Clinical trial NCT02453555: Empagliflozin Add on to Linagliptin Study in Japanese Patient With Type 2 Diabetes Mellitus
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Eli Lilly and Company
First posted: 2015-05-25
Enrollment: 275
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility 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

Primary outcomes:
measure: Change of Glycosylated Haemoglobin A1c (Glycosylated Haemoglobin A1c After 24 Weeks of Double-blind Treatment From Baseline)
timeFrame: Baseline and 24 week
Secondary outcomes:
measure: Change in HbA1c From Week 28 at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Only)
timeFrame: 28 Week (pre up-titration) and 52 Week
measure: Change in HbA1c From Baseline at Week 52 (All Empagliflozin Versus All Placebo)
timeFrame: Baseline and 52 week
measure: Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus Linagliptin 5 mg + Placebo 25 mg)
timeFrame: Baseline and 52 week
measure: Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus All Placebo)
timeFrame: Baseline and 52 week
Other outcomes:
Locations:
city: Aichi, Nagoya
country: Japan
facility: Nagoya Kyoritsu Hospital
city: Chiba, Kashiwa
country: Japan
facility: Kashiwa City Hospital
city: Fukuoka, Fukuoka
country: Japan
facility: Otabe internal medicine clinic
city: Fukuoka, Itoshima
country: Japan
facility: Nakamura Cardiovascular Clinic
city: Fukuoka, Kurume
country: Japan
facility: Tanaka I.M. Clinic, Fukuoka, I.M.
city: Fukushima, Koriyama
country: Japan
facility: Seino I.M. Clinic, Fukushima, I.M.
city: Hiroshima, Hiroshima
country: Japan
facility: Hiraoka Naika Clinic, Hiroshima, I.M.
city: Hokkaido, Sapporo
country: Japan
facility: Matsuda Cardiovascular Clinic
city: Hokkaido, Sapporo
country: Japan
facility: Teine Keijinkai Clinic
city: Hokkaido, Sapporo
country: Japan
facility: Mita Internal Medicine Cardiology Clinic
city: Hokkaido, Sapporo
country: Japan
facility: Miyanosawa Clinic of Internal Medicine and Cardiology
city: Ibaraki, Koga
country: Japan
facility: Itabashi Diabetic medicine and Dermatology Clinic
city: Ibaraki, Naka
country: Japan
facility: Nakakinen Clinic
city: Kanagawa, Kawasaki
country: Japan
facility: Kubota Clinic
city: Kanagawa, Sagamihara
country: Japan
facility: Kitasato University Hospital
city: Kanagawa, Yokohama
country: Japan
facility: H.E.C Science Clinic
city: Kyoto, Kyoto
country: Japan
facility: Yoshimasa Diabetes & Endocrine Clinic
city: Kyoto, Kyoto
country: Japan
facility: Rakuwakai Otowa Hospital
city: Kyoto, Kyoto
country: Japan
facility: Medical Corporation Hayashi Katagihara Clinic
city: Nagano, Matsumoto
country: Japan
facility: Miyamoto Naika Clinic, Nagano, I.M.
city: Nagano, Matsumoto
country: Japan
facility: Gibo Hepatology Clinic, Nagano, Digestive Tract I.M.
city: Osaka, Higashi-Osaka
country: Japan
facility: Takekawa Clinic, Osaka, I.M.
city: Osaka, Osaka
country: Japan
facility: Medical Corporation Koseikai Fukuda Naika Clinic
city: Osaka, Osaka
country: Japan
facility: Kinugawa Cardiovascular Internal Medicine clinic
city: Osaka, Osaka
country: Japan
facility: Sato Hospital
city: Osaka, Osaka
country: Japan
facility: Nakaoka Clinic
city: Osaka, Suita
country: Japan
facility: OCROM Clinic
city: Osaka, Takatsuki
country: Japan
facility: Miyauchi Medical Center
city: Saitama, Hanno
country: Japan
facility: Medical Corporation Shinseikai Mashiba Clinic
city: Saitama, Kawagoe
country: Japan
facility: Asano Clinic
city: Saitama, Saitama
country: Japan
facility: Medical Corporation Fusa Shimizu Clinic Fusa
city: Saitama, Tokorozawa
country: Japan
facility: Ogino Clinic
city: Tokyo, Chiyoda-ku
country: Japan
facility: Kanda Clinic
city: Tokyo, Chuo-ku
country: Japan
facility: Fukuwa Clinic
city: Tokyo, Chuo-ku
country: Japan
facility: Tokyo-Eki Center-building Clinic
city: Tokyo, Hachioji
country: Japan
facility: Myojin Tou Clinic
city: Tokyo, Koto-ku
country: Japan
facility: Sawai Medical Clinic
city: Tokyo, Meguro-ku
country: Japan
facility: Mishuku Hospital
city: Tokyo, Shinagawa-ku
country: Japan
facility: Toshiba General Hospital
city: Tokyo, Shinjuku-ku
country: Japan
facility: ToCROM Clinic
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Kawamori R, Haneda M, Suzaki K, Cheng G, Shiki K, Miyamoto Y, Solimando F, Lee C, Lee J, George J. Empagliflozin as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2018 Sep;20(9):2200-2209. doi: 10.1111/dom.13352. Epub 2018 Jun 1.