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Bioequivalence of Metformin Under Fed Conditions After Administration of Linagliptin / Metformin Fixed Dose Combination Tablet and Single Tablets

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ClinicalTrials.gov Identifier: NCT01581931
Recruitment Status : Completed
First Posted : April 20, 2012
Results First Posted : August 20, 2013
Last Update Posted : August 20, 2013
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: Treatment
Condition Healthy
Interventions Drug: Linagliptin/metformin
Drug: Metformin
Drug: Linagliptin
Enrollment 32
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Lina+Met Single Tablets / Lina+Met FDC Tablet Lina+Met FDC Tablet / Lina+Met Single Tablets
Hide Arm/Group Description Subjects are treated with single linagliptin 2.5 mg and metformin 500 mg tablets in the first period. After a washout period of at least 35 days, the subjects are treated with a 2.5 mg linagliptin / 500 mg metformin fixed-dose-combination (FDC) tablet in period 2. Subjects are treated with a 2.5 mg linagliptin / 500 mg metformin fixed-dose-combination (FDC) tablet in the first period. After a washout period of at least 35 days, the subjects are treated with single linagliptin 2.5 mg and metformin 500 mg tablets in period 2.
Period Title: First Period
Started 16 16
Completed 16 16
Not Completed 0 0
Period Title: Washout
Started 16 16
Completed 16 15
Not Completed 0 1
Reason Not Completed
Adverse Event             0             1
Period Title: Second Period
Started 16 15
Completed 16 15
Not Completed 0 0
Arm/Group Title Overall Study
Hide Arm/Group Description This was an open-label, randomised, single dose, 2-way crossover trial with 2 treatments and 2 treatment sequences. The single dose administrations in each treatment period were separated by a washout period of at least 35 days.
Overall Number of Baseline Participants 32
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 32 participants
38.8  (9.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 32 participants
Female
17
  53.1%
Male
15
  46.9%
1.Primary Outcome
Title Area Under Curve From 0 to tz Hours (AUC0-tz) of Metformin
Hide Description AUC0-tz represents the area under the concentration curve of metformin in plasma from 0 to the time of the last quantifiable plasma contentration of the analyte. Note, the geometric mean is actually an adjusted geometric mean.
Time Frame 0:20, 0:40, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 24, 34, 48, 72 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set - all subjects taking at least 1 dose of trial medication
Arm/Group Title Lina+Met Single Tablets Lina+Met FDC Tablet
Hide Arm/Group Description:
Subjects are treated with single linagliptin 2.5 mg and metformin 500 mg tablets
Subjects are treated with a 2.5 mg linagliptin / 500 mg metformin fixed-dose-combination (FDC) tablet
Overall Number of Participants Analyzed 30 32
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng·h/mL
7219.03
(9.8%)
7057.52
(9.8%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lina+Met Single Tablets, Lina+Met FDC Tablet
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Equivalence margin: the 90% confidence intervall has to be within the intervall (80%, 125%)
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted geometric mean ratio
Estimated Value 97.76
Confidence Interval (2-Sided) 90%
93.64 to 102.07
Parameter Dispersion
Type: Standard Deviation
Value: 9.8
Estimation Comments Numerator: FDC tablet; denominator: single tablets of linagliptin and metformin; The dispersion parameter is actually the geometric coefficient of variation.
2.Primary Outcome
Title Maximum Concentration (Cmax) of Metformin
Hide Description Cmax represents the maximum concentration of metformin in plasma. Note, the geometric mean is actually an adjusted geometric mean.
Time Frame 0:20, 0:40, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 24, 34, 48, 72 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set - all subjects taking at least 1 dose of trial medication
Arm/Group Title Lina+Met Single Tablets Lina+Met FDC Tablet
Hide Arm/Group Description:
Subjects are treated with single linagliptin 2.5 mg and metformin 500 mg tablets
Subjects are treated with a 2.5 mg linagliptin / 500 mg metformin fixed-dose-combination (FDC) tablet
Overall Number of Participants Analyzed 30 32
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
855.09
(10.0%)
844.72
(10.0%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lina+Met Single Tablets, Lina+Met FDC Tablet
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Equivalence margin: the 90% confidence intervall has to be within the intervall (80%, 125%)
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted geometric mean ratio
Estimated Value 98.79
Confidence Interval (2-Sided) 90%
94.55 to 103.21
Parameter Dispersion
Type: Standard Deviation
Value: 10.0
Estimation Comments Numerator: FDC tablet; denominator: single tablets of linagliptin and metformin; The dispersion parameter is actually the geometric coefficient of variation.
3.Secondary Outcome
Title Area Under Curve From 0 to Infinity Hours (AUC0-infty) of Metformin
Hide Description AUC0-infty represents the area under the concentration curve of metformin in plasma from time 0 extrapolated to infinity. Note, the geometric mean is actually an adjusted geometric mean.
