Trial Outcomes & Findings for Liquid Meal Study With Insulin Lispro With/Without Recombinant Human Hyaluronidase PH20 (rHuPH20) and Regular Human Insulin With rHuPH20 to Compare Pharmacokinetics, Postprandial Glycemic Response, and Optimal Insulin Dose in Participants With Type 2 Diabetes Mellitus (T2DM) (NCT NCT00916357)

Last Updated: 2014-08-18

Results Overview

Postprandial glucose (PPG) values in participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal are reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug. Least square mean difference was calculated and tested using repeated measures analysis of variance with fixed effect for treatment.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

23 participants

Primary outcome timeframe

Predose up to 480 minutes after study drug injection

Results posted on

2014-08-18

Participant Flow

Participant milestones

Participant milestones
Measure	Humalog, Then Humalog + rHuPH20, Then Humulin-R + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout period), followed by a SC injection of the appropriate dose of Humalog. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with up to 0.3- to 0.5-U/kg Humalog + 3.75 nanograms/kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20). The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	Humalog, Then Humulin-R + rHuPH20, Then Humalog + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 nanograms/kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20). The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	Humalog + rHuPH20, Then Humalog, Then Humulin-R + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog alone. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period	Humalog + rHuPH20, Then Humulin-R + rHuPH20, Then Humalog A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humulin-R + rHuPH20. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog following a 3- to 14-day washout period.	Humulin-R + rHuPH20, Then Humalog, Then Humalog + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog alone. The DF process and injection of appropriate dose was then repeated with 0.3-to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	Humulin-R + rHuPH20, Then Humalog + rHuPH20, Then Humalog A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog alone following a 3- to 14-day washout period.
Period 1 STARTED	4	4	4	4	3	4
Period 1 Received at Least 1 Dose of Study Drug	4	4	4	4	3	4
Period 1 COMPLETED	3	4	4	4	3	4
Period 1 NOT COMPLETED	1	0	0	0	0	0
Washout (3 to 14 Days) STARTED	3	4	4	3	3	4
Washout (3 to 14 Days) COMPLETED	3	4	4	3	3	4
Washout (3 to 14 Days) NOT COMPLETED	0	0	0	0	0	0
Period 2 STARTED	3	4	4	4	3	4
Period 2 COMPLETED	3	4	4	3	3	4
Period 2 NOT COMPLETED	0	0	0	1	0	0
Period 3 STARTED	3	4	4	3	3	4
Period 3 COMPLETED	3	4	4	3	3	4
Period 3 NOT COMPLETED	0	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Humalog, Then Humalog + rHuPH20, Then Humulin-R + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout period), followed by a SC injection of the appropriate dose of Humalog. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with up to 0.3- to 0.5-U/kg Humalog + 3.75 nanograms/kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20). The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	Humalog, Then Humulin-R + rHuPH20, Then Humalog + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 nanograms/kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20). The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	Humalog + rHuPH20, Then Humalog, Then Humulin-R + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog alone. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period	Humalog + rHuPH20, Then Humulin-R + rHuPH20, Then Humalog A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humulin-R + rHuPH20. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog following a 3- to 14-day washout period.	Humulin-R + rHuPH20, Then Humalog, Then Humalog + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog alone. The DF process and injection of appropriate dose was then repeated with 0.3-to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	Humulin-R + rHuPH20, Then Humalog + rHuPH20, Then Humalog A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog alone following a 3- to 14-day washout period.
Period 1 Withdrawal by Subject	1	0	0	0	0	0
Period 2 Weight loss > 3 kilograms (kg)	0	0	0	1	0	0

