Safety/Efficacy Study of Subcutaneously Injected Prandial Insulins Compared to Insulin Lispro Alone in Patients With Type 2 Diabetes Mellitus

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Halozyme Therapeutics
ClinicalTrials.gov Identifier:
NCT01194258
First received: August 31, 2010
Last updated: August 1, 2014
Last verified: August 2014
Results First Received: August 1, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Crossover Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Diabetes Mellitus, Type II
Interventions: Drug: Insulin lispro
Drug: Insulin aspart
Drug: Recombinant human hyaluronidase PH20
Drug: Insulin glulisine
Drug: Insulin glargine

  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
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study included an open-label titration period of at least 4 weeks and up to 6 weeks prior to randomization at Week 0.

Reporting Groups
  Description
All Enrolled Participants

Prior to randomization, all enrolled participants underwent a titration period of 4 to 6 weeks in which they received 100 U/mL insulin glulisine, injected SC, pre-meals, with doses titrated to each participant individually.

Participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.

Insulin Lispro, Then Lispro-PH20

Participants received a subcutaneous (SC) injection of 100 units per milliliter (U/mL) insulin lispro alone pre-meals for 12 weeks during Treatment Period 1 of the study.

Then, participants received a SC injection of 100 U insulin lispro and 5 micrograms (µg) recombinant human hyaluronidase PH20 (rHuPH20) (combined: Lispro-PH20) pre-meals for 12 weeks during Treatment Period 2 of the study.

Lispro-PH20, Then Insulin Lispro

Participants received a SC injection of 100 U/mL insulin lispro and 5 µg rHuPH20 (Lispro-PH20) pre-meals for 12 weeks during Treatment Period 1 of the study.

Then, participants received a SC injection of 100 U/mL insulin lispro alone pre-meals for 12 weeks during Treatment Period 2 of the study.

Insulin Lispro, Then Aspart-PH20

Participants received a SC injection of 100 U/mL insulin lispro alone pre-meals for 12 weeks during Treatment Period 1 of the study.

Then, participants received a SC injection of 100 U/mL insulin aspart and 5 µg rHuPH20 (combined: Aspart-PH20) pre-meals for 12 weeks during Treatment Period 2 of the study.

Aspart-PH20, Then Insulin Lispro

Participants received SC injection of 100 U/mL insulin aspart and 5 µg rHuPH20 (Aspart-PH20) pre-meals for 12 weeks during Treatment Period 1 of the study.

Then, participants received a SC injection of 100 U/mL insulin lispro alone pre-meals for 12 weeks during Treatment Period 2 of the study.


Participant Flow for 3 periods

Period 1:   Titration Period
    All Enrolled Participants     Insulin Lispro, Then Lispro-PH20     Lispro-PH20, Then Insulin Lispro     Insulin Lispro, Then Aspart-PH20     Aspart-PH20, Then Insulin Lispro  
STARTED     132     0     0     0     0  
COMPLETED     121     0     0     0     0  
NOT COMPLETED     11     0     0     0     0  
Withdrawal by Subject                 6                 0                 0                 0                 0  
Lost to Follow-up                 2                 0                 0                 0                 0  
Titration failure                 3                 0                 0                 0                 0  

Period 2:   Period 1 (12 Weeks)
    All Enrolled Participants     Insulin Lispro, Then Lispro-PH20     Lispro-PH20, Then Insulin Lispro     Insulin Lispro, Then Aspart-PH20     Aspart-PH20, Then Insulin Lispro  
STARTED     0 [1]   29 [2]   30 [3]   29 [4]   33 [5]
Received at Least 1 Dose of Study Drug     0     29     30     29     33  
COMPLETED     0     29     30     29     32  
NOT COMPLETED     0     0     0     0     1  
Death                 0                 0                 0                 0                 1  
[1] Participants were randomized to the Insulin lispro or an Analog-PH20 group after titration.
[2] After the titration phase, 29 participants were randomized to the Insulin lispro/Lispro-PH20 group.
[3] After the titration phase, 30 participants were randomized to the Lispro-PH20/Insulin lispro group.
[4] After the titration phase, 29 participants were randomized to the Insulin lispro/Aspart-PH20 group.
[5] After the titration phase, 33 participants were randomized to the Aspart-PH20/Insulin lispro group.

