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Trial record 21 of 199 for:    Protamine

A Comparison Study of Basal Bolus Therapies Together With Lispro Insulin in Type 2 Diabetes Patients

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ClinicalTrials.gov Identifier: NCT00666718
Recruitment Status : Completed
First Posted : April 25, 2008
Results First Posted : March 25, 2011
Last Update Posted : May 13, 2011
Sponsor:
Information provided by:
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Diabetes Mellitus, Type 2
Interventions Drug: Insulin Glargine
Drug: Insulin Lispro Protamine Suspension (ILPS)
Drug: Insulin Lispro
Enrollment 374
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Glargine ILPS
Hide Arm/Group Description Glargine plus Insulin Lispro (2-3 injections) plus metformin Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin
Period Title: Overall Study
Started 187 187
Completed 175 169
Not Completed 12 18
Reason Not Completed
Adverse Event             0             1
Death             1             0
Lost to Follow-up             1             0
Entry Criteria Not Met             2             0
Protocol Violation             1             3
Withdrawal by Subject             7             12
Physician Decision             0             2
Arm/Group Title Glargine ILPS Total
Hide Arm/Group Description Glargine plus Insulin Lispro (2-3 injections) plus metformin Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin Total of all reporting groups
Overall Number of Baseline Participants 187 187 374
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 187 participants 187 participants 374 participants
60.3  (8.07) 59.3  (8.36) 59.8  (8.22)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 187 participants 187 participants 374 participants
Female
101
  54.0%
111
  59.4%
212
  56.7%
Male
86
  46.0%
76
  40.6%
162
  43.3%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 187 participants 187 participants 374 participants
Caucasian 186 186 372
African 0 1 1
Hispanic 1 0 1
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 187 participants 187 participants 374 participants
Belgium 5 2 7
Czech Republic 42 35 77
Germany 22 20 42
United Kingdom 10 2 12
Greece 12 15 27
Italy 19 26 45
Poland 32 43 75
Romania 15 25 40
Slovakia 22 12 34
Turkey 8 7 15
Number of Insulin Injections/Inhalations Per Day   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 187 participants 187 participants 374 participants
1 Insulin Injection/Inhalation per day 104 106 210
2 Insulin Injections/Inhalations per day 31 34 65
3 Insulin Injections/Inhalations per day 30 32 62
4 Insulin Injections/Inhalations per day 16 14 30
>=5 Insulin Injections/Inhalations per day 6 0 6
Missing Data 0 1 1
[1]
Measure Description: The number of insulin injections/inhalations is calculated as the sum of injections per day from the most recently applied insulins before randomization.
Body Weight  
Mean (Standard Deviation)
Unit of measure:  Kilograms (kg)
Number Analyzed 187 participants 187 participants 374 participants
93.53  (17.168) 90.60  (17.075) 92.06  (17.161)
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kilograms per square meter (kg/m^2)
Number Analyzed 187 participants 187 participants 374 participants
33.27  (5.040) 33.00  (5.004) 33.13  (5.017)
[1]
Measure Description: Body mass index is an estimate of body fat based on body weight divided by height squared.
Hemoglobin A1c (HbA1c)  
Mean (Standard Deviation)
Unit of measure:  Percent of glycosylated hemoglobin
Number Analyzed 187 participants 187 participants 374 participants
8.83  (0.896) 8.82  (0.895) 8.82  (0.894)
Duration of Diabetes  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 187 participants 187 participants 374 participants
12.7  (7.04) 11.8  (6.66) 12.3  (6.86)
Previous Insulin Treatment   [1] 
Mean (Standard Deviation)
Unit of measure:  Units (IU)
Number Analyzed 187 participants 187 participants 374 participants
36.9  (25.65) 37.6  (25.75) 37.3  (25.67)
[1]
Measure Description: The dose is calculated as the total dose from the most recently applied previous insulins before randomization.
1.Primary Outcome
Title Change From Baseline in Hemoglobin A1c (HbA1c) to Week 24
Hide Description Least Squares Mean (LSMean) values reported in the table were controlled for treatment, country, and baseline HbA1c value.
