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Finding a Safe and Effective Dose of Linagliptin in Pediatric Patients With Type 2 Diabetes

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ClinicalTrials.gov Identifier: NCT01342484
Recruitment Status : Completed
First Posted : April 27, 2011
Results First Posted : September 15, 2016
Last Update Posted : September 15, 2016
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
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: placebo
Drug: BI1356 low dose
Drug: BI1356 high dose
Enrollment 40
Recruitment Details Randomised, double-blind, placebo-controlled parallel group dose-finding study of linagliptin over 12 weeks in children and adolescents, from 10 to 17 years of age, with type 2 diabetes mellitus. Due to serious Good clinical practice (GCP) breach, 1 patient excluded from all analyses. So protocol section has 40 subjects and participant flow has 39
Pre-assignment Details All patients suitable after screening underwent a 2-week open-label placebo run-in period before randomisation. Patients who successfully completed this period and who still met the inclusion/exclusion criteria were randomised to the 12-week randomised period in which they received either 1 of the 2 doses of linagliptin or placebo.
Arm/Group Title Placebo Linagliptin 1 mg Linagliptin 5 mg
Hide Arm/Group Description Matching placebo dose was administered orally once daily for 12 weeks Linagliptin 1 mg dose was administered orally once daily for 12 weeks Linagliptin 5 mg dose was administered orally once daily for 12 weeks
Period Title: Overall Study
Started 15 10 14
Completed 13 10 13
Not Completed 2 0 1
Reason Not Completed
Other Reasons             1             0             0
Protocol Violation             0             0             1
Withdrawal by Subject             1             0             0
Arm/Group Title Placebo Linagliptin 1 mg Linagliptin 5 mg Total
Hide Arm/Group Description Matching placebo dose was administered orally once daily for 12 weeks Linagliptin 1 mg dose was administered orally once daily for 12 weeks Linagliptin 5 mg dose was administered orally once daily for 12 weeks Total of all reporting groups
Overall Number of Baseline Participants 15 10 14 39
Hide Baseline Analysis Population Description
Treated set (TS) including all patients who were treated with at least one dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 15 participants 10 participants 14 participants 39 participants
13.7  (2.0) 14.0  (1.8) 14.3  (2.1) 14.0  (1.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants 10 participants 14 participants 39 participants
Female
8
  53.3%
4
  40.0%
9
  64.3%
21
  53.8%
Male
7
  46.7%
6
  60.0%
5
  35.7%
18
  46.2%
1.Primary Outcome
Title Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%) After 12 Weeks of Treatment
Hide Description Change from baseline in Glycosylated haemoglobin (HbA1c) [%] after 12 weeks of treatment with double-blind trial medication. Baseline was defined as the last observation before the first intake of any double-blind randomised trial medication. The number of participants analysed displays the number of participants with available data at the timepoint of interest.
Time Frame Baseline and 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) including all randomised patients who were treated with at least one dose of study drug and had a baseline and at least one on-treatment HbA1c assessment. Observed Case (OC): In the OC analysis, values after the use of rescue medication were set to missing.
Arm/Group Title Placebo Linagliptin 1 mg Linagliptin 5 mg
Hide Arm/Group Description:
Matching placebo dose was administered orally once daily for 12 weeks
Linagliptin 1 mg dose was administered orally once daily for 12 weeks
Linagliptin 5 mg dose was administered orally once daily for 12 weeks
Overall Number of Participants Analyzed 11 8 13
Least Squares Mean (Standard Error)
Unit of Measure: Percentage of HbA1c
0.45  (0.31) -0.03  (0.38) -0.19  (0.30)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin 1 mg
Comments Superiority of Linagliptin 1 mg vs. placebo: change from baseline in HbA1c using a restricted maximum likelihood (REML) - based mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c and age as linear covariates; treatment, gender, pharmacokinetic (PK) / pharmacodynamics (PD) subgroup, background therapy, visit and visit by treatment interaction as fixed effects and patient as a random effect. The unstructured covariance structure has been used to fit the mixed model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3295
Comments [Not Specified]
Method Mixed Models Analysis
Comments The Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.48
Confidence Interval (2-Sided) 95%
-1.47 to 0.51
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.48
Estimation Comments Mean Difference (Net Values) is actually the adjusted mean difference calculated as Linagliptin 1 mg minus Placebo.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin 5 mg
Comments Superiority of Linagliptin 5 mg vs. placebo: change from baseline in HbA1c using a restricted maximum likelihood (REML) - based mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c and age as linear covariates; treatment, gender, PK/PD subgroup, background therapy, visit and visit by treatment interaction as fixed effects and patient as a random effect. The unstructured covariance structure has been used to fit the mixed model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1447
Comments [Not Specified]
Method Mixed Models Analysis
Comments The Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.63
Confidence Interval (2-Sided) 95%
-1.50 to 0.23
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.42
Estimation Comments Mean Difference (Net Values) is actually the adjusted mean difference calculated as Linagliptin 5 mg minus Placebo.
