Pharmacokinetic (PK), Pharmacodynamic (PD), and Safety Study of Subcutaneously Administered Humalog® With and Without Recombinant Human Hyaluronidase (rHuPH20)and Humulin-R® With and Without rHuPH20

• Sponsor: Halozyme Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00705536
• Collaborator: (none)
• Enrollment: 26
• Location: 1
• Arms: 4
• Duration (Months): 2
• Patients Per Site Per Month: 12.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: Humalog; Drug: Humulin-R; Drug: Recombinant human hyaluronidase PH20 (rHuPH20)	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Health Services Research
• Official Title: A Phase I, Randomized, Double-Blind Crossover Pharmacokinetic, Pharmacodynamic, and Safety Study of Subcutaneously Administered Humalog® (Insulin Lispro Injection; Rapid-Acting Insulin) With and Without Recombinant Human Hyaluronidase (rHuPH20) Versus Subcutaneously Administered Humulin R® (Regular Insulin Injection) With and Without rHuPH20
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Humalog first, then Humalog + rHuPH20 Humalog first, then Humalog + recombinant human hyaluronidase PH20 (rHuPH20) A single subcutaneous (SC) injection of 20 units (U) Humalog on Day 1 of the study, followed by a single SC injection of 20 U Humalog + 300 U rHuPH20 after a washout period of at least 6 days	Drug: Humalog; Other Names: Insulin lispro ; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20 HYLENEX
Active Comparator: Humalog + rHuPH20 first, then Humalog Humalog + recombinant human hyaluronidase PH20 (rHuPH20) first, then Humalog A single subcutaneous (SC) injection of 20 units (U) Humalog + 300 U rHuPH20 on Day 1 of the study, followed by a single SC injection of 20 U Humalog after a washout period of at least 6 days	Drug: Humalog; Other Names: Insulin lispro ; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20 HYLENEX
Active Comparator: Humulin-R first, then Humulin-R + rHuPH20 Humulin-R (recombinant human insulin) first, then Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20) A single subcutaneous (SC) injection of 20 units (U) Humulin-R on Day 1 of the study, followed by a single SC injection of 20 U Humulin-R + 240 U rHuPH20 after a washout period of at least 6 days	Drug: Humulin-R; Other Names: Humulin Recombinant human insulin ; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20 HYLENEX
Active Comparator: Humulin-R + rHuPH20 first, then Humulin-R Humulin-R (recombinant human insulin) + recombinant human hyaluronidase PH20 (rHuPH20) first, then Humulin-R A single subcutaneous (SC) injection of 20 units (U) Humulin-R + 240 U rHuPH20 on Day 1 of the study, followed by a single SC injection of 20 U Humulin-R after a washout period of at least 6 days	Drug: Humulin-R; Other Names: Humulin Recombinant human insulin ; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20 HYLENEX

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Diabetes and Glandular Disease Research, Inc.	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• Halozyme Therapeutics

Investigators

• Principal Investigator: Mark S. Kipnes, MD, Diabetes and Glandular Disease Research Associates Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Halozyme Therapeutics
• ClinicalTrials.gov Identifier: NCT00705536
• Other Study ID Numbers: HZ2-07-04
• First Posted: Jun 26, 2008
• Last Update Posted: Feb 26, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Halozyme Therapeutics: rHuPH20; Hyaluronidase; Insulin
• Additional relevant MeSH terms: Insulin; Insulin, Globin Zinc; Insulin Lispro

Study Results

Participant Flow

Arm/Group Title	Stage 1: Humalog First, Then Humalog + rHuPH20	Stage 1: Humalog + rHuPH20 First, Then Humalog	Stage 2: Humulin-R First, Then Humulin-R + rHuPH20	Stage 2: Humulin-R + rHuPH20 First, Then Humulin-R
Arm/Group Description	Stage 1 of the study: A single subcutaneous (SC) injection of 20 units (U) Humalog alone on Day 1 of Stage 1, followed by a washout period of at least 6 days. Then, a single SC injection of 20 U Humalog + 300 U recombinant human hyaluronidase PH20 (rHuPH20).	Stage 1 of the study: A single subcutaneous (SC) injection of 20 units (U) Humalog + 300 U recombinant human hyaluronidase PH20 (rHuPH20) on Day 1 of Stage 1, followed by a washout period of at least 6 days. Then, a single SC injection of 20 U Humalog alone.	Stage 2 of the study: A single subcutaneous (SC) injection of 20 units (U) Humulin-R alone on Day 1 of Stage 2, followed by a washout period of at least 6 days. Then, a single SC injection of 20 U Humulin-R + 240 U recombinant human hyaluronidase PH20 (rHuPH20).	Stage 2 of the study. A single subcutaneous (SC) injection of 20 units (U) Humulin-R + 240 U recombinant human hyaluronidase PH20 (rHuPH20) on Day 1 of Stage 2, followed by a washout period of at least 6 days. Then, a single SC injection of 20 U Humulin-R alone.
Period Title: Start Period 1
STARTED	6	6	7	7
Received at Least 1 Dose of Study Drug	6	6	7	7
COMPLETED	6	6	7	6
NOT COMPLETED	0	0	0	1
Period Title: Start Period 1
STARTED	6	6	7	6
COMPLETED	6	6	7	6
NOT COMPLETED	0	0	0	0
Period Title: Start Period 1
STARTED	6	6	7	6
COMPLETED	6	6	7	6
NOT COMPLETED	0	0	0	0
Period Title: Start Period 1
STARTED	6	6	7	6
COMPLETED	6	6	7	6
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Stage 1: Humalog Alone or Humalog + rHuPH20	Stage 2: Humulin-R Alone or Humulin-R + rHuPH20	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	12	14	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.7 (7.8)	36.7 (8.9)	37.2 (8.3)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	12 100%	14 100%	26 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 75%	10 71.4%	19 73.1%
Not Hispanic or Latino	3 25%	4 28.6%	7 26.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 25%	0 0%	3 11.5%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 16.7%	3 21.4%	5 19.2%
White	7 58.3%	11 78.6%	18 69.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%	14 100%	26 100%

