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

Diabetes Mellitus, Type 2 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03429543
• Other study ID #: 1218-0091
• Secondary ID: 2016-000669-21
• Status: Completed
• Phase: Phase 3
• Start date: March 20, 2018
• Est. completion date: May 31, 2023

Study information

• Verified date: February 2024
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 175
• Est. completion date: May 31, 2023
• Est. primary completion date: October 19, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
Argentina	Sanatorio Allende S.A.	Nueva Córdoba
Argentina	Hospital de Clínicas Pte. Dr. Nicolás Avellaneda	San Miguel de Tucumán
Brazil	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	Ribeirao Preto
Canada	The Hospital for Sick Children	Toronto	Ontario
Canada	University of Manitoba - Health Sciences Centre	Winnipeg	Manitoba
China	The First Hospital of Jilin University	Changchun
China	Zhengzhou Children'S Hospital	Zhengzhou
Colombia	Centro de Diabetes Cardiovascular IPS	Barranquilla
Colombia	Dexa-Diab IPS	Bogotá DC
Germany	Universitätsklinikum Freiburg	Freiburg
Israel	Soroka Univ. Medical Center	Beer Sheva
Israel	Rambam Medical Center	Haifa
Israel	The Chaim Sheba Medical Center Tel HaShomer	Ramat-Gan
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Severance Hospital	Seoul
Korea, Republic of	Ajou University Hospital	Suwon
Mexico	Investigación en Salud y Metabolismo S.C.	Chihuahua
Mexico	CAIMED Investigacion en Salud, S.A. de C.V.	Ciudad de México
Mexico	Centro de Estudios de Investigación Metabólicos y Cardiovasculares, S.C.	Ciudad Madero
Mexico	Consultorio Medico	Puebla
Mexico	Investigacion Medica Sonora S.C.	Sonora
Mexico	Centro de Investigación Médica de Ocidente, S.C.	Zapopan
Puerto Rico	San Juan Bautista School of Medicine	Caguas
Russian Federation	Regional Clinical Hospital 'The Badge of Honor Order'	Irkutsk
Russian Federation	Ivanovo Reg.Clin.Hosp.	Ivanovo
Russian Federation	Rep.childrens clin.hosp.	Izhevsk
Russian Federation	State Medical University, Kazan	Kazan
Russian Federation	Munic. Instit. of HC "Kirov clin. hosp.#7 n.a.V.I.Urlova"	Kirov
Russian Federation	Endocrinology Scientific Center, MoH and Social Development	Moscow
Russian Federation	State Novosibirsk Regional Clinical Hospital	Novosibirsk
Russian Federation	Fed. State Budget Educational Instit. of Higher Education "Rostov State Med. Univ." of MoH of RF	Rostov-on-Don
Russian Federation	St. Petersburg State Pediatric University	St. Petersburg
Russian Federation	Siberian State Med.Uni,Faculty Therapy Dep.w/ Clin.Pharmacol	Tomsk
Russian Federation	Bahkir state med. Univ. of the Ministry Polyclinic Pediatric	Ufa
Thailand	Srinagarind Hospital	Khon Kaen
Thailand	Rajavithi Hospital	Krung Thep Maha Nakhon
United Kingdom	St George's Hospital	London
United Kingdom	Royal Berkshire Hospital	Reading
United States	Atlanta Center	Atlanta	Georgia
United States	Children's Center for Advanced Pediatrics	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	Advantage Clinical Trials	Bronx	New York
United States	UBMD Pediatrics	Buffalo	New York
United States	The University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Columbus Regional Research Institute	Columbus	Georgia
United States	Integrative Biosciences Center	Detroit	Michigan
United States	Penn State College of Medicine	Hershey	Pennsylvania
United States	Office of Amir A. Hassan, MD, P.A.	Houston	Texas
United States	Rocky Mountain Diabetes and Osteoporosis Center	Idaho Falls	Idaho
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University Of Mississippi Medical Center	Jackson	Mississippi
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	Saenz Medical Center	La Joya	Texas
United States	Novak Center for Children's Health	Louisville	Kentucky
United States	LifeDoc Research, PLLC	Memphis	Tennessee
United States	Oceane7 Clinical Research	Miami	Florida
United States	Empire Clinical Research, LLC	Miami Lakes	Florida
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	New York University Langone Medical Center	New York	New York
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	CHOC Children's Hospital	Orange	California
United States	Pediatric and Adult Research Center	Orlando	Florida
United States	Stanford University Medical Center	Palo Alto	California
United States	Nemours Clinic	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Monument Health Rapid City Hospital, Inc.	Rapid City	South Dakota
United States	Children's Hospital of Richmond at VCU	Richmond	Virginia
United States	Texas Diabetes Institute	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	University of California San Francisco	San Francisco	California
United States	SUNY Upstate Medical University	Syracuse	New York
United States	University of South Florida	Tampa	Florida
United States	University of Arizona	Tucson	Arizona
United States	University of Oklahoma	Tulsa	Oklahoma
United States	AdventHealth Medical Group, Pediatric Diabetes and Endocrinology at Winter Park	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  China,  Colombia,  Germany,  Israel,  Korea, Republic of,  Mexico,  Puerto Rico,  Russian Federation,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Glycated Haemoglobin (HbA1c) (%) From Baseline to the End of 26 Weeks - DINAMO??	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 a 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.
Primary	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	Change in HbA1c (%) From Baseline to the End of 26 Weeks - DINAMO?? 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.	Baseline (Day 1) and week 26 of treatment.
Secondary	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.	Up to 395 days.
Secondary	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.	Baseline (Day 1) and week 26.
Secondary	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.	Baseline (Day 1) and week 26.
Secondary	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.	Baseline (Day 1) and week 26.
Secondary	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.	Baseline (Day 1) and week 26.
Secondary	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.	Baseline (Day 1) and week 26.
Secondary	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.	Baseline (Day 1) and week 26.

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