2.Secondary Outcome
Title Dipeptidyl-peptidase-4 (DPP-4) Inhibition (%) at Trough at Steady State
Hide Description DPP-4 inhibition (%) at trough at steady state is the relative change between the measurement of DPP-4 activity taken 0.5 hours before dosing at baseline and the first available on-treatment measurement of DPP-4 activity taken 0.5 hour before dosing at week 4, 8 or 12: DPP-4 inhibition (%) = 100 - (DPP-4 activity at week X / DPP-4 activity at baseline) x 100.
Time Frame Baseline and 4 weeks or 8 weeks or 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) including all randomised patients who were treated with at least one dose of study drug and had a baseline and at least one on-treatment HbA1c assessment. OR (Original Results). The analysis excludes placebo patients and 1 FAS patient from Linagliptin 1 mg group.
Arm/Group Title Placebo Linagliptin 1 mg Linagliptin 5 mg
Hide Arm/Group Description:
Matching placebo dose was administered orally once daily for 12 weeks
Linagliptin 1 mg dose was administered orally once daily for 12 weeks
Linagliptin 5 mg dose was administered orally once daily for 12 weeks
Overall Number of Participants Analyzed 0 9 13
Median (Inter-Quartile Range)
Unit of Measure: Percentage of DPP-4 inhibition
38.4
(26.9 to 48.8)
78.9
(67.7 to 84.0)
3.Secondary Outcome
Title Change From Baseline in Fasting Plasma Glucose (FPG) After 12 Weeks of Treatment
Hide Description Change from baseline in FPG (mmol/L) after 12 weeks of treatment with double-blind trial medication. The number of participants analysed displays the number of participants with available data at the timepoint of interest.
Time Frame Baseline and 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) including all randomised patients who were treated with at least one dose of study drug and had a baseline and at least one on-treatment HbA1c assessment. Observed Case (OC): In the OC analysis, values after the use of rescue medication were set to missing.
Arm/Group Title Placebo Linagliptin 1 mg Linagliptin 5 mg
Hide Arm/Group Description:
Matching placebo dose was administered orally once daily for 12 weeks
Linagliptin 1 mg dose was administered orally once daily for 12 weeks
Linagliptin 5 mg dose was administered orally once daily for 12 weeks
Overall Number of Participants Analyzed 12 8 13
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
1.70  (0.85) 1.39  (1.07) -0.19  (0.83)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin 1 mg
Comments Superiority of Linagliptin 1 mg vs. placebo: change from baseline in FPG using a restricted maximum likelihood (REML) - based mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c, baseline FPG and age as linear covariates; treatment, gender, PK/PD subgroup, background therapy, visit and visit by treatment interaction as fixed effects and patient as a random effect. The unstructured covariance structure has been used to fit the mixed model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8216
Comments [Not Specified]
Method Mixed Models Analysis
Comments The Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.31
Confidence Interval (2-Sided) 95%
-3.08 to 2.46
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.36
Estimation Comments Mean Difference (Net Values) is actually the adjusted mean difference calculated as Linagliptin 1 mg minus Placebo.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin 5 mg
Comments Superiority of Linagliptin 5 mg vs. placebo: change from baseline in FPG using a restricted maximum likelihood (REML) - based mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c, baseline FPG and age as linear covariates; treatment, gender, PK/PD subgroup, background therapy, visit and visit by treatment interaction as fixed effects and patient as a random effect. The unstructured covariance structure has been used to fit the mixed model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1189
Comments [Not Specified]
Method Mixed Models Analysis
Comments The Kenward-Roger approximation was used to estimate denominator degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -1.90
Confidence Interval (2-Sided) 95%
-4.31 to 0.52
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.18
Estimation Comments Mean Difference (Net Values) is actually the adjusted mean difference calculated as Linagliptin 5 mg minus Placebo.
