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Effect of Insulin Glulisine Compared to Insulin Aspart and Insulin Lispro When Administered by Continuous Subcutaneous Insulin Infusion (CSII) on Specific Pump Parameters in Patient With Type 1 Diabetes Mellitus (PUMP)

This study has been completed.
Sponsor:
Information provided by:
Sanofi
ClinicalTrials.gov Identifier:
NCT00607087
First received: January 23, 2008
Last updated: August 26, 2010
Last verified: August 2010
History of Changes
Results First Received: June 30, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Crossover Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Diabetes Mellitus, Type 1
Interventions: Drug: Insulin glulisine
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
Multicenter study: 44 active centers from 12 countries in Europe, USA and Asia Pacific region. Study Initiation date: January 8, 2008, Study Completion Date: June 15, 2009.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

359 participants screened; 289 randomized; 288 patients treated (1 patient not treated per physician's decision): 274 with insulin glulisine, 269 with insulin lispro, 266 with insulin aspart.

The safety population, (N=288 patients randomized and treated) is described in the participant flow and baseline characteristics.

Reporting Groups
  Description
Sequence 1 insulin glulisine / insulin aspart / insulin lispro
Sequence 2 insulin aspart / insulin lispro / insulin glulisine
Sequence 3 insulin lispro / insulin glulisine / insulin aspart

Participant Flow for 4 periods

 Period 1:   Overall Study
    Sequence 1     Sequence 2     Sequence 3  
STARTED     99     95     94  
COMPLETED     84     84     84  
NOT COMPLETED     15     11     10  
Withdrawal by Subject                 9                 4                 4  
Adverse Event                 3                 2                 3  
Other reason                 1                 5                 2  
Poor compliance to protocol                 1                 0                 1  
Lost to Follow-up                 1                 0                 0  

Period 2:   Period 1
    Sequence 1     Sequence 2     Sequence 3  
STARTED     99     95     94  
COMPLETED     87     89     89  
NOT COMPLETED     12     6     5  
Withdrawal by Subject                 7                 2                 3  
Adverse Event                 3                 0                 0  
Poor compliance to protocol                 1                 0                 0  
Lost to Follow-up                 1                 0                 0  
Other reason                 0                 4                 2  

Period 3:   Period 2
    Sequence 1     Sequence 2     Sequence 3  
STARTED     87     89     89  
COMPLETED     86     86     84  
NOT COMPLETED     1     3     5  
Withdrawal by Subject                 0                 1                 1  
Other reason                 1                 1                 0  
Adverse Event                 0                 1                 3  
Poor compliance to protocol                 0                 0                 1  

Period 4:   Period 3
    Sequence 1     Sequence 2     Sequence 3  
STARTED     86     86     84  
COMPLETED     84     84     84  
NOT COMPLETED     2     2     0  
Withdrawal by Subject                 2                 1                 0  
Adverse Event                 0                 1                 0  



  Baseline Characteristics
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Reporting Groups
  Description
Sequence 1 insulin glulisine / insulin aspart / insulin lispro
Sequence 2 insulin aspart / insulin lispro / insulin glulisine
Sequence 3 insulin lispro / insulin glulisine / insulin aspart
Total Total of all reporting groups

Baseline Measures
    Sequence 1     Sequence 2     Sequence 3     Total  
Number of Participants  
[units: participants]
 		  99     95     94     288  
Age  
[units: years]
Mean ± Standard Deviation 		  43.45  ± 13.71     45.84  ± 13.59     44.04  ± 12.87     44.43  ± 13.39  
Gender  
[units: participants]
 		       
Female     49     54     48     151  
Male     50     41     46     137  
Region of Enrollment  
[units: participants]
 		       
United States     22     21     21     64  
France     8     9     10     27  
Hungary     4     4     6     14  
Spain     11     9     10     30  
Austria     7     9     8     24  
Australia     4     4     3     11  
Israel     11     11     10     32  
Netherlands     8     8     7     23  
United Kingdom     5     4     4     13  
Italy     9     7     7     23  
Sweden     9     8     7     24  
Korea, Republic of     1     1     1     3  
Previous insulin at study entry [1]
[units: participants]
 		       
Insulin glulisine     4     2     2     8  
Insulin aspart     32     43     42     117  
Insulin lispro     63     49     50     162  
Duration of treatment with previous insulin at study entry [2]
[units: years]
Mean ± Standard Deviation 		  4.84  ± 3.58     4.37  ± 3.05     4.79  ± 3.00     4.67  ± 3.22  
Duration of treatment with insulin at study entry  
[units: years]
Mean ± Standard Deviation 		  22.39  ± 13.53     23.07  ± 13.33     22.75  ± 11.08     22.73  ± 12.67  
Total daily bolus insulin dose [3]
[units: Units]
Mean ± Standard Deviation 		  19.61  ± 9.40     18.58  ± 10.34     19.35  ± 7.78     19.18  ± 9.22  
Duration of treatment with CSII (continuous subcutaneous insulin infusion) at study entry  
[units: years]
Mean ± Standard Deviation 		  5.99  ± 4.83     5.52  ± 5.27     6.31  ± 4.95     5.94  ± 5.01  
Total daily basal insulin infusion [3]
[units: Units]
Mean ± Standard Deviation 		  20.98  ± 8.84     19.99  ± 9.38     22.03  ± 9.17     21.00  ± 9.13  
Body Mass Index (BMI)  
[units: kg/m²]
Mean ± Standard Deviation 		  25.01  ± 3.53     25.25  ± 3.91     25.92  ± 3.98     25.39  ± 3.81  
Central fasting plasma glucose [4]
[units: mg/dL]
Mean ± Standard Deviation 		  149.84  ± 59.03     147.45  ± 61.63     151.18  ± 64.06     149.48  ± 61.37  
Glycosylated Haemoglobin (HbA1c)  
[units: Percent]
Mean ± Standard Deviation 		  7.38  ± 0.69     7.36  ± 0.61     7.41  ± 0.69     7.38  ± 0.66  
[1] Total patients analyzed n=287 due to one missing data in the "sequence 2" group
[2] Total patients analyzed n=286 due to one missing data in the "sequence 1" and in the "sequence 2" groups
[3] Total patients analyzed n=285 due to 3 missing data: 2 in the "sequence 1" and 1 in the "sequence 2" groups
[4] Total patients analyzed n=284 due to 4 missing data: 2 in the "sequence 1" and 2 in the "sequence 3" groups



  Outcome Measures
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1.  Primary:   Percentage of Patients With at Least One Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 1

2.  Secondary:   Monthly Rate of Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 2

3.  Secondary:   Percentage of Patients With at Least One Unexplained Hyperglycemia   [ Time Frame: over 13 weeks of each treatment period ]
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4.  Secondary:   Monthly Rate of Unexplained Hyperglycemia   [ Time Frame: over 13 weeks of each treatment period ]
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5.  Secondary:   Percentage of Patients With at Least One Confirmed Infusion Set Occlusion   [ Time Frame: over 13 weeks of each treatment period ]
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6.  Secondary:   Monthly Rate of Confirmed Infusion Set Occlusion   [ Time Frame: over 13 weeks of each treatment period ]
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7.  Secondary:   Percentage of Patients With at Least One Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 7

8.  Secondary:   Monthly Rate of Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis   [ Time Frame: over 13 weeks of each treatment period ]
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9.  Secondary:   Rate of Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤ 70 mg/dL Per Patient-year   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 9

10.  Secondary:   Rate of Severe Symptomatic Hypoglycemia Per Patient-year   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 10

11.  Secondary:   Rate of Nocturnal Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤70 mg/dL Per Patient-year   [ Time Frame: over 13 weeks of each treatment period ]
  Hide Outcome Measure 11

Measure Type Secondary
Measure Title Rate of Nocturnal Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤70 mg/dL Per Patient-year
Measure Description Nocturnal Symptomatic hypoglycemia was defined as an event with clinical symptoms that are considered to result from hypoglycemia (confirmed or not by a glucose measurement) and associated with prompt recovery after oral carbohydrate administration which occurs while the patient is asleep, after bedtime and before getting up in the morning.
Time Frame over 13 weeks of each treatment period  
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.
Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).

Reporting Groups
  Description
Insulin Glulisine 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump
Insulin Aspart 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump
Insulin Lispro 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump

Measured Values
    Insulin Glulisine     Insulin Aspart     Insulin Lispro  
Number of Participants Analyzed  
[units: participants]
 		  256     256     256  
Rate of Nocturnal Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤70 mg/dL Per Patient-year  
[units: events in patient-year]
Mean ± Standard Error 		  12.80  ± 0.95     9.66  ± 0.95     9.48  ± 0.95  


Statistical Analysis 1 for Rate of Nocturnal Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤70 mg/dL Per Patient-year
Groups [1] Insulin Glulisine vs. Insulin Aspart
Method [2] Mixed Models Analysis
P Value [3] <0.001
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant 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:
  The p-value is adjusted for multiple comparisons. Each comparison is performed at the alpha level=2.5% (instead of 5%). Consequently a difference between 2 treatments is statistically significant if the corresponding p-value is <0.025

Statistical Analysis 2 for Rate of Nocturnal Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤70 mg/dL Per Patient-year
Groups [1] Insulin Glulisine vs. Insulin Lispro
Method [2] Mixed Models Analysis
P Value [3] <0.001
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant 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:
  The p-value is adjusted for multiple comparisons. Each comparison is performed at the alpha level=2.5% (instead of 5%). Consequently a difference between 2 treatments is statistically significant if the corresponding p-value is <0.025



12.  Secondary:   Patients With at Least One Site Infection, Site Inflammation/Erythema, Pruritus or Isolated Pain at Injection Site   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 12

13.  Secondary:   Time Interval Between Infusion Set Changes: All Changes   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 13

14.  Secondary:   Time Interval Between Infusion Set Changes in Routine   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 14

15.  Secondary:   Glycosylated Hemoglobin: HbA1c   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 15

16.  Secondary:   Total Daily Basal Insulin Infusion   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 16

17.  Secondary:   Total Daily Bolus Insulin Dose   [ Time Frame: over 13 weeks of each treatment period ]
  Show Outcome Measure 17


  Serious Adverse Events
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  Other Adverse Events
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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:
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.


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.  


Results Point of Contact:  
Name/Title: Medical Affairs Study Director
Organization: sanofi-aventis
e-mail: publicregistryGMA@sanofi-aventis.com


No publications provided by Sanofi

Publications automatically indexed to this study:


Responsible Party: Medical Affairs Study Director, sanofi-aventis
ClinicalTrials.gov Identifier: NCT00607087     History of Changes
Other Study ID Numbers: APIDR_C_02083, 2007-003579-38
Study First Received: January 23, 2008
Results First Received: June 30, 2010
Last Updated: August 26, 2010
Health Authority: Sweden: Regional Ethical Review Board