Diabetes Study of Linagliptin and Empagliflozin in Children and Adolescents (DINAMO)TM
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
2 other identifiers
interventional
175
14 countries
83
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_3 diabetes-mellitus-type-2
Started Mar 2018
Longer than P75 for phase_3 diabetes-mellitus-type-2
83 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
February 6, 2018
CompletedFirst Posted
Study publicly available on registry
February 12, 2018
CompletedStudy Start
First participant enrolled
March 20, 2018
CompletedPrimary Completion
Last participant's last visit for primary outcome
October 19, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
May 31, 2023
CompletedResults Posted
Study results publicly available
February 23, 2024
CompletedFebruary 23, 2024
February 1, 2024
4.6 years
February 6, 2018
November 28, 2023
February 22, 2024
Conditions
Outcome Measures
Primary Outcomes (2)
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.
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%
Up to 26 weeks.
Secondary Outcomes (8)
Change in HbA1c (%) From Baseline to the End of 26 Weeks - DINAMOᵀᴹ Mono
Baseline (Day 1) and week 26 of treatment.
Time to Treatment Failure
Up to 395 days.
Change in Fasting Plasma Glucose (FPG, mg/dL) From Baseline to the End of 26 Weeks
Baseline (Day 1) and week 26.
Change in Body Weight (kg) From Baseline to the End of 26 Weeks
Baseline (Day 1) and week 26.
Change in Systolic Blood Pressure (SBP, mmHg) From Baseline to the End of 26 Weeks
Baseline (Day 1) and week 26.
- +3 more secondary outcomes
Study Arms (7)
Placebo - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
PLACEBO COMPARATORPatients 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.
Placebo - Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
EXPERIMENTALPatients 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.
Placebo - Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
EXPERIMENTALPatients 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.
Placebo - Empagliflozin 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
EXPERIMENTALPatients 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.
Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
EXPERIMENTALPatients 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.
Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
EXPERIMENTALPatients 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.
Empagliflozin 10 mg - Empagliflozin 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
EXPERIMENTALPatients 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.
Interventions
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.
Eligibility Criteria
You may qualify if:
- 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
- +1 more criteria
You may not qualify if:
- 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)
- +9 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (83)
Phoenix Children's Hospital
Phoenix, Arizona, 85016, United States
University of Arizona
Tucson, Arizona, 85724, United States
CHOC Children's Hospital
Orange, California, 92868, United States
Stanford University Medical Center
Palo Alto, California, 94304, United States
Rady Children's Hospital - San Diego
San Diego, California, 92123, United States
University of California San Francisco
San Francisco, California, 94158, United States
Children's Hospital Colorado
Aurora, Colorado, 80045, United States
Yale University School of Medicine
New Haven, Connecticut, 06511, United States
Oceane7 Clinical Research
Miami, Florida, 33144, United States
Empire Clinical Research, LLC
Miami Lakes, Florida, 33016, United States
Pediatric and Adult Research Center
Orlando, Florida, 32825, United States
Nemours Clinic
Pensacola, Florida, 32514, United States
University of South Florida
Tampa, Florida, 33612, United States
AdventHealth Medical Group, Pediatric Diabetes and Endocrinology at Winter Park
Winter Park, Florida, 32789, United States
Children's Center for Advanced Pediatrics
Atlanta, Georgia, 30329, United States
Atlanta Center
Atlanta, Georgia, 30331, United States
Columbus Regional Research Institute
Columbus, Georgia, 31904, United States
Rocky Mountain Diabetes and Osteoporosis Center
Idaho Falls, Idaho, 83404, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242, United States
Novak Center for Children's Health
Louisville, Kentucky, 40202, United States
Johns Hopkins Hospital
Baltimore, Maryland, 21287, United States
Boston Children's Hospital
Boston, Massachusetts, 02115, United States
Joslin Diabetes Center
Boston, Massachusetts, 02215, United States
Integrative Biosciences Center
Detroit, Michigan, 48202, United States
University Of Mississippi Medical Center
Jackson, Mississippi, 39216-4505, United States
Children's Mercy Hospitals and Clinics
Kansas City, Missouri, 64108, United States
UBMD Pediatrics
Buffalo, New York, 14203, United States
New York University Langone Medical Center
New York, New York, 10016, United States
SUNY Upstate Medical University
Syracuse, New York, 13210, United States
Advantage Clinical Trials
The Bronx, New York, 10468, United States
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27514, United States
University Hospitals of Cleveland
Cleveland, Ohio, 44106, United States
University of Oklahoma
Oklahoma City, Oklahoma, 73104, United States
University of Oklahoma
Tulsa, Oklahoma, 74135, United States
Penn State College of Medicine
Hershey, Pennsylvania, 17033, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104, United States
Monument Health Rapid City Hospital, Inc.
Rapid City, South Dakota, 57701, United States
LifeDoc Research, PLLC
Memphis, Tennessee, 38119, United States
Vanderbilt University Medical Center
Nashville, Tennessee, 37232, United States
Office of Amir A. Hassan, MD, P.A.
