Diabetes Study of Linagliptin and Empagliflozin in Children and Adolescents (DINAMO)TM

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.


Eligibility Criteria:
Inclusion Criteria:

* Patients aged 10 to 17 years (inclusive) at the time of randomisation (Visit 2)
* Male and female patients
* Women of childbearing potential (WOCBP) must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient's legal representative information sheet.
* Signed and dated written informed consent provided by the patient's parent(s) (or legal guardian) and patient's assent in accordance with ICH-GCP and local legislation prior to admission to the trial (informed assent will be sought according to the patient's age, level of maturity, competence and capacity)
* Documented diagnosis of T2DM at Visit 1A:

  * DINAMO TM: Documented diagnosis of T2DM for at least 8 weeks at Visit 1A
  * DINAMO TM Mono: Confirmation of T2DM at Visit 1A
* Insufficient glycaemic control as measured by the central laboratory at Visit 1A:

  * DINAMO TM: HbA1c ≥ 6.5% and ≤ 10.5%
  * DINAMO TM Mono: HbA1c ≥ 6.5% and ≤ 9.0%
* DINAMO TM: Patients treated with

  * diet and exercise plus metformin at a stable dose for 8 weeks prior to Visit 2 or not tolerating metformin (defined as patients who were on metformin treatment for at least 1 week and had to discontinue metformin due to metformin-related side effects as assessed by the investigator) AND/OR
  * diet and exercise plus stable basal or MDI insulin therapy,, defined as a weekly average variation of the basal insulin dose ≤ 0.1 IU/kg over 8 weeks prior to Visit 2. - DINAMOTM Mono: Drug-naïve patients or patients not on active treatment (including discontinuation of metformin due to intolerance \[or previous discontinuation for other reasons\] and/or discontinuation of insulin \[insulin use must be 8 weeks or less\] at investigator's discretion) prior to or at Visit 1A)
* BMI ≥ 85th percentile for age and sex according to WHO references at Visit 1B
* Non-fasting serum C-peptide levels ≥ 0.6 ng/ml as measured by the central laboratory at Visit 1A
* Compliance with trial medication intake must be between 75% and 125% during the open-label placebo run-in period
* Further inclusion criteria apply

Exclusion Criteria:

* Any history of acute metabolic decompensation such as diabetic ketoacidosis within 8 weeks prior to Visit 1A and up to randomisation (mild to moderate polyuria at the time of randomisation is acceptable)
* Diagnosis of monogenic diabetes (e.g. MODY)
* History of pancreatitis
* Diagnosis of metabolic bone disease
* Gastrointestinal disorders that might interfere with study drug absorption according to investigator assessment
* Secondary obesity as part of a syndrome (e.g. Prader-Willi syndrome)
* Any antidiabetic medication (with the exception of metformin and/or insulin background therapy) within 8 weeks prior to Visit 1A and until Visit 2
* Treatment with weight reduction medications (including anti-obesity drugs) within 3 months prior to Visit 1A and until Visit 2
* History of weight-loss surgery or current aggressive diet regimen (according to investigator assessment) at Visit 1A and until Visit 2
* Treatment with systemic corticosteroids for \> 1 week within 4 weeks prior to Visit 1A and up to Visit 2 Inhaled or topical use of corticosteroids (e.g. for asthma/chronic obstructive pulmonary disease) is acceptable.
* Change in dose of thyroid hormones within 6 weeks prior to Visit 1A or planned change or initiation of such therapy before Visit 2
* Known hypersensitivity or allergy to the investigational products or their excipients
* Impaired renal function defined as estimated Glomerular Filtration Rate (eGFR) \< 60 ml/min/1.73m² (according to Zappitelli formula) as measured by the central laboratory at Visit 1A
* Indication of liver disease defined by serum level of either alanine transaminase (ALT), aspartate transaminase (AST) or alkaline phosphatase above 3 fold upper limit of normal (ULN) at Visit 1A as measured by the central laboratory at Visit 1A
* History of belonephobia (needle phobia)
* Any documented active or suspected malignancy or history of malignancy within 5 years prior to Visit 1A, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix
* Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. malaria, babesiosis, haemolytic anaemia)
* Any other acute or chronic medical or psychiatric condition or laboratory abnormality that, based on investigator's judgement, would jeopardize patient safety during trial participation or would affect the study outcome
* Medical contraindications to metformin according to the local label (for patient on metformin background therapy)
* Patient not able or cannot be supported by his/her parent(s) or legal guardian to understand and comply with study requirements based on investigator's judgement
* Previous randomisation in this trial
* Currently enrolled in another investigational device or drug trial, or less than 30 days since ending another investigational device or drug trial(s), or receiving other investigational treatment(s)
* Chronic alcohol or drug abuse within 3 months prior to Visit 1A or any condition that, in the investigator's opinion, makes them an unreliable trial patient or unlikely to complete the trial
* Female patients who are pregnant, nursing, or who plan to become pregnant in the trial