Linagliptin as Add on Therapy to Empagliflozin 10 mg or 25 mg With Japanese Patients With Type 2 Diabetes Mellitus

A Phase III, Randomised, Double-blind, Parallel Group, 24-week Study to Evaluate Efficacy and Safety of Once Daily Empagliflozin 10 mg and Linagliptin 5 mg Fixed Dose Combination Compared With Empagliflozin 10 mg Plus Placebo and a 52-week Study to Evaluate Efficacy and Safety of Once Daily Empagliflozin 25 mg and Linagliptin 5 mg Fixed Dose Combination Compared With Empagliflozin 25 mg Plus Placebo in Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control After 16-week Treatment With Empagliflozin (10 mg or 25 mg) Alone Once Daily.

Two independent study parts (i.e. Part A and Part B) are included in this trial. Part A will evaluate empagliflozin 10 mg + linagliptin and Part B will evaluate empagliflozin 25 mg + linagliptin. All analyses will be carried out separately for these study parts. The objective of Part A is to investigate the efficacy, safety and tolerability of the fixed dose combination (FDC) of empagliflozin 10 mg / linagliptin 5 mg compared with empagliflozin 10 mg plus FDC matching placebo administered orally once daily for 24 weeks in Japanese patients with T2DM (Type 2 Diabetes Mellitus) who have insufficient glycaemic control after 16 weeks of treatment with empagliflozin 10 mg alone once daily. The study is designed to show superiority of the FDC of empagliflozin 10 mg / linagliptin 5 mg over empagliflozin 10 mg plus FDC matching placebo after 24 weeks of treatment. The objective of Part B is to investigate the efficacy, safety and tolerability of the FDC of empagliflozin 25 mg / linagliptin 5 mg compared with empagliflozin 25 mg plus FDC matching placebo administered orally once daily for 24 weeks in Japanese patients with T2DM who have insufficient glycaemic control after 16 weeks of treatment with empagliflozin 25 mg alone once daily. The study is designed to show superiority of the FDC of empagliflozin 25 mg / linagliptin 5 mg over empagliflozin 25 mg plus FDC matching placebo after 24 weeks of treatment. The 24 week treatment period will be followed by a 28 week extension treatment period to evaluate further efficacy and safety up to 52 weeks.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Placebo; Drug: empagliflozin 10 mg + linagliptin 5 mg; Drug: empagliflozin 10 mg; Drug: empagliflozin 25 mg + linagliptin 5 mg; Drug: empagliflozin 25 mg

