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A Randomised, db, Placebo-controlled Study of BI 1356 for 18 Weeks Followed by a 34 Week Double-blind Extension Period (Placebo Patients Switched to Glimepiride) in Type 2 Diabetic Patients for Whom Treatment With Metformin is Inappropriate

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ClinicalTrials.gov Identifier: NCT00740051
Recruitment Status : Completed
First Posted : August 22, 2008
Results First Posted : October 26, 2011
Last Update Posted : June 27, 2014
Sponsor:
Information provided by:
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Diabetes Mellitus, Type 2
Interventions Drug: Linagliptin
Drug: Linagliptin Placebo
Drug: Glimepiride
Enrollment 227
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo/Glimepiride Linagliptin
Hide Arm/Group Description Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks) Patients treated with Linagliptin 5mg once daily (up to 52 weeks)
Period Title: Overall Study
Started 76 151
Completed 58 119
Not Completed 18 32
Reason Not Completed
Lack of Efficacy             2             5
Adverse Event             1             4
Protocol Violation             2             6
Lost to Follow-up             3             8
Withdrawal by Subject             6             8
Other reason (not specified)             4             1
Arm/Group Title Placebo/Glimepiride Linagliptin Total
Hide Arm/Group Description Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks) Patients treated with Linagliptin 5mg once daily (up to 52 weeks) Total of all reporting groups
Overall Number of Baseline Participants 76 151 227
Hide Baseline Analysis Population Description
Number of participants and other baseline values taken from interim analysis.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 76 participants 151 participants 227 participants
56.7  (9.7) 56.4  (10.6) 56.5  (10.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 76 participants 151 participants 227 participants
Female
43
  56.6%
96
  63.6%
139
  61.2%
Male
33
  43.4%
55
  36.4%
88
  38.8%
Body Mass Index (BMI) continuous  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 76 participants 151 participants 227 participants
30.19  (4.97) 29.09  (5.62) 29.46  (5.42)
Glycosylated hemoglobin (HbA1c) - Interim Analysis   [1] 
Mean (Standard Deviation)
Unit of measure:  Percent
Number Analyzed 76 participants 151 participants 227 participants
8.06  (0.89) 8.11  (0.95) 8.09  (0.93)
[1]
Measure Description: Baseline HbA1c was determined for the Full Analysis Set with a total of 73 patients treated with Placebo and 147 patients treated with Linagliptin (220 in total).
Fasting blood plasma (FPG) glucose   [1] 
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 76 participants 151 participants 227 participants
180.5  (44.7) 183.3  (46.4) 182.4  (45.8)
[1]
Measure Description: Baseline fasting blood plasma glucose was determined for the Full Analysis Set with a total of 73 patients treated with Placebo and 147 patients treated with Linagliptin (220 in total).
1.Primary Outcome
Title HbA1c Change From Baseline at Week 18 (Interim Analysis)
Hide Description HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the Week 0 HbA1c percent. Means are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance.
Time Frame Baseline and week 18
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) included all treated patients with a baseline and at least one on-treatment HbA1c measurement available during the first phase of the study. Last Observation Carried Forward (LOCF) was used as the imputation rule.
Arm/Group Title Placebo Linagliptin
Hide Arm/Group Description:
Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks)
Patients treated with Linagliptin 5mg once daily (up to 52 weeks)
Overall Number of Participants Analyzed 73 147
Mean (Standard Error)
Unit of Measure: percent
0.14  (0.16) -0.44  (0.14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin
Comments Linagliptin versus Placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No adjustment of p-values
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.57
Confidence Interval 95%
-0.86 to -0.29
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.14
Estimation Comments [Not Specified]
2.Primary Outcome
Title HbA1c Change From Baseline at Week 18 (Final Analysis)
Hide Description HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the Week 0 HbA1c percent. Means are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance. HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the Week 0 HbA1c percent. Means are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance. The primary analysis was re-run at the completion of the study in the final study report.
Time Frame Baseline and week 18
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) included all treated patients with a baseline and at least one on-treatment HbA1c measurement available during the first phase of the study. Last observation carried forward (LOCF) was used as the imputation rule.
Arm/Group Title Placebo Linagliptin
Hide Arm/Group Description:
Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks)
Patients treated with Linagliptin 5mg once daily (up to 52 weeks)
Overall Number of Participants Analyzed 73 147
Mean (Standard Error)
Unit of Measure: percent
0.21  (0.16) -0.39  (0.14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin
Comments Linagliptin versus Placebo. The primary analysis performed at the interim was re-run at the end of the study to accommodate changes made to the final study database.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No adjustment of p-values
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.60
Confidence Interval 95%
-0.88 to -0.32
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.14
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Fasting Plasma Glucose (FPG) Change From Baseline at Week 18 (Interim Analysis)
Hide Description This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. Means are adjusted for baseline FPG, baseline HbA1c, prior OADs and reason for metformin intolerance (Interim Analysis).
