes that the time required to reach maximum insulin concentration (tmax) when insulin is administered with rHuPH20 will be comparable or shorter than the time required without rHuPH20.
Interventions
Sponsors
Halozyme Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male participants aged 18 to 55 years. 2. Body mass index (BMI) 18 to 28 kilograms per meter squared (kg/m\^2) and total body weight \>70 kilograms (kg) (154 pounds \[lb\]). 3. Willingness and ability to comply with the protocol. 4. Vital signs within the normal range. 5. Within 7 days before the first injection, metabolic panel results and complete blood count (CBC) within the laboratory normal reference range. 6. Fasting plasma glucose within the normal range of 90 to 110 milligrams per deciliter (mg/dL) on the morning of the glucose clamp. 7. Agreement not to father a child or donate sperm and to use effective contraception during the study and for at least 30 days after study completion. 8. Willingness and ability to sign an informed consent form.
Exclusion criteria
1. Evidence or history of clinically significant hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic (to include history of seizures) or allergic disease, or history of hypoglycemic episodes. 2. Known history of diabetes mellitus. 3. Prior exposure to any insulin or insulin analogs. 4. Known allergy to hyaluronidase or any other ingredient in HYLENEX. 5. Known allergy to bee or vespid venom. 6. Positive urine drug screen results. 7. Positive human immunodeficiency virus (HIV) 1, HIV 2, hepatitis B, or hepatitis C antibody test result. 8. Any history or evidence of alcohol or drug abuse. 9. History or evidence of use of any tobacco- or nicotine-containing product within 6 months of screening, or screening urine nicotine concentration \>50 nanograms per milliliter (ng/mL). 10. Use of prescription or nonprescription drugs within 7 days or 5 half-lives, whichever was shorter, except acetaminophen at doses of less than or equal to 1 gram per day (g/day). 11. Donation of blood in excess of 500 milliliters (mL) within 56 days before dosing. 12. Failure to limit alcohol consumption and refrain from exercise within 48 hours before each injection. 13. Known clinically significant intercurrent illness or other major systemic disease that would unduly risk the participant's safety or interfere with the interpretation of results. 14. Participation in a study of any investigational drug or device 30 days before enrollment in this study. 15. Unfitness for the study, in the investigator's opinion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Serum Insulin Concentration (Tmax) | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | Time to maximum serum insulin concentration (tmax) values for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from 3 milliliter (mL) blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
| Maximum Serum Insulin Concentration (Cmax) | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | Maximum serum insulin concentration (Cmax) values for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from 3 milliliter (mL) blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
| Area Under the Serum Concentration-Time Curve From Time Zero to the Time Required to Reach Endogenous Plasma Glucose Levels (AUC[0-t']) | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | Area under the serum concentration-time curve from time zero to the time required to reach endogenous plasma glucose levels (AUC\[0-t'\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from 3 milliliter (mL) blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
| Area Under the Concentration-Time Curve From Time 0 to Time to Reach Maximum Concentration (Tmax) for Serum Insulin With Recombinant Human Hyaluronidase PH20 (rHuPH20) (AUC[0-tmaxPH20]) | Predose and up to 48 minutes postdose during Stage 1, or up to 68 minutes postdose during Stage 2 | Area under the concentration-time curve from time 0 to time to reach maximum concentration (tmax) for serum insulin (Humalog or Humulin-R) with recombinant human hyaluronidase (rHuPH20) (AUC\[0-tmaxPH20\]) for participants who received Humalog or Humulin-R and with rHuPH20 were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment and every 3 min from min 0 through 48 for Stage 1 and, and every 3 min from min 0 through 68 for Stage 2 during the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
| Relative Bioavailability (Area Under the Curve [AUC] for Insulin + Recombinant Human Hyaluronidase [rHuPH20] / AUC for Insulin Alone) | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | Relative bioavailability was determined by dividing the baseline-corrected geometric mean of the area under the curve (AUC) for insulin (ins) (Humalog or Humulin-R) with recombinant human hyaluronidase PH20 (rHuPH20) by the baseline-corrected geometric mean of the AUC for insulin alone (AUC\[insulin+rHuPH20\]/AUC\[insulin\]). Bioavailability values for participants who received Humalog or Humulin-R and rHuPH20 were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Glucose Infusion Rate Curve From 0 to 120 Minutes After Injection (AUC[GIR{0-120}]) | Predose and up to 120 minutes postdose during Stage 1 or Stage 2 | The area under the glucose infusion rate curve from minutes 0 to 120 after injection (AUC\[GIR{0-120}\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, and every 15 min from min 60 through 120 during the clamp. Means were calculated using analysis of variance with fixed effects of participant, sequence within participant, treatment, and period. |
| Area Under the Glucose Infusion Rate Curve From 0 to 180 Minutes After Injection (AUC[GIR{0-180}]) | Predose and up to 180 minutes postdose during Stage 1 or Stage 2 | The area under the curve for the glucose infusion rate from minutes (min) 0 to 180 after injection (AUC\[GIR{0-180}\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment, every 3 min from min 0 through 60, and every 15 min from min 60 through 180 during the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
| Time to Maximum Glucose Infusion Rate (tGIR[Max]) | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | Time to maximal effect for glucose infusion rate (tGIR\[max\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from blood samples obtained every 3 minutes during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
| Area Under the Glucose Infusion Rate Curve From 0 to 360 Minutes After Injection (AUC[GIR{0-360}]) | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | The area under glucose infusion rate curve from minutes (min) 0 to 360 after injection (AUC\[GIR{0-360}\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 to 360 during the clamp. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
| Area Under the Glucose Infusion Rate Curve From 0 to 240 Minutes After Injection (AUC[GIR{0-240}]) | Predose up to 240 minutes postdose during Stage 1 or Stage 2 | The area the glucose infusion rate curve from minutes (min) 0 to 240 after injection (AUC\[GIR{0-240}\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 to 240 during the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
| Time to Early Half-Maximal Effect for Glucose Infusion Rate (tGIR[early50%]) | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | Time to early half-maximal effect for glucose infusion rate (tGIR\[early50%\]) for participants who were randomized to Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
| Time to Late Half-Maximal Effect for Glucose Infusion Rate (tGIR[late50%]) | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | Time to late half-maximal effect for glucose infusion rate (tGIR\[late50%\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. Because the study was only 360 minutes in duration, there was not sufficient time for regular human insulin to show an effect and therefore tGIR(late50%) could not be calculated for participants receiving Humulin-R alone. |
| Maximum Glucose Infusion Rate (GIR[Max]) | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | Maximum glucose infusion rate (GIR\[max\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. |
| Area Under the Glucose Infusion Rate Curve From 0 to 60 Minutes After Injection (AUC[GIR{0-60}]) | Predose and up to 60 minutes postdose during Stage 1 or Stage 2 | The area under the curve for the glucose infusion rate from minutes (min) 0 to 60 after injection (AUC\[GIR{0-60}\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment and every 3 min from min 0 through 60 during the clamp procedure. Means were calculated using analysis of variance with fixed of participant, sequence within participant, treatment, and period. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stage 1: Humalog Alone or Humalog + rHuPH20 Participants randomized to treatment with a single subcutaneous (SC) injection of 20 units (U) Humalog alone or 20 U Humalog + 300 U recombinant human hyaluronidase (rHuPH20), followed by crossover treatment after a washout period of at least 6 days. | 12 |
