30 Week Parallel Group Comparison Study of Linagliptin + Pioglitazone (5+15, 5+30 and 5+45 mg) qd Versus Respective Monotherapies, Followed by a Comparison of 5mg+30mg and 5mg+45mg Versus Respective Monotherapies in Type 2 Diabetes for up to 54 Weeks

This study has been completed.
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01183013
First received: August 16, 2010
Last updated: June 3, 2014
Last verified: May 2014
Results First Received: March 12, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double-Blind;   Primary Purpose: Treatment
Condition: Diabetes Mellitus, Type 2
Interventions: Drug: Pioglitazone 15 mg
Drug: Pioglitazone 45 mg
Drug: Pioglitazone 30 mg
Drug: Linagliptin 5mg / Pioglitazone 45 mg FDC
Drug: Linagliptin 5mg / Pioglitazone 30 mg FDC
Drug: Linagliptin 5mg
Drug: Linagliptin 5mg / Pioglitazone 15 mg FDC

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
After Amendment #5, patients were considered COMPLETED at the end of Part A (30 weeks) or after their next Part B visit (up to 54 weeks) if already in Part B. Before Amendment #5, all patients were considered COMPLETED at the end of Part A + Part B (84 weeks).

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

Reporting Groups
  Description
Pio15/Pio30 Participants treated with pioglitazone 15mg for 30 weeks followed by pioglitazone 30mg for up to 54 weeks.
Pio30/Pio30 Participants treated with pioglitazone 30mg for 30 weeks followed by pioglitazone 30mg for up to 54 weeks.
Pio45/Pio45 Participants treated with pioglitazone 30 mg for 6 weeks and then were titrated up to pioglitazone 45mg for 24 weeks followed by pioglitazone 45mg for up to 54 weeks.
Lina5/Lina5 Participants treated with linagliptin 5mg once daily for 30 weeks followed by linagliptin 5mg once daily for up to 54 weeks.
Lina5Pio15/Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for 30 weeks followed by linagliptin 5mg + pioglitazone 30mg FDC for up to 54 weeks.
Lina5Pio30/Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for 30 weeks followed by linagliptin 5mg + pioglitazone 30mg FDC for up to 54 weeks.
Lina5Pio45/Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for 6 weeks and linagliptin 5mg + pioglitazone 45mg FDC for 24 weeks followed by linagliptin 5mg + pioglitazone 45mg FDC for up to 54 weeks.

Participant Flow:   Overall Study
    Pio15/Pio30     Pio30/Pio30     Pio45/Pio45     Lina5/Lina5     Lina5Pio15/Lina5Pio30     Lina5Pio30/Lina5Pio30     Lina5Pio45/Lina5Pio45  
STARTED     131     140     138     135     126     133     133  
COMPLETED     86 [1]   101 [1]   97 [1]   105 [1]   90 [1]   88 [1]   96 [1]
NOT COMPLETED     45     39     41     30     36     45     37  
Adverse Event                 6                 8                 5                 5                 10                 10                 6  
Lack of Efficacy                 3                 2                 1                 2                 1                 2                 0  
Protocol Violation                 5                 2                 4                 0                 4                 3                 3  
Lost to Follow-up                 7                 3                 4                 3                 2                 6                 5  
Withdrawal by Subject                 9                 13                 10                 8                 7                 9                 10  
Reasons other than stated above                 15                 11                 17                 12                 12                 15                 13  
[1] Completed is first 30 weeks (Part A) or up to 84 weeks in relation to Protocol Amendment #5



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All patients from the Full Analysis Set (FAS) which includes those patients in the treated set who had a baseline HbA1c value and at least one on-treatment HbA1c value.

Reporting Groups
  Description
Pio15/Pio30 Participants treated with pioglitazone 15mg for 30 weeks followed by pioglitazone 30mg for up to 54 weeks.
Pio30/Pio30 Participants treated with pioglitazone 30mg for 30 weeks followed by pioglitazone 30mg for up to 54 weeks.
Pio45/Pio45 Participants treated with pioglitazone 30 mg for 6 weeks and then were titrated up to pioglitazone 45mg for 24 weeks followed by pioglitazone 45mg for up to 54 weeks.
Lina5/Lina5 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for 30 weeks followed by linagliptin 5mg + pioglitazone 30mg FDC for up to 54 weeks.
Lina5Pio15/Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for 30 weeks followed by a blinded trial period on linagliptin 5mg + pioglitazone 30mg FDC
Lina5Pio30/Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for 30 weeks followed by linagliptin 5mg + pioglitazone 30mg FDC for up to 54 weeks.
Lina5Pio45/Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for 6 weeks and linagliptin 5mg + pioglitazone 45mg FDC for 24 weeks followed by linagliptin 5mg + pioglitazone 45mg FDC for up to 54 weeks.
Total Total of all reporting groups