Baseline Characteristics

Liquid Meal Study With Insulin Lispro With/Without Recombinant Human Hyaluronidase PH20 (rHuPH20) and Regular Human Insulin With rHuPH20 to Compare Pharmacokinetics, Postprandial Glycemic Response, and Optimal Insulin Dose in Participants With Type 2 Diabetes Mellitus (T2DM)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Overall Study n=23 Participants Participants who received at least 1 dose of Humalog, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 during dose-finding (DV) visits or experimental (data gathering) visits.
Age, Continuous	52.2 Years (yr) STANDARD_DEVIATION 8.07 • n=93 Participants
Sex: Female, Male Female	9 Participants n=93 Participants
Sex: Female, Male Male	14 Participants n=93 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants n=93 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants n=93 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=93 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=93 Participants
Race (NIH/OMB) Black or African American	4 Participants n=93 Participants
Race (NIH/OMB) White	17 Participants n=93 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Region of Enrollment United States	23 Participants n=93 Participants

PRIMARY outcome

Timeframe: Predose up to 480 minutes after study drug injection

Population: Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable postprandial glucose (PPG) excursion data.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Postprandial Glucose (PPG) Excursion Following a Liquid Meal 60-minute PPG	162.71 Milligrams per deciliter (mg/dL) Standard Deviation 32.28	144.67 Milligrams per deciliter (mg/dL) Standard Deviation 28.08	169.38 Milligrams per deciliter (mg/dL) Standard Deviation 28.64
Postprandial Glucose (PPG) Excursion Following a Liquid Meal 90-minute PPG	166.05 Milligrams per deciliter (mg/dL) Standard Deviation 34.53	143.62 Milligrams per deciliter (mg/dL) Standard Deviation 30.75	166.71 Milligrams per deciliter (mg/dL) Standard Deviation 33.83
Postprandial Glucose (PPG) Excursion Following a Liquid Meal 120-minute PPG	159.10 Milligrams per deciliter (mg/dL) Standard Deviation 30.73	138.24 Milligrams per deciliter (mg/dL) Standard Deviation 32.34	159.90 Milligrams per deciliter (mg/dL) Standard Deviation 39.56
Postprandial Glucose (PPG) Excursion Following a Liquid Meal CBGMax(0-4hr)	177.81 Milligrams per deciliter (mg/dL) Standard Deviation 33.46	165.38 Milligrams per deciliter (mg/dL) Standard Deviation 21.39	181.62 Milligrams per deciliter (mg/dL) Standard Deviation 31.61

SECONDARY outcome

Timeframe: Predose up to 480 minutes after study drug injection

Population: Participants who received at least one dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable maximum serum insulin concentration (Cmax) data.

Maximum serum insulin concentration (Cmax) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Maximum Serum Insulin Concentration (Cmax)	3329.49 Picomoles per liter (pm/L) Standard Deviation 1090.02	5661.92 Picomoles per liter (pm/L) Standard Deviation 1307.75	3011.56 Picomoles per liter (pm/L) Standard Deviation 962.31

SECONDARY outcome

Timeframe: Predose up to 480 minutes after study drug injection

Population: Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable time to maximum serum insulin concentration (Tmax) data.

Time to maximum serum insulin concentration (Tmax) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Time To Maximum Serum Insulin Concentration (Tmax)	74.29 Minutes (min) Standard Deviation 36.27	43.10 Minutes (min) Standard Deviation 16.01	81.67 Minutes (min) Standard Deviation 40.26

SECONDARY outcome

Timeframe: Predose up to 120 minutes after study drug injection

Time to early 50% maximum serum insulin concentration (early\[t50%\]) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, and 120 minutes after injection of each study drug.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Time to Early 50% Maximum Serum Insulin Concentration (Early[t50%])	27.02 Minutes (min) Standard Deviation 8.67	18.71 Minutes (min) Standard Deviation 5.80	21.46 Minutes (min) Standard Deviation 8.19

SECONDARY outcome

Timeframe: Predose up to 480 minutes after study drug injection

Time to late 50% maximum serum insulin concentration (late\[t50%\]) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Time to Late 50% Maximum Serum Insulin Concentration (Late[t50%])	206.86 Minutes (min) Standard Deviation 41.66	123.93 Minutes (min) Standard Deviation 44.59	220.33 Minutes (min) Standard Deviation 51.98

SECONDARY outcome

Timeframe: Predose up to 480 minutes after study drug injection

Population: Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable mean residence time from time 0 to the end of blood sampling (MRT\[last\]) data.