Outcome Measures

1. Primary Outcome

Title	Time to Maximum Serum Insulin Concentration (Tmax)
Description	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

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable tmax data.

Arm/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Minutes]	97.5 (35.9)	48.0 (7.99)	163 (51.5)	67.8 (19.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: Humalog Alone, Stage 1: Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments	Treatment comparison of Humalog alone and Humalog + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Humulin-R Alone, Stage 2: Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Treatment comparison of Humulin-R alone and Humulin-R + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

2. Primary Outcome

Title	Maximum Serum Insulin Concentration (Cmax)
Description	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

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, Humulin-R alone, or Humulin-R + rHuPH20 with evaluable Cmax data.

Arm/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Picomoles per liter]	680 (361)	1290 (471)	390 (137)	944 (257)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: Humalog Alone, Stage 1: Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	Treatment comparison of Humalog alone and Humalog + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Humulin-R Alone, Stage 2: Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humulin-R alone and Humulin-R + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Time to Maximum Glucose Infusion Rate (tGIR[Max])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Minutes]	193 (58.2)	114 (43.0)	253 (61.8)	165 (51.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: Humalog Alone, Stage 1: Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0059
	Comments	Treatment comparison of Humalog alone and Humalog + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Humulin-R Alone, Stage 2: Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0105
	Comments	Treatment comparison of Humulin-R alone and Humulin-R + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Time to Early Half-Maximal Effect for Glucose Infusion Rate (tGIR[early50%])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1. Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20) : A single subcutaneous (SC) injection of 20 units (U) Humalog + 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Minutes]	72.3 (16.6)	43.8 (15.1)	104 (33.3)	47.4 (13.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: Humalog Alone, Stage 1: Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Treatment comparison for Humalog alone and Humalog + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Humulin-R Alone, Stage 2: Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humulin-R alone and Humulin-R + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Time to Late Half-Maximal Effect for Glucose Infusion Rate (tGIR[late50%])
Description	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

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + rHuPH20, or Humulin-R + rHuPH20 with evaluable tGIR(late50%) data.

Arm/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13
Mean (Standard Deviation) [Minutes]	324 (32.9)	275 (48.0)	282 (68.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: Humalog Alone, Stage 1: Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3019
	Comments	Treatment comparison for Humalog alone and Humalog + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

6. Primary Outcome

Title	Area Under the Serum Concentration-Time Curve From Time Zero to the Time Required to Reach Endogenous Plasma Glucose Levels (AUC[0-t'])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Picomoles per liter times minutes]	116000 (23000)	133000 (21800)	91400 (25700)	137000 (32800)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: Humalog Alone, Stage 1: Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0401
	Comments	Treatment comparison of Humalog alone and Humalog + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Humulin-R Alone, Stage 2: Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments	Treatment comparison of Humulin-R alone and Humulin-R + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

7. Primary Outcome

Title	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])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Picomoles per liter times minutes]	9530 (10500)	27900 (14300)	8780 (3010)	34800 (9150)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: Humalog Alone, Stage 1: Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog alone and Humalog +rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Humulin-R Alone, Stage 2: Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humulin-R alone and Humulin-R + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

8. Primary Outcome

Title	Relative Bioavailability (Area Under the Curve [AUC] for Insulin + Recombinant Human Hyaluronidase [rHuPH20] / AUC for Insulin Alone)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog + recombinant human hyaluronidase (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) of Humalog and 300 U of rHuPH20	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) of Humulin-R and 240 U of rHuPH20
Measure Participants	12	13
Mean (Standard Deviation) [Ratio of AUC(ins+rHuPH20)/AUC(ins alone)]	1.18 (0.221)	1.57 (0.406)

