Randomized, Double Blind, 2 Way Crossover Study of CSII With, Versus Without, Pretreatment With Human Hyaluronidase

• Sponsor: Halozyme Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01526733
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arms: 2
• Duration (Months): 21
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate consistency of accelerated insulin absorption and onset-of-action and shortened duration of action for bolus insulin infusions after pretreatment with 150 units (U) of Hylenex® (recombinant human hyaluronidase PH20 [rHuPH20]) injection at the time of infusion set insertion compared to sham injection.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: Sham Injection; Drug: Recombinant human hyaluronidase PH20; Drug: Insulin aspart; Drug: Insulin lispro	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 4, Randomized, Double-Blind, 2-Way Crossover Study of Continuous Subcutaneous Insulin Infusion (CSII) With, Compared to Without, Pretreatment With Recombinant Human Hyaluronidase (rHuPH20)
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Sham Comparator: Insulin (Aspart or Lispro)-Sham In Phase I or Phase II of the study, participants received 0.15 units per kilogram (U/kg) insulin (either insulin aspart or insulin lispro) as a continuous subcutaneous insulin infusion (CSII) for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.	Drug: Sham Injection; Drug: Insulin aspart; Other Names: Novolog Aspart ; Drug: Insulin lispro; Other Names: Humalog Lispro
Experimental: Insulin (Aspart or Lispro)-rHuPH20 In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of recombinant human hyaluronidase (rHuPH20). Each Phase was separated by a washout period of 5 to 21 days.	Drug: Recombinant human hyaluronidase PH20; Other Names: rHuPH20 PH20 Hylenex ; Drug: Insulin aspart; Other Names: Novolog Aspart ; Drug: Insulin lispro; Other Names: Humalog Lispro

Outcome Measures

Primary Outcome Measures

1. Early Insulin Exposure (%AUC[0-60]) [10 minutes predose; 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose on Days 1 and 4]

   Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve [AUC{0 360}]) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose during a euglycemic clamp.

Secondary Outcome Measures

1. Maximum Glucose Infusion Rate (GIRmax) [0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4]

   Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

2. Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax) [0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4]

   Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

3. Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) [0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4]

   Early and late tGIR50%max are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

4. Time to 50% Total Glucose Infused (50%Gtot) [0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4]

   Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

5. Area Under the Glucose Concentration Curve (AUC[0-360]) [30 minutes and 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4]

   Area under the glucose concentration curve from 0 to 360 minutes (AUC[0-360]) is presented. Blood samples were collected 30 and 10 minutes prior to insulin bolus and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

6. Duration of Insulin Action (AUMC[0-360]/AUC[0-360]) [10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4]

   Duration of insulin action was calculated by dividing the area under the first moment curve (AUMC[0-360]) by the area under the concentration versus time curve (AUC[0-360]). AUCM is the total area under the first moment curve. First moment curve is obtained by plotting concentration-time versus time. It can be used to measure how long a drug stays in the body. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males or females of age 18 to 65 years, inclusive. Females of child-bearing potential must use a standard and effective means of birth control for the duration of the study.

2. Non-smoking participants with Type 1 diabetes mellitus (T1DM) treated with insulin for ≥12 months. Nonsmoking means abstinence from cigarettes and cigars for 3 months and negative cotinine screening tests at screening.

3. Body mass index (BMI) 18.0 to 35.0 kilograms per meter squared (kg/m²), inclusive.

4. Glycosylated hemoglobin A1c (HbA1c) ≤10% based on local laboratory results.

5. Fasting connecting peptide of insulin (C-peptide) <0.6 nanograms per milliliter (ng/mL).

6. Current treatment with insulin <90 units per day (U/d).

7. Current use of rapid acting insulin analog.

8. Routine use of CSII as the primary route of insulin administration for at least 3 months prior to screening

9. Participants should be in good general health based on medical history and physical examination without medical conditions that might prevent the completion of study drug infusions and assessments required in the study protocol.

Exclusion Criteria:

1. Known or suspected allergy to any component of any of the study drugs in this study.

2. Previous enrollment in this study.

3. Use of drugs that may interfere with the interpretation of study results or are known to cause clinically relevant interference with insulin action, glucose utilization, or recovery from hypoglycemia. Participants taking maintenance doses of blood thinners (for example, coumadin or heparin) will be excluded.

4. Use of any long-acting insulin injection within 72 hours of Study Day 1; participants will continue to refrain from use throughout the duration of the study (Phases I and II).

5. Recurrent major hypoglycemia or hypoglycemic unawareness, as judged by the Investigator.

6. Current addiction to alcohol or substances of abuse as determined by the Investigator.

7. Blood donation or phlebotomy (>500 milliliters [mL]) within the previous 8 weeks of the Screening Visit(s) in this study.

8. Pregnancy, breastfeeding, the intention of becoming pregnant, or not using adequate contraceptive measures (adequate contraceptive measures consist of sterilization, intra-uterine device [IUD], oral or injectable contraceptives, or barrier methods).