Baseline Measures
    Pio15/Pio30     Pio30/Pio30     Pio45/Pio45     Lina5/Lina5     Lina5Pio15/Lina5Pio30     Lina5Pio30/Lina5Pio30     Lina5Pio45/Lina5Pio45     Total  
Number of Participants  
[units: participants]
  124     134     134     130     120     125     126     893  
Age  
[units: years]
Mean ± Standard Deviation
  56.4  ± 10.4     57.2  ± 11.1     56.5  ± 11.1     56.3  ± 10.1     57.1  ± 10.2     56.4  ± 10.0     60.1  ± 10.2     57.1  ± 10.5  
Gender  
[units: participants]
               
Female     57     64     66     51     54     61     57     410  
Male     67     70     68     79     66     64     69     483  
Baseline HbA1c  
[units: percent]
Mean ± Standard Deviation
  8.33  ± 0.93     7.99  ± 0.85     8.12  ± 0.87     8.01  ± 0.88     8.13  ± 0.94     8.17  ± 1.07     8.01  ± 0.81     8.11  ± 0.91  
Baseline fasting plasma glucose (FPG)  
[units: mg/dL]
Mean ± Standard Deviation
  171.3  ± 39.3     165.8  ± 40.0     167.5  ± 37.9     161.4  ± 38.1     167.3  ± 39.5     168.8  ± 46.8     162.3  ± 36.8     166.3  ± 39.9  



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Change From Baseline in HbA1c After 30 Weeks of Treatment.   [ Time Frame: Baseline and 30 weeks ]

Measure Type Primary
Measure Title Change From Baseline in HbA1c After 30 Weeks of Treatment.
Measure Description HbA1c is measured as a percentage. The change from baseline is the Week 30 HbA1c minus the baseline HbA1c.
Time Frame Baseline and 30 weeks  
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.
Patients from Full Analysis Set (FAS) with last observation carried forward (LOCF) used to handle missing values at Week 30. FAS is the patient set which includes all patients who were documented to have taken at least one dose of treatment and who had a baseline HbA1c value at at least one on-treatment HbA1c.

Reporting Groups
  Description
Pio15 Participants treated with pioglitazone 15mg monotherapy for the first 30 weeks
Pio30 Participants treated with pioglitazone 30mg monotherapy for the first 30 weeks
Pio45 Participants treated with pioglitazone 30mg monotherapy for 6 weeks and were titrated to pioglitazone 45mg monotherapy for the next 24 weeks.
Lina5 Participants treated with linagliptin 5mg once daily for the first 30 weeks
Lina5Pio15 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 6 weeks and were titrated to linagliptin 5mg + pioglitazone 45mg for the next 24 weeks.

Measured Values
    Pio15     Pio30     Pio45     Lina5     Lina5Pio15     Lina5Pio30     Lina5Pio45  
Number of Participants Analyzed  
[units: participants]
  124     134     134     130     120     125     126  
Change From Baseline in HbA1c After 30 Weeks of Treatment.  
[units: percent]
Mean ± Standard Error
  -0.66  ± 0.09     -0.69  ± 0.09     -0.87  ± 0.09     -0.39  ± 0.09     -0.83  ± 0.09     -1.06  ± 0.09     -1.28  ± 0.09  


