Diabetes Mellitus, Type 2
Conditions
Brief summary
The main objective of this study is to identify the dose of linagliptin in paediatric patients. Other efficacy objectives include the comparison of the lowering effect of linagliptin low dose, high dose and placebo on the fasting plasma glucose (FPG) observed after 12 wk of treatment. Furthermore, the study will investigate the pharmacokinetics (PK), the pharmacodynamics (PD) and the PK/PD relationship of linagliptin in the paediatric population.
Interventions
DRUGplacebo
comparison of different dosages of drug (low vs high) vs placebo
DRUGBI1356 low dose
comparison of different dosages of drug (low vs high) vs placebo
DRUGBI1356 high dose
comparison of different dosages of drug (low vs high) vs placebo
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Paediatric patients (children and adolescents), aged 10 to 17 years with documented diagnosis of type 2 diabetes mellitus 2. Insufficient glycaemic control (i.e. an HbA1c \> 6.5% and \<= 10.5%) despite treatment with diet and exercise and/or metformin (\>= 1000 mg per day (or the maximum tolerated dose) at a stable dose or dosing frequency for 8 weeks prior to randomisation) and/or concomitant stable basal insulin (total daily dose must be \<= 0.5U/kg with less than 10% of weekly dose change for 12 weeks prior to randomisation) 3. Negative for islet cell antigen (ICA) auto-antibodies and glutamic acid decarboxylase (GAD) auto-antibodies 4. C-peptide levels (serum) \>= 1.5 ng/ml (at 90 min following a Boost challenge)
Exclusion criteria
1. History of acute metabolic decompensation, such as diabetic ketoacidosis, within 3 months 2. Current short-acting insulin or having received short-acting insulin for more than 3 days within 1 month prior to randomisation 3. Treatment with weight reduction medications (including anti-obesity treatments)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%) After 12 Weeks of Treatment | Baseline and 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dipeptidyl-peptidase-4 (DPP-4) Inhibition (%) at Trough at Steady State | Baseline and 4 weeks or 8 weeks or 12 weeks | 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. |
| Change From Baseline in Fasting Plasma Glucose (FPG) After 12 Weeks of Treatment | Baseline and 12 weeks | 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. |
Countries
Canada, France, Guatemala, Italy, Mexico, Poland, Russia, South Korea, United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo dose was administered orally once daily for 12 weeks | 15 |
| Linagliptin 1 mg Linagliptin 1 mg dose was administered orally once daily for 12 weeks | 10 |
| Linagliptin 5 mg Linagliptin 5 mg dose was administered orally once daily for 12 weeks | 14 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Other Reasons | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Linagliptin 1 mg | Linagliptin 5 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 13.7 Years STANDARD_DEVIATION 2 | 14.0 Years STANDARD_DEVIATION 1.8 | 14.3 Years STANDARD_DEVIATION 2.1 | 14.0 Years STANDARD_DEVIATION 1.9 |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 9 Participants | 21 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 5 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 15 | 8 / 10 | 6 / 14 |
| serious Total, serious adverse events | 1 / 15 | 0 / 10 | 0 / 14 |
Outcome results
Primary
Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%) After 12 Weeks of Treatment
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%) After 12 Weeks of Treatment | 0.45 Percentage of HbA1c | Standard Error 0.31 |
| Linagliptin 1 mg | Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%) After 12 Weeks of Treatment | -0.03 Percentage of HbA1c | Standard Error 0.38 |
| Linagliptin 5 mg | Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%) After 12 Weeks of Treatment | -0.19 Percentage of HbA1c | Standard Error 0.3 |
Comparison: 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.p-value: 0.329595% CI: [-1.47, 0.51]Mixed Models Analysis
Comparison: 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.p-value: 0.144795% CI: [-1.5, 0.23]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) After 12 Weeks of Treatment
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) After 12 Weeks of Treatment | 1.70 mmol/L | Standard Error 0.85 |
| Linagliptin 1 mg | Change From Baseline in Fasting Plasma Glucose (FPG) After 12 Weeks of Treatment | 1.39 mmol/L | Standard Error 1.07 |
| Linagliptin 5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) After 12 Weeks of Treatment | -0.19 mmol/L | Standard Error 0.83 |
Comparison: 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.p-value: 0.821695% CI: [-3.08, 2.46]Mixed Models Analysis
Comparison: 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.p-value: 0.118995% CI: [-4.31, 0.52]Mixed Models Analysis
Secondary
Dipeptidyl-peptidase-4 (DPP-4) Inhibition (%) at Trough at Steady State
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Linagliptin 1 mg | Dipeptidyl-peptidase-4 (DPP-4) Inhibition (%) at Trough at Steady State | 38.4 Percentage of DPP-4 inhibition |
| Linagliptin 5 mg | Dipeptidyl-peptidase-4 (DPP-4) Inhibition (%) at Trough at Steady State | 78.9 Percentage of DPP-4 inhibition |