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Empagliflozin Add on to Linagliptin Study in Japanese Patient With Type 2 Diabetes Mellitus

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ClinicalTrials.gov Identifier: NCT02453555
Recruitment Status : Completed
First Posted : May 25, 2015
Results First Posted : February 15, 2019
Last Update Posted : February 15, 2019
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:
This trial will compare the use of fixed dose combination of empagliflozin and linagliptin to linagliptin alone in patient with type 2 diabetes mellitus

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Drug: Linagliptin Drug: Empagliflozin placebo + linagliptin placebo low dose Drug: Empagliflozin + linagliptin low dose Drug: Linagliptin placebo Drug: Empagliflozin + linagliptin high dose Drug: Empa + lina highdose placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 275 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Randomised, Double-blind, Parallel Group, 52 Week Study to Evaluate Efficacy and Safety of Once Daily Empagliflozin and Linagliptin Fixed Dose Combination Compared With Linagliptin Plus Placebo in Japanese Type 2 Diabetes Mellitus Patients With Insufficient Glycaemic Control After 16 Weeks Treatment With Once Daily Linagliptin 5 mg.
Actual Study Start Date : May 14, 2015
Actual Primary Completion Date : August 26, 2016
Actual Study Completion Date : March 27, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Linagliptin
patient to receive 5 mg linagliptin once daily
Drug: Linagliptin
Other Name: tablet

Drug: Empagliflozin placebo + linagliptin placebo low dose
Matching placebo empagliflozin + linagliptin

Drug: Empa + lina highdose placebo
Experimental: Empagliflozin + linagliptin low dose
patient to receive one tablet once daily
Drug: Empagliflozin + linagliptin low dose
tablet

Drug: Linagliptin placebo
Matching placebo linagliptin

Experimental: Empagliflozin + linagliptin high dose
patient to receive one tablet once daily
Drug: Linagliptin placebo
Matching placebo linagliptin

Drug: Empagliflozin + linagliptin high dose
tablet

Placebo Comparator: Linagliptin placebo Drug: Empagliflozin + linagliptin low dose
tablet

Drug: Linagliptin placebo
Matching placebo linagliptin

Drug: Empagliflozin + linagliptin high dose
tablet

Placebo Comparator: Empagliflozin + linagliptin high dose placebo Drug: Linagliptin
Other Name: tablet

Drug: Empa + lina highdose placebo
Placebo Comparator: Empagliflozin + linagliptin low dose placebo Drug: Linagliptin
Other Name: tablet

Drug: Empagliflozin placebo + linagliptin placebo low dose
Matching placebo empagliflozin + linagliptin




Primary Outcome Measures :
  1. Change of Glycosylated Haemoglobin A1c (Glycosylated Haemoglobin A1c After 24 Weeks of Double-blind Treatment From Baseline) [ Time Frame: Baseline and 24 week ]
    Change from baseline in Glycosylated haemoglobin A1c (HbA1c) at Week 24 was calculated as: HbA1c at Week 24 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.


Secondary Outcome Measures :
  1. Change in HbA1c From Week 28 at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Only) [ Time Frame: 28 Week (pre up-titration) and 52 Week ]

    Change from Week 28 in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at Week 28. Week 28 (pre up-titration) is referred to the last observed measurement prior to the first administration of any double-blind randomized trial medication in the up-titration period. Adjusted mean (Least square mean) and its standard error (SE) is presented.

    This endpoint was based on 1 group of the Full analysis set with up-titration (FASUT-II) whose dose was up-titrated to Empagliflozin 25 mg/Linagliptin 5 mg fixed dose combination thus there is no comparison group. Hence, no comparison is made. A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline eGFR, prior use of antidiabetic drug, visit as fixed effect(s). The covariance used to fit the model was unstructured.


  2. Change in HbA1c From Baseline at Week 52 (All Empagliflozin Versus All Placebo) [ Time Frame: Baseline and 52 week ]
    Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.

  3. Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus Linagliptin 5 mg + Placebo 25 mg) [ Time Frame: Baseline and 52 week ]
    Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.

