Diabetes Mellitus, Type 2
Conditions
Brief summary
The aim of the study is to generate pharmacokinetic and pharmacodynamic data to identify the safe-effective dose of empagliflozin in children and adolescents aged 10 to less than 18 years with type 2 diabetes mellitus.
Interventions
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Children and adolescents with type 2 diabetes mellitus * Insufficient glycaemic control (HbA1c \<=10.5%) despite diet and exercise and/or metformin and/or stable basal or MDI insulin * Negative for Islet Cell Antigen and Glutamic Acid Decarboxylase autoantibodies and fasting C-peptide levels \>= 0.85 ng/ml * BMI \> 50th percentile for age and sex
Exclusion criteria
* Uncontrolled hyperglycaemia with a glucose level \> 240 mg/dl (\> 13.3 mmol/l) * History of acute metabolic decompensation such as diabetic ketoacidosis within 3 months before the screening visit with the exception of acute de-compensation at the time of type 2 diabetes diagnosis * Treatment with weight reduction medications within 4 weeks before randomisation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| t1/2 | Before drug administration (-0:30 hours (h)) and 0:30h, 1:00h, 1:30h, 2:00h, 4:00h, 8:00h, 12:00 (Day 1), 24:00 (Day 2), 34:00 (Day 2), 48:00 (Day 3) after drug administration. | Terminal half-life in plasma (t1/2). |
| AUC0-tz | Before drug administration (-0:30 hours (h)) and 0:30h, 1:00h, 1:30h, 2:00h, 4:00h, 8:00h, 12:00 (Day 1), 24:00 (Day 2), 34:00 (Day 2), 48:00 (Day 3) after drug administration. | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz). |
| Cmax | Before drug administration (-0:30 hours (h)) and 0:30h, 1:00h, 1:30h, 2:00h, 4:00h, 8:00h, 12:00 (Day 1), 24:00 (Day 2), 34:00 (Day 2), 48:00 (Day 3) after drug administration. | Maximum measured concentration in plasma (Cmax). |
| Tmax | Before drug administration (-0:30 hours (h)) and 0:30h, 1:00h, 1:30h, 2:00h, 4:00h, 8:00h, 12:00 (Day 1), 24:00 (Day 2), 34:00 (Day 2), 48:00 (Day 3) after drug administration. | Maximum measured concentration in plasma (tmax). |
| AUC0-inf | Before drug administration (-0:30 hours (h)) and 0:30h, 1:00h, 1:30h, 2:00h, 4:00h, 8:00h, 12:00 (Day 1), 24:00 (Day 2), 34:00 (Day 2), 48:00 (Day 3) after drug administration. | Area under the concentration-time curve of analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) at 24 h After Study Drug Intake | baseline and 24 hours | Change from baseline in Fasting Plasma Glucose (FPG) at 24h after study drug intake. For the change from baseline in FPG at 24 h postdose (in the morning of Day 2), adjusted means per treatment group were to be calculated based on an ANCOVA including 'treatment' as a fixed effect and 'FPG at baseline' as continuous covariate. Means presented are the adjusted means. |
| Change From Baseline in 8-point Plasma Glucose Profile Over 24 h After Study Drug Intake | baseline and 24 hours | Change from baseline in 8-point plasma glucose profile over 24h after study drug intake (as defined by change from baseline in Mean Daily Glucose (MDG) calculated at Day 1). For the changes from baseline in MDG on Day 1, adjusted means per treatment group were to be calculated based on an ANCOVA including 'treatment' as fixed effect and 'MDG at baseline' as continuous covariate. Means presented are the adjusted means. |
| Change From Baseline in Urinary Glucose Excretion (UGE) Over 24 h After Study Drug Intake | baseline and 24 hours | Change from baseline in Urinary Glucose Excretion (UGE) over 24 h after study drug intake. For the changes from baseline in UGE on Day 1 (0 to 24 h postdose) , adjusted means per treatment group were to be calculated based on an ANCOVA including 'treatment' as a fixed effect and 'UGE at baseline' and 'FPG at baseline' as continuous covariates. Means presented are the adjusted means. |
Countries
France, Israel, Mexico, South Africa, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Empagliflozin 5mg Single dose (1 tablet) of 5mg, empagliflozin, film-coated tablet administered orally. | 9 |
| Empagliflozin 10mg Single dose (1 tablet) of 10mg, empagliflozin, film-coated tablet administered orally. | 8 |
| Empagliflozin 25mg Single dose (1 tablet) of 25mg, empagliflozin, film-coated tablet administered orally. | 10 |
| Total | 27 |
Baseline characteristics
| Characteristic | Empagliflozin 5mg | Empagliflozin 10mg | Empagliflozin 25mg | Total |
|---|---|---|---|---|
| Age, Continuous | 13.7 Years STANDARD_DEVIATION 2 | 14.5 Years STANDARD_DEVIATION 1.9 | 14.2 Years STANDARD_DEVIATION 2.1 | 14.1 Years STANDARD_DEVIATION 2 |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 7 Participants | 18 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 3 Participants | 9 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 | 4 / 9 | 1 / 8 | 2 / 10 |
| serious Total, serious adverse events | 0 / 9 | 0 / 8 | 0 / 10 |
Outcome results
Primary
AUC0-inf
Area under the concentration-time curve of analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf).