Time Frame Baseline and week 18
Hide Outcome Measure Data
Hide Analysis Population Description
All patients in FAS with values for FPG at baseline and at week 18. Last Observation Carried Forward (LOCF) was used as the imputation rule (Interim Analysis).
Arm/Group Title Placebo Linagliptin
Hide Arm/Group Description:
Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks)
Patients treated with Linagliptin 5mg once daily (up to 52 weeks)
Overall Number of Participants Analyzed 66 138
Mean (Standard Error)
Unit of Measure: mg/dl
7.2  (6.0) -13.3  (5.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin
Comments Linagliptin versus Placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments No adjustment of p-values
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -20.5
Confidence Interval 95%
-31.1 to -9.9
Parameter Dispersion
Type: Standard Error of the mean
Value: 5.4
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Patients With HbA1c<7.0 at Week 18 (Interim Analysis)
Hide Description Odds ratios are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance.
Time Frame Week 18
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) patients with baseline HbA1c >= 7.0%. Patients without a value at week 18 were analysed as non-responders.
Arm/Group Title Placebo Linagliptin
Hide Arm/Group Description:
Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks)
Patients treated with Linagliptin 5mg once daily (up to 52 weeks)
Overall Number of Participants Analyzed 68 136
Measure Type: Number
Unit of Measure: percent of patients
11.8 23.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin
Comments Linagliptin versus Placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0374
Comments No adjustment of p-values
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.576
Confidence Interval 95%
1.057 to 6.279
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentage of Patients With HbA1c<6.5 at Week 18 (Interim Analysis)
Hide Description Odds ratios are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance.
Time Frame Week 18
Hide Outcome Measure Data
Hide Analysis Population Description
FAS patients with baseline HbA1c >= 6.5%. Patients without a value at Week 18 were analysed as non-responders.
Arm/Group Title Placebo Linagliptin
Hide Arm/Group Description:
Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks)
Patients treated with Linagliptin 5mg once daily (up to 52 weeks)
Overall Number of Participants Analyzed 70 146
Measure Type: Number
Unit of Measure: percent of patients
2.9 8.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin
Comments Linagliptin vs. Placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1281
Comments No adjustment of p-values
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.285
Confidence Interval 95%
0.710 to 15.196
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Percentage of Patients With HbA1c Lowering by 0.5% at Week 18 (Interim Analysis)
Hide Description Odds ratios are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance.
Time Frame Week 18
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) included all treated patients with a baseline and at least one on-treatment HbA1c measurement available during the first phase of the study. Patients without a value at week 18 were analysed as non-responders.
Arm/Group Title Placebo Linagliptin
Hide Arm/Group Description:
Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks)
Patients treated with Linagliptin 5mg once daily (up to 52 weeks)
Overall Number of Participants Analyzed 73 147
Measure Type: Number
Unit of Measure: percent of patients
17.8 36.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin
Comments Linagliptin versus Placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0046
Comments No adjustment of p-values
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.801
Confidence Interval 95%
1.374 to 5.711
Estimation Comments [Not Specified]
7.Secondary Outcome
Title The Change in HbA1c From Baseline by Visit Over Time
Hide Description HbA1c is measured as a percentage. Thus, this change from baseline reflects the HbA1c percent (at weeks 6, 12, 18, 22, 26, 30, 34, 40, 46, 52) minus the Week 0 HbA1c percent.
Time Frame Baseline and weeks 6,12, 18, 22, 26, 30, 34, 40, 46, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set (OC)
Arm/Group Title Placebo/Glimepiride Linagliptin
Hide Arm/Group Description:
Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks)
Patients treated with Linagliptin 5mg once daily (up to 52 weeks)
Overall Number of Participants Analyzed 76 151
Mean (Standard Deviation)
Unit of Measure: percent
Change from baseline at week 6 (N=64, 136) 0.26  (0.98) -0.21  (0.77)
Change from baseline at week 12 (N=57, 129) 0.26  (1.08) -0.43  (0.84)
Change from baseline at week 18 (N=47, 118) 0.10  (1.06) -0.38  (0.87)
Change from baseline at week 22 (N=46, 113) -0.32  (0.82) -0.40  (0.94)
Change from baseline at week 26 (N=50, 110) -0.53  (0.93) -0.48  (0.92)
Change from baseline at week 30 (N=49, 98) -0.79  (1.06) -0.49  (0.92)
Change from baseline at week 34 (N=50, 96) -0.75  (0.95) -0.49  (0.88)
Change from baseline at week 40 (N=49, 94) -0.73  (1.11) -0.45  (0.90)
Change from baseline at week 46 (N=45, 92) -0.78  (1.04) -0.42  (0.96)
Change from baseline at week 52 (N=45, 92) -0.72  (1.01) -0.44  (1.00)
8.Secondary Outcome
Title The Change in FPG From Baseline by Visit Over Time
Hide Description This change from baseline reflects the FPG (at weeks 6, 12, 18, 22, 26, 30, 34, 40, 46, 52) minus the Week 0 FPG.