Period 3:   Period 2 (12 Weeks)
    All Enrolled Participants     Insulin Lispro, Then Lispro-PH20     Lispro-PH20, Then Insulin Lispro     Insulin Lispro, Then Aspart-PH20     Aspart-PH20, Then Insulin Lispro  
STARTED     0     29     30     29     32  
COMPLETED     0     27     29     29     30  
NOT COMPLETED     0     2     1     0     2  
Lost to Follow-up                 0                 0                 0                 0                 2  
Adverse Event                 0                 1                 0                 0                 0  
Withdrawal by Subject                 0                 1                 1                 0                 0  



  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 in the study, including those who were enrolled but were not randomized.

Reporting Groups
  Description
All Study Participants All participants in the study, including those who were enrolled but were not randomized.

Baseline Measures
    All Study Participants  
Number of Participants  
[units: participants]
  132  
Age  
[units: years]
Mean ± Standard Deviation
  58.7  ± 9.85  
Gender  
[units: participants]
 
Female     53  
Male     79  
Race (NIH/OMB)  
[units: participants]
 
American Indian or Alaska Native     0  
Asian     3  
Native Hawaiian or Other Pacific Islander     1  
Black or African American     10  
White     115  
More than one race     1  
Unknown or Not Reported     2  
Ethnicity (NIH/OMB)  
[units: participants]
 
Hispanic or Latino     19  
Not Hispanic or Latino     113  
Unknown or Not Reported     0  
Region of Enrollment  
[units: participants]
 
United States     132  



  Outcome Measures
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1.  Primary:   Change From Baseline in Glycosylated Hemoglobin A1C (HbA1C) at the End of Each Treatment Period   [ Time Frame: Baseline, Week 12 and Week 24 ]

Measure Type Primary
Measure Title Change From Baseline in Glycosylated Hemoglobin A1C (HbA1C) at the End of Each Treatment Period
Measure Description Change in glycosylated hemoglobin A1C (HbA1C) from baseline (Week 0) to end of treatment period (Week 12 and Week 24) is presented. Data are presented by combined treatment group (Lispro-recombinant human hyaluronidase PH20 (PH20) + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin lispro from both groups). Least squares (LS) means were calculated from linear contrasts of mixed effects linear models with treatment (Lispro, Aspart), PH20 (yes, no), and treatment sequence as fixed effects and participant within treatment sequence as a random effect.
Time Frame Baseline, Week 12 and Week 24  
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.
All participants who completed both Treatment Period 1 and Treatment Period 2 with evaluable HbA1C data.

Reporting Groups
  Description
Analog-PH20 100 U/mL insulin analog (insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
Insulin Lispro 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Measured Values
    Analog-PH20     Insulin Lispro  
Number of Participants Analyzed  
[units: participants]
  115     115  
Change From Baseline in Glycosylated Hemoglobin A1C (HbA1C) at the End of Each Treatment Period  
[units: percentage of HbA1C]
Mean ± Standard Deviation
  -0.48  ± 0.590     -0.46  ± 0.571  


Statistical Analysis 1 for Change From Baseline in Glycosylated Hemoglobin A1C (HbA1C) at the End of Each Treatment Period
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Mixed Models Analysis
P Value [4] 0.3876
LS Mean difference [5] -0.04
Standard Error of the mean ± 0.041
95% Confidence Interval ( -0.12 to 0.05 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Approximately 110 participants were planned to be enrolled to allow approximately 88 participants to complete both treatment periods. Assuming a dropout rate of ≤20%, an intra-participant correlation of 0.80, a standard deviation of 1.2, and a true difference of 0, the study would have >90% power to show that either Lispro-PH20 or Aspart-PH20 (each tested separately) was non-inferior to insulin lispro alone with respect to the change from baseline in A1C at the end of each treatment period.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Non-inferiority margin was set at 0.40.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.



