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Comparison of the Bioavailability of Metformin Between Medium Dose Linagliptin/Metformin Tablets and Medium Dose Glucophage Tablet Given With Linagliptin Tablet

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ClinicalTrials.gov Identifier: NCT01383356
Recruitment Status : Completed
First Posted : June 28, 2011
Results First Posted : January 24, 2013
Last Update Posted : March 28, 2014
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Diabetes Mellitus, Type 2
Interventions Drug: Metformin Single Tablet
Drug: Linagliptin/Metformin Combo
Drug: Linagliptin Single Tablet
Enrollment 58

Recruitment Details 18 subjects were enrolled in the original study (June 2011 to July 2011) and 40 in the add-on study (November 2011 to December 2011) which was an option provided by protocol to increase the subject number. As no significant STUDY and STUDY-by-TREATMENT effect was revealed in analysis of pooled data, final analysis was performed on pooled data.
Pre-assignment Details This is a 2 period, 2 sequence, 2 treatment crossover. Subjects were randomized to one of the two sequences AB or BA. The duration of washout was at least 35 days between dosing.
Arm/Group Title Lina/Met 2.5mg/500mg Then Lina 2.5mg Plus Met 500mg Lina 2.5mg Plus Met 500mg Then Lina/Met 2.5mg/500mg
Hide Arm/Group Description Combination tablet Linagliptin (Lina) /Metformin (Met) 2.5mg/500mg followed by single tablets Linagliptin 2.5mg plus Metformin 500mg Single tablets Linagliptin 2.5mg plus Metformin 500mg followed by combination tablet Linagliptin/Metformin 2.5mg/500mg
Period Title: Period 1
Started 29 [1] 29 [1]
Completed 21 [2] 23 [2]
Not Completed 8 6
Reason Not Completed
Adverse Event             5             3
Non-compliance             3             0
Out of Range Mid-study-Test             0             1
Personal             0             2
[1]
Entered and treated.
[2]
Completed period 1.
Period Title: Washout Period (at Least 35 Days)
Started 21 23
Completed 21 23
Not Completed 0 0
Period Title: Period 2
Started 21 [1] 23 [1]
Completed 21 [2] 23 [2]
Not Completed 0 0
[1]
Entered and treated.
[2]
Completed period 2.
Arm/Group Title Entire Study Population
Hide Arm/Group Description Total number of subjects randomised and treated in the study.
Overall Number of Baseline Participants 58
Hide Baseline Analysis Population Description
Dosed participants from combined studies
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 58 participants
35  (9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants
Female
32
  55.2%
Male
26
  44.8%
1.Primary Outcome
Title Maximum Plasma Concentration (Cmax)
Hide Description Maximum measured concentration of metformin in plasma, per period.
Time Frame Prior to drug administration and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 24, 30, and 36 hours post dose in each treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All subjects having all samples in all periods and subjects who missed samples that may not affect the estimation of pharmacokinetic parameters in any period.
Arm/Group Title Lina/Met 2.5mg/500mg Lina 2.5mg Plus Met 500mg
Hide Arm/Group Description:
Combination tablet
Single tablets
Overall Number of Participants Analyzed 44 44
Mean (Standard Deviation)
Unit of Measure: ng/ml
901.82  (262.45) 770.52  (189.44)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lina/Met 2.5mg/500mg, Lina 2.5mg Plus Met 500mg
Comments The two formulations are shown to be bioequivalent if the geometric mean ratio is contained within the 80 to 125 percent range both on measured data (statistical analysis 1) and on potency corrected data (percent potency of label claim) (statistical analysis 2). ANOVA was applied to log-transformed Cmax and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence
Method of Estimation Estimation Parameter Geometric mean ratio (GMR) in percent
Estimated Value 118
Confidence Interval (2-Sided) 90%
111 to 125
Estimation Comments Lina/Met 2.5mg/500mg versus (vs.) Lina 2.5mg plus Met 500mg.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Lina/Met 2.5mg/500mg, Lina 2.5mg Plus Met 500mg
Comments ANOVA was applied to log-transformed Cmax and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction. Results were potency corrected (GMR multiplied by the quotient of drug potency (DP) of Met in single tablet and DP of Met in combination tablet).
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence
Method of Estimation Estimation Parameter GMR, potency corrected (percent)
Estimated Value 122
Confidence Interval (2-Sided) 90%
114 to 130
Estimation Comments Lina/Met 2.5mg/500mg vs. Lina 2.5mg plus Met 500mg.
2.Primary Outcome
Title Area Under the Curve 0 to Last Measurable Value (AUC0-t)
Hide Description AUC0-t is the area under the concentration versus time curve of metformin in plasma, from time zero (0) to the time of the last measurable analyte concentration (t), as calculated by the linear trapezoidal method.