Statistical Analysis 1 for Change From Baseline in HbA1c After 30 Weeks of Treatment.
Groups [1] Pio15 vs. Lina5Pio15
Method [2] ANCOVA
P Value [3] 0.1571
Mean Difference (Final Values) [4] -0.17
95% Confidence Interval ( -0.41 to 0.07 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[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:
  The model includes fixed effects for treatment, continuous baseline HbA1c, prior anti-diabetic medication and country.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Change From Baseline in HbA1c After 30 Weeks of Treatment.
Groups [1] Pio30 vs. Lina5Pio30
Method [2] ANCOVA
P Value [3] 0.0016
Mean Difference (Final Values) [4] -0.37
95% Confidence Interval ( -0.60 to -0.14 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 3 for Change From Baseline in HbA1c After 30 Weeks of Treatment.
Groups [1] Pio45 vs. Lina5Pio45
Method [2] ANCOVA
P Value [3] 0.0006
Mean Difference (Final Values) [4] -0.41
95% Confidence Interval ( -0.64 to -0.18 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 4 for Change From Baseline in HbA1c After 30 Weeks of Treatment.
Groups [1] Lina5 vs. Lina5Pio15
Method [2] ANCOVA
P Value [3] 0.0003
Mean Difference (Final Values) [4] -0.44
95% Confidence Interval ( -0.67 to -0.20 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 5 for Change From Baseline in HbA1c After 30 Weeks of Treatment.
Groups [1] Lina5 vs. Lina5Pio30
Method [2] ANCOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] -0.68
95% Confidence Interval ( -0.91 to -0.44 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 6 for Change From Baseline in HbA1c After 30 Weeks of Treatment.
Groups [1] Lina5 vs. Lina5Pio45
Method [2] ANCOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] -0.89
95% Confidence Interval ( -1.12 to -0.66 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, prior anti-diabetic medication and country.
[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:
  No text entered.



2.  Secondary:   Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment   [ Time Frame: Baseline and 30 weeks ]

Measure Type Secondary
Measure Title Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment
Measure Description Glycosylated hemoglobin is reported as a percentage of the total hemoglobin.
Time Frame Baseline and 30 weeks  
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.
FAS patients who also had baseline HbA1c>=7%.Non-completers (patients without a value at Week 30) were considered as failures (NCF).

Reporting Groups
  Description
Pio15 Participants treated with pioglitazone 15mg monotherapy for the first 30 weeks
Pio30 Participants treated with pioglitazone 30mg monotherapy for the first 30 weeks
Pio45 Participants treated with pioglitazone 30mg monotherapy for 6 weeks and were titrated to pioglitazone 45mg monotherapy for the next 24 weeks
Lina5 Participants treated with linagliptin 5mg once daily for the first 30 weeks
Lina5Pio15 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 6 weeks and were titrated to linagliptin 5mg + pioglitazone 45mg for the next 24 weeks.

Measured Values
    Pio15     Pio30     Pio45     Lina5     Lina5Pio15     Lina5Pio30     Lina5Pio45  
Number of Participants Analyzed  
[units: participants]
  121     125     129     124     112     118     121  
Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment  
[units: participants]
  39     55     68     29     45     61     81  


Statistical Analysis 1 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment
Groups [1] Pio15 vs. Lina5Pio15
Method [2] Regression, Logistic
P Value [3] 0.4639
Odds Ratio (OR) [4] 1.246
95% Confidence Interval ( 0.692 to 2.242 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 2 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment
Groups [1] Pio30 vs. Lina5Pio30
Method [2] Regression, Logistic
P Value [3] 0.0546
Odds Ratio (OR) [4] 1.746
95% Confidence Interval ( 0.989 to 3.083 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 3 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment
Groups [1] Pio45 vs. Lina5Pio45
Method [2] Regression, Logistic
P Value [3] 0.0254
Odds Ratio (OR) [4] 1.903
95% Confidence Interval ( 1.083 to 3.345 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 4 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio15
Method [2] Regression, Logistic
P Value [3] 0.0009
Odds Ratio (OR) [4] 2.804
95% Confidence Interval ( 1.524 to 5.159 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 5 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio30
Method [2] Regression, Logistic
P Value [3] <0.0001
Odds Ratio (OR) [4] 5.429
95% Confidence Interval ( 2.947 to 10.001 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 6 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio45
Method [2] Regression, Logistic
P Value [3] <0.0001
Odds Ratio (OR) [4] 9.614
95% Confidence Interval ( 5.187 to 17.821 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.



3.  Secondary:   Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment   [ Time Frame: Baseline and 30 weeks ]

Measure Type Secondary
Measure Title Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment
Measure Description Glycosylated hemoglobin is reported as a percentage of the total hemoglobin.
Time Frame Baseline and 30 weeks  
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.
FAS patients who also had baseline HbA1c >=6.5%. Non-completers (patients without a value at Week 30) were considered as failures (NCF)

Reporting Groups
  Description
Pio15 Participants treated with pioglitazone 15mg monotherapy for the first 30 weeks
Pio30 Participants treated with pioglitazone 30mg monotherapy for the first 30 weeks
Pio45 Participants treated with pioglitazone 30mg monotherapy for 6 weeks and were titrated to pioglitazone 45mg monotherapy for the next 24 weeks
Lina5 Participants treated with linagliptin 5mg once daily for the first 30 weeks
Lina5Pio15 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 6 weeks and were titrated to linagliptin 5mg + pioglitazone 45mg for the next 24 weeks.