• Study Type: Interventional
• Enrollment (Actual): 880
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Aichi, Kasugai, Japan, 487-0031
    • Tokai Memorial Hospital
  • Aichi, Nagoya, Japan, 455-8530
    • Japan Organization of Occupational Health and Safety Chubu Rosai Hospital
  • Chiba, Chiba, Japan, 261-0004
    • Tokuyama Clinic
  • Ehime, Matsuyama, Japan, 790-0067
    • Matsuyama Shimin Hospital
  • Ehime, Niihama, Japan, 792-0045
    • Tanaka Int. Clinic, Ehime, DIA Med.,CV Med.
  • Ehime, Saijo, Japan, 793-0030
    • Murakami Memorial Hp., Ehime, I.M.
  • Fukuoka, Fukuoka, Japan, 819-0168
    • Kunisaki Makoto Clinic, Fukuoka, I.M./CV Med.
  • Fukuoka, Onga, Japan, 807-0051
    • Fukuoka Shin Mizumaki Hospital
  • Fukuoka, Yukuhashi, Japan, 824-0026
    • Shin Yukuhashi Hospital
  • Gifu, Gifu, Japan, 500-8225
    • Hashimoto I.M., Gifu, I.M.
  • Gunma, Maebashi, Japan, 370-3573
    • Kikuchi Naika Clinic, Gunma, I.M.
  • Hokkaido, Chitose, Japan, 066-0032
    • Hasegawa Internal Medicine Clinic
  • Hokkaido, Ebetsu, Japan, 067-0041
    • Ebetsu Internal Medicine Clinic
  • Hokkaido, Hakodate, Japan, 042-0942
    • Iida Medical Clinic
  • Hokkaido, Hakodate, Japan, 040-8585
    • Hakodate Koseiin Hakodate Central General Hospital
  • Hokkaido, Sapporo, Japan, 062-8618
    • Japan Community Health Care Organization Hokkaido Hospital
  • Hokkaido, Sapporo, Japan, 004-0053
    • Kurihara Clinic
  • Hokkaido, Sapporo, Japan, 006-0031
    • Uehara Clinic
  • Hokkaido, Sapporo, Japan, 060-0062
    • Manda Memorial Hospital
  • Hokkaido, Sapporo, Japan, 060-0807
    • Sapporo Diabetes, Thyroid Clinic
  • Hyogo, Ashiya, Japan, 659-8502
    • Ashiya Municipal Hospital
  • Ibaraki, Koga, Japan, 306-0232
    • Itabashi DIA Med. and DERM Clinic, Ibaraki, I.M.
  • Ibaraki, Namegata, Japan, 311-3516
    • Namegata District General Hospital
  • Ishikawa, Kanazawa, Japan, 921-8035
    • Hokuriku Hp., Ishikawa, I.M.
  • Iwate, Morioka, Japan, 020-0066
    • Oikawa Clinic
  • Iwate, Morioka, Japan, 020-0132
    • Hirano Medical Clinic
  • Kagawa, Zentsuji, Japan, 765-0071
    • Iwamoto Clinic, Kagawa, DIAB I.M.
  • Kagoshima, Kagoshima, Japan, 890-0061
    • Tenpozan Clinic of I.M., Kagoshima, I.M.
  • Kanagawa, Chigasaki, Japan, 253-0044
    • Hayashi DIA Clinic, Kanagawa, DIA Tract Med.·I.M.
  • Kanagawa, Kamakura, Japan, 247-0056
    • Takai Naika Clinic
  • Kanagawa, Yokohama, Japan, 232-0064
    • Yokohama Minoru Clinic
  • Kanagawa, Yokohama, Japan, 226-0027
    • Nagatsuta Family Clinic, Kanagawa, I.M.
  • Kanagawa, Yokohama, Japan, 231-0023
    • Motomachi Takatsuka Naika Clinic, Kanagawa, I.M.
  • Kumamoto, Kumamoto, Japan, 860-8556
    • Kumamoto University Hospital
  • Kumamoto, Kumamoto, Japan, 862-0976
    • Jinnouchi Clinic Diabetes Care Center
  • Kumamoto, Kumamoto, Japan, 860-0863
    • Morinagaueno clinic, Kumamoto, Digestive Tract I.M.
  • Kyoto, Kyoto, Japan, 615-0035
    • Kajiyama Clinic, Kyoto, I.M.
  • Nagano, Matsumoto, Japan, 399-0006
    • Matsumoto Nakagawa Hospital
  • Nagano, Nagano, Japan, 380-0802
    • Ota DIA I.M. Clinic, Nagano, I.M.
  • Niigata, Niigata, Japan, 950-1104