  4. Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus All Placebo) [ Time Frame: Baseline and 52 week ]
    Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. Diagnosis of Type-2 Diabetes Mellitus (T2DM) prior to informed consent
  2. Male and female patients on diet and exercise regimen for at least 12 weeks prior to informed consent who are:

    • 1 drug-naïve, defined as no antidiabetic drugs for at least 12 weeks prior to informed consent, or
    • 2 pre-treated with one oral antidiabetic drug (for sulfonylurea, with up to half of the maximum approved dose) on stable dosage for at least 12 weeks prior to informed consent (for thiazolidinedione, therapy has to be unchanged for at least 18 weeks prior to the informed consent, for linagliptin 5 mg at least 16 weeks prior to Visit 1). Individual antidiabetic drug (except linagliptin) will have to be discontinued at Visit 1.
  3. HbA1c at Visit 1

    • 1 HbA1c =8.0% and =10.5% for patients who are drug-naïve, or
    • 2 HbA1c =7.5% and =10.5% for patients with one oral antidiabetic drug (except linagliptin), or
    • 3 HbA1c =7.5% and =10.0% for patients with linagliptin 5 mg
  4. HbA1c =7.5% and =10.0% at Visit 4 for randomisation into the double-blind treatment period. Patient who are pre-treated with linagliptin 5 mg for 16 weeks or more prior to Visit 1 and meet the criteria of HbA1c can directly move on to the run-in (Visit 4).
  5. Age =20 years at informed consent
  6. BMI =40.0 kg/m2 at Visit 1 (screening)
  7. Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation

Exclusion criteria:

  1. Uncontrolled hyperglycemia with a glucose level >270 mg/dL (>15.0 mmol/L) after an overnight fast during the open-label stabilisation period (from Visit 2 to Visit 4) and run-in period (from Visit 4 to Visit 5) , confirmed by a second measurement (not on the same day and done either at the central or at local laboratory).
  2. Acute coronary syndrome (ST-elevation myocardial infarction [STEMI], non-STEMI, and unstable angina pectoris), stroke or transient ischemic attack within 12 weeks prior to informed consent
  3. Indication of liver disease, defined by serum levels of either alanine aminotransferase (ALT Serum glutamic pyruvate transaminase [SGPT]), aspartate aminotransferase (AST, Serum glutamic oxaloacetic transaminase [SGOT]), or alkaline phosphatase (ALP) above 3 x upper limit of normal (ULN) as determined during screening, open-label stabilisation period and/or run-in period
  4. Impaired renal function, defined as estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 (MDRD formula) as determined during screening, open-label stabilisation period and/or run-in period
  5. Known hereditary galactose intolerance
  6. Known contraindications to linagliptin and empagliflozin according to the Japanese label
  7. Any previous (within 2 years prior to informed consent) or planned bariatric surgery (or any other weight loss surgery) or other gastrointestinal surgery that induce chronic malabsorption
  8. Medical history of cancer (except for resected non-invasive basal cell or squamous carcinoma) and/or treatment for cancer within the last 5 years
  9. Known blood dyscrasias or any disorders causing haemolysis or unstable red blood cell (RBC) count (e.g. malaria, babesiosis, haemolytic anaemia).
  10. Treatment with insulin, Glucagon-like peptide-1 agonists, within 12 weeks prior to informed consent
  11. Treatment with anti-obesity drugs within 12 weeks prior to informed consent or any other treatment at the time of screening (i.e., surgery, aggressive diet regimen, etc.) leading to unstable body weight
  12. Current treatment with systemic steroids (other than inhaled or topical steroids) at informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except T2DM
  13. Pre-menopausal women (last menstruation =1 year prior to informed consent) who:

    • 1 are nursing or pregnant or
    • 2 are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the trial and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, intra uterine devices/systems, oral contraceptives, complete sexual abstinence, double barrier method and vasectomised partner
  14. Known or suspected allergy or hypersensitivity to trial products or related products (e.g., Dipeptidyl-peptidase-4 inhibitors or Sodium-glucose co-transporter-2 inhibitors)
  15. Alcohol or drug abuse within the 12 weeks prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to trial procedures or trial drug intake, by the judgment of the investigator
  16. Intake of an investigational drug in another trial within 30 days prior to Visit 1 or participation in the follow-up period of another trial (participation in observational studies is permitted)
  17. Any other clinical condition that, in the opinion of the investigator, would jeopardize patient's safety while participating in this clinical trial

