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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Metformin; Drug: Insulin; Drug: Placebo; Drug: Linagliptin; Drug: Empagliflozin

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Nueva Córdoba, Argentina, X5000JHQ
    • Sanatorio Allende S.A.
  • San Miguel de Tucumán, Argentina, 4000
    • Hospital de Clínicas Pte. Dr. Nicolás Avellaneda
• Brazil
  • Fortaleza, Brazil, 60160-230
    • Instituto de Estudos e Pesquisas Clínicas IEP-CE
  • Ribeirao Preto, Brazil, 14048-900
    • Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto
• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • University of Manitoba - Health Sciences Centre
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
• China
  • Changchun, China, 130021
    • The First Hospital of Jilin University
  • Zhengzhou, China, 450017
    • Zhengzhou Children'S Hospital
• Colombia
  • Barranquilla, Colombia, 80020
    • Centro de Diabetes Cardiovascular IPS
  • Bogotá DC, Colombia, 110221
    • Dexa-Diab IPS
• Germany
  • Freiburg, Germany, 79106
    • Universitätsklinikum Freiburg
• Israel
  • Beer Sheva, Israel, 84101
    • Soroka Univ. Medical Center
  • Haifa, Israel, 31096
    • Rambam Medical Center
  • Ramat-Gan, Israel, 5265601
    • The Chaim Sheba Medical Center Tel HaShomer
• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Suwon, Korea, Republic of, 16499
    • Ajou University Hospital
• Mexico
  • Chihuahua, Mexico, 31217
    • Investigación en Salud y Metabolismo S.C.
  • Ciudad Madero, Mexico, 89440
    • Centro de Estudios de Investigacion Metabolicos y Cardiovasculares, S.C.
  • Ciudad de México, Mexico, 06760
    • CAIMED Investigacion en Salud, S.A. de C.V.
  • Puebla, Mexico, 72190
    • Consultorio Médico
  • Sonora, Mexico, 83280
    • Investigación Médica Sonora S.C.
  • Zapopan, Mexico, 45116
    • Centro de Investigación Médica de Ocidente, S.C.
• Puerto Rico
  • Caguas, Puerto Rico, 00726
    • San Juan Bautista School of Medicine
• Russian Federation
  • Irkutsk, Russian Federation, 664049
    • Regional Clinical Hospital 'The Badge of Honor Order'
  • Ivanovo, Russian Federation, 153040
    • Ivanovo Reg.Clin.Hosp.
  • Izhevsk, Russian Federation, 426009
    • Rep.childrens clin.hosp.
  • Kazan, Russian Federation, 420012
    • State Medical University, Kazan
  • Kirov, Russian Federation, 610014
    • Munic. Instit. of HC "Kirov clin. hosp.#7 n.a.V.I.Urlova"
  • Moscow, Russian Federation, 117036
    • Endocrinology Scientific Center, MoH and Social Development
  • Novosibirsk, Russian Federation, 630091
    • State Novosibirsk Regional Clinical Hospital
  • Rostov-on-Don, Russian Federation, 344022
    • Fed. State Budget Educational Instit. of Higher Education "Rostov State Med. Univ." of MoH of RF
  • St. Petersburg, Russian Federation, 194100
    • St. Petersburg State Pediatric University
  • Tomsk, Russian Federation, 634050
    • Siberian State Med.Uni,Faculty Therapy Dep.w/ Clin.Pharmacol
  • Ufa, Russian Federation, 450106
    • Bahkir state med. Univ. of the Ministry Polyclinic Pediatric
• Thailand
  • Khon Kaen, Thailand, 40002
    • Srinagarind Hospital
  • Krung Thep Maha Nakhon, Thailand, 10400
    • Rajavithi Hospital
• United Kingdom
  • London, United Kingdom, SW17 0QT
    • St George's Hospital
  • Reading, United Kingdom, RG1 5AN
    • Royal Berkshire Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Orange, California, United States, 92868
      • CHOC Children's Hospital
    • Palo Alto, California, United States, 94304
      • Stanford University Medical Center
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94158
      • University of California San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale University School of Medicine
  • Florida
    • Miami, Florida, United States, 33144
      • Oceane7 Clinical Research
    • Miami Lakes, Florida, United States, 33016
      • Empire Clinical Research, LLC
    • Orlando, Florida, United States, 32825
      • Pediatric and Adult Research Center
    • Pensacola, Florida, United States, 32514
      • Nemours Clinic
    • Tampa, Florida, United States, 33612
      • University of South Florida
    • Winter Park, Florida, United States, 32789
      • AdventHealth Medical Group, Pediatric Diabetes and Endocrinology at Winter Park
  • Georgia
    • Atlanta, Georgia, United States, 30331
      • Atlanta Center
    • Atlanta, Georgia, United States, 30329
      • Children's Center for Advanced Pediatrics
    • Columbus, Georgia, United States, 31904
      • Columbus Regional Research Institute
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Rocky Mountain Diabetes and Osteoporosis Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Novak Center for Children's Health
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Integrative Biosciences Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
  • New York
    • Bronx, New York, United States, 10468
      • Advantage Clinical Trials
    • Buffalo, New York, United States, 14203
      • UBMD Pediatrics
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • The University of North Carolina at Chapel Hill
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma
    • Tulsa, Oklahoma, United States, 74135
      • University of Oklahoma
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State College of Medicine
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Monument Health Rapid City Hospital, Inc.
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • LifeDoc Research, PLLC
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77089
      • Office of Amir A. Hassan, MD, P.A.
    • La Joya, Texas, United States, 78560
      • Saenz Medical Center
    • San Antonio, Texas, United States, 78207
      • Texas Diabetes Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
    • Richmond, Virginia, United States, 23219
      • Children's Hospital of Richmond at VCU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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.
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.	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 Names: Trajenta(R)
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.	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 Names: Jardiance(R)
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.	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 Names: Jardiance(R)
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.	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 Names: Trajenta(R)
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.	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 Names: Jardiance(R)
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.	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 Names: Jardiance(R)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c (%) From Baseline to the End of 26 Weeks - DINAMOᵀᴹ 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.
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.
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.
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.
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.
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.
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.
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.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2018
• Primary Completion (Actual): October 19, 2022
• Study Completion (Actual): May 31, 2023

Study Registration Dates

• First Submitted: February 6, 2018
• First Submitted That Met QC Criteria: February 6, 2018
• First Posted (Actual): February 12, 2018

Study Record Updates

• Last Update Posted (Actual): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Empagliflozin; Linagliptin
• Other Study ID Numbers: 1218-0091; 2016-000669-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

• IPD Sharing 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.
• IPD Sharing 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'.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No