Mean residence time from time 0 to the end of blood sampling (MRT\[last\]) for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Mean Residence Time From Time 0 to the End of Blood Sampling (MRT[Last])	148.79 Minutes (min) Standard Deviation 22.46	108.23 Minutes (min) Standard Deviation 20.56	150.24 Minutes (min) Standard Deviation 27.32

SECONDARY outcome

Timeframe: Predose up to 480 minutes after study drug injection

Population: Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable area under the concentration time-curve for serum insulin from time 0 to the end of blood sampling (AUC\[last\]) data.

Area under the concentration time-curve for serum insulin from time 0 to the end of blood sampling (AUC\[last\]) for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 during a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug. Least squares mean difference was calculated and tested using repeated measures analysis of variance with fixed effect for treatment.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Area Under the Concentration Time-Curve for Serum Insulin From Time 0 to the End of Blood Sampling (AUC[Last])	578.67 Minutes * picomoles /1000 (min*pm/1000) Standard Deviation 144.66	668.33 Minutes * picomoles /1000 (min*pm/1000) Standard Deviation 146.52	571.42 Minutes * picomoles /1000 (min*pm/1000) Standard Deviation 132.04

SECONDARY outcome

Timeframe: Predose up to 480 minutes after study drug injection

Population: Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable area under the time-concentration curve for blood glucose (AUC\[BG\]) data.

Area under the time-concentration curve for blood glucose (AUC\[BG\]) for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), and Humulin-R + rHuPH20 following a liquid meal is reported. AUC(BG) values are reported for participants whose blood glucose (BG) was elevated higher than 160 milligrams per deciliter (mg/dL) or 140 mg/dL, or lower than 70 mg/dL within 4 hours of consuming a liquid meal. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug. Least squares mean difference was calculated and tested using repeated measures analysis of variance with fixed effect for treatment.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Area Under the Time-Concentration Curve for Blood Glucose (AUC[BG]) AUC(BG) >160 mg/dL	2017.46 Milligrams per deciliter * minutes Standard Deviation 2811.82	722.82 Milligrams per deciliter * minutes Standard Deviation 1030.52	2509.65 Milligrams per deciliter * minutes Standard Deviation 3332.36
Area Under the Time-Concentration Curve for Blood Glucose (AUC[BG]) AUC(BG) >140 mg/dL	4233.71 Milligrams per deciliter * minutes Standard Deviation 4383.35	2696.54 Milligrams per deciliter * minutes Standard Deviation 2548.03	4905.92 Milligrams per deciliter * minutes Standard Deviation 4829.71
Area Under the Time-Concentration Curve for Blood Glucose (AUC[BG]) AUC(BG) <70 mg/dL	571.20 Milligrams per deciliter * minutes Standard Deviation 850.07	197.00 Milligrams per deciliter * minutes Standard Deviation 480.75	408.50 Milligrams per deciliter * minutes Standard Deviation 602.29

SECONDARY outcome

Timeframe: Predose up to 480 minutes after study drug injection

Population: Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable minimum postprandial glucose (PPG) data.

Minimum postprandial glucose (PPG) in participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Minimum Postprandial Glucose (PPG)	76.38 Milligrams per deciliter (mg/dL) Standard Deviation 22.58	88.52 Milligrams per deciliter (mg/dL) Standard Deviation 27.37	75.62 Milligrams per deciliter (mg/dL) Standard Deviation 20.15

SECONDARY outcome

Timeframe: Predose up to 480 minutes after study drug injection

Population: Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20.