Measured Values
    Pio15     Pio30     Pio45     Lina5     Lina5Pio15     Lina5Pio30     Lina5Pio45  
Number of Participants Analyzed  
[units: participants]
  124     132     134     129     120     123     125  
Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment  
[units: participants]
  20     28     39     14     24     38     43  


Statistical Analysis 1 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment
Groups [1] Pio15 vs. Lina5Pio15
Method [2] Regression, Logistic
P Value [3] 0.7359
Odds Ratio (OR) [4] 1.126
95% Confidence Interval ( 0.565 to 2.243 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 2 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment
Groups [1] Pio30 vs. Lina5Pio30
Method [2] Regression, Logistic
P Value [3] 0.0363
Odds Ratio (OR) [4] 1.905
95% Confidence Interval ( 1.042 to 3.484 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 3 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment
Groups [1] Pio45 vs. Lina5Pio45
Method [2] Regression, Logistic
P Value [3] 0.4039
Odds Ratio (OR) [4] 1.269
95% Confidence Interval ( 0.726 to 2.217 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 4 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio15
Method [2] Regression, Logistic
P Value [3] 0.0345
Odds Ratio (OR) [4] 2.220
95% Confidence Interval ( 1.060 to 4.649 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 5 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio30
Method [2] Regression, Logistic
P Value [3] <0.0001
Odds Ratio (OR) [4] 4.580
95% Confidence Interval ( 2.263 to 9.266 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 6 for Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio45
Method [2] Regression, Logistic
P Value [3] <0.0001
Odds Ratio (OR) [4] 5.066
95% Confidence Interval ( 2.530 to 10.145 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.



4.  Secondary:   Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)   [ Time Frame: Baseline and 30 weeks ]

Measure Type Secondary
Measure Title Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)
Measure Description Glycosylated hemoglobin is reported as a percentage of the total hemoglobin.
Time Frame Baseline and 30 weeks  
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.
FAS with non-completers (without a value at Week 30) considered as failure

Reporting Groups
  Description
Pio15 Participants treated with pioglitazone 15mg monotherapy for the first 30 weeks
Pio30 Participants treated with pioglitazone 30mg monotherapy for the first 30 weeks
Pio45 Participants treated with pioglitazone 30mg monotherapy for 6 weeks and were titrated to pioglitazone 45mg monotherapy for the next 24 weeks.
Lina5 Participants treated with linagliptin 5mg once daily for the first 30 weeks
Lina5Pio15 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 6 weeks and were titrated to linagliptin 5mg + pioglitazone 45mg for the next 24 weeks.

Measured Values
    Pio15     Pio30     Pio45     Lina5     Lina5Pio15     Lina5Pio30     Lina5Pio45  
Number of Participants Analyzed  
[units: participants]
  124     134     134     130     120     125     126  
Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)  
[units: participants]
  79     83     90     54     79     91     107  


Statistical Analysis 1 for Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)
Groups [1] Pio15 vs. Lina5Pio15
Method [2] Regression, Logistic
P Value [3] 0.7540
Odds Ratio (OR) [4] 1.090
95% Confidence Interval ( 0.637 to 1.863 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 2 for Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)
Groups [1] Pio30 vs. Lina5Pio30
Method [2] Regression, Logistic
P Value [3] 0.0506
Odds Ratio (OR) [4] 1.707
95% Confidence Interval ( 0.999 to 2.918 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 3 for Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)
Groups [1] Pio45 vs. Lina5Pio45
Method [2] Regression, Logistic
P Value [3] 0.0005
Odds Ratio (OR) [4] 2.966
95% Confidence Interval ( 1.604 to 5.485 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 4 for Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)
Groups [1] Lina5 vs. Lina5Pio15
Method [2] Regression, Logistic
P Value [3] 0.0002
Odds Ratio (OR) [4] 2.696
95% Confidence Interval ( 1.594 to 4.559 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 5 for Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)
Groups [1] Lina5 vs. Lina5Pio30
Method [2] Regression, Logistic
P Value [3] <0.0001
Odds Ratio (OR) [4] 4.017
95% Confidence Interval ( 2.348 to 6.873 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 6 for Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)
Groups [1] Lina5 vs. Lina5Pio45
Method [2] Regression, Logistic
P Value [3] <0.0001
Odds Ratio (OR) [4] 8.521
95% Confidence Interval ( 4.630 to 15.681 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.