9. Secondary Outcome

Title	Maximum Glucose Infusion Rate (GIR[Max])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Milligrams per kilogram per minute]	8.11 (4.48)	8.57 (4.24)	7.82 (2.52)	10.5 (3.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1: Humalog Alone, Stage 1: Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5589
	Comments	Treatment comparison of Humalog alone and Humalog + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Humulin-R Alone, Stage 2: Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0067
	Comments	Treatment comparison of Humulin-R alone and Humulin-R + rHuPH20 using a pairwise t-test.
	Method	ANOVA
	Comments

10. Secondary Outcome

Title	Area Under the Glucose Infusion Rate Curve From 0 to 60 Minutes After Injection (AUC[GIR{0-60}])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Grams per kilogram]	82.8 (51.9)	167 (81.0)	74.3 (40.4)	180 (57.7)

11. Secondary Outcome

Title	Area Under the Glucose Infusion Rate Curve From 0 to 120 Minutes After Injection (AUC[GIR{0-120}])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Grams per kilogram]	393 (242)	597 (278)	281 (123)	637 (216)

12. Secondary Outcome

Title	Area Under the Glucose Infusion Rate Curve From 0 to 180 Minutes After Injection (AUC[GIR{0-180}])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Grams per kilogram]	801 (420)	1040 (501)	604 (262)	1150 (348)

13. Secondary Outcome

Title	Area Under the Glucose Infusion Rate Curve From 0 to 240 Minutes After Injection (AUC[GIR{0-240}])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin-R: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Grams per kilogram]	1240 (618)	1430 (706)	1010 (411)	1630 (467)

14. Secondary Outcome

Title	Area Under the Glucose Infusion Rate Curve From 0 to 360 Minutes After Injection (AUC[GIR{0-360}])
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Stage 1: Humalog Alone	Stage 1: Humalog + rHuPH20	Stage 2: Humulin-R Alone	Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Humalog: A single subcutaneous (SC) injection of 20 units (U)	Humalog + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humalog and 300 U rHuPH20	Humulin: A single subcutaneous (SC) injection of 20 units (U)	Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20): A single subcutaneous (SC) injection of 20 units (U) Humulin-R and 240 U rHuPH20
Measure Participants	12	12	13	13
Mean (Standard Deviation) [Grams per kilogram]	1940 (963)	1930 (988)	1860 (672)	2260 (611)

Adverse Events

Adverse Event Reporting Description	AEs were classified by the body system affected.
Arm/Group Title	Stage 1: Humalog Alone		Stage 1: Humalog + rHuPH20		Stage 2: Humulin-R Alone		Stage 2: Humulin-R + rHuPH20
Arm/Group Description	Participants randomized to treatment with a single subcutaneous (SC) injection of 20 units (U) Humalog alone during Stage 1 of the study		Participants randomized to treatment with a single subcutaneous (SC) injection of 20 units (U) Humalog + 300 U recombinant human hyaluronidase (rHuPH20) during Stage 1 of the study		Participants randomized to treatment with a single subcutaneous (SC) injection of 20 units (U) Humulin-R alone during Stage 2 of the study		Participants randomized to treatment with a single subcutaneous (SC) injection of 20 units (U) Humulin-R + 240 U recombinant human hyaluronidase (rHuPH20) during Stage 2 of the study
All Cause Mortality
	Stage 1: Humalog Alone		Stage 1: Humalog + rHuPH20		Stage 2: Humulin-R Alone		Stage 2: Humulin-R + rHuPH20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Stage 1: Humalog Alone		Stage 1: Humalog + rHuPH20		Stage 2: Humulin-R Alone		Stage 2: Humulin-R + rHuPH20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/13 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Stage 1: Humalog Alone		Stage 1: Humalog + rHuPH20		Stage 2: Humulin-R Alone		Stage 2: Humulin-R + rHuPH20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/12 (25%)		3/12 (25%)		2/13 (15.4%)		3/14 (21.4%)
General disorders
Infusion site pain	1/12 (8.3%)	1	3/12 (25%)	3	0/13 (0%)	0	1/14 (7.1%)	1
Infusion site reaction	0/12 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/14 (7.1%)	1
Influenza-like illness	0/12 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/14 (7.1%)	1
Injection site pruritus	0/12 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/14 (0%)	0
Chest discomfort	0/12 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/14 (7.1%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	0/12 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/14 (0%)	0
Nervous system disorders
Dysgeusia	1/12 (8.3%)	1	0/12 (0%)	0	0/13 (0%)	0	0/14 (0%)	0
Headache	1/12 (8.3%)	1	0/12 (0%)	0	0/13 (0%)	0	0/14 (0%)	0
Vascular disorders
Hematoma	0/12 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/14 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All information obtained as a result of this study or during the conduct of this study will be regarded as confidential. The investigator agrees to use the information for the purpose of carrying out this study and for no other purpose, unless written permission from the sponsor (Halozyme) is obtained.