Time Frame 0:20, 0:40, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 24, 34, 48, 72 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set - all subjects taking at least 1 dose of trial medication
Arm/Group Title Lina+Met Single Tablets Lina+Met FDC Tablet
Hide Arm/Group Description:
Subjects are treated with single linagliptin 2.5 mg and metformin 500 mg tablets
Subjects are treated with a 2.5 mg linagliptin / 500 mg metformin fixed-dose-combination (FDC) tablet
Overall Number of Participants Analyzed 30 32
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng·h/mL
7343.59
(9.7%)
7174.30
(9.7%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lina+Met Single Tablets, Lina+Met FDC Tablet
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Equivalence margin: the 90% confidence intervall has to be within the intervall (80%, 125%)
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted geometric mean ratio
Estimated Value 97.69
Confidence Interval (2-Sided) 95%
93.63 to 101.94
Parameter Dispersion
Type: Standard Deviation
Value: 9.7
Estimation Comments Numerator: FDC tablet; denominator: single tablets of linagliptin and metformin; The dispersion parameter is actually the geometric coefficient of variation.
4.Secondary Outcome
Title Time to Maximum Concentration (Tmax) of Metformin
Hide Description Time from dosing to the maximum concentration of metformin in plasma.
Time Frame 0:20, 0:40, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 24, 34, 48, 72 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set - all subjects taking at least 1 dose of trial medication
Arm/Group Title Lina+Met Single Tablets Lina+Met FDC Tablet
Hide Arm/Group Description:
Subjects are treated with single linagliptin 2.5 mg and metformin 500 mg tablets
Subjects are treated with a 2.5 mg linagliptin / 500 mg metformin fixed-dose-combination (FDC) tablet
Overall Number of Participants Analyzed 30 32
Median (Full Range)
Unit of Measure: Hours
4.00
(2.00 to 6.00)
4.00
(1.00 to 6.00)
5.Secondary Outcome
Title Terminal Half-life t1/2 of Metformin
Hide Description The terminal half-life of metformin in plasma is denoted by t1/2.
Time Frame 0:20, 0:40, 1, 1:30, 2, 3, 4, 5, 6, 8, 12, 24, 34, 48, 72 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set - all subjects taking at least 1 dose of trial medication
Arm/Group Title Lina+Met Single Tablets Lina+Met FDC Tablet
Hide Arm/Group Description:
Subjects are treated with single linagliptin 2.5 mg and metformin 500 mg tablets
Subjects are treated with a 2.5 mg linagliptin / 500 mg metformin fixed-dose-combination (FDC) tablet
Overall Number of Participants Analyzed 30 32
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Hours
9.14
(87.4%)
8.03
(86.0%)
Time Frame First treatment with study drug until End-of-Study (which was within 4 to 14 days after last study drug administration), i.e., 39 to 49 days after first treatment with study drug.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Lina+Met Single Tablets Lina+Met FDC Tablet
Hide Arm/Group Description Subjects are treated with single linagliptin 2.5 mg and metformin 500 mg tablets Subjects are treated with a 2.5 mg linagliptin / 500 mg metformin fixed-dose-combination (FDC) tablet
All-Cause Mortality
Lina+Met Single Tablets Lina+Met FDC Tablet
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Lina+Met Single Tablets Lina+Met FDC Tablet
Affected / at Risk (%) Affected / at Risk (%)
Total   0/31 (0.00%)   1/32 (3.13%) 
Injury, poisoning and procedural complications     
Clavicle fracture  1  0/31 (0.00%)  1/32 (3.13%) 
Road traffic accident  1  0/31 (0.00%)  1/32 (3.13%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 15.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Lina+Met Single Tablets Lina+Met FDC Tablet
Affected / at Risk (%) Affected / at Risk (%)
Total   6/31 (19.35%)   9/32 (28.13%) 
Gastrointestinal disorders     
Diarrhoea  1  1/31 (3.23%)  2/32 (6.25%) 
Nausea  1  2/31 (6.45%)  2/32 (6.25%) 
Vomiting  1  2/31 (6.45%)  0/32 (0.00%) 
Infections and infestations     
Nasopharyngitis  1  0/31 (0.00%)  2/32 (6.25%) 
Nervous system disorders     
Headache  1  5/31 (16.13%)  5/32 (15.63%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 15.0
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
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
ClinicalTrials.gov Identifier: NCT01581931     History of Changes
Other Study ID Numbers: 1288.20
2011-005423-41 ( EudraCT Number: EudraCT )
First Submitted: April 19, 2012
First Posted: April 20, 2012
Results First Submitted: June 14, 2013
Results First Posted: August 20, 2013
Last Update Posted: August 20, 2013