5.  Secondary:   HbA1c Change From Baseline by Visit Over Time   [ Time Frame: Baseline, week 6, week 12, week 18, week 24, week 30 ]

Measure Type Secondary
Measure Title HbA1c Change From Baseline by Visit Over Time
Measure Description

HbA1c is measured as a percentage. The change from baseline is the HbA1c over time minus the baseline HbA1c. The model includes fixed effects for treatment, continuous baseline HbA1c, prior andi-diabetic medication, country, visit and treatment.

by visit interaction.

Time Frame Baseline, week 6, week 12, week 18, week 24, week 30  
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.
FAS (observed cases)

Reporting Groups
  Description
Pio15 Participants treated with pioglitazone 15mg monotherapy for the first 30 weeks
Pio30 Participants treated with pioglitazone 30mg monotherapy for the first 30 weeks
Pio45 Participants treated with pioglitazone 30mg monotherapy for 6 weeks and were titrated to pioglitazone 45mg monotherapy for the next 24 weeks.
Lina5 Participants treated with linagliptin 5mg once daily for the first 30 weeks
Lina5Pio15 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 6 weeks and were titrated to linagliptin 5mg + pioglitazone 45mg for the next 24 weeks.

Measured Values
    Pio15     Pio30     Pio45     Lina5     Lina5Pio15     Lina5Pio30     Lina5Pio45  
Number of Participants Analyzed  
[units: participants]
  124     134     134     130     120     125     126  
HbA1c Change From Baseline by Visit Over Time  
[units: percent]
Mean ± Standard Error
             
Change to week 6 (N=121,133,133,130,119,124,125)     -0.22  ± 0.06     -0.16  ± 0.06     -0.20  ± 0.06     -0.23  ± 0.06     -0.43  ± 0.06     -0.47  ± -0.06     -0.62  ± 0.06  
Change to week 12 (N=112,124,127,122,111,117,120)     -0.47  ± 0.08     -0.43  ± 0.07     -0.59  ± 0.07     -0.36  ± 0.08     -0.71  ± 0.08     -0.92  ± 0.08     -1.01  ± 0.08  
Change to week 18 (N=101,121,122,112,104,104,115)     -0.63  ± 0.09     -0.58  ± 0.08     -0.82  ± 0.08     -0.39  ± 0.08     -0.81  ± 0.09     -1.07  ± 0.09     -1.22  ± 0.09  
Change to week 24 (N=91,108,110,95,92,96,109)     -0.75  ± 0.09     -0.67  ± 0.09     -0.87  ± 0.09     -0.39  ± 0.09     -0.84  ± 0.09     -1.10  ± 0.09     -1.23  ± 0.09  
Change to week 30 (N=78,93,91,79,86,87,97)     -0.77  ± 0.09     -0.73  ± 0.08     -0.94  ± 0.09     -0.37  ± 0.09     -0.87  ± 0.09     -1.09  ± 0.09     -1.27  ± 0.09  

No statistical analysis provided for HbA1c Change From Baseline by Visit Over Time



6.  Secondary:   Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment   [ Time Frame: Baseline and 30 weeks ]

Measure Type Secondary
Measure Title Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment
Measure Description The change from baseline is the FPG after 30 weeks minus the baseline FPG.
Time Frame Baseline and 30 weeks  
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.
Patients from Full Analysis Set (FAS) with a value for FPG at baseline and on-treatment. Last observation carried forward (LOCF) used to handle missing values at Week 30.

Reporting Groups
  Description
Pio15 Participants treated with pioglitazone 15mg monotherapy for the first 30 weeks
Pio30 Participants treated with pioglitazone 30mg monotherapy for the first 30 weeks
Pio45 Participants treated with pioglitazone 30mg monotherapy for 6 weeks and were titrated to pioglitazone 45mg monotherapy for the next 24 weeks.
Lina5 Participants treated with linagliptin 5mg once daily for the first 30 weeks
Lina5Pio15 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 6 weeks and were titrated to linagliptin 5mg + pioglitazone 45mg for the next 24 weeks.