Time Frame Baseline, Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Per-Protocol Population: All enrolled participants who were randomized and met the following criteria: no violations of Inclusion/Exclusion Criteria have not discontinued study prior to Week 24, compliant as assessed by investigator, and have not been on systemic glucocorticoid therapy for more than 14 consecutive days.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 163 148
Least Squares Mean (Standard Error)
Unit of Measure: Percent of Glycosylated Hemoglobin
-1.28  (0.08) -1.18  (0.09)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Assuming a drop-out rate after randomization of approximately 15%, the remaining 160 patients in each treatment group should allow confirmation of noninferiority with no true treatment difference and a noninferiority limit of 0.4% using the upper limit of a 2-sided 95% confidence interval (“insulin lispro protamine suspension + insulin lispro" minus “insulin glargine+insulin lispro”) at a significance level of 0.025 with 90% power.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.10
Confidence Interval (2-Sided) 95%
-0.11 to 0.31
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in HbA1c at Week 12 and Week 24
Hide Description LSMean values presented were controlled for treatment, country, baseline HbA1C value and week.
Time Frame Baseline, Week 12, Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants who enrolled in this study, were randomized to 1 of the study treatments, and had at least 1 post baseline measurement for the dependent variable, according to intent-to-treat (ITT) principles.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 180 179
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percent of Glycosylated Hemoglobin
Week 12 Change (n=172, n=168)
-0.99
(-1.14 to -0.84)
-0.90
(-1.10 to -0.69)
Week 24 Change (n=170, n=166)
-1.29
(-1.45 to -1.13)
-1.07
(-1.28 to -0.86)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4580
Comments p-value is for Week 12 Change.
Method Mixed Models Analysis
Comments Change from baseline=Treatment+country+baseline HbA1c+week+treatment*country+treatment*week+baseline HbA1c*treatment (unstructured covariance used).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1070
Comments p-value is for Week 24 Change.
Method Mixed Models Analysis
Comments Change from baseline=Treatment+country+baseline HbA1c+week+treatment*country+treatment*week+baseline HbA1c*treatment (unstructured covariance used).
3.Secondary Outcome
Title Percentage of Participants With HbA1c Less Than 7.0% and Less Than or Equal to 6.5% at Endpoint
Hide Description [Not Specified]
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All patients who enrolled in this study, were randomized to 1 of the study treatments, and had at least 1 post baseline measurement for the dependent variable, according to intent-to-treat (ITT) principles.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 180 179
Measure Type: Number
Unit of Measure: Percent of Participants
HbA1c < 7.0% 50 36
HbA1c <= 6.5% 24 14
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1333
Comments p-value is for HbA1c <7.0%.
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1213
Comments p-value is for HbA1c <=6.5%
Method Fisher Exact
Comments [Not Specified]
4.Secondary Outcome
Title 7-point Self-monitored Blood Glucose Profiles (SMBG) at Endpoint
Hide Description LSMean values presented were controlled for treatment, country, and baseline HbA1C value. SMBG at morning pre-meal, morning postprandial, midday pre-meal, midday postprandial, evening pre-meal, evening postprandial, 0300 hours. Postprandial glucose is measured 2 hours after the start of the meal.
Time Frame 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants who enrolled in this study, were randomized to 1 of the study treatments, and had at least 1 post baseline measurement for the dependent variable, according to intent-to-treat (ITT) principles.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 180 179
Least Squares Mean (Standard Error)
Unit of Measure: millimoles per liter (mmol/L)
Morning Pre-Meal 8.26  (0.22) 8.63  (0.34)
Morning Postprandial 8.93  (0.25) 9.19  (0.40)
Midday Pre-Meal 8.19  (0.23) 7.90  (0.37)
Midday Postprandial 9.11  (0.25) 9.58  (0.40)
Evening Pre-Meal 8.80  (0.24) 8.75  (0.38)
Evening Postprandial 9.27  (0.24) 9.73  (0.37)
0300 Hours 8.16  (0.22) 8.30  (0.35)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Morning Pre-Meal measurement = Treatment+country+week+treatment*country + treatment*week (unstructured covariance was used)
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.37
Confidence Interval (2-Sided) 95%
-0.43 to 1.17
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Morning Postprandial measurement = Treatment +country+week+treatment*country + treatment*week (unstructured covariance was used)
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.26
Confidence Interval (2-Sided) 95%
-0.66 to 1.19
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Midday Pre-Meal measurement = Treatment +country + week +treatment*country + treatment*week (unstructured covariance was used).
