The purpose of this research study is to evaluate the efficacy and safety of an empagliflozin dosing regimen and one dose of linagliptin in patients with type 2 diabetes who are aged 10 to below 18 years and are currently taking metformin, insulin or both drugs (DINAMO TM) or who are treatment naïve or not on active treatment after metformin withdrawal (DINAMO TM MONO) . Empagliflozin and linagliptin are both approved for use in adult patients with type 2 diabetes. This study will assess how well empagliflozin and linagliptin work by finding out how these treatments affect blood glucose (sugar) levels compared to placebo (a pill that contains no active drug), in children and adolescents. Empagliflozin and linagliptin are considered investigational products in this study since while they have been approved for use in adults, they have not been approved for children and adolescents due to lack of clinical studies in this specific population. Patients with type 2 diabetes have higher levels of blood glucose (sugar) than patients who do not have this disease. The high level of sugar in the blood can lead to serious short-term and long-term medical problems. The main goal of treating diabetic patients is to lower blood glucose to a normal level. Lowering and controlling blood glucose help prevent or delay complications of diabetes such as heart disease, kidney, eye and nerve diseases, and the possibility of amputation. Empagliflozin is a drug that helps to reduce blood glucose (sugar) levels by causing glucose to be excreted in the urines. Linagliptin works by increasing the production of insulin (a hormone that controls the level of blood glucose) after meals when blood glucose (sugar) levels are too high. This helps to lower blood sugar levels. The subject will either receive one of the active study drugs or a placebo. This study will be double blind; this means that neither the subject, nor the study doctor will know which treatment the subject will receive. Which treatment the subject receives is decided by a computer, purely by chance; this is called a "random assignment". For this study, there will first be a screening visit, followed by a 2-week placebo run-in period (all subjects will take placebo once daily). This run-in period is designed to ensure subjects are able to take the study drugs as described in the study protocol. Thereafter there will be a 26-week treatment phase (week 1-week 26) and a 26-week safety extension period (week 27-week 52). Following this there will be a follow-up visit at week 55. On Day 1 after the placebo run-in phase, the subject will be randomly assigned to receive one of the 3 treatments: empagliflozin 10 mg, linagliptin 5 mg or placebo in a blinded manner. This treatment will continue up to week 14. Then after week 14, the subject will be assigned to receive one of the following 4 treatments: empagliflozin 10 mg, empagliflozin 25 mg, linagliptin 5 mg or placebo in a blinded manner. The drugs assigned after week 14 will be the same drugs as on Day 1 but some subjects will receive a higher dose of empagliflozin. After the completion of the 26-week treatment period, the subject will enter a 26-week safety extension period. The same active treatment that the subject had been assigned to at week 14 visit will be continued. Subjects assigned to placebo on Day 1 will be randomly assigned to receive one of the 3 active treatments: empagliflozin 10 mg, empagliflozin 25 mg or linagliptin 5 mg in a blinded manner. This safety extension period is primarily designed to provide additional information on how well empagliflozin and linagliptin are tolerated. Following the treatment phases, there will be a follow-up visit at week 55 Intervention model description: Eligible subjects with HbA1c of 6.5% to 10.5% at screening will be randomized in a 1:1:1 ratio to receive empagliflozin 10 mg, linagliptin 5 mg or placebo. HbA1c assessment will be performed at Week 12. All subjects with Week 12 HbA1c \< 7% will remain on previously assigned randomized treatment. Subjects taking empagliflozin with Week 12 HbA1c \>= 7% will be re-randomized in a 1:1 ratio to continue on the low dose treatment (empagliflozin 10 mg) or up-titrate to the high dose treatment (empagliflozin 25 mg). Subjects taking linagliptin or placebo with Week 12 HbA1c \>= 7% will remain on previously assigned treatment. All subjects will get new medication kits dispensed at Week 14 to maintain the blinding. At Week 26, all subjects previously assigned to placebo will be re-randomized in a 1:1:1: ratio to receive one of the active treatments: empagliflozin 10 mg, empagliflozin 25 mg or linagliptin 5 mg. All subjects will get new medication kits dispensed at Week 14 to maintain the blinding.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
175
At least 1000 mg/day or up to a maximal tolerated dose.
Basal or multiple dose injection.
1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.
1 film-coated tablet Linagliptin once daily, until end of treatment.
1 film-coated tablet of Empagliflozin once daily, until end of treatment.