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02453555


Locations
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Japan
Nagoya Kyoritsu Hospital
Aichi, Nagoya, Japan, 454-0933
Kashiwa City Hospital
Chiba, Kashiwa, Japan, 277-0825
Otabe internal medicine clinic
Fukuoka, Fukuoka, Japan, 811-1346
Nakamura Cardiovascular Clinic
Fukuoka, Itoshima, Japan, 819-1104
Tanaka I.M. Clinic, Fukuoka, I.M.
Fukuoka, Kurume, Japan, 830-0023
Seino I.M. Clinic, Fukushima, I.M.
Fukushima, Koriyama, Japan, 963-8851
Hiraoka Naika Clinic, Hiroshima, I.M.
Hiroshima, Hiroshima, Japan, 733-0011
Matsuda Cardiovascular Clinic
Hokkaido, Sapporo, Japan, 003-0026
Teine Keijinkai Clinic
Hokkaido, Sapporo, Japan, 006-0811
Mita Internal Medicine Cardiology Clinic
Hokkaido, Sapporo, Japan, 006-0852
Miyanosawa Clinic of Internal Medicine and Cardiology
Hokkaido, Sapporo, Japan, 063-0826
Itabashi Diabetic medicine and Dermatology Clinic
Ibaraki, Koga, Japan, 306-0232
Nakakinen Clinic
Ibaraki, Naka, Japan, 311-0113
Kubota Clinic
Kanagawa, Kawasaki, Japan, 214-0014
Kitasato University Hospital
Kanagawa, Sagamihara, Japan, 252-0375
H.E.C Science Clinic
Kanagawa, Yokohama, Japan, 235-0045
Yoshimasa Diabetes & Endocrine Clinic
Kyoto, Kyoto, Japan, 604-8151
Rakuwakai Otowa Hospital
Kyoto, Kyoto, Japan, 607-8062
Medical Corporation Hayashi Katagihara Clinic
Kyoto, Kyoto, Japan, 615-8125
Miyamoto Naika Clinic, Nagano, I.M.
Nagano, Matsumoto, Japan, 390-0848
Gibo Hepatology Clinic, Nagano, Digestive Tract I.M.
Nagano, Matsumoto, Japan, 399-0036
Takekawa Clinic, Osaka, I.M.
Osaka, Higashi-Osaka, Japan, 577-0803
Medical Corporation Koseikai Fukuda Naika Clinic
Osaka, Osaka, Japan, 532-0003
Kinugawa Cardiovascular Internal Medicine clinic
Osaka, Osaka, Japan, 532-0026
Sato Hospital
Osaka, Osaka, Japan, 536-0023
Nakaoka Clinic
Osaka, Osaka, Japan, 555-0032
OCROM Clinic
Osaka, Suita, Japan, 565-0853
Miyauchi Medical Center
Osaka, Takatsuki, Japan, 569-1123
Medical Corporation Shinseikai Mashiba Clinic
Saitama, Hanno, Japan, 357-0024
Asano Clinic
Saitama, Kawagoe, Japan, 350-0851
Medical Corporation Fusa Shimizu Clinic Fusa
Saitama, Saitama, Japan, 336-0963
Ogino Clinic
Saitama, Tokorozawa, Japan, 359-1161
Kanda Clinic
Tokyo, Chiyoda-ku, Japan, 101-0047
Fukuwa Clinic
Tokyo, Chuo-ku, Japan, 103-0027
Tokyo-Eki Center-building Clinic
Tokyo, Chuo-ku, Japan, 103-0027
Myojin Tou Clinic
Tokyo, Hachioji, Japan, 192-0046
Sawai Medical Clinic
Tokyo, Koto-ku, Japan, 136-0073
Mishuku Hospital
Tokyo, Meguro-ku, Japan, 153-0051
Toshiba General Hospital
Tokyo, Shinagawa-ku, Japan, 140-8522
ToCROM Clinic
Tokyo, Shinjuku-ku, Japan, 160-0022
Sponsors and Collaborators
Boehringer Ingelheim
Eli Lilly and Company
Investigators
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Study Chair: Boehringer Ingelheim Boehringer Ingelheim

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02453555     History of Changes
Other Study ID Numbers: 1275.19
First Posted: May 25, 2015    Key Record Dates
Results First Posted: February 15, 2019
Last Update Posted: February 15, 2019
Last Verified: September 2018
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Empagliflozin
Linagliptin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors