Diabetes Study of Linagliptin and Empagliflozin in Children and Adolescents (DINAMO)TM
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT03429543 |
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Recruitment Status :
Completed
First Posted : February 12, 2018
Results First Posted : February 23, 2024
Last Update Posted : February 23, 2024
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Diabetes Mellitus, Type 2 | Drug: Metformin Drug: Insulin Drug: Placebo Drug: Linagliptin Drug: Empagliflozin | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 175 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | A Double-blind, Randomised, Placebo-controlled, Parallel Group Trial to Evaluate the Efficacy and Safety of Empagliflozin and Linagliptin Over 26 Weeks, With a Double-blind Active Treatment Safety Extension Period up to 52 Weeks, in Children and Adolescents With Type 2 Diabetes Mellitus |
| Actual Study Start Date : | March 20, 2018 |
| Actual Primary Completion Date : | October 19, 2022 |
| Actual Study Completion Date : | May 31, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Placebo Comparator: Placebo - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily, until end of treatment.
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Drug: Metformin
At least 1000 mg/day or up to a maximal tolerated dose. Drug: Insulin Basal or multiple dose injection. Drug: Placebo 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily. |
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Experimental: Placebo - Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily, until end of treatment.
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Drug: Metformin
At least 1000 mg/day or up to a maximal tolerated dose. Drug: Insulin Basal or multiple dose injection. Drug: Placebo 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily. Drug: Linagliptin 1 film-coated tablet Linagliptin once daily, until end of treatment.
Other Name: Trajenta(R) |
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Experimental: Placebo - Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily. At week 26, patients were re-randomised to receive 10 milligram (mg) empagliflozin, taken once daily, until end of treatment.
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Drug: Metformin
At least 1000 mg/day or up to a maximal tolerated dose. Drug: Insulin Basal or multiple dose injection. Drug: Placebo 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily. Drug: Empagliflozin 1 film-coated tablet of Empagliflozin once daily, until end of treatment.
Other Name: Jardiance(R) |
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Experimental: Placebo - Empagliflozin 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily. At week 26, patients were re-randomised to receive 25 milligram (mg) empagliflozin, taken once daily, until end of treatment.
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Drug: Metformin
At least 1000 mg/day or up to a maximal tolerated dose. Drug: Insulin Basal or multiple dose injection. Drug: Placebo 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily. Drug: Empagliflozin 1 film-coated tablet of Empagliflozin once daily, until end of treatment.
Other Name: Jardiance(R) |
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Experimental: Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of 5 milligram (mg) Linagliptin once daily, until end of treatment.
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Drug: Metformin
At least 1000 mg/day or up to a maximal tolerated dose. Drug: Insulin Basal or multiple dose injection. Drug: Linagliptin 1 film-coated tablet Linagliptin once daily, until end of treatment.
Other Name: Trajenta(R) |
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Experimental: Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily, until Week 14. Responder patients were not re-randomised at week 14 and continued 10 mg empagliflozin, taken once daily, until end of treatment. Non responder patients were re-randomised at Week 14 to receive 10 mg empagliflozin, taken once daily, until end of treatment.
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Drug: Metformin
At least 1000 mg/day or up to a maximal tolerated dose. Drug: Insulin Basal or multiple dose injection. Drug: Empagliflozin 1 film-coated tablet of Empagliflozin once daily, until end of treatment.
Other Name: Jardiance(R) |
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Experimental: Empagliflozin 10 mg - Empagliflozin 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily until Week 14. Non responder patients were re-randomised at Week 14 to receive 25 mg empagliflozin, taken once daily, until end of treatment.
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Drug: Metformin
At least 1000 mg/day or up to a maximal tolerated dose. Drug: Insulin Basal or multiple dose injection. Drug: Empagliflozin 1 film-coated tablet of Empagliflozin once daily, until end of treatment.
Other Name: Jardiance(R) |
- Change in Glycated Haemoglobin (HbA1c) (%) From Baseline to the End of 26 Weeks - DINAMOᵀᴹ [ Time Frame: Baseline (Day 1) and week 26 of treatment. ]
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.
- Percentage of Patients With Treatment Failure up to or at Week 26 [ Time Frame: Up to 26 weeks. ]
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%
- Change in HbA1c (%) From Baseline to the End of 26 Weeks - DINAMOᵀᴹ Mono [ Time Frame: Baseline (Day 1) and week 26 of treatment. ]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 to Treatment Failure [ Time Frame: Up to 395 days. ]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.
- Change in Fasting Plasma Glucose (FPG, mg/dL) From Baseline to the End of 26 Weeks [ Time Frame: Baseline (Day 1) and week 26. ]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.
- Change in Body Weight (kg) From Baseline to the End of 26 Weeks [ Time Frame: Baseline (Day 1) and week 26. ]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.
- Change in Systolic Blood Pressure (SBP, mmHg) From Baseline to the End of 26 Weeks [ Time Frame: Baseline (Day 1) and week 26. ]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.
- Change in Diastolic Blood Pressure (DBP, mmHg) From Baseline to the End of 26 Weeks [ Time Frame: Baseline (Day 1) and week 26. ]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.
- 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 <6.5% 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. ]Percentage of patients who achieve HbA1c <7.0% at the end of 26 weeks.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 10 Years to 17 Years (Child) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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)
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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
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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%
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03429543
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Documents provided by Boehringer Ingelheim:
| Responsible Party: | Boehringer Ingelheim |
| ClinicalTrials.gov Identifier: | NCT03429543 |
| Other Study ID Numbers: |
1218-0091 2016-000669-21 ( EudraCT Number ) |
| First Posted: | February 12, 2018 Key Record Dates |
| Results First Posted: | February 23, 2024 |
| Last Update Posted: | February 23, 2024 |
| Last Verified: | February 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | After the study is completed and the primary manuscript is accepted for publishing, researchers can use this following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement". Also, Researchers can use the following link https://www.mystudywindow.com/msw/datasharing to find information in order to request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website. The data shared are the raw clinical study data sets. |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Clinical Study Report (CSR) |
| Time Frame: | After all regulatory activities are completed in the US and EU for the product and indication, and after the primary manuscript has been accepted for publication. |
| Access Criteria: | For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by both the independent review panel and the sponsor, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a 'Data Sharing Agreement'. |
| URL: | https://www.mystudywindow.com/msw/datasharing |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Diabetes Mellitus Diabetes Mellitus, Type 2 Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Metformin Empagliflozin Linagliptin Hypoglycemic Agents |
Physiological Effects of Drugs Sodium-Glucose Transporter 2 Inhibitors Molecular Mechanisms of Pharmacological Action Incretins Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Dipeptidyl-Peptidase IV Inhibitors Protease Inhibitors Enzyme Inhibitors |