| Stage 2: Humulin-R Alone or Humulin-R + rHuPH20 Participants randomized to treatment with a single subcutaneous (SC) injection of 20 units (U) Humulin-R alone or 20 U Humulin-R + 240 U recombinant human hyaluronidase (rHuPH20), followed by crossover treatment after a washout period of at least 6 days. | 14 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Start Period 1 | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Stage 1: Humalog Alone or Humalog + rHuPH20 | Total | Stage 2: Humulin-R Alone or Humulin-R + rHuPH20 |
|---|---|---|---|
| Age, Continuous | 37.7 years STANDARD_DEVIATION 7.8 | 37.2 years STANDARD_DEVIATION 8.3 | 36.7 years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 19 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 18 Participants | 11 Participants |
| Region of Enrollment United States | 12 participants | 26 participants | 14 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 26 Participants | 14 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 | 3 / 12 | 3 / 12 | 2 / 13 | 3 / 14 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 13 | 0 / 14 |
Outcome results
Primary
Area Under the Concentration-Time Curve From Time 0 to Time to Reach Maximum Concentration (Tmax) for Serum Insulin With Recombinant Human Hyaluronidase PH20 (rHuPH20) (AUC[0-tmaxPH20])
Area under the concentration-time curve from time 0 to time to reach maximum concentration (tmax) for serum insulin (Humalog or Humulin-R) with recombinant human hyaluronidase (rHuPH20) (AUC\[0-tmaxPH20\]) for participants who received Humalog or Humulin-R and with rHuPH20 were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment and every 3 min from min 0 through 48 for Stage 1 and, and every 3 min from min 0 through 68 for Stage 2 during the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 48 minutes postdose during Stage 1, or up to 68 minutes postdose during Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable AUC(0-tmaxPH20) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Area Under the Concentration-Time Curve From Time 0 to Time to Reach Maximum Concentration (Tmax) for Serum Insulin With Recombinant Human Hyaluronidase PH20 (rHuPH20) (AUC[0-tmaxPH20]) | 9530 Picomoles per liter times minutes | Standard Deviation 10500 |
| Stage 1: Humalog + rHuPH20 | Area Under the Concentration-Time Curve From Time 0 to Time to Reach Maximum Concentration (Tmax) for Serum Insulin With Recombinant Human Hyaluronidase PH20 (rHuPH20) (AUC[0-tmaxPH20]) | 27900 Picomoles per liter times minutes | Standard Deviation 14300 |
| Stage 2: Humulin-R Alone | Area Under the Concentration-Time Curve From Time 0 to Time to Reach Maximum Concentration (Tmax) for Serum Insulin With Recombinant Human Hyaluronidase PH20 (rHuPH20) (AUC[0-tmaxPH20]) | 8780 Picomoles per liter times minutes | Standard Deviation 3010 |
| Stage 2: Humulin-R + rHuPH20 | Area Under the Concentration-Time Curve From Time 0 to Time to Reach Maximum Concentration (Tmax) for Serum Insulin With Recombinant Human Hyaluronidase PH20 (rHuPH20) (AUC[0-tmaxPH20]) | 34800 Picomoles per liter times minutes | Standard Deviation 9150 |
p-value: <0.0001ANOVA
p-value: <0.0001ANOVA
Primary
Area Under the Serum Concentration-Time Curve From Time Zero to the Time Required to Reach Endogenous Plasma Glucose Levels (AUC[0-t'])
Area under the serum concentration-time curve from time zero to the time required to reach endogenous plasma glucose levels (AUC\[0-t'\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from 3 milliliter (mL) blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 360 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable AUC(0-t') data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Area Under the Serum Concentration-Time Curve From Time Zero to the Time Required to Reach Endogenous Plasma Glucose Levels (AUC[0-t']) | 116000 Picomoles per liter times minutes | Standard Deviation 23000 |
| Stage 1: Humalog + rHuPH20 | Area Under the Serum Concentration-Time Curve From Time Zero to the Time Required to Reach Endogenous Plasma Glucose Levels (AUC[0-t']) | 133000 Picomoles per liter times minutes | Standard Deviation 21800 |
| Stage 2: Humulin-R Alone | Area Under the Serum Concentration-Time Curve From Time Zero to the Time Required to Reach Endogenous Plasma Glucose Levels (AUC[0-t']) | 91400 Picomoles per liter times minutes | Standard Deviation 25700 |