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.29
Confidence Interval (2-Sided) 95%
-1.15 to 0.57
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Midday Postprandial measurement = Treatment+country+week+treatment*country + treatment*week (unstructured covariance was used).
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.47
Confidence Interval (2-Sided) 95%
-0.46 to 1.40
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Evening Pre-Meal measurement = Treatment +country+week+treatment*country + treatment*week (unstructured covariance was used).
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.05
Confidence Interval (2-Sided) 95%
-0.93 to 0.83
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Evening Postprandial measurement = Treatment+country+week +treatment*country + treatment*week (unstructured covariance was used).
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.46
Confidence Interval (2-Sided) 95%
-0.41 to 1.34
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments 0300 Hours measurement = Treatment+country+week+treatment*country+treatment*week (unstructured covariance was used).
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.14
Confidence Interval (2-Sided) 95%
-0.67 to 0.96
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Glycemic Variability at Endpoint
Hide Description LSMeans were controlled for treatment and country grouping (Mediterranean, rest of Europe). Glycemic variability was assessed as the standard deviations of 4 fasting SMBG samples, 4 post-breakfast measurements, 4 post-lunch measurements, 4 post-evening meal measurements.
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants who enrolled in this study, were randomized to 1 of the study treatments, and had at least 1 post baseline measurement for the dependent variable, according to intent-to-treat (ITT) principles.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 180 179
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
Fasting 0.86  (0.10) 0.95  (0.10)
Post-breakfast 1.56  (0.17) 1.64  (0.18)
Post-lunch 1.61  (0.15) 1.51  (0.16)
Post-dinner 1.43  (0.17) 1.40  (0.17)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5568
Comments p-value is for Fasting.
Method ANCOVA
Comments Glycemic variability = Treatment+country grouping (Mediterranean, rest of Europe)+treatment*country (Mediterranean, rest of Europe)
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7523
Comments p-value is for Post-breakfast.
Method ANCOVA
Comments Glycemic variability = Treatment+country grouping (Mediterranean, rest of Europe)+treatment*country (Mediterranean, rest of Europe)
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6448
Comments p-value is for Post-lunch.
Method ANCOVA
Comments Glycemic variability = Treatment+country grouping (Mediterranean, rest of Europe)+treatment*country (Mediterranean, rest of Europe)
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9122
Comments p-value is for Post-dinner.
Method ANCOVA
Comments Glycemic variability = Treatment+country grouping (Mediterranean, rest of Europe)+ treatment*country (Mediterranean, rest of Europe)
6.Secondary Outcome
Title Rate Of All Self-reported Hypoglycemic Episodes
Hide Description Rate of self-reported hypoglycemic episodes, all, non-nocturnal,and nocturnal, severe, documented ≤3.9 mmol/L and ≤3.0 mmol/L. Rate=episodes/30 days/patient/. Episode=any time a patient has a symptom associated with hypoglycemia or blood glucose level of ≤70 mg/dL,even if not associated with symptoms.Overall=any time post-randomization in the study period. Nocturnal=Episode between bedtime and waking. Non-Nocturnal=Episode between waking and bedtime.Severe:episode in which patient requires assistance,and has glucose <50 mg/dL or prompt recovery after oral carbohydrate, glucagon, or IV glucose.