Time frame: Before drug administration (-0:30 hours (h)) and 0:30h, 1:00h, 1:30h, 2:00h, 4:00h, 8:00h, 12:00 (Day 1), 24:00 (Day 2), 34:00 (Day 2), 48:00 (Day 3) after drug administration.
Population: Pharmacokinetic Set (PKS): The PKS included all treated patients who provided at least 1 primary or secondary pharmacokinetic parameter for statistical assessment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 5mg | AUC0-inf | 1150 nmol*h/L | Geometric Coefficient of Variation 47.6 |
| Empagliflozin 10mg | AUC0-inf | 1430 nmol*h/L | Geometric Coefficient of Variation 17.2 |
| Empagliflozin 25mg | AUC0-inf | 5060 nmol*h/L | Geometric Coefficient of Variation 29.5 |
95% CI: [0.7276, 1.1704]
Primary
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz).
Time frame: Before drug administration (-0:30 hours (h)) and 0:30h, 1:00h, 1:30h, 2:00h, 4:00h, 8:00h, 12:00 (Day 1), 24:00 (Day 2), 34:00 (Day 2), 48:00 (Day 3) after drug administration.
Population: Pharmacokinetic Set (PKS): The PKS included all treated patients who provided at least 1 primary or secondary pharmacokinetic parameter for statistical assessment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 5mg | AUC0-tz | 1110 nmol*h/L | Geometric Coefficient of Variation 49.9 |
| Empagliflozin 10mg | AUC0-tz | 1400 nmol*h/L | Geometric Coefficient of Variation 17.1 |
| Empagliflozin 25mg | AUC0-tz | 4980 nmol*h/L | Geometric Coefficient of Variation 29.1 |
95% CI: [0.7356, 1.1838]
Primary
Cmax
Maximum measured concentration in plasma (Cmax).
Time frame: Before drug administration (-0:30 hours (h)) and 0:30h, 1:00h, 1:30h, 2:00h, 4:00h, 8:00h, 12:00 (Day 1), 24:00 (Day 2), 34:00 (Day 2), 48:00 (Day 3) after drug administration.
Population: Pharmacokinetic Set (PKS): The PKS included all treated patients who provided at least 1 primary or secondary pharmacokinetic parameter for statistical assessment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 5mg | Cmax | 159 nmol/L | Geometric Coefficient of Variation 44.5 |
| Empagliflozin 10mg | Cmax | 188 nmol/L | Geometric Coefficient of Variation 50.2 |
| Empagliflozin 25mg | Cmax | 602 nmol/L | Geometric Coefficient of Variation 61.1 |
95% CI: [0.5504, 1.1603]
Primary
t1/2
Terminal half-life in plasma (t1/2).
Time frame: Before drug administration (-0:30 hours (h)) and 0:30h, 1:00h, 1:30h, 2:00h, 4:00h, 8:00h, 12:00 (Day 1), 24:00 (Day 2), 34:00 (Day 2), 48:00 (Day 3) after drug administration.