Phoenix Children's Hospital
Phoenix, Arizona, United States
University of Arizona
Tucson, Arizona, United States
CHOC Children's Hospital
Orange, California, United States
Stanford University Medical Center
Palo Alto, California, United States
Rady Children's Hospital - San Diego
San Diego, California, United States
Change in Glycated Haemoglobin (HbA1c) (%) From Baseline to the End of 26 Weeks - DINAMOᵀᴹ
Adjusted means taken from the following three models, as pre-specified in the protocol: Treatment group 1 (TG1): \[Placebo\], \[Linagliptin 5mg\] and \[Empagliflozin pooled\] Treatment group 2 (TG2): \[Placebo\] and \[Empagliflozin 10mg and 10+25mg\] Treatment group 3 (TG3): \[Placebo\] and \[Empagliflozin 10mg\] ANCOVA with continuous covariate (baseline HbA1c) and categorical covariates (treatment \& age). Effect of linagliptin and of empagliflozin was compared with placebo at an overall α of 0.05 (2-sided) using the Hochberg method to account for multiple testing. After having obtained statistically significant results for both hypotheses of the primary family of hypotheses (TG1), the secondary hypotheses were to compare the individual empagliflozin doses versus placebo (TG2 \& TG3). ANCOVA utilized a weight of zero for patients who were not in the hypothesis test of interest, a value of 2 for re-randomised patients who were in the hypothesis test of interest and a value of 1 otherwise.
Time frame: Baseline (Day 1) and week 26 of treatment.
Percentage of Patients With Treatment Failure up to or at Week 26
Percentage of patients with treatment failure up to or at Week 26 as a binary endpoint, defined as meeting at least one of the following criteria: * Use of rescue medication at any time up to Week 26 * Increase from baseline in HbA1c by 0.5% at Week 26 . Increase from baseline in HbA1c to above 7.0% at Week 26 in patients with baseline HbA1c \<7.0%
Time frame: Up to 26 weeks.
Change in HbA1c (%) From Baseline to the End of 26 Weeks - DINAMOᵀᴹ Mono
Change in Glycated haemoglobin (HbA1c) (%) from baseline to the end of 26 weeks. Adjusted values came from a restricted maximum likelihood (REML) approach with mixed model for repeated measures (MMRM). Analyses included fixed categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the categorical covariate age at randomisation and the continuous, fixed covariates of baseline of the response variable and baseline of the response variable-by-visit interaction. The covariate visit was treated as the repeated measure with an unstructured covariance structure used to model the within-patient measurements.
Time frame: Baseline (Day 1) and week 26 of treatment.
Time to Treatment Failure
Time to treatment failure was analysed by Kaplan-Meier estimates up to the end of the study (Week 52). Patients in the placebo group were censored after 26 weeks unless a prior treatment failure was observed.
Time frame: Up to 395 days.
Change in Fasting Plasma Glucose (FPG, mg/dL) From Baseline to the End of 26 Weeks
Change in fasting plasma glucose (FPG, Milligrams Per Deciliter (mg/dL)) from baseline to the end of 26 weeks. Adjusted values taken from analysis of covariance (ANCOVA) model with treatment as a fixed classification effect, baseline FPG as linear covariate and age at randomisation as categorical covariate. The random error was assumed to be normally distributed.
Time frame: Baseline (Day 1) and week 26.
Change in Body Weight (kg) From Baseline to the End of 26 Weeks
Change in body weight (kg) from baseline to the end of 26 weeks. Adjusted values taken from mixed model for repeated measures (MMRM) with the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the categorical covariate age at randomisation and the continuous, fixed covariates of baseline of the response variable and baseline of the response variable-by-visit interaction. The covariate visit was treated as repeated measure with an unstructured covariance structure used to model the within-patient measurements.
Time frame: Baseline (Day 1) and week 26.
Change in Systolic Blood Pressure (SBP, mmHg) From Baseline to the End of 26 Weeks
Change in systolic blood pressure (SBP, millimeters of mercury (mmHg)) from baseline to the end of 26 weeks. Adjusted values taken from mixed model for repeated measures (MMRM) with the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the categorical covariate age at randomisation and the continuous, fixed covariates of baseline of the response variable and baseline of the response variable-by-visit interaction. The covariate visit was treated as repeated measure with an unstructured covariance structure used to model the within-patient measurements.
Time frame: Baseline (Day 1) and week 26.
Change in Diastolic Blood Pressure (DBP, mmHg) From Baseline to the End of 26 Weeks
Change in diastolic blood pressure (DBP, millimeters of mercury (mmHg)) from baseline to the end of 26 weeks. Adjusted values taken from mixed model for repeated measures (MMRM) with the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the categorical covariate age at randomisation and the continuous, fixed covariates of baseline of the response variable and baseline of the response variable-by-visit interaction. The covariate visit was treated as repeated measure with an unstructured covariance structure used to model the within-patient measurements.
Time frame: Baseline (Day 1) and week 26.
Percentage of Patients Who Achieve HbA1c <6.5% at the End of 26 Weeks
Percentage of patients who achieve HbA1c \<6.5% at the end of 26 weeks.
Time frame: Baseline (Day 1) and week 26.
Percentage of Patients Who Achieve HbA1c <7.0% at the End of 26 Weeks
Percentage of patients who achieve HbA1c \<7.0% at the end of 26 weeks.
Time frame: Baseline (Day 1) and week 26.
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University of California San Francisco
San Francisco, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Yale University School of Medicine
New Haven, Connecticut, United States
Oceane7 Clinical Research
Miami, Florida, United States
Empire Clinical Research, LLC
Miami Lakes, Florida, United States
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