Randomized, Double-blind, Crossover, Pharmacokinetic (PK) and Glucodynamic (GD) Study of Continuous Subcutaneous Insulin Infusion (CSII) in Participants With Type 1 Diabetes Mellitus (T1DM)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Halozyme Therapeutics

ClinicalTrials.gov Identifier:

NCT01275131

First received: January 10, 2011

Last updated: June 26, 2014

Last verified: June 2014

History of Changes

Results First Received: June 26, 2014

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Pharmacokinetics/Dynamics Study; Intervention Model: Crossover Assignment; Masking: Double Blind (Subject, Caregiver, Investigator); Primary Purpose: Basic Science
Condition:	Type 1 Diabetes Mellitus
Interventions:	Drug: Insulin aspart Drug: Recombinant human hyaluronidase PH20 (rHuPH20)

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20	Participants first received 0.15 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart and 5-micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8.
Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart	Participants first received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart alone as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8.
Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20	Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp. After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a 1.0 milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the 6-hr euglycemic clamp.
Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart	Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a 1.0 milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the 6-hr euglycemic clamp . After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp.

Participant Flow for 3 periods

Period 1: Period 1

	Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20	Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart	Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20	Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart
STARTED	11	9	13	12
Received at Least One Dose of Study Drug	11	9	13	12
COMPLETED	9	9	10	10
NOT COMPLETED	2	0	3	2
Withdrawal by Subject	1	0	3	2
Physician Decision	1	0	0	0

Period 2: 5- to 14-Day Washout Period

	Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20	Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart	Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20	Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart
STARTED	9	9	10	10
COMPLETED	9	9	10	10
NOT COMPLETED	0	0	0	0

Period 3: Period 2 (Crossover)

	Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20	Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart	Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20	Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart
STARTED	9	9	10	10
COMPLETED	8	8	9	8
NOT COMPLETED	1	1	1	2
Adverse Event	0	1	0	0
Withdrawal by Subject	1	0	1	2

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received at least one dose of study drug.

Reporting Groups

	Description
Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20	Participants first received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8.
Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart	Participants first received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart alone as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8.
Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20	Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp. After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a 1.0-milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to a 6-hr euglycemic clamp.
Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart	Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a 1.0-milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the euglycemic clamp . After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a sham injection was administered 2.5 hr prior to a 6-hr euglycemic clamp.
Total	Total of all reporting groups

Baseline Measures

	Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20	Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart	Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20	Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart	Total
Number of Participants [units: participants]	11	9	13	12	45
Age [units: Years] Mean (Standard Deviation)	31.3 (6.39)	44.6 (9.00)	35.5 (9.50)	32.3 (10.29)	35.44 (9.95)
Gender [units: Participants]
Female	6	3	7	6	22
Male	5	6	6	6	23
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0	0	0	0	0
Asian	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	0	1	1	2
White	11	9	11	11	42
More than one race	0	0	0	0	0
Unknown or Not Reported	0	0	1	0	1
Ethnicity (NIH/OMB) [units: Participants]
Hispanic or Latino	1	1	0	0	2
Not Hispanic or Latino	10	8	13	12	43
Unknown or Not Reported	0	0	0	0	0
Region of Enrollment [units: Participants]
United States	11	9	13	12	45

Outcome Measures

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1. Primary:

Early Insulin Exposure (%AUC[0-60]), Stage 1 [ Time Frame: 10 minutes predose up to 60 minutes postdose ]

Show Outcome Measure 1

2. Primary:

Early Exposure to Insulin (%AUC[0-60]), Stage 3 [ Time Frame: 10 minutes predose up to 60 minutes postdose on Days 2/7, 3/8, and 5/10 ]

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3. Secondary:

Maximum Glucose Infusion Rate (GIRmax), Stage 1 [ Time Frame: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 ]

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Measure Type	Secondary
Measure Title	Maximum Glucose Infusion Rate (GIRmax), Stage 1
Measure Description	Maximum glucose infusion rates (GIRmax) for Stage1 are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.
Time Frame	0 up to 360 minutes postdose on Day 2/6 and Day 4/8
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who completed all periods of study within a given stage with evaluable GIRmax data.

Reporting Groups

	Description
Stage 1: Insulin Aspart Alone	Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Day 6 and 8 of Period 2.
Stage 1: Insulin Aspart-rHuPH20	Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) administered together as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2.

Measured Values

	Stage 1: Insulin Aspart Alone	Stage 1: Insulin Aspart-rHuPH20
Number of Participants Analyzed [units: participants]	16	16
Maximum Glucose Infusion Rate (GIRmax), Stage 1 [units: Milligrams/kilogram/minute] Mean (Standard Deviation)
Stage 1, Day 2/6	13.37 (4.23)	12.51 (3.19)
Stage 1, Day 4/8	11.88 (3.64)	11.52 (3.67)

No statistical analysis provided for Maximum Glucose Infusion Rate (GIRmax), Stage 1

4. Secondary:

Maximum Glucose Infusion Rate (GIRmax), Stage 3 [ Time Frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 ]

Show Outcome Measure 4

5. Secondary:

Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1 [ Time Frame: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 ]

Show Outcome Measure 5

6. Secondary:

Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 [ Time Frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 ]

Show Outcome Measure 6

7. Secondary:

Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 [ Time Frame: 0 up to 360 minutes postdose on day 2/6 and Day 4/8 ]

Show Outcome Measure 7

8. Secondary:

Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 [ Time Frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 ]

Show Outcome Measure 8

9. Secondary:

Time to 50% Total Glucose Infused (50%Gtot), Stage 1 [ Time Frame: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 ]

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10. Secondary:

Time to 50% Total Glucose Infused (50%Gtot), Stage 3 [ Time Frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 ]

Show Outcome Measure 10

11. Secondary:

Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1 [ Time Frame: 30 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8 ]

Show Outcome Measure 11

12. Secondary:

Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 [ Time Frame: 30 minutes predose up to 360 minutes postdose Days 2/7, 3/8, and 5/10 ]

Show Outcome Measure 12

13. Secondary:

Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1 [ Time Frame: 10 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8 ]

Show Outcome Measure 13

14. Secondary:

Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 [ Time Frame: 10 minutes predose up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 ]

Show Outcome Measure 14

Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: No text entered.

Results Point of Contact:

Name/Title: Vice President, Endocrinology Clinical Development
Organization: Halozyme Therapeutics, Inc
phone: (858)794-8889

Responsible Party:	Halozyme Therapeutics
ClinicalTrials.gov Identifier:	NCT01275131 History of Changes
Other Study ID Numbers:	HALO-117-105
Study First Received:	January 10, 2011
Results First Received:	June 26, 2014
Last Updated:	June 26, 2014
Health Authority:	United States: Food and Drug Administration

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