2.  Secondary:   Mean Daily Insulin Dose as Recorded During 10-Point Glucose Monitoring   [ Time Frame: Week 10 and Week 22 ]

Measure Type Secondary
Measure Title Mean Daily Insulin Dose as Recorded During 10-Point Glucose Monitoring
Measure Description Mean daily insulin dose as recorded during 10-point glucose monitoring is reported. Blood glucose values were obtained during a total of 3 days during each treatment period (3 days during Week 10 of Treatment Period 1 and 3 days during Week 22 of Treatment Period 2) at the following timepoints: immediately prior to breakfast (fasting), 1 hour (hr) after breakfast, 2 hr after breakfast, immediately prior to lunch, 1 hr after lunch, 2 hr after lunch, immediately prior to dinner, 1 hr after dinner, 2 hr after dinner, and at 03:00. A minimum of 7 determinations were required for each day during the 3 days of 10-point glucose profiles. Prandial insulin doses were also recorded during the 10-point glucose monitoring and the mean daily insulin dose over the 3 days was calculated. Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts).
Time Frame Week 10 and Week 22  
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.
All participants who completed both Treatment Period 1 and Treatment Period 2 with evaluable insulin dosing data.

Reporting Groups
  Description
Analog-PH20 100 U/mL insulin analog (insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
Insulin Lispro 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Measured Values
    Analog-PH20     Insulin Lispro  
Number of Participants Analyzed  
[units: participants]
  104     107  
Mean Daily Insulin Dose as Recorded During 10-Point Glucose Monitoring  
[units: units of Insulin]
Mean ± Standard Deviation
  122.99  ± 67.150     127.47  ± 69.483  

No statistical analysis provided for Mean Daily Insulin Dose as Recorded During 10-Point Glucose Monitoring



3.  Secondary:   Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time   [ Time Frame: Baseline through Week 24, excluding 10-point glucose monitoring days ]

Measure Type Secondary
Measure Title Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time
Measure Description Participants were instructed to monitor their blood glucose levels a minimum of 4 times per day on all non-10-point glucose monitoring days. The number of participants meeting 90-minute postprandial plasma glucose (PPG) targets of <140 and <180 milligrams per deciliter (mg/dL) for at least 2/3 of values was recorded during non-10-point glucose monitoring was recorded. The number of participants was recorded, and the percentage of participants meeting glucose targets was calculated by the number of participants with values meeting the specified target at least 2/3 of the time by the total number of participants analyzed, multiplied by 100. Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts).
Time Frame Baseline through Week 24, excluding 10-point glucose monitoring days  
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 in Treatment Period 1 or Treatment Period 2 who received at least 1 dose of study drug and had evaluable postprandial blood glucose data.

Reporting Groups
  Description
Analog-PH20 100 U/mL insulin analog (insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
Insulin Lispro 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Measured Values
    Analog-PH20     Insulin Lispro  
Number of Participants Analyzed  
[units: participants]
  115     115  
Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time  
[units: Percentage of participants]
   
Overall 90-minute PPG <140 mg/dL     13.9     14.8  
PPG <140 mg/dL for breakfast     24.3     17.4  
PPG <140 mg/dL for lunch     28.7     26.1  
PPG <140 mg/dL for dinner     13.0     15.7  
Overall 90 minute PPG <180 mg/dL     71.3     74.8  
PPG <180 mg/dL for breakfast     70.4     65.2  
PPG <180 mg/dL for lunch     83.5     80.0  
PPG <180 mg/dL for dinner     67.0     70.4  

No statistical analysis provided for Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time



4.  Secondary:   Rates of Hypoglycemia at the End of Each Treatment Period   [ Time Frame: Week 12 and Week 24 ]

Measure Type Secondary
Measure Title Rates of Hypoglycemia at the End of Each Treatment Period
Measure Description The rate of hypoglycemia, defined as blood glucose levels ≤70 mg/dL and <56 mg/dL, was calculated based on 4 weeks of observation prior to the end of treatment period (that is, Week 12 and Week 24). Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin lispro from both groups). A summary of serious and other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Time Frame Week 12 and Week 24  
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.
All participants who completed both Treatment Period 1 and Treatment Period 2.