Houston, Texas, 77089, United States
Saenz Medical Center
La Joya, Texas, 78560, United States
Texas Diabetes Institute
San Antonio, Texas, 78207, United States
University of Virginia Health System
Charlottesville, Virginia, 22908, United States
Children's Hospital of Richmond at VCU
Richmond, Virginia, 23219, United States
Sanatorio Allende S.A.
Nueva Córdoba, X5000JHQ, Argentina
Hospital de Clínicas Pte. Dr. Nicolás Avellaneda
San Miguel de Tucumán, 4000, Argentina
Instituto de Estudos e Pesquisas Clínicas IEP-CE
Fortaleza, 60160-230, Brazil
Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto
Ribeirão Preto, 14048-900, Brazil
University of Manitoba - Health Sciences Centre
Winnipeg, Manitoba, R3E 3P4, Canada
The Hospital for Sick Children
Toronto, Ontario, M5G 1X8, Canada
The First Hospital of Jilin University
Changchun, 130021, China
Zhengzhou Children'S Hospital
Zhengzhou, 450017, China
Centro de Diabetes Cardiovascular IPS
Barranquilla, 80020, Colombia
Dexa-Diab IPS
Bogotá DC, 110221, Colombia
Universitätsklinikum Freiburg
Freiburg im Breisgau, 79106, Germany
Soroka Univ. Medical Center
Beersheba, 84101, Israel
Rambam Medical Center
Haifa, 31096, Israel
The Chaim Sheba Medical Center Tel HaShomer
Ramat Gan, 5265601, Israel
Investigación en Salud y Metabolismo S.C.
Chihuahua City, 31217, Mexico
Centro de Estudios de Investigación Metabólicos y Cardiovasculares, S.C.
Ciudad Madero, 89440, Mexico
CAIMED Investigacion en Salud, S.A. de C.V.
Mexico City, 06760, Mexico
Consultorio Medico
Puebla City, 72190, Mexico
Investigacion Medica Sonora S.C.
Sonora, 83280, Mexico
Centro de Investigación Médica de Ocidente, S.C.
Zapopan, 45116, Mexico
San Juan Bautista School of Medicine
Caguas, 00726, Puerto Rico
Regional Clinical Hospital 'The Badge of Honor Order'
Irkutsk, 664049, Russia
Ivanovo Reg.Clin.Hosp.
Ivanovo, 153040, Russia
Rep.childrens clin.hosp.
Izhevsk, 426009, Russia
State Medical University, Kazan
Kazan', 420012, Russia
Munic. Instit. of HC "Kirov clin. hosp.#7 n.a.V.I.Urlova"
Kirov, 610014, Russia
Endocrinology Scientific Center, MoH and Social Development
Moscow, 117036, Russia
State Novosibirsk Regional Clinical Hospital
Novosibirsk, 630091, Russia
Fed. State Budget Educational Instit. of Higher Education "Rostov State Med. Univ." of MoH of RF
Rostov-on-Don, 344022, Russia
St. Petersburg State Pediatric University
Saint Petersburg, 194100, Russia
Siberian State Med.Uni,Faculty Therapy Dep.w/ Clin.Pharmacol
Tomsk, 634050, Russia
Bahkir state med. Univ. of the Ministry Polyclinic Pediatric
Ufa, 450106, Russia
Severance Hospital
Seoul, 03722, South Korea
Asan Medical Center
Seoul, 05505, South Korea
Ajou University Hospital
Suwon, 16499, South Korea
Rajavithi Hospital
Bangkok, 10400, Thailand
Srinagarind Hospital
Khon Kaen, 40002, Thailand
St George's Hospital
London, SW17 0QT, United Kingdom
Royal Berkshire Hospital
Reading, RG1 5AN, United Kingdom
Related Publications (1)
Laffel LM, Danne T, Klingensmith GJ, Tamborlane WV, Willi S, Zeitler P, Neubacher D, Marquard J; DINAMO Study Group. Efficacy and safety of the SGLT2 inhibitor empagliflozin versus placebo and the DPP-4 inhibitor linagliptin versus placebo in young people with type 2 diabetes (DINAMO): a multicentre, randomised, double-blind, parallel group, phase 3 trial. Lancet Diabetes Endocrinol. 2023 Mar;11(3):169-181. doi: 10.1016/S2213-8587(22)00387-4. Epub 2023 Feb 1.
PMID: 36738751DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Boehringer Ingelheim, Call Center
- Organization
- Boehringer Ingelheim
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- PARTICIPANT, INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
February 6, 2018
First Posted
February 12, 2018
Study Start
March 20, 2018
Primary Completion
October 19, 2022
Study Completion
May 31, 2023
Last Updated
February 23, 2024
Results First Posted
February 23, 2024
Record last verified: 2024-02
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, 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'.
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.