Safety and Efficacy Study of Insulin Lispro Versus Insulin Aspart in Participants With Type 2 Diabetes on Insulin Pump Therapy

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT01474538
First received: November 15, 2011
Last updated: February 4, 2014
Last verified: February 2014
Results First Received: February 4, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Crossover Assignment;   Masking: Double Blind (Subject, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Type 2 Diabetes Mellitus
Interventions: Drug: Insulin Lispro
Drug: Insulin Aspart

  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
Insulin Lispro / Insulin Aspart Insulin lispro [100 units/milliliter (U/mL)] administered by continuous subcutaneous insulin infusion (CSII) pump for 16 weeks in Treatment Period 1, followed by insulin aspart (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 2.
Insulin Aspart / Insulin Lispro Insulin aspart (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 1, followed by insulin lispro (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 2.

Participant Flow for 2 periods

Period 1:   Treatment Period 1
    Insulin Lispro / Insulin Aspart     Insulin Aspart / Insulin Lispro  
STARTED     60     62  
Received at Least 1 Dose of Study Drug     60     62  
COMPLETED     57     58  
NOT COMPLETED     3     4  
Death                 1                 0  
Physician Decision                 1                 0  
Withdrawal by Subject                 1                 3  
Protocol Violation                 0                 1  

Period 2:   Treatment Period 2
    Insulin Lispro / Insulin Aspart     Insulin Aspart / Insulin Lispro  
STARTED     57     58  
Received at Least 1 Dose of Study Drug     57     58  
COMPLETED     51     56  
NOT COMPLETED     6     2  
Death                 1                 0  
Adverse Event                 1                 1  
Withdrawal by Subject                 2                 0  
Sponsor decision                 1                 0  
Physician Decision                 0                 1  
Protocol Violation                 1                 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 randomized participants who received at least 1 dose of study drug.

Reporting Groups
  Description
Insulin Lispro / Insulin Aspart Insulin lispro [100 units/milliliter (U/mL)] administered by continuous subcutaneous insulin infusion (CSII) pump for 16 weeks in Treatment Period 1, followed by insulin aspart (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 2.
Insulin Aspart / Insulin Lispro Insulin aspart (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 1, followed by insulin lispro (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 2.
Total Total of all reporting groups

Baseline Measures
    Insulin Lispro / Insulin Aspart     Insulin Aspart / Insulin Lispro     Total  
Number of Participants  
[units: participants]
  60     62     122  
Age  
[units: years]
Mean ± Standard Deviation
  58.73  ± 10.41     60.40  ± 9.72     59.58  ± 10.06  
Gender  
[units: participants]
     
Female     33     32     65  
Male     27     30     57  
Race (NIH/OMB)  
[units: participants]
     
American Indian or Alaska Native     1     0     1  
Asian     0     2     2  
Native Hawaiian or Other Pacific Islander     0     0     0  
Black or African American     5     5     10  
White     53     54     107  
More than one race     1     1     2  
Unknown or Not Reported     0     0     0  
Race/Ethnicity, Customized  
[units: participants]
     
Hispanic or Latino     2     1     3  
Not Hispanic or Latino     58     61     119  
Region of Enrollment  
[units: participants]
     
United States     60     62     122  



  Outcome Measures
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1.  Primary:   Glycosylated Hemoglobin A1C (HbA1c) at Endpoint   [ Time Frame: After 16 weeks of each treatment (Periods1 and 2) ]

Measure Type Primary
Measure Title Glycosylated Hemoglobin A1C (HbA1c) at Endpoint
Measure Description Hemoglobin A1c (HbA1c) is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over the last 8-12 weeks. Least Squares (LS) means were adjusted for treatment, period, sequence, thiazolidinedione use (Yes/No), baseline HbA1c (>8% or ≤8%) and participants.
Time Frame After 16 weeks of each treatment (Periods1 and 2)  
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 randomized participants who received at least 1 dose of study drug and had HbA1c measured at Week 16 of treatment Period 1 or 2. Participants were analyzed based on the treatment they received.