Time Frame Baseline through Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population - all participants who received at least one dose of study drug.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 187 187
Least Squares Mean (Standard Error)
Unit of Measure: episode/30 days/participant
All reported episodes rate 1.38  (0.21) 0.84  (0.26)
Nocturnal reported episodes rate 0.19  (0.05) 0.15  (0.06)
Non-Nocturnal reported episodes rate 1.16  (0.20) 0.71  (0.24)
Severe reported episodes rate 0  (0.013) 0  (0.029)
Documented <=3.9 millimoles per liter(mmol/L) rate 0.89  (0.15) 0.49  (0.18)
Documented <=3.0 mmol/L rate 0.13  (0.04) 0.12  (0.05)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Hypoglycemia rate per 30 days = Treatment+Country+Week+Treatment*Country+Treatment*Week (unstructured covariance structure was used)
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.53
Confidence Interval (2-Sided) 95%
-1.19 to 0.12
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Hypoglycemia rate per 30 days = Treatment+Country+Week+Treatment*Country+Treatment*Week (unstructured covariance structure was used)
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.04
Confidence Interval (2-Sided) 95%
-0.20 to 0.11
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Hypoglycemia rate per 30 days = Treatment+Country+Week+Treatment*Country+Treatment*Week (unstructured covariance structure was used)
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.45
Confidence Interval (2-Sided) 95%
-1.06 to 0.16
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Hypoglycemia rate per 30 days = Treatment+Country+Week+Treatment*Country+Treatment*Week (unstructured covariance structure was used)
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.40
Confidence Interval (2-Sided) 95%
-0.86 to 0.06
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Hypoglycemia rate per 30 days=Treatment+Country+Week+Treatment*Country+Treatment*Week (unstructured covariance structure was used)
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.14 to 0.12
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Percentage of Participants With Self-Reported Hypoglycemic Episodes
Hide Description Episode=any time a patient feels that he/she is experiencing a sign or symptom associated with hypoglycemia or has a blood glucose level of ≤70 mg/dL, even if not associated with signs,symptoms, or treatment. Overall=any time post-randomization visits in the study period. Nocturnal=Episode that occurs between bedtime and waking. Non-Nocturnal=Episode occurring between waking and bedtime. Severe=episode with symptoms of neuroglycopenia in which patient requires assistance,and has blood glucose value <50 mg/dL or prompt recovery after oral carbohydrate, glucagon, or intravenous glucose.
Time Frame Baseline through Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population - all participants who received at least one dose of study drug.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 187 187
Measure Type: Number
Unit of Measure: percentage of participants
>=1 hypoglycemic episode 63.6 56.1
>=1 nocturnal hypoglycemic episode 19.3 25.7
>=1 non-nocturnal hypoglycemic episode 61.0 54.0
>=1 severe hypoglycemic episode 0.5 1.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1701
Comments p-value is for >=1 hypoglycemic episode.
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1727
Comments p-value is for >=1 nocturnal hypoglycemic episode.
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2094
Comments p-value is for >=1 non-nocturnal hypoglycemic episode.
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6230
Comments p-value is for >=1 severe hypoglycemic episode.
Method Fisher Exact
Comments [Not Specified]
8.Secondary Outcome
Title Number of Participants With Adverse Events (AE)
Hide Description A listing of adverse events is located in the Reported Adverse Event module.
Time Frame Baseline through Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population - all participants who received at least one dose of study drug.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 187 187
Measure Type: Number
Unit of Measure: participants
AEs 81 65
Serious adverse events (SAE) 9 14
9.Secondary Outcome
Title Change in Body Weight From Baseline to Week 24
Hide Description LSMean values presented were controlled for treatment, country, and baseline HbA1C value.
Time Frame Baseline, Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Per-Protocol Population: All enrolled participants who were randomized and met the following criteria: no violations of Inclusion/Exclusion Criteria have not discontinued study prior to Week 24, compliant as assessed by investigator, and have not been on systemic glucocorticoid therapy for more than 14 consecutive days.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 187 187
Least Squares Mean (Standard Error)
Unit of Measure: Kilograms (kg)
1.19  (0.27) 1.03  (0.30)
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Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANCOVA
Comments weight change from baseline = Treatment + country + baseline Hb1Ac + baseline weight + treatment*HbA1c baseline value
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.16
Confidence Interval (2-Sided) 95%
-0.86 to 0.55
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Total Daily Insulin Dose at Endpoint
Hide Description LSMean values presented were controlled for treatment, country, and baseline HbA1C value.