Measured Values
    Pio15     Pio30     Pio45     Lina5     Lina5Pio15     Lina5Pio30     Lina5Pio45  
Number of Participants Analyzed  
[units: participants]
  123     133     134     130     119     123     125  
Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment  
[units: mg/dL]
Mean ± Standard Error
  -15.16  ± 3.49     -25.49  ± 3.28     -28.69  ± 3.29     -1.46  ± 3.35     -18.84  ± 3.47     -27.33  ± 3.46     -35.19  ± 3.40  


Statistical Analysis 1 for Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment
Groups [1] Pio15 vs. Lina5Pio15
Method [2] ANCOVA
P Value [3] 0.4275
Mean Difference (Final Values) [4] -3.68
95% Confidence Interval ( -12.77 to 5.42 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, continuous baseline FPG, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 2 for Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment
Groups [1] Pio30 vs. Lina5Pio30
Method [2] ANCOVA
P Value [3] 0.6839
Mean Difference (Final Values) [4] -1.84
95% Confidence Interval ( -10.69 to 7.02 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, continuous baseline FPG, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 3 for Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment
Groups [1] Pio45 vs. Lina5Pio45
Method [2] ANCOVA
P Value [3] 0.1466
Mean Difference (Final Values) [4] -6.50
95% Confidence Interval ( -15.29 to 2.28 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, continuous baseline FPG, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 4 for Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio15
Method [2] ANCOVA
P Value [3] 0.0002
Mean Difference (Final Values) [4] -17.38
95% Confidence Interval ( -26.35 to -8.41 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, continuous baseline FPG, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 5 for Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio30
Method [2] ANCOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] -25.87
95% Confidence Interval ( -34.77 to -16.98 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, continuous baseline FPG, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 6 for Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio45
Method [2] ANCOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] -33.73
95% Confidence Interval ( -42.57 to -24.89 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c, continuous baseline FPG, prior anti-diabetic medication and country.
[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:
  No text entered.



7.  Secondary:   Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time   [ Time Frame: Baseline, week 6, week 12, week 18, week 24, week 30 ]

Measure Type Secondary
Measure Title Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time
Measure Description The change from baseline is the FPG over time minus the baseline FPG. Model includes fixed effects for treatment, continuous baseline FPG, continuous baseline HbA1c, prior anti-diabetic medication, country, visit and treatment by visit interaction
Time Frame Baseline, week 6, week 12, week 18, week 24, week 30  
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.
FAS (observed cases)

Reporting Groups
  Description
Pio15 Participants treated with pioglitazone 15mg monotherapy for the first 30 weeks
Pio30 Participants treated with pioglitazone 30mg monotherapy for the first 30 weeks
Pio45 Participants treated with pioglitazone 30mg monotherapy for 6 weeks and were titrated to pioglitazone 45mg monotherapy for the next 24 weeks.
Lina5 Participants treated with linagliptin 5mg once daily for the first 30 weeks
Lina5Pio15 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 6 weeks and were titrated to linagliptin 5mg + pioglitazone 45mg for the next 24 weeks.

Measured Values
    Pio15     Pio30     Pio45     Lina5     Lina5Pio15     Lina5Pio30     Lina5Pio45  
Number of Participants Analyzed  
[units: participants]
  124     134     134     130     120     125     126  
Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time  
[units: mg/dL]
Mean ± Standard Error
             
Change at week 6 (N=118,132,133,130,119,122,124)     -14.43  ± 2.99     -16.38  ± 2.80     -15.72  ± 2.81     -4.25  ± 2.84     -19.25  ± 2.96     -26.89  ± 2.94     -28.36  ± 2.89  
Change at week 12 (N=111,124,126,122,108,114,118)     -10.63  ± 3.24     -21.36  ± 3.04     -25.30  ± 3.03     -7.43  ± 3.08     -17.99  ± 3.24     -31.25  ± 3.19     -28.53  ± 3.13  
Change at week 18 (N=100,122,121,111,104,103,114)     -16.68  ± 3.29     -20.69  ± 3.02     -28.68  ± 3.03     -7.06  ± 3.13     -19.01  ± 3.24     -31.22  ± 3.25     -30.66  ± 3.12  
Change at week 24 (N=90,108,108,96,93,93,108)     -16.25  ± 3.25     -21.57  ± 2.99     -27.67  ± 3.00     -4.60  ± 3.13     -16.68  ± 3.20     -31.48  ± 3.20     -31.49  ± 3.03  
Change at week 30 (N=76,91,89,79,82,87,98)     -17.66  ± 3.35     -26.09  ± 3.08     -31.76  ± 3.11     -0.09  ± 3.24     -17.93  ± 3.27     -27.11  ± 3.22     -34.04  ± 3.07  

No statistical analysis provided for Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time



8.  Secondary:   Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)   [ Time Frame: Baseline and 30 weeks ]

Measure Type Secondary
Measure Title Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)
Measure Description The change from baseline is the 2hPPG after 30 weeks minus the baseline 2hPPG.
Time Frame Baseline and 30 weeks  
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.
MTT set: This patient set includes those patients in the FAS who had a valid MTT at baseline and at least one valid on-treatment MTT. An MTT is considered valid if both an FPG and a 2-hour PPG value are available.