Time Frame Baseline and weeks 6,12,18, 22, 26, 30, 34, 40, 46, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set (OC)
Arm/Group Title Placebo/Glimepiride Linagliptin
Hide Arm/Group Description:
Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks)
Patients treated with Linagliptin 5mg once daily (up to 52 weeks)
Overall Number of Participants Analyzed 76 151
Mean (Standard Deviation)
Unit of Measure: mg/dL
Change from baseline at week 6 (N=63, 134) 9.7  (30.7) -8.4  (41.0)
Change from baseline at week 12 (N=55,92) 5.4  (33.0) -14.3  (37.3)
Change from baseline at week 18 (N=47, 115) 5.0  (32.4) -12.9  (35.9)
Change from baseline at week 22 (N=46, 110) -19.3  (33.3) -14.0  (41.8)
Change from baseline at week 26 (N=50, 108) -22.6  (33.8) -17.0  (37.8)
Change from baseline at week 30 (N=48, 95) -31.4  (29.5) -19.1  (39.1)
Change from baseline at week 34 (N=48, 95) -25.6  (35.2) -15.8  (36.0)
Change from baseline at week 40 (N=47, 92) -19.5  (33.2) -19.0  (36.9)
Change from baseline at week 46 (N=47, 92) -22.8  (32.3) -18.1  (38.8)
Change from baseline at week 52 (N=43, 86) -19.1  (30.1) -14.0  (37.1)
Time Frame 52 weeks + 7 days
Adverse Event Reporting Description These are the total results after the final completion of the study after 52 weeks. The time frame 52 weeks + 7 days (post-trt) is the maximum time frame. Some patients were not followed up for this long, and will correspondingly have had less opportunity to report the events.
 
Arm/Group Title Placebo/Glimepiride Linagliptin
Hide Arm/Group Description Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks) Patients treated with Linagliptin 5mg once daily (up to 52 weeks)
All-Cause Mortality
Placebo/Glimepiride Linagliptin
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Placebo/Glimepiride Linagliptin
Affected / at Risk (%) Affected / at Risk (%)
Total   3/76 (3.95%)   1/151 (0.66%) 
Cardiac disorders     
Acute myocardial infarction  1  1/76 (1.32%)  0/151 (0.00%) 
Myocardial infarction  1  0/76 (0.00%)  1/151 (0.66%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Colon cancer  1  1/76 (1.32%)  0/151 (0.00%) 
Nervous system disorders     
Cerebral infarction  1  1/76 (1.32%)  0/151 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo/Glimepiride Linagliptin
Affected / at Risk (%) Affected / at Risk (%)
Total   40/76 (52.63%)   59/151 (39.07%) 
Gastrointestinal disorders     
Abdominal pain upper  1  4/76 (5.26%)  3/151 (1.99%) 
General disorders     
Fatigue  1  5/76 (6.58%)  2/151 (1.32%) 
Infections and infestations     
Influenza  1  2/76 (2.63%)  8/151 (5.30%) 
Nasopharyngitis  1  6/76 (7.89%)  15/151 (9.93%) 
Upper respiratory tract infection  1  7/76 (9.21%)  6/151 (3.97%) 
Metabolism and nutrition disorders     
Hyperglycaemia  1  14/76 (18.42%)  22/151 (14.57%) 
Hypoglycaemia  1  4/76 (5.26%)  5/151 (3.31%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  4/76 (5.26%)  6/151 (3.97%) 
Nervous system disorders     
Dizziness  1  4/76 (5.26%)  11/151 (7.28%) 
Headache  1  6/76 (7.89%)  8/151 (5.30%) 
Psychiatric disorders     
Anxiety  1  4/76 (5.26%)  0/151 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Primary analysis (at interim) was rerun using final study database
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.
Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00740051    
Other Study ID Numbers: 1218.50
2007-007485-38 ( EudraCT Number: EudraCT )
First Submitted: August 21, 2008
First Posted: August 22, 2008
Results First Submitted: August 3, 2011
Results First Posted: October 26, 2011
Last Update Posted: June 27, 2014