Population: Pharmacokinetic Set (PKS): The PKS included all treated patients who provided at least 1 primary or secondary pharmacokinetic parameter for statistical assessment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 5mg | t1/2 | 6.92 hours | Geometric Coefficient of Variation 19.4 |
| Empagliflozin 10mg | t1/2 | 7.35 hours | Geometric Coefficient of Variation 29.3 |
| Empagliflozin 25mg | t1/2 | 7.80 hours | Geometric Coefficient of Variation 29.6 |
Primary
Tmax
Maximum measured concentration in plasma (tmax).
Time frame: Before drug administration (-0:30 hours (h)) and 0:30h, 1:00h, 1:30h, 2:00h, 4:00h, 8:00h, 12:00 (Day 1), 24:00 (Day 2), 34:00 (Day 2), 48:00 (Day 3) after drug administration.
Population: Pharmacokinetic Set (PKS): The PKS included all treated patients who provided at least 1 primary or secondary pharmacokinetic parameter for statistical assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Empagliflozin 5mg | Tmax | 1.50 hours |
| Empagliflozin 10mg | Tmax | 1.25 hours |
| Empagliflozin 25mg | Tmax | 1.78 hours |
Secondary
Change From Baseline in 8-point Plasma Glucose Profile Over 24 h After Study Drug Intake
Change from baseline in 8-point plasma glucose profile over 24h after study drug intake (as defined by change from baseline in Mean Daily Glucose (MDG) calculated at Day 1). For the changes from baseline in MDG on Day 1, adjusted means per treatment group were to be calculated based on an ANCOVA including 'treatment' as fixed effect and 'MDG at baseline' as continuous covariate. Means presented are the adjusted means.
Time frame: baseline and 24 hours
Population: Treated Set (TS) including patients with plasma glucose profile data on both visits
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 5mg | Change From Baseline in 8-point Plasma Glucose Profile Over 24 h After Study Drug Intake | -12.9 mg/dL | Standard Error 7.95 |
| Empagliflozin 10mg | Change From Baseline in 8-point Plasma Glucose Profile Over 24 h After Study Drug Intake | -6.5 mg/dL | Standard Error 9.21 |
| Empagliflozin 25mg | Change From Baseline in 8-point Plasma Glucose Profile Over 24 h After Study Drug Intake | -13.2 mg/dL | Standard Error 7 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at 24 h After Study Drug Intake
Change from baseline in Fasting Plasma Glucose (FPG) at 24h after study drug intake. For the change from baseline in FPG at 24 h postdose (in the morning of Day 2), adjusted means per treatment group were to be calculated based on an ANCOVA including 'treatment' as a fixed effect and 'FPG at baseline' as continuous covariate. Means presented are the adjusted means.
Time frame: baseline and 24 hours
Population: Treated Set (TS) including patients with FPG data on both visits
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 5mg | Change From Baseline in Fasting Plasma Glucose (FPG) at 24 h After Study Drug Intake | -15.5 mg/dL | Standard Error 6.53 |
| Empagliflozin 10mg | Change From Baseline in Fasting Plasma Glucose (FPG) at 24 h After Study Drug Intake | -16.6 mg/dL | Standard Error 6.29 |
| Empagliflozin 25mg | Change From Baseline in Fasting Plasma Glucose (FPG) at 24 h After Study Drug Intake | -20.4 mg/dL | Standard Error 5.68 |
Secondary
Change From Baseline in Urinary Glucose Excretion (UGE) Over 24 h After Study Drug Intake
Change from baseline in Urinary Glucose Excretion (UGE) over 24 h after study drug intake. For the changes from baseline in UGE on Day 1 (0 to 24 h postdose) , adjusted means per treatment group were to be calculated based on an ANCOVA including 'treatment' as a fixed effect and 'UGE at baseline' and 'FPG at baseline' as continuous covariates. Means presented are the adjusted means.
Time frame: baseline and 24 hours
Population: Treated Set (TS) including patients with UGE data on both visits
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 5mg | Change From Baseline in Urinary Glucose Excretion (UGE) Over 24 h After Study Drug Intake | 53.1 g/24h | Standard Error 10.24 |
| Empagliflozin 10mg | Change From Baseline in Urinary Glucose Excretion (UGE) Over 24 h After Study Drug Intake | 73.0 g/24h | Standard Error 10.14 |
| Empagliflozin 25mg | Change From Baseline in Urinary Glucose Excretion (UGE) Over 24 h After Study Drug Intake | 87.4 g/24h | Standard Error 9.39 |