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

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ClinicalTrials.gov Identifier: NCT01275131
Recruitment Status : Completed
First Posted : January 12, 2011
Results First Posted : July 25, 2014
Last Update Posted : July 25, 2014
Sponsor:
Information provided by (Responsible Party):
Halozyme Therapeutics

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Basic Science
Condition: Type 1 Diabetes Mellitus
Interventions: Drug: Insulin aspart
Drug: Recombinant human hyaluronidase PH20 (rHuPH20)

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

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

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 
Overall Participants Analyzed 
[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

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 ]
  Show Outcome Measure 2

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 ]
  Hide Outcome Measure 3

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  

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 
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 ]
  Show Outcome Measure 9

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


  Other Adverse Events


  Limitations and Caveats

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
No text entered.


  More Information

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:
unchecked 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.
unchecked 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.


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
First Submitted: January 10, 2011
First Posted: January 12, 2011
Results First Submitted: June 26, 2014
Results First Posted: July 25, 2014
Last Update Posted: July 25, 2014