    • Saiseikai Niigata Daini Hp., Niigata, METAB ENDO
  • Okayama, Tsuyama, Japan, 708-0841
    • Tsuyama Chuo Hospital
  • Okinawa, Naha, Japan, 900-0032
    • Yaesu Clinic, Okinawa, I.M.
  • Okinawa, Tomigusuku, Japan, 901-0244
    • Tanaka Clinic, Okinawa, I.M.
  • Osaka, Japan, 530-0001
    • AMC Nishi-umeda Clinic
  • Osaka, Japan, 582-0005
    • Shiraiwa Medical Clinic, Osaka, I.M.
  • Osaka, Osaka, Japan, 530-0057
    • Umeda Oak Clinic, Osaka, I.M.
  • Osaka, Osaka, Japan, 532-0026
    • Kinugawa CARDIOL Clinic, Osaka, I.M.
  • Osaka, Osaka, Japan, 536-0008
    • Ikeoka Clinic, Osaka, I.M.
  • Osaka, Osaka, Japan, 559-0011
    • Nanko Clinic, Osaka, I.M.
  • Osaka, Suita, Japan, 565-0853
    • OCROM Clinic
  • Saga, Saga, Japan, 849-0917
    • Saga Memorial Hospital
  • Saitama, Koshigaya, Japan, 343-0828
    • Odayaka Life Naika Clinic, Saitama, I.M.
  • Saitama, Okegawa, Japan, 363-0022
    • Medical corporation Chisei-kai Watanabe clinic
  • Saitama, Sakado, Japan, 350-0233
    • Medical Corporation Toujinkai Sakado Central Hospital
  • Saitama, Tokorozawa, Japan, 359-1141
    • SAINO Clinic,
  • Shizuoka, Hamamatsu, Japan, 430-8525
    • Hamamatsu Rosai Hospital
  • Shizuoka, Shizuoka, Japan, 422-8006
    • Plumeria Clinic, Shizuoka, I.M.
  • Tochigi, Shimotsuke, Japan, 329-0433
    • Wakakusa Clinic, Tochigi, I.M.
  • Tokyo, Japan, 101-0047
    • Kanda Clinic, Tokyo, I.M.
  • Tokyo, Chuo-ku, Japan, 103-0027
    • Fukuwa Clinic
  • Tokyo, Chuo-ku, Japan, 103-0027
    • Tokyo-Eki Center-building Clinic
  • Tokyo, Chuo-ku, Japan, 103-0028
    • Tokyo Center Clinic
  • Tokyo, Chuo-ku, Japan, 103-0025
    • Nihonbashi Sakura Clinic
  • Tokyo, Chuo-ku, Japan, 104-0061
    • AGE Makita Medical Clinic
  • Tokyo, Chuo-ku, Japan, 103-0027
    • Nihonbashi Enomoto Internal Medicine
  • Tokyo, Chuo-ku, Japan, 104-0031
    • Hosono Clinic
  • Tokyo, Edogawa-ku, Japan, 134-0084
    • Kasai Diabetes Clinic
  • Tokyo, Hachioji, Japan, 192-0918
    • Minamino Heart Clinic
  • Tokyo, Hachioji, Japan, 192-0046
    • New Medical Research System Clinic
  • Tokyo, Hachioji, Japan, 192-0071
    • Medical Corporation Keikokai P1-Clinic
  • Tokyo, Katushika-ku, Japan, 124-0024
    • Shinkoiwa Ekimae Sougou Clinic
  • Tokyo, Kiyose, Japan, 204-0021
    • Musashino Polyclinic
  • Tokyo, Minato-ku, Japan, 108-0075
    • Shinagawa East one Medical Clinic
  • Tokyo, Minato-ku, Japan, 105-7390
    • Pedi Shiodome Clinic
  • Tokyo, Nerima-ku, Japan, 177-0051
    • Shimamura Kinen Hospital
  • Tokyo, Ota-ku, Japan, 143-0015
    • Kenkoukan Suzuki Clinic
  • Tokyo, Ota-ku, Japan, 143-0023
    • Honda Hidehiko Clinic
  • Tokyo, Shinagawa-ku, Japan, 141-0032
    • Miho Clinic
  • Tokyo, Shinagawa-ku, Japan, 140-0011
    • Sakayori Clinic
  • Tokyo, Shinjuku-ku, Japan, 160-0022
    • ToCROM Clinic
  • Tokyo, Toshima-ku, Japan, 171-0021
    • Ikebukuro Metropolitan Clinic
  • Toyama, Toyama, Japan, 930-0964
    • Fujikoshi Hp., Toyama, I.M.
  • Yamagata, Yamagata, Japan, 990-0885
    • Clinic Sugiyama, Yamagata, I.M.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Diagnosis of type 2 diabetes prior to informed consent