Time Frame From the first intake of study drug until 7 days after the last drug administration, up to 13 weeks.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Linagliptin 1 mg Linagliptin 5 mg
Hide Arm/Group Description Matching placebo dose was administered orally once daily for 12 weeks Linagliptin 1 mg dose was administered orally once daily for 12 weeks Linagliptin 5 mg dose was administered orally once daily for 12 weeks
All-Cause Mortality
Placebo Linagliptin 1 mg Linagliptin 5 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Linagliptin 1 mg Linagliptin 5 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/15 (6.67%)   0/10 (0.00%)   0/14 (0.00%) 
Metabolism and nutrition disorders       
Hyperglycaemia  1  1/15 (6.67%)  0/10 (0.00%)  0/14 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Linagliptin 1 mg Linagliptin 5 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   7/15 (46.67%)   8/10 (80.00%)   6/14 (42.86%) 
Endocrine disorders       
Hyperthyroidism  1  1/15 (6.67%)  0/10 (0.00%)  0/14 (0.00%) 
Eye disorders       
Eye haemorrhage  1  0/15 (0.00%)  1/10 (10.00%)  0/14 (0.00%) 
Gastrointestinal disorders       
Diarrhoea  1  0/15 (0.00%)  1/10 (10.00%)  0/14 (0.00%) 
Lip oedema  1  1/15 (6.67%)  0/10 (0.00%)  0/14 (0.00%) 
Toothache  1  1/15 (6.67%)  0/10 (0.00%)  0/14 (0.00%) 
Infections and infestations       
Conjunctivitis bacterial  1  0/15 (0.00%)  1/10 (10.00%)  0/14 (0.00%) 
Influenza  1  1/15 (6.67%)  0/10 (0.00%)  0/14 (0.00%) 
Nasopharyngitis  1  1/15 (6.67%)  3/10 (30.00%)  0/14 (0.00%) 
Respiratory tract infection  1  1/15 (6.67%)  0/10 (0.00%)  0/14 (0.00%) 
Vulvovaginitis  1  0/15 (0.00%)  0/10 (0.00%)  1/14 (7.14%) 
Injury, poisoning and procedural complications       
Joint injury  1  1/15 (6.67%)  0/10 (0.00%)  0/14 (0.00%) 
Investigations       
Blood creatinine increased  1  0/15 (0.00%)  1/10 (10.00%)  0/14 (0.00%) 
Metabolism and nutrition disorders       
Hyperglycaemia  1  0/15 (0.00%)  2/10 (20.00%)  0/14 (0.00%) 
Hypoglycaemia  1  0/15 (0.00%)  0/10 (0.00%)  1/14 (7.14%) 
Nervous system disorders       
Dizziness  1  0/15 (0.00%)  1/10 (10.00%)  0/14 (0.00%) 
Headache  1  1/15 (6.67%)  0/10 (0.00%)  4/14 (28.57%) 
Paraesthesia  1  0/15 (0.00%)  1/10 (10.00%)  1/14 (7.14%) 
Reproductive system and breast disorders       
Menorrhagia  1  0/15 (0.00%)  1/10 (10.00%)  0/14 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Cough  1  1/15 (6.67%)  1/10 (10.00%)  0/14 (0.00%) 
Epistaxis  1  1/15 (6.67%)  0/10 (0.00%)  0/14 (0.00%) 
Rhinorrhoea  1  0/15 (0.00%)  0/10 (0.00%)  1/14 (7.14%) 
Skin and subcutaneous tissue disorders       
Dermatitis  1  0/15 (0.00%)  1/10 (10.00%)  0/14 (0.00%) 
Dermatitis allergic  1  0/15 (0.00%)  0/10 (0.00%)  1/14 (7.14%) 
Skin hyperpigmentation  1  0/15 (0.00%)  0/10 (0.00%)  1/14 (7.14%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
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.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01342484     History of Changes
Other Study ID Numbers: 1218.56
2009-017004-91 ( EudraCT Number: EudraCT )
First Submitted: April 26, 2011
First Posted: April 27, 2011
Results First Submitted: July 27, 2016
Results First Posted: September 15, 2016
Last Update Posted: September 15, 2016