Time Frame Prior to drug administration and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 24, 30, and 36 hours post dose in each treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All subjects having all samples in all periods and subjects who missed samples that may not affect the estimation of pharmacokinetic parameters in any period
Arm/Group Title Lina/Met 2.5mg/500mg Lina 2.5mg Plus Met 500mg
Hide Arm/Group Description:
Combination tablet
Single tablets
Overall Number of Participants Analyzed 44 44
Mean (Standard Deviation)
Unit of Measure: ng*h/ml
7079.65  (1688.14) 6808.27  (1708.20)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lina/Met 2.5mg/500mg, Lina 2.5mg Plus Met 500mg
Comments The two formulations are shown to be bioequivalent if the 90 percent confidence interval of geometric mean ratio is entirely contained within the 80 to125 percent range both on measured data (statistical analysis 1) and potency corrected data (percent potency of label claim) (statistical analysis 2). ANOVA was applied to log-transformed AUC0-t and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence
Method of Estimation Estimation Parameter Geometric mean ratio (percent)
Estimated Value 105
Confidence Interval 90%
101 to 108
Estimation Comments Lina/Met 2.5mg/500mg vs. Lina 2.5mg plus Met 500mg.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Lina/Met 2.5mg/500mg, Lina 2.5mg Plus Met 500mg
Comments ANOVA was applied to log-transformed AUC0-t and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction. Results were potency corrected (GMR multiplied by the quotient of DP of Met in single tablet and DP of Met in combination tablet).
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence
Method of Estimation Estimation Parameter GMR, potency corrected (percent)
Estimated Value 108
Confidence Interval 90%
105 to 112
Estimation Comments Lina/Met 2.5mg/500mg vs.Lina 2.5mg plus Met 500mg.
3.Secondary Outcome
Title Area Under the Curve 0 to Inf (AUC0-inf)
Hide Description AUC0-inf is the area under the concentration versus time curve of metformin in plasma from time zero extrapolated to infinity.
Time Frame Prior to drug administration and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 24, 30, and 36 hours post dose in each treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All subjects having all samples in all periods and subjects who missed samples that may not affect the estimation of pharmacokinetic parameters in any period
Arm/Group Title Lina/Met 2.5mg/500mg Lina 2.5mg Plus Met 500mg
Hide Arm/Group Description:
Combination tablet
Single tablets
Overall Number of Participants Analyzed 44 44
Mean (Standard Deviation)
Unit of Measure: ng*h/ml
7198.79  (1689.89) 6923.79  (1714.08)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lina/Met 2.5mg/500mg, Lina 2.5mg Plus Met 500mg
Comments ANOVA was applied to log-transformed AUC0-inf and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence (BE), AUC0-inf was no BE criteria
Method of Estimation Estimation Parameter Geometric mean ratio (percent)
Estimated Value 105
Confidence Interval 90%
101 to 108
Estimation Comments Lina/Met 2.5mg/500mg vs. Lina 2.5mg plus Met 500mg.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Lina/Met 2.5mg/500mg, Lina 2.5mg Plus Met 500mg
Comments ANOVA was applied to log-transformed AUC0-inf and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction. Results were potency corrected (GMR multiplied by the quotient of DP of Met in single tablet and DP of Met in combination tablet).
Type of Statistical Test Non-Inferiority or Equivalence
Comments BE, AUC0-inf was no BE criteria
Method of Estimation Estimation Parameter GMR, potency corrected (percent)
Estimated Value 108
Confidence Interval 90%
105 to 112
Estimation Comments Lina/Met 2.5mg/500mg vs. Lina 2.5mg plus Met 500mg.
Time Frame Period 1 (36 hours)+ Washout (35 days) +Period 2 (36 hours)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Lina/Met 2.5mg/500mg Lina 2.5mg Plus Met 500mg
Hide Arm/Group Description Combination tablet Single tablets
All-Cause Mortality
Lina/Met 2.5mg/500mg Lina 2.5mg Plus Met 500mg
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Lina/Met 2.5mg/500mg Lina 2.5mg Plus Met 500mg
Affected / at Risk (%) Affected / at Risk (%)
Total   0/52 (0.00%)   0/50 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Lina/Met 2.5mg/500mg Lina 2.5mg Plus Met 500mg
Affected / at Risk (%) Affected / at Risk (%)
Total   17/52 (32.69%)   21/50 (42.00%) 
Gastrointestinal disorders     
Diarrhoea  1  0/52 (0.00%)  3/50 (6.00%) 
Nausea  1  9/52 (17.31%)  8/50 (16.00%) 
Vomiting  1  4/52 (7.69%)  3/50 (6.00%) 
Metabolism and nutrition disorders     
Decreased appetite  1  0/52 (0.00%)  3/50 (6.00%) 
Hypoglycaemia  1  0/52 (0.00%)  3/50 (6.00%) 
Nervous system disorders     
Dizziness  1  6/52 (11.54%)  4/50 (8.00%) 
Headache  1  7/52 (13.46%)  9/50 (18.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
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
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01383356     History of Changes
Other Study ID Numbers: 1288.19
First Submitted: June 27, 2011
First Posted: June 28, 2011
Results First Submitted: December 18, 2012
Results First Posted: January 24, 2013
Last Update Posted: March 28, 2014