Reporting Groups
  Description
Analog-PH20 100 U/mL insulin analog (insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
Insulin Lispro 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Measured Values
    Analog-PH20     Insulin Lispro  
Number of Participants Analyzed  
[units: participants]
  115     115  
Rates of Hypoglycemia at the End of Each Treatment Period  
[units: Events per participant per month]
   
Blood glucose <70 mg/dL (n=111, n=113)     7.92     7.66  
Blood glucose <56 mg/dL (n=91, n=86)     1.99     1.78  

No statistical analysis provided for Rates of Hypoglycemia at the End of Each Treatment Period



5.  Secondary:   Change From Baseline in Body Weight at the End of Each Treatment Period   [ Time Frame: Baseline, Week 12 and Week 24 ]

Measure Type Secondary
Measure Title Change From Baseline in Body Weight at the End of Each Treatment Period
Measure Description Change from baseline in body weight at the end of each treatment period (Week 12 and Week 24) is presented. Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin lispro from both cohorts).
Time Frame Baseline, Week 12 and Week 24  
Safety Issue Yes  

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 completed both Period 1 and Period 2 with evaluable body weight data.

Reporting Groups
  Description
Analog-PH20 100 U/mL insulin analog (Insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
Insulin-lispro 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Measured Values
    Analog-PH20     Insulin-lispro  
Number of Participants Analyzed  
[units: participants]
  115     115  
Change From Baseline in Body Weight at the End of Each Treatment Period  
[units: pounds]
Mean ± Standard Deviation
  3.35  ± 5.466     3.44  ± 5.852  

No statistical analysis provided for Change From Baseline in Body Weight at the End of Each Treatment Period



6.  Secondary:   Mean Daily PPG Excursions   [ Time Frame: Week 10 and Week 22 ]

Measure Type Secondary
Measure Title Mean Daily PPG Excursions
Measure Description Participants performed 10-point glucose monitoring for a total of 3 days during each treatment period (3 days during Week 10 of Treatment Period 1 and 3 days during Week 22 of Treatment Period 2). Mean daily PPG excursions during 10-point glucose monitoring for breakfast, lunch, and dinner from Treatment Period 1 or Treatment Period 2 are presented. PPG refers to the change in glucose concentration before to after a meal. Data were collected 1 and 2 hours (hr) after each meal. Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (insulin lispro from both cohorts).
Time Frame Week 10 and Week 22  
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.
All participants who completed both Period 1 and Period 2 with evaluable PPG excursion data.

Reporting Groups
  Description
Analog-PH20 100 U/mL insulin analog (insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
Insulin Lispro 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Measured Values
    Analog-PH20     Insulin Lispro  
Number of Participants Analyzed  
[units: participants]
  105     107  
Mean Daily PPG Excursions  
[units: mg/dL]
Mean ± Standard Deviation
   
1 hr after breakfast excursion (n=105, n=107)     33.67  ± 34.480     40.38  ± 30.213  
2 hr after breakfast excursion (n=105, n=107)     16.64  ± 40.463     22.94  ± 33.514  
1 hr after lunch excursion (n=105, n=106)     18.47  ± 35.419     27.28  ± 30.075  
2 hr after lunch excursion (n=104, n=106)     20.76  ± 38.939     25.27  ± 34.288  
1 hr after dinner excursion (n=104, n=107)     21.24  ± 32.807     18.09  ± 28.869  
2 hr after dinner excursion (n=104, n=107)     12.72  ± 35.917     15.75  ± 36.104  

No statistical analysis provided for Mean Daily PPG Excursions




  Serious Adverse Events


  Other Adverse Events


  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
No text entered.


  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:
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
phone: 858-794-8889


No publications provided


Responsible Party: Halozyme Therapeutics
ClinicalTrials.gov Identifier: NCT01194258     History of Changes
Other Study ID Numbers: HALO-117-206
Study First Received: August 31, 2010
Results First Received: August 1, 2014
Last Updated: August 1, 2014
Health Authority: United States: Food and Drug Administration