Reporting Groups
  Description
Insulin Lispro Insulin lispro [100 units/milliliter (U/mL)] administered by continuous subcutaneous insulin infusion (CSII) pump for 16 weeks in Treatment Period 1 or Treatment Period 2.
Insulin Aspart Insulin aspart (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 1 or Treatment Period 2.

Measured Values
    Insulin Lispro     Insulin Aspart  
Number of Participants Analyzed  
[units: participants]
  112     111  
Glycosylated Hemoglobin A1C (HbA1c) at Endpoint  
[units: percentage of glycosylated hemoglobin]
Least Squares Mean ± Standard Error
  7.50  ± 0.12     7.40  ± 0.12  


Statistical Analysis 1 for Glycosylated Hemoglobin A1C (HbA1c) at Endpoint
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Mixed Models Analysis
LS Mean difference [4] 0.10
95% Confidence Interval ( -0.002 to 0.210 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
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[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  If the upper limit of the 95% confidence interval (CI) was below 0.4%, lispro was declared non-inferior to aspart.
[3] Other relevant method information, such as adjustments or degrees of freedom:
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[4] Other relevant estimation information:
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2.  Secondary:   Total Daily Insulin Dose   [ Time Frame: Week 16 of each treatment (Periods 1 and 2) ]

Measure Type Secondary
Measure Title Total Daily Insulin Dose
Measure Description Total daily insulin dose was the average of the last 3 days total insulin dose immediately prior to the Week 16 (endpoint) visit of each treatment period. Least Squares (LS) means were adjusted for treatment, period, sequence, thiazolidinedione use (Yes/No), baseline Hemoglobin A1c (HbA1c) (>8% or ≤8%) and participants.
Time Frame Week 16 of each treatment (Periods 1 and 2)  
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 randomized participants who received at least 1 dose of study drug and had total daily insulin dose recorded during Treatment Period (TP) 1 or 2. If endpoint data was missing for a specific TP, last observation carried forward (LOCF) method was implemented for that respective TP. Participants were analyzed based on the treatment they received.

Reporting Groups
  Description
Insulin Lispro Insulin lispro [100 units/milliliter (U/mL)] administered by continuous subcutaneous insulin infusion (CSII) pump for 16 weeks in Treatment Period 1 or Treatment Period 2.
Insulin Aspart Insulin aspart (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 1 or Treatment Period 2.

Measured Values
    Insulin Lispro     Insulin Aspart  
Number of Participants Analyzed  
[units: participants]
  116     117  
Total Daily Insulin Dose  
[units: units of insulin]
Least Squares Mean ± Standard Error
  80.41  ± 4.78     80.69  ± 4.77  


Statistical Analysis 1 for Total Daily Insulin Dose
Groups [1] All groups
Method [2] Mixed Models Analysis
LS Mean difference [3] -0.28
95% Confidence Interval ( -2.92 to 2.35 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
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[2] Other relevant method information, such as adjustments or degrees of freedom:
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[3] Other relevant estimation information:
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3.  Secondary:   Rate of Hypoglycemic Events Per 30 Days   [ Time Frame: Baseline through 16 weeks of each treatment (Periods 1 and 2) ]

Measure Type Secondary
Measure Title Rate of Hypoglycemic Events Per 30 Days
Measure Description A hypoglycemic episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia, or has blood glucose concentration of ≤70 milligrams/deciliter [mg/dL (3.9 millimoles/liter (mmol/L)]. Least Squares (LS) means were adjusted for treatment, period, sequence, baseline hypoglycemic event rate, thiazolidinedione use (Yes/No) and baseline Hemoglobin A1c (HbA1c) (>8% or ≤8%).
Time Frame Baseline through 16 weeks of each treatment (Periods 1 and 2)  
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 randomized participants who received at least 1 dose of study drug. Participants were analyzed based on the treatment they received.