Reporting Groups
  Description
Pio15 Participants treated with pioglitazone 15mg monotherapy for the first 30 weeks
Pio30 Participants treated with pioglitazone 30mg monotherapy for the first 30 weeks
Pio45 Participants treated with pioglitazone 30mg monotherapy for 6 weeks and were titrated to pioglitazone 45mg monotherapy for the next 24 weeks.
Lina5 Participants treated with linagliptin 5mg once daily for the first 30 weeks
Lina5Pio15 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 6 weeks and were titrated to linagliptin 5mg + pioglitazone 45mg for the next 24 weeks.

Measured Values
    Pio15     Pio30     Pio45     Lina5     Lina5Pio15     Lina5Pio30     Lina5Pio45  
Number of Participants Analyzed  
[units: participants]
  29     34     25     22     28     26     31  
Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)  
[units: mg/dL]
Least Squares Mean ± Standard Error
  -30.65  ± 10.93     -83.00  ± 9.85     -82.98  ± 10.92     -51.61  ± 11.67     -67.26  ± 11.15     -87.94  ± 11.14     -84.77  ± 10.28  


Statistical Analysis 1 for Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)
Groups [1] Pio15 vs. Lina5Pio15
Method [2] ANCOVA
P Value [3] 0.0057
Mean Difference (Final Values) [4] -36.61
95% Confidence Interval ( -62.42 to -10.80 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c and 2-hour PPG, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 2 for Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)
Groups [1] Pio30 vs. Lina5Pio30
Method [2] ANCOVA
P Value [3] 0.7021
Mean Difference (Final Values) [4] -4.94
95% Confidence Interval ( -30.39 to 20.51 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c and 2-hour PPG, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 3 for Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)
Groups [1] Pio45 vs. Lina5Pio45
Method [2] ANCOVA
P Value [3] 0.8932
Mean Difference (Final Values) [4] -1.78
95% Confidence Interval ( -27.95 to 24.38 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c and 2-hour PPG, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 4 for Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)
Groups [1] Lina5 vs. Lina5Pio15
Method [2] ANCOVA
P Value [3] 0.2706
Mean Difference (Final Values) [4] -15.65
95% Confidence Interval ( -43.60 to 12.30 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c and 2-hour PPG, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 5 for Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)
Groups [1] Lina5 vs. Lina5Pio30
Method [2] ANCOVA
P Value [3] 0.0126
Mean Difference (Final Values) [4] -36.33
95% Confidence Interval ( -64.78 to -7.89 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c and 2-hour PPG, prior anti-diabetic medication and country.
[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:
  No text entered.

Statistical Analysis 6 for Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)
Groups [1] Lina5 vs. Lina5Pio45
Method [2] ANCOVA
P Value [3] 0.0167
Mean Difference (Final Values) [4] -33.16
95% Confidence Interval ( -60.23 to -6.08 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The model includes fixed effects for treatment, continuous baseline HbA1c and 2-hour PPG, prior anti-diabetic medication and country.
[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:
  No text entered.



9.  Secondary:   Time to First Use of Rescue Therapy   [ Time Frame: 30 weeks ]

Measure Type Secondary
Measure Title Time to First Use of Rescue Therapy
Measure Description Proportion of patients at 30 weeks with rescue therapy using Kaplan-Meier analysis.
Time Frame 30 weeks  
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.
FAS

Reporting Groups
  Description
Pio15 Participants treated with pioglitazone 15mg monotherapy for the first 30 weeks
Pio30 Participants treated with pioglitazone 30mg monotherapy for the first 30 weeks
Pio45 Participants treated with pioglitazone 30mg monotherapy for 6 weeks and were titrated to pioglitazone 45mg monotherapy for the next 24 weeks.
Lina5 Participants treated with linagliptin 5mg once daily for the first 30 weeks
Lina5Pio15 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 6 weeks and were titrated to linagliptin 5mg + pioglitazone 45mg for the next 24 weeks.