Percentage of participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 who did not experience hypoglycemia following a liquid meal is reported. Hypoglycemia was defined as any blood glucose values lower than 70 milligrams per deciliter (mg/dL) or symptoms of hypoglycemia responding to treatment with glucose. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Percentage of Participants Without Hypoglycemia	81.0 Percentage of participants	71.4 Percentage of participants	71.4 Percentage of participants

SECONDARY outcome

Timeframe: Predose up to 480 minutes following after injection of study drug

Time to percentage of exposure to insulin, as measured by area under the curve (AUC), following a liquid meal for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

Outcome measures

Outcome measures
Measure	Humalog Alone n=21 Participants Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20 n=21 Participants Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20 n=21 Participants Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Time to Percentage of Insulin Exposure (as Measured by Area Under the Curve [AUC]) Time to 10% Insulin Exposure	46.05 Minutes (min) Standard Deviation 8.98	30.49 Minutes (min) Standard Deviation 7.13	43.41 Minutes (min) Standard Deviation 10.21
Time to Percentage of Insulin Exposure (as Measured by Area Under the Curve [AUC]) Time to 50% Insulin Exposure	135.73 Minutes (min) Standard Deviation 21.18	94.49 Minutes (min) Standard Deviation 20.06	137.52 Minutes (min) Standard Deviation 27.35

Adverse Events

Humalog Alone

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Humalog + rHuPH20

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Humulin-R + rHuPH20

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Humalog Alone n=22 participants at risk Participants who received a subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout period), followed by a SC injection of the appropriate dose of Humalog during Periods 1, 2, or 3 of the study.	Humalog + rHuPH20 n=22 participants at risk Participants who received a subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20 during Periods 1, 2, or 3 of the study.	Humulin-R + rHuPH20 n=22 participants at risk Participants who received a subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20 during Periods 1, 2, or 3 of the Study
Infections and infestations Urosepsis	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Infections and infestations Pyelonephritis acute	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Metabolism and nutrition disorders Dehydration	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Renal and urinary disorders Nephrolithiasis	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Renal and urinary disorders Renal colic	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Renal and urinary disorders Ureteric obstruction	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.

Other adverse events

Additional Information

Vice President, Endocrinology Clinical Development

Halozyme

Phone: 858-794-8889

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Humalog Alone n=22 participants at risk Participants who received a subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout period), followed by a SC injection of the appropriate dose of Humalog during Periods 1, 2, or 3 of the study.	Humalog + rHuPH20 n=22 participants at risk Participants who received a subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20 during Periods 1, 2, or 3 of the study.	Humulin-R + rHuPH20 n=22 participants at risk Participants who received a subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20 during Periods 1, 2, or 3 of the Study
Injury, poisoning and procedural complications Limb injury	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 2 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Injury, poisoning and procedural complications Skin laceration	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Gastrointestinal disorders Nausea	9.1% 2/22 • Number of events 2 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.
General disorders Injection site pain	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.
Gastrointestinal disorders Diarrhoea	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Gastrointestinal disorders Abdominal pain	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.
Infections and infestations Influenza	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Nervous system disorders Headache	13.6% 3/22 • Number of events 4 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	9.1% 2/22 • Number of events 4 Adverse events were classified by the body system affected.
Surgical and medical procedures Tooth extraction	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Musculoskeletal and connective tissue disorders Arthralgia	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
General disorders Injection site erythema	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
General disorders Induration	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Musculoskeletal and connective tissue disorders Nodule on extremity	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Infections and infestations Rhinitis	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
General disorders Asthenia	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Gastrointestinal disorders Vomiting	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.
Infections and infestations Nasopharyngitis	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.
General disorders Pyrexia	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.
Musculoskeletal and connective tissue disorders Coccydynia	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.
Nervous system disorders Dizziness	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.
Infections and infestations Oral herpes	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.
Infections and infestations Upper respiratory tract infection	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	9.1% 2/22 • Number of events 2 Adverse events were classified by the body system affected.
Skin and subcutaneous tissue disorders Erythema	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/22 Adverse events were classified by the body system affected.	0.00% 0/22 Adverse events were classified by the body system affected.	4.5% 1/22 • Number of events 1 Adverse events were classified by the body system affected.