| Stage 2: Humulin-R + rHuPH20 | Area Under the Serum Concentration-Time Curve From Time Zero to the Time Required to Reach Endogenous Plasma Glucose Levels (AUC[0-t']) | 137000 Picomoles per liter times minutes | Standard Deviation 32800 |
p-value: 0.0401ANOVA
p-value: 0.0004ANOVA
Primary
Maximum Serum Insulin Concentration (Cmax)
Maximum serum insulin concentration (Cmax) values for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from 3 milliliter (mL) blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 360 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable Cmax data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Maximum Serum Insulin Concentration (Cmax) | 680 Picomoles per liter | Standard Deviation 361 |
| Stage 1: Humalog + rHuPH20 | Maximum Serum Insulin Concentration (Cmax) | 1290 Picomoles per liter | Standard Deviation 471 |
| Stage 2: Humulin-R Alone | Maximum Serum Insulin Concentration (Cmax) | 390 Picomoles per liter | Standard Deviation 137 |
| Stage 2: Humulin-R + rHuPH20 | Maximum Serum Insulin Concentration (Cmax) | 944 Picomoles per liter | Standard Deviation 257 |
p-value: 0.0003ANOVA
p-value: <0.0001ANOVA
Primary
Relative Bioavailability (Area Under the Curve [AUC] for Insulin + Recombinant Human Hyaluronidase [rHuPH20] / AUC for Insulin Alone)
Relative bioavailability was determined by dividing the baseline-corrected geometric mean of the area under the curve (AUC) for insulin (ins) (Humalog or Humulin-R) with recombinant human hyaluronidase PH20 (rHuPH20) by the baseline-corrected geometric mean of the AUC for insulin alone (AUC\[insulin+rHuPH20\]/AUC\[insulin\]). Bioavailability values for participants who received Humalog or Humulin-R and rHuPH20 were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 360 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog + rHuPH20 or Humulin-R + rHuPH20 with evaluable relative bioavailability (AUC\[insulin+rHuPH20\]/AUC\[insulin alone\]) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Relative Bioavailability (Area Under the Curve [AUC] for Insulin + Recombinant Human Hyaluronidase [rHuPH20] / AUC for Insulin Alone) | 1.18 Ratio of AUC(ins+rHuPH20)/AUC(ins alone) | Standard Deviation 0.221 |
| Stage 1: Humalog + rHuPH20 | Relative Bioavailability (Area Under the Curve [AUC] for Insulin + Recombinant Human Hyaluronidase [rHuPH20] / AUC for Insulin Alone) | 1.57 Ratio of AUC(ins+rHuPH20)/AUC(ins alone) | Standard Deviation 0.406 |
Primary
Time to Maximum Serum Insulin Concentration (Tmax)
Time to maximum serum insulin concentration (tmax) values for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from 3 milliliter (mL) blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 360 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable tmax data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Time to Maximum Serum Insulin Concentration (Tmax) | 97.5 Minutes | Standard Deviation 35.9 |
| Stage 1: Humalog + rHuPH20 | Time to Maximum Serum Insulin Concentration (Tmax) | 48.0 Minutes | Standard Deviation 7.99 |
| Stage 2: Humulin-R Alone | Time to Maximum Serum Insulin Concentration (Tmax) | 163 Minutes | Standard Deviation 51.5 |
| Stage 2: Humulin-R + rHuPH20 | Time to Maximum Serum Insulin Concentration (Tmax) | 67.8 Minutes | Standard Deviation 19.1 |
p-value: 0.0006ANOVA
p-value: 0.0002ANOVA
Secondary
Area Under the Glucose Infusion Rate Curve From 0 to 120 Minutes After Injection (AUC[GIR{0-120}])
The area under the glucose infusion rate curve from minutes 0 to 120 after injection (AUC\[GIR{0-120}\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, and every 15 min from min 60 through 120 during the clamp. Means were calculated using analysis of variance with fixed effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 120 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable AUC(GIR\[0-120\]) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Area Under the Glucose Infusion Rate Curve From 0 to 120 Minutes After Injection (AUC[GIR{0-120}]) | 393 Grams per kilogram | Standard Deviation 242 |
| Stage 1: Humalog + rHuPH20 | Area Under the Glucose Infusion Rate Curve From 0 to 120 Minutes After Injection (AUC[GIR{0-120}]) | 597 Grams per kilogram | Standard Deviation 278 |
| Stage 2: Humulin-R Alone | Area Under the Glucose Infusion Rate Curve From 0 to 120 Minutes After Injection (AUC[GIR{0-120}]) | 281 Grams per kilogram | Standard Deviation 123 |