9. Symptomatic gastroparesis.

10. Receipt of any investigational drug within 4 weeks of Study Day 1.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Profil Institute for Clinical Research	Chula Vista	California	United States	91911

Sponsors and Collaborators

• Halozyme Therapeutics

Investigators

• Principal Investigator: Linda Morrow, MD, Profil Institute for Clinical Research, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Sponsor's Website

Publications

None provided.

• Responsible Party: Halozyme Therapeutics
• ClinicalTrials.gov Identifier: NCT01526733
• Other Study ID Numbers: Halo-117-401
• First Posted: Feb 6, 2012
• Last Update Posted: Feb 26, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Halozyme Therapeutics: Type 1 Diabetes; Continuous Subcutaneous Insulin Infusion (CSII)
• Additional relevant MeSH terms: Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin Lispro

Study Results

Participant Flow

Arm/Group Title	Insulin-rHuPH20, Then Insulin-sham	Insulin-sham, Then Insulin-rHuPH20
Arm/Group Description	In Phase I, participants received 0.15 units per kilogram (U/kg) insulin (either insulin aspart or insulin lispro) as a continuous subcutaneous insulin infusion (CSII) for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 milliliter (mL) (150 U) injection of recombinant human hyaluronidase PH20 (rHuPH20). In Phase II, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with a sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Phase I and II were separated by a washout period of 5 to 21 days.	In Phase I, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with a sham injection administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. In Phase II, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Phase I and Phase II were separated by a washout period of 5 to 21 days.
Period Title: Phase 1
STARTED	12	13
Received at Least 1 Dose of Study Drug	12	13
COMPLETED	10	12
NOT COMPLETED	2	1
Period Title: Phase 1
STARTED	10	12
COMPLETED	10	12
NOT COMPLETED	0	0
Period Title: Phase 1
STARTED	10	12
COMPLETED	10	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Enrolled Participants
Arm/Group Description	All participants enrolled in the study.
Overall Participants	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.6 (9.13)
Sex: Female, Male (Count of Participants)
Female	14 56%
Male	11 44%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	2 8%
Black or African American	0 0%
White	23 92%
More than one race	0 0%
Unknown or Not Reported	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 8%
Not Hispanic or Latino	23 92%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	25 100%

Outcome Measures

1. Primary Outcome

Title	Early Insulin Exposure (%AUC[0-60])
Description	Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve [AUC{0 360}]) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose during a euglycemic clamp.
Time Frame	10 minutes predose; 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose on Days 1 and 4

Outcome Measure Data

Analysis Population Description

Participants who completed both phases of the study and with evaluable %AUC(0-60) data.

Arm/Group Title	Insulin (Aspart or Lispro)-rHuPH20	Insulin (Aspart or Lispro)-Sham
Arm/Group Description	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Measure Participants	21	21
Day 1	33.53 (11.81)	17.85 (8.24)
Day 4	39.45 (9.72)	33.52 (10.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin (Aspart or Lispro)-rHuPH20, Insulin (Aspart or Lispro)-Sham
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Comparison of Day 1 Insulin (Aspart or Lispro)-rHuPH20 versus Day 1 Insulin-sham.
	Method	Mixed Models Analysis
	Comments	A mixed model with fixed effects for treatment, day, and interaction of treatment with day was performed using a compound symmetric covariance matrix.
Method of Estimation	Estimation Parameter	Geometric Least Squares Mean Ratio
	Estimated Value	2.15
	Confidence Interval	(2-Sided) 90%; 1.71 to 2.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin (Aspart or Lispro)-rHuPH20, Insulin (Aspart or Lispro)-Sham
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Comparison of Day 4 Insulin (Aspart or Lispro)-rHuPH20 versus Day 1 Insulin-sham.
	Method	Mixed Models Analysis
	Comments	A mixed model with fixed effects for treatment, day, and interaction of treatment with day was performed using a compound symmetric covariance matrix.
Method of Estimation	Estimation Parameter	Geometric Least Squares Mean Ratio
	Estimated Value	2.62
	Confidence Interval	(2-Sided) 90%; 2.08 to 3.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Maximum Glucose Infusion Rate (GIRmax)
Description	Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time Frame	0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Outcome Measure Data

Analysis Population Description

Participants who completed both phases of the study and with evaluable GIRmax data.

Arm/Group Title	Insulin (Aspart or Lispro)-rHuPH20	Insulin (Aspart or Lispro)-Sham
Arm/Group Description	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Measure Participants	21	21
Day 1	13.47 (5.46)	11.14 (4.21)
Day 4	10.75 (3.73)	11.83 (3.26)

3. Secondary Outcome

Title	Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax)
Description	Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time Frame	0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Outcome Measure Data

Analysis Population Description

Participants who completed both phases of the study and with evaluable tGIRmax data.

Arm/Group Title	Insulin (Aspart or Lispro)-rHuPH20	Insulin (Aspart or Lispro)-Sham
Arm/Group Description	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Measure Participants	21	21
Day 1	78.95 (37.16)	132.62 (55.07)
Day 4	81.86 (45.99)	97.38 (47.31)

4. Secondary Outcome

Title	Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max)
Description	Early and late tGIR50%max are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time Frame	0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Outcome Measure Data

Analysis Population Description

Participants who completed both phases of the study and with evaluable early and late tGIR50%max data.