Reporting Groups
  Description
Insulin Lispro Insulin lispro [100 units/milliliter (U/mL)] administered by continuous subcutaneous insulin infusion (CSII) pump for 16 weeks in Treatment Period 1 or Treatment Period 2.
Insulin Aspart Insulin aspart (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 1 or Treatment Period 2.

Measured Values
    Insulin Lispro     Insulin Aspart  
Number of Participants Analyzed  
[units: participants]
  118     119  
Rate of Hypoglycemic Events Per 30 Days  
[units: hypoglycemic events per 30 days]
Least Squares Mean ± Standard Error
  2.24  ± 0.28     2.38  ± 0.29  


Statistical Analysis 1 for Rate of Hypoglycemic Events Per 30 Days
Groups [1] All groups
Method [2] Negative binomial
P Value [3] 0.522
LS Mean Ratio [4] 0.94
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
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4.  Secondary:   Change From Baseline in Weight   [ Time Frame: Baseline, Week 16 of treatment Periods 1 and 2 ]

Measure Type Secondary
Measure Title Change From Baseline in Weight
Measure Description Least Squares (LS) means were adjusted for treatment, period, sequence, thiazolidinedione use (Yes/No), baseline Hemoglobin A1c (HbA1c) (>8% or ≤8%), baseline weight and participants.
Time Frame Baseline, Week 16 of treatment Periods 1 and 2  
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 randomized participants who received at least 1 dose of study drug and had weight measured at baseline and Week 16 of Treatment Period 1 or 2. Participants were analyzed based on the treatment they received.

Reporting Groups
  Description
Insulin Lispro Insulin lispro [100 units/milliliter (U/mL)] administered by continuous subcutaneous insulin infusion (CSII) pump for 16 weeks in Treatment Period 1 or Treatment Period 2.
Insulin Aspart Insulin aspart (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 1 or Treatment Period 2.

Measured Values
    Insulin Lispro     Insulin Aspart  
Number of Participants Analyzed  
[units: participants]
  116     117  
Change From Baseline in Weight  
[units: kilograms (kg)]
Least Squares Mean ± Standard Error
  0.31  ± 0.53     0.89  ± 0.52  


Statistical Analysis 1 for Change From Baseline in Weight
Groups [1] All groups
Method [2] Grizzle Model
P Value [3] 0.216
LS Mean difference [4] -0.58
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
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[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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[4] Other relevant estimation information:
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5.  Secondary:   Percentage of Participants With Hypoglycemic Events   [ Time Frame: Baseline through 16 weeks of each treatment (Periods 1 and 2) ]

Measure Type Secondary
Measure Title Percentage of Participants With Hypoglycemic Events
Measure Description A hypoglycemic episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia, or has blood glucose concentration of ≤ 70 milligrams/deciliter [mg/dL (3.9 millimoles/liter (mmol/L)]. The percentage of participants is the total number of participants experiencing hypoglycemic events divided by number of participants in the treatment arm multiplied by 100.
Time Frame Baseline through 16 weeks of each treatment (Periods 1 and 2)  
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 randomized participants who received at least 1 dose of study drug. Participants were analyzed based on the treatment they received.

Reporting Groups
  Description
Insulin Lispro Insulin lispro [100 units/milliliter (U/mL)] administered by continuous subcutaneous insulin infusion (CSII) pump for 16 weeks in Treatment Period 1 or Treatment Period 2.
Insulin Aspart Insulin aspart (100 U/mL) administered by CSII pump for 16 weeks in Treatment Period 1 or Treatment Period 2.

Measured Values
    Insulin Lispro     Insulin Aspart  
Number of Participants Analyzed  
[units: participants]
  118     119  
Percentage of Participants With Hypoglycemic Events  
[units: percentage of participants]
  71.2     74.8  


Statistical Analysis 1 for Percentage of Participants With Hypoglycemic Events
Groups [1] All groups
Method [2] Prescott test
P Value [3] 0.471
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.




  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
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