| Stage 2: Humulin-R + rHuPH20 | Area Under the Glucose Infusion Rate Curve From 0 to 120 Minutes After Injection (AUC[GIR{0-120}]) | 637 Grams per kilogram | Standard Deviation 216 |
Secondary
Area Under the Glucose Infusion Rate Curve From 0 to 180 Minutes After Injection (AUC[GIR{0-180}])
The area under the curve for the glucose infusion rate from minutes (min) 0 to 180 after injection (AUC\[GIR{0-180}\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment, every 3 min from min 0 through 60, and every 15 min from min 60 through 180 during the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 180 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable AUC(GIR\[180\]) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Area Under the Glucose Infusion Rate Curve From 0 to 180 Minutes After Injection (AUC[GIR{0-180}]) | 801 Grams per kilogram | Standard Deviation 420 |
| Stage 1: Humalog + rHuPH20 | Area Under the Glucose Infusion Rate Curve From 0 to 180 Minutes After Injection (AUC[GIR{0-180}]) | 1040 Grams per kilogram | Standard Deviation 501 |
| Stage 2: Humulin-R Alone | Area Under the Glucose Infusion Rate Curve From 0 to 180 Minutes After Injection (AUC[GIR{0-180}]) | 604 Grams per kilogram | Standard Deviation 262 |
| Stage 2: Humulin-R + rHuPH20 | Area Under the Glucose Infusion Rate Curve From 0 to 180 Minutes After Injection (AUC[GIR{0-180}]) | 1150 Grams per kilogram | Standard Deviation 348 |
Secondary
Area Under the Glucose Infusion Rate Curve From 0 to 240 Minutes After Injection (AUC[GIR{0-240}])
The area the glucose infusion rate curve from minutes (min) 0 to 240 after injection (AUC\[GIR{0-240}\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 to 240 during the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose up to 240 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable AUC(GIR\[240\]) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Area Under the Glucose Infusion Rate Curve From 0 to 240 Minutes After Injection (AUC[GIR{0-240}]) | 1240 Grams per kilogram | Standard Deviation 618 |
| Stage 1: Humalog + rHuPH20 | Area Under the Glucose Infusion Rate Curve From 0 to 240 Minutes After Injection (AUC[GIR{0-240}]) | 1430 Grams per kilogram | Standard Deviation 706 |
| Stage 2: Humulin-R Alone | Area Under the Glucose Infusion Rate Curve From 0 to 240 Minutes After Injection (AUC[GIR{0-240}]) | 1010 Grams per kilogram | Standard Deviation 411 |
| Stage 2: Humulin-R + rHuPH20 | Area Under the Glucose Infusion Rate Curve From 0 to 240 Minutes After Injection (AUC[GIR{0-240}]) | 1630 Grams per kilogram | Standard Deviation 467 |
Secondary
Area Under the Glucose Infusion Rate Curve From 0 to 360 Minutes After Injection (AUC[GIR{0-360}])
The area under glucose infusion rate curve from minutes (min) 0 to 360 after injection (AUC\[GIR{0-360}\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 to 360 during the clamp. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 360 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable AUC(GIR\[360\]) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Area Under the Glucose Infusion Rate Curve From 0 to 360 Minutes After Injection (AUC[GIR{0-360}]) | 1940 Grams per kilogram | Standard Deviation 963 |
| Stage 1: Humalog + rHuPH20 | Area Under the Glucose Infusion Rate Curve From 0 to 360 Minutes After Injection (AUC[GIR{0-360}]) | 1930 Grams per kilogram | Standard Deviation 988 |
| Stage 2: Humulin-R Alone | Area Under the Glucose Infusion Rate Curve From 0 to 360 Minutes After Injection (AUC[GIR{0-360}]) | 1860 Grams per kilogram | Standard Deviation 672 |
| Stage 2: Humulin-R + rHuPH20 | Area Under the Glucose Infusion Rate Curve From 0 to 360 Minutes After Injection (AUC[GIR{0-360}]) | 2260 Grams per kilogram | Standard Deviation 611 |
Secondary
Area Under the Glucose Infusion Rate Curve From 0 to 60 Minutes After Injection (AUC[GIR{0-60}])
The area under the curve for the glucose infusion rate from minutes (min) 0 to 60 after injection (AUC\[GIR{0-60}\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment and every 3 min from min 0 through 60 during the clamp procedure. Means were calculated using analysis of variance with fixed of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 60 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable AUC(GIR\[0-60\]) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Area Under the Glucose Infusion Rate Curve From 0 to 60 Minutes After Injection (AUC[GIR{0-60}]) | 82.8 Grams per kilogram | Standard Deviation 51.9 |