Arm/Group Title	Insulin (Aspart or Lispro)-rHuPH20	Insulin (Aspart or Lispro)-Sham
Arm/Group Description	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Measure Participants	21	21
Early tGIR50%, Day 1	40.33 (20.13)	54.67 (33.97)
Late tGIR50%, Day 1	114.52 (54.33)	152.14 (61.00)
Early tGIR50%, Day 4	32.57 (14.50)	39.67 (15.51)
Late tGIR50%, Day 4	113.24 (48.72)	126.71 (50.37)

5. Secondary Outcome

Title	Time to 50% Total Glucose Infused (50%Gtot)
Description	Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time Frame	0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Outcome Measure Data

Analysis Population Description

Participants who completed both phases of the study and with evaluable 50%Gtot data.

Arm/Group Title	Insulin (Aspart or Lispro)-rHuPH20	Insulin (Aspart or Lispro)-Sham
Arm/Group Description	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Measure Participants	21	21
Day 1	40.33 (20.13)	32.57 (14.50)
Day 4	54.67 (54.67)	39.67 (15.51)

6. Secondary Outcome

Title	Area Under the Glucose Concentration Curve (AUC[0-360])
Description	Area under the glucose concentration curve from 0 to 360 minutes (AUC[0-360]) is presented. Blood samples were collected 30 and 10 minutes prior to insulin bolus and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time Frame	30 minutes and 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Outcome Measure Data

Analysis Population Description

Participants who completed both phases of the study and with evaluable AUC(0-360) data.

Arm/Group Title	Insulin (Aspart or Lispro)-rHuPH20	Insulin (Aspart or Lispro)-Sham
Arm/Group Description	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Measure Participants	21	21
Day 1	1312.41 (627.33)	1199.54 (535.80)
Day 4	1063.77 (500.06)	1139.65 (414.94)

7. Secondary Outcome

Title	Duration of Insulin Action (AUMC[0-360]/AUC[0-360])
Description	Duration of insulin action was calculated by dividing the area under the first moment curve (AUMC[0-360]) by the area under the concentration versus time curve (AUC[0-360]). AUCM is the total area under the first moment curve. First moment curve is obtained by plotting concentration-time versus time. It can be used to measure how long a drug stays in the body. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time Frame	10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Outcome Measure Data

Analysis Population Description

Participants who completed both phases of the study and with evaluable AUMC(0-360)/AUC(0-360) data.

Arm/Group Title	Insulin (Aspart or Lispro)-rHuPH20	Insulin (Aspart or Lispro)-Sham
Arm/Group Description	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Measure Participants	21	21
Day 1	119.02 (21.18)	154.03 (27.58)
Day 4	111.25 (20.59)	120.57 (20.85)

Adverse Events

Adverse Event Reporting Description	Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Arm/Group Title	Insulin (Aspart or Lispro)-rHuPH20		Insulin (Aspart or Lispro)-Sham
Arm/Group Description	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.		In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
All Cause Mortality
	Insulin (Aspart or Lispro)-rHuPH20		Insulin (Aspart or Lispro)-Sham
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Insulin (Aspart or Lispro)-rHuPH20		Insulin (Aspart or Lispro)-Sham
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Insulin (Aspart or Lispro)-rHuPH20		Insulin (Aspart or Lispro)-Sham
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/24 (54.2%)		9/23 (39.1%)
Blood and lymphatic system disorders
Anaemia	2/24 (8.3%)		4/23 (17.4%)
Gastrointestinal disorders
Nausea	2/24 (8.3%)		1/23 (4.3%)
Vomiting	2/24 (8.3%)		0/23 (0%)
Constipation	1/24 (4.2%)		0/23 (0%)
General disorders
Injection site pain	3/24 (12.5%)		1/23 (4.3%)
Injection site pruritus	1/24 (4.2%)		2/23 (8.7%)
Injection site haemorrhage	1/24 (4.2%)		0/23 (0%)
Injection site haematoma	1/24 (4.2%)		0/23 (0%)
Injection site induration	1/24 (4.2%)		0/23 (0%)
Injection site inflammation	0/24 (0%)		1/23 (4.3%)
Tenderness	0/24 (0%)		1/23 (4.3%)
Infections and infestations
Upper respiratory tract infection	1/24 (4.2%)		1/23 (4.3%)
Injury, poisoning and procedural complications
Clavicle fracture	0/24 (0%)		1/23 (4.3%)
Sunburn	1/24 (4.2%)		0/23 (0%)
Musculoskeletal and connective tissue disorders
Neck pain	0/24 (0%)		1/23 (4.3%)
Nervous system disorders
Headache	2/24 (8.3%)		3/23 (13%)
Respiratory, thoracic and mediastinal disorders
Cough	1/24 (4.2%)		0/23 (0%)
Dysphonia	1/24 (4.2%)		0/23 (0%)
Oropharyngeal pain	1/24 (4.2%)		0/23 (0%)
Skin and subcutaneous tissue disorders
Ecchymosis	1/24 (4.2%)		0/23 (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 prior written permission from the Sponsor (Halozyme) is obtained.