• Male and female patients on diet and exercise regimen for at least 12 weeks prior to informed consent who are:

  • drug-naïve, defined as no antidiabetic drugs for at least 12 weeks prior to informed consent or,
  • 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 the informed consent (for thiazolidinedione, therapy has to be unchanged for at least 18 weeks prior to the informed consent). Individual antidiabetic drug will have to be discontinued at Visit 1.

• haemoglobin A1c (HbA1c) at Visit 1 (screening)

  • for patients without antidiabetic therapy : HbA1c >=8.0 to =<10.5%
  • for patients with one oral antidiabetic drug : HbA1c >=7.5 to =<10.5%
• HbA1c >=7.5 to =<10.0% at Visit 4 for randomisation into the double blind treatment period

Exclusion criteria:

• Uncontrolled hyperglycaemia with a glucose level >270 mg/dL (>15.0 mmol/L) during the open label stabilisation period and placebo run in period
• Impaired renal function, defined as estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2 (modification of diet in renal disease (MDRD) formula)
• Acute coronary syndrome, stroke or transient ischemic attack (TIA) within 12 weeks prior to informed consent
• Indication of liver disease, defined by serum levels of either alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase (ALP) above 3 x upper limit of normal (ULN)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: empagliflozin 10 mg + linagliptin 5 mg; patient to receive a tablet containing low dose empagliflozin and linagliptin once daily	Drug: empagliflozin 10 mg + linagliptin 5 mg; empagliflozin low dose + linagliptin once daily
Experimental: empagliflozin 10 mg; patient to receive a tablet containing low dose empagliflozin once daily	Drug: Placebo; Drug: empagliflozin 10 mg; empagliflozin low dose once daily
Experimental: empagliflozin 25 mg + linagliptin 5 mg; patient to receive a tablet containing high dose empagliflozin and linagliptin once daily	Drug: empagliflozin 25 mg + linagliptin 5 mg; empagliflozin high dose + linagliptin once daily
Experimental: empagliflozin 25 mg; patients to receive a tablet containing high dose empagliflozin once daily	Drug: Placebo; Drug: empagliflozin 25 mg; empagliflozin high dose once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Glycated Haemoglobin A1c (HbA1c) (%) From Baseline After 24 Weeks of Treatment	Change from baseline in HbA1c (%) after 24 weeks of treatment with double-blind trial medication. Change was calculated as: HbA1c value at 24-week - HbA1c value at baseline, for each patient. Baseline was defined as the last observation before the first intake of double-blind randomised trial medication. Statistical analysis presented is based on a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach. Full Analysis Set (Observed Cases) [FAS (OC)]: This analysis set consisted of all patients who were randomised and treated with at least 1 dose of trial drug during the double-blind part of the trial and who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the 24-week double-blind part of the trial. Observed cases analysis included only the available data that were observed while patients were on treatment, i.e., excluding the missing data.	Baseline and 24 week

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Collaborators: Eli Lilly and Company

Publications and helpful links

General Publications

• Kaku K, Haneda M, Tanaka Y, Lee G, Shiki K, Miyamoto Y, Solimando F, Lee J, Lee C, George J. Linagliptin as add-on to empagliflozin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a two-part, randomized, placebo-controlled trial. Diabetes Obes Metab. 2019 Jan;21(1):136-145. doi: 10.1111/dom.13496. Epub 2018 Sep 6.

Helpful Links

• Synopsis Link

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2015
• Primary Completion (Actual): November 18, 2016
• Study Completion (Actual): June 16, 2017

Study Registration Dates

• First Submitted: May 27, 2015
• First Submitted That Met QC Criteria: July 1, 2015
• First Posted (Estimate): July 3, 2015

Study Record Updates

• Last Update Posted (Actual): September 6, 2018
• Last Update Submitted That Met QC Criteria: September 3, 2018
• Last Verified: September 1, 2018

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; Empagliflozin; Linagliptin
• Other Study ID Numbers: 1275.13