| Stage 1: Humalog + rHuPH20 | Area Under the Glucose Infusion Rate Curve From 0 to 60 Minutes After Injection (AUC[GIR{0-60}]) | 167 Grams per kilogram | Standard Deviation 81 |
| Stage 2: Humulin-R Alone | Area Under the Glucose Infusion Rate Curve From 0 to 60 Minutes After Injection (AUC[GIR{0-60}]) | 74.3 Grams per kilogram | Standard Deviation 40.4 |
| Stage 2: Humulin-R + rHuPH20 | Area Under the Glucose Infusion Rate Curve From 0 to 60 Minutes After Injection (AUC[GIR{0-60}]) | 180 Grams per kilogram | Standard Deviation 57.7 |
Secondary
Maximum Glucose Infusion Rate (GIR[Max])
Maximum glucose infusion rate (GIR\[max\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 360 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable GIR(max) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Maximum Glucose Infusion Rate (GIR[Max]) | 8.11 Milligrams per kilogram per minute | Standard Deviation 4.48 |
| Stage 1: Humalog + rHuPH20 | Maximum Glucose Infusion Rate (GIR[Max]) | 8.57 Milligrams per kilogram per minute | Standard Deviation 4.24 |
| Stage 2: Humulin-R Alone | Maximum Glucose Infusion Rate (GIR[Max]) | 7.82 Milligrams per kilogram per minute | Standard Deviation 2.52 |
| Stage 2: Humulin-R + rHuPH20 | Maximum Glucose Infusion Rate (GIR[Max]) | 10.5 Milligrams per kilogram per minute | Standard Deviation 3.89 |
p-value: 0.5589ANOVA
p-value: 0.0067ANOVA
Secondary
Time to Early Half-Maximal Effect for Glucose Infusion Rate (tGIR[early50%])
Time to early half-maximal effect for glucose infusion rate (tGIR\[early50%\]) for participants who were randomized to Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 360 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable tGIR(early50%) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Time to Early Half-Maximal Effect for Glucose Infusion Rate (tGIR[early50%]) | 72.3 Minutes | Standard Deviation 16.6 |
| Stage 1: Humalog + rHuPH20 | Time to Early Half-Maximal Effect for Glucose Infusion Rate (tGIR[early50%]) | 43.8 Minutes | Standard Deviation 15.1 |
| Stage 2: Humulin-R Alone | Time to Early Half-Maximal Effect for Glucose Infusion Rate (tGIR[early50%]) | 104 Minutes | Standard Deviation 33.3 |
| Stage 2: Humulin-R + rHuPH20 | Time to Early Half-Maximal Effect for Glucose Infusion Rate (tGIR[early50%]) | 47.4 Minutes | Standard Deviation 13.1 |
p-value: 0.0002ANOVA
p-value: <0.0001ANOVA
Secondary
Time to Late Half-Maximal Effect for Glucose Infusion Rate (tGIR[late50%])
Time to late half-maximal effect for glucose infusion rate (tGIR\[late50%\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. Because the study was only 360 minutes in duration, there was not sufficient time for regular human insulin to show an effect and therefore tGIR(late50%) could not be calculated for participants receiving Humulin-R alone.
Time frame: Predose and up to 360 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, or Humulin-R + rHuPH20 with evaluable tGIR(late50%) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Time to Late Half-Maximal Effect for Glucose Infusion Rate (tGIR[late50%]) | 324 Minutes | Standard Deviation 32.9 |
| Stage 1: Humalog + rHuPH20 | Time to Late Half-Maximal Effect for Glucose Infusion Rate (tGIR[late50%]) | 275 Minutes | Standard Deviation 48 |
| Stage 2: Humulin-R Alone | Time to Late Half-Maximal Effect for Glucose Infusion Rate (tGIR[late50%]) | 282 Minutes | Standard Deviation 68 |
p-value: 0.3019ANOVA
Secondary
Time to Maximum Glucose Infusion Rate (tGIR[Max])
Time to maximal effect for glucose infusion rate (tGIR\[max\]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from blood samples obtained every 3 minutes during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period.
Time frame: Predose and up to 360 minutes postdose during Stage 1 or Stage 2
Population: Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable tGIR(max) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Humalog Alone | Time to Maximum Glucose Infusion Rate (tGIR[Max]) | 193 Minutes | Standard Deviation 58.2 |
| Stage 1: Humalog + rHuPH20 | Time to Maximum Glucose Infusion Rate (tGIR[Max]) | 114 Minutes | Standard Deviation 43 |
| Stage 2: Humulin-R Alone | Time to Maximum Glucose Infusion Rate (tGIR[Max]) | 253 Minutes | Standard Deviation 61.8 |
| Stage 2: Humulin-R + rHuPH20 | Time to Maximum Glucose Infusion Rate (tGIR[Max]) | 165 Minutes | Standard Deviation 51.2 |
p-value: 0.0059ANOVA
p-value: 0.0105ANOVA