Time Frame Week 24
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Hide Analysis Population Description
Full Analysis Set: All participants who enrolled in this study, were randomized to 1 of the study treatments, and had at least 1 post baseline measurement for the dependent variable, according to intent-to-treat (ITT) principles.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 180 179
Least Squares Mean (Standard Error)
Unit of Measure: Units
78.05  (3.15) 80.23  (4.31)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Glargine, ILPS
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments Total daily insulin dose=Treatment+country+week+treatment*country+ treatment*week (unstructured covariance was used).
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 2.18
Confidence Interval (2-Sided) 95%
-8.33 to 12.68
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Number of Injections of Insulin at Week 24
Hide Description [Not Specified]
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants who enrolled in this study, were randomized to 1 of the study treatments, and had at least 1 post baseline measurement for the dependent variable, according to intent-to-treat (ITT) principles.
Arm/Group Title Glargine ILPS
Hide Arm/Group Description:
Glargine plus Insulin Lispro (2-3 injections) plus metformin. Participant glucose-level dependent, injection, once daily in the evening, 24 weeks
Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin. Patient glucose-level dependent, injection, once daily in the evening, 24 weeks
Overall Number of Participants Analyzed 141 113
Measure Type: Number
Unit of Measure: Participants
2 to <3 per day 8 10
3 to <4 per day 129 102
≥4 per day 4 1
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Glargine/Lispro Lispro/Metformin
Hide Arm/Group Description Glargine plus Insulin Lispro (2-3 injections) plus metformin Insulin Lispro Protamine Suspension plus Insulin Lispro (2-3 injections) plus metformin
All-Cause Mortality
Glargine/Lispro Lispro/Metformin
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Glargine/Lispro Lispro/Metformin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   9/187 (4.81%)      14/187 (7.49%)    
Cardiac disorders     
Acute myocardial infarction  1  1/187 (0.53%)  1 1/187 (0.53%)  1
Atrial fibrillation  1  1/187 (0.53%)  1 0/187 (0.00%)  0
Atrioventricular block second degree  1  1/187 (0.53%)  1 0/187 (0.00%)  0
Coronary artery disease  1  1/187 (0.53%)  1 0/187 (0.00%)  0
Coronary artery perforation  1  1/187 (0.53%)  1 0/187 (0.00%)  0
Myocardial infarction  1 [1]  1/187 (0.53%)  1 0/187 (0.00%)  0
Myocardial ischaemia  1  1/187 (0.53%)  1 0/187 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain upper  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Diarrhoea  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Gastritis erosive  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Gastroduodenal ulcer  1  0/187 (0.00%)  0 1/187 (0.53%)  1
General disorders     
Impaired healing  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Oedema mucosal  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Infections and infestations     
Bronchopneumonia  1  1/187 (0.53%)  1 0/187 (0.00%)  0
Injection site abscess  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Injury, poisoning and procedural complications     
Lower limb fracture  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Metabolism and nutrition disorders     
Diabetes mellitus inadequate control  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Musculoskeletal and connective tissue disorders     
Chondromalacia  1  1/187 (0.53%)  1 0/187 (0.00%)  0
Dupuytren's contracture  1  1/187 (0.53%)  1 0/187 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Adrenal adenoma  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Nervous system disorders     
Headache  1  1/187 (0.53%)  1 0/187 (0.00%)  0
Renal and urinary disorders     
Renal colic  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Skin and subcutaneous tissue disorders     
Skin ulcer  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Surgical and medical procedures     
Physiotherapy  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Vascular disorders     
Arterial stenosis  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Deep vein thrombosis  1  0/187 (0.00%)  0 1/187 (0.53%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 12.0
[1]
This event resulted in death.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Glargine/Lispro Lispro/Metformin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   81/187 (43.32%)      65/187 (34.76%)    
Blood and lymphatic system disorders     
Anaemia  1  3/187 (1.60%)  3 0/187 (0.00%)  0
Eye disorders     
Diabetic retinopathy  1  1/187 (0.53%)  1 3/187 (1.60%)  3
Gastrointestinal disorders     
Abdominal pain upper  1  3/187 (1.60%)  4 2/187 (1.07%)  2
Diarrhoea  1  8/187 (4.28%)  8 3/187 (1.60%)  4
Nausea  1  5/187 (2.67%)  6 1/187 (0.53%)  1
Toothache  1  2/187 (1.07%)  2 4/187 (2.14%)  6
General disorders     
Chest discomfort  1  2/187 (1.07%)  2 0/187 (0.00%)  0
Fatigue  1  1/187 (0.53%)  1 2/187 (1.07%)  3
Infections and infestations     
Bronchitis  1  3/187 (1.60%)  3 0/187 (0.00%)  0
Cystitis  1  5/187 (2.67%)  5 1/187 (0.53%)  1
Influenza  1  5/187 (2.67%)  5 4/187 (2.14%)  4
Lower respiratory tract infection  1  2/187 (1.07%)  2 0/187 (0.00%)  0
Nasopharyngitis  1  12/187 (6.42%)  17 10/187 (5.35%)  12
Pharyngitis  1  0/187 (0.00%)  0 2/187 (1.07%)  2
Pulpitis dental  1  2/187 (1.07%)  2 0/187 (0.00%)  0
Rhinitis  1  3/187 (1.60%)  4 3/187 (1.60%)  3
Sinusitis  1  2/187 (1.07%)  2 0/187 (0.00%)  0
Tonsillitis  1  4/187 (2.14%)  4 1/187 (0.53%)  1
Urinary tract infection  1  1/187 (0.53%)  1 2/187 (1.07%)  2
Viral infection  1  5/187 (2.67%)  7 7/187 (3.74%)  7
Musculoskeletal and connective tissue disorders     
Arthralgia  1  5/187 (2.67%)  7 3/187 (1.60%)  3
Back pain  1  6/187 (3.21%)  7 3/187 (1.60%)  6
Musculoskeletal pain  1  0/187 (0.00%)  0 3/187 (1.60%)  3
Pain in extremity  1  3/187 (1.60%)  3 0/187 (0.00%)  0
Nervous system disorders     
Diabetic neuropathy  1  2/187 (1.07%)  2 1/187 (0.53%)  1
Headache  1  11/187 (5.88%)  20 9/187 (4.81%)  39
Sciatica  1  2/187 (1.07%)  2 0/187 (0.00%)  0
Tremor  1  2/187 (1.07%)  2 0/187 (0.00%)  0
Psychiatric disorders     
Anxiety  1  3/187 (1.60%)  4 0/187 (0.00%)  0
Depression  1  0/187 (0.00%)  0 2/187 (1.07%)  2
Insomnia  1  2/187 (1.07%)  7 0/187 (0.00%)  0
Renal and urinary disorders     
Nephrolithiasis  1  0/187 (0.00%)  0 2/187 (1.07%)  2
Respiratory, thoracic and mediastinal disorders     
Cough  1  7/187 (3.74%)  9 4/187 (2.14%)  5
Oropharyngeal pain  1  4/187 (2.14%)  4 3/187 (1.60%)  3
Surgical and medical procedures     
Cataract operation  1  2/187 (1.07%)  2 0/187 (0.00%)  0
Vascular disorders     
Hypertension  1  2/187 (1.07%)  2 4/187 (2.14%)  4
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 12.0
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
Phone: 800-545-5979
Layout table for additonal information
Responsible Party: Chief Medical Officer, Eli Lilly
ClinicalTrials.gov Identifier: NCT00666718     History of Changes
Other Study ID Numbers: 12047
F3Z-EW-IOPJ ( Other Identifier: Eli Lilly and Company )
First Submitted: April 23, 2008
First Posted: April 25, 2008
Results First Submitted: February 18, 2011
Results First Posted: March 25, 2011
Last Update Posted: May 13, 2011