Diabetes Study of Linagliptin and Empagliflozin in Children and Adolescents (DINAMO)TM
NCT ID: NCT03429543
Last Updated: 2024-02-23
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
175 participants
INTERVENTIONAL
2018-03-20
2023-05-31
Brief Summary
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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.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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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.
Metformin
At least 1000 mg/day or up to a maximal tolerated dose.
Insulin
Basal or multiple dose injection.
Placebo
1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.
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.
Metformin
At least 1000 mg/day or up to a maximal tolerated dose.
Insulin
Basal or multiple dose injection.
Placebo
1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.
Linagliptin
1 film-coated tablet Linagliptin once daily, until end of treatment.
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.
Metformin
At least 1000 mg/day or up to a maximal tolerated dose.
Insulin
Basal or multiple dose injection.
Placebo
1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.
Empagliflozin
1 film-coated tablet of Empagliflozin once daily, until end of treatment.
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.
Metformin
At least 1000 mg/day or up to a maximal tolerated dose.
Insulin
Basal or multiple dose injection.
Placebo
1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.
Empagliflozin
1 film-coated tablet of Empagliflozin once daily, until end of treatment.
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.
Metformin
At least 1000 mg/day or up to a maximal tolerated dose.
Insulin
Basal or multiple dose injection.
Linagliptin
1 film-coated tablet Linagliptin once daily, until end of treatment.
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.
Metformin
At least 1000 mg/day or up to a maximal tolerated dose.
Insulin
Basal or multiple dose injection.
Empagliflozin
1 film-coated tablet of Empagliflozin once daily, until end of treatment.
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.
Metformin
At least 1000 mg/day or up to a maximal tolerated dose.
Insulin
Basal or multiple dose injection.
Empagliflozin
1 film-coated tablet of Empagliflozin once daily, until end of treatment.
Interventions
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Metformin
At least 1000 mg/day or up to a maximal tolerated dose.
Insulin
Basal or multiple dose injection.
Placebo
1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.
Linagliptin
1 film-coated tablet Linagliptin once daily, until end of treatment.
Empagliflozin
1 film-coated tablet of Empagliflozin once daily, until end of treatment.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
Exclusion Criteria
* 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
10 Years
17 Years
ALL
No
Sponsors
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Boehringer Ingelheim
INDUSTRY
Responsible Party
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Locations
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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
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
Pediatric and Adult Research Center
Orlando, Florida, United States
Nemours Clinic
Pensacola, Florida, United States
University of South Florida
Tampa, Florida, United States
AdventHealth Medical Group, Pediatric Diabetes and Endocrinology at Winter Park
Winter Park, Florida, United States
Children's Center for Advanced Pediatrics
Atlanta, Georgia, United States
Atlanta Center
Atlanta, Georgia, United States
Columbus Regional Research Institute
Columbus, Georgia, United States
Rocky Mountain Diabetes and Osteoporosis Center
Idaho Falls, Idaho, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States
Novak Center for Children's Health
Louisville, Kentucky, United States
Johns Hopkins Hospital
Baltimore, Maryland, United States
Boston Children's Hospital
Boston, Massachusetts, United States
Joslin Diabetes Center
Boston, Massachusetts, United States
Integrative Biosciences Center
Detroit, Michigan, United States
University Of Mississippi Medical Center
Jackson, Mississippi, United States
Children's Mercy Hospitals and Clinics
Kansas City, Missouri, United States
UBMD Pediatrics
Buffalo, New York, United States
New York University Langone Medical Center
New York, New York, United States
SUNY Upstate Medical University
Syracuse, New York, United States
Advantage Clinical Trials
The Bronx, New York, United States
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
University Hospitals of Cleveland
Cleveland, Ohio, United States
University of Oklahoma
Oklahoma City, Oklahoma, United States
University of Oklahoma
Tulsa, Oklahoma, United States
Penn State College of Medicine
Hershey, Pennsylvania, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Monument Health Rapid City Hospital, Inc.
Rapid City, South Dakota, United States
LifeDoc Research, PLLC
Memphis, Tennessee, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Office of Amir A. Hassan, MD, P.A.
Houston, Texas, United States
Saenz Medical Center
La Joya, Texas, United States
Texas Diabetes Institute
San Antonio, Texas, United States
University of Virginia Health System
Charlottesville, Virginia, United States
Children's Hospital of Richmond at VCU
Richmond, Virginia, United States
Sanatorio Allende S.A.
Nueva Córdoba, , Argentina
Hospital de Clínicas Pte. Dr. Nicolás Avellaneda
San Miguel de Tucumán, , Argentina
Instituto de Estudos e Pesquisas Clínicas IEP-CE
Fortaleza, , Brazil
Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto
Ribeirão Preto, , Brazil
University of Manitoba - Health Sciences Centre
Winnipeg, Manitoba, Canada
The Hospital for Sick Children
Toronto, Ontario, Canada
The First Hospital of Jilin University
Changchun, , China
Zhengzhou Children'S Hospital
Zhengzhou, , China
Centro de Diabetes Cardiovascular IPS
Barranquilla, , Colombia
Dexa-Diab IPS
Bogotá DC, , Colombia
Universitätsklinikum Freiburg
Freiburg im Breisgau, , Germany
Soroka Univ. Medical Center
Beersheba, , Israel
Rambam Medical Center
Haifa, , Israel
The Chaim Sheba Medical Center Tel HaShomer
Ramat Gan, , Israel
Investigación en Salud y Metabolismo S.C.
Chihuahua City, , Mexico
Centro de Estudios de Investigación Metabólicos y Cardiovasculares, S.C.
Ciudad Madero, , Mexico
CAIMED Investigacion en Salud, S.A. de C.V.
Mexico City, , Mexico
Consultorio Medico
Puebla City, , Mexico
Investigacion Medica Sonora S.C.
Sonora, , Mexico
Centro de Investigación Médica de Ocidente, S.C.
Zapopan, , Mexico
San Juan Bautista School of Medicine
Caguas, , Puerto Rico
Regional Clinical Hospital 'The Badge of Honor Order'
Irkutsk, , Russia
Ivanovo Reg.Clin.Hosp.
Ivanovo, , Russia
Rep.childrens clin.hosp.
Izhevsk, , Russia
State Medical University, Kazan
Kazan', , Russia
Munic. Instit. of HC "Kirov clin. hosp.#7 n.a.V.I.Urlova"
Kirov, , Russia
Endocrinology Scientific Center, MoH and Social Development
Moscow, , Russia
State Novosibirsk Regional Clinical Hospital
Novosibirsk, , Russia
Fed. State Budget Educational Instit. of Higher Education "Rostov State Med. Univ." of MoH of RF
Rostov-on-Don, , Russia
St. Petersburg State Pediatric University
Saint Petersburg, , Russia
Siberian State Med.Uni,Faculty Therapy Dep.w/ Clin.Pharmacol
Tomsk, , Russia
Bahkir state med. Univ. of the Ministry Polyclinic Pediatric
Ufa, , Russia
Severance Hospital
Seoul, , South Korea
Asan Medical Center
Seoul, , South Korea
Ajou University Hospital
Suwon, , South Korea
Rajavithi Hospital
Bangkok, , Thailand
Srinagarind Hospital
Khon Kaen, , Thailand
St George's Hospital
London, , United Kingdom
Royal Berkshire Hospital
Reading, , United Kingdom
Countries
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References
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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.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Related Links
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Related Info
Other Identifiers
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2016-000669-21
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
1218-0091
Identifier Type: -
Identifier Source: org_study_id
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