Measured Values
    Pio15     Pio30     Pio45     Lina5     Lina5Pio15     Lina5Pio30     Lina5Pio45  
Number of Participants Analyzed  
[units: participants]
  124     134     134     130     120     125     126  
Time to First Use of Rescue Therapy  
[units: Proportion¬†of¬†participants]
             
Proportion event-free     0.8117     0.8533     0.9051     0.7756     0.8854     0.9078     0.9548  
Standard Error     0.0382     0.0330     0.0273     0.0390     0.0313     0.0279     0.0198  

No statistical analysis provided for Time to First Use of Rescue Therapy



10.  Secondary:   Incidence of Rescue Therapy During the First 30 Weeks of Treatment   [ Time Frame: 30 weeks ]

Measure Type Secondary
Measure Title Incidence of Rescue Therapy During the First 30 Weeks of Treatment
Measure Description Rescue therapy was defined to include any new antidiabetic medication taken for hyperglycemia and introduced on or after the start date of study treatment and before the end date of study treatment.
Time Frame 30 weeks  
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.
FAS

Reporting Groups
  Description
Pio15 Participants treated with pioglitazone 15mg monotherapy for the first 30 weeks
Pio30 Participants treated with pioglitazone 30mg monotherapy for the first 30 weeks
Pio45 Participants treated with pioglitazone 30mg monotherapy for 6 weeks and were titrated to pioglitazone 45mg monotherapy for the next 24 weeks.
Lina5 Participants treated with linagliptin 5mg once daily for the first 30 weeks
Lina5Pio15 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 30 weeks
Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for the first 6 weeks and were titrated to linagliptin 5mg + pioglitazone 45mg for the next 24 weeks.

Measured Values
    Pio15     Pio30     Pio45     Lina5     Lina5Pio15     Lina5Pio30     Lina5Pio45  
Number of Participants Analyzed  
[units: participants]
  124     134     134     130     120     125     126  
Incidence of Rescue Therapy During the First 30 Weeks of Treatment  
[units: participants]
  20     17     11     26     12     10     5  


Statistical Analysis 1 for Incidence of Rescue Therapy During the First 30 Weeks of Treatment
Groups [1] Pio15 vs. Lina5Pio15
Method [2] Regression, Logistic
P Value [3] 0.3052
Odds Ratio (OR) [4] 0.649
95% Confidence Interval ( 0.284 to 1.482 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 2 for Incidence of Rescue Therapy During the First 30 Weeks of Treatment
Groups [1] Pio30 vs. Lina5Pio30
Method [2] Regression, Logistic
P Value [3] 0.0844
Odds Ratio (OR) [4] 0.456
95% Confidence Interval ( 0.187 to 1.112 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 3 for Incidence of Rescue Therapy During the First 30 Weeks of Treatment
Groups [1] Pio45 vs. Lina5Pio45
Method [2] Regression, Logistic
P Value [3] 0.1561
Odds Ratio (OR) [4] 0.443
95% Confidence Interval ( 0.143 to 1.365 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 4 for Incidence of Rescue Therapy During the First 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio15
Method [2] Regression, Logistic
P Value [3] 0.0146
Odds Ratio (OR) [4] 0.368
95% Confidence Interval ( 0.165 to 0.821 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 5 for Incidence of Rescue Therapy During the First 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio30
Method [2] Regression, Logistic
P Value [3] 0.0009
Odds Ratio (OR) [4] 0.238
95% Confidence Interval ( 0.102 to 0.557 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.

Statistical Analysis 6 for Incidence of Rescue Therapy During the First 30 Weeks of Treatment
Groups [1] Lina5 vs. Lina5Pio45
Method [2] Regression, Logistic
P Value [3] 0.0002
Odds Ratio (OR) [4] 0.141
95% Confidence Interval ( 0.050 to 0.397 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Treatment comparisons are for fixed dose combination versus monotherapy.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A logistic regression model with terms for treatment, continuous HbA1c baseline, prior use of antidiabetic agents and country.
[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:
  No text entered.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide 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
The study (Part B treatment only) was stopped early by protocol amendment #5, although Part A (time frame for all efficacy outcomes) proceeded to completion


  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: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
phone: 1-800-243-0127
e-mail: clintriage.rdg@boehringer-ingelheim.com


No publications provided


Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01183013     History of Changes
Other Study ID Numbers: 1264.3, 2008-008127-15
Study First Received: August 16, 2010
Results First Received: March 12, 2014
Last Updated: June 3, 2014
Health Authority: Estonia: The State Agency of Medicine
Germany: Federal Institute for Drugs and Medical Devices
Latvia: State Agency of Medicines
Spain: Spanish Agency of Medicines
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration