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

Diabetes Mellitus, Type 2 Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02453555
• Other study ID #: 1275.19
• Status: Completed
• Phase: Phase 3
• Start date: May 14, 2015
• Est. completion date: March 27, 2017

Study information

• Verified date: September 2018
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 275
• Est. completion date: March 27, 2017
• Est. primary completion date: August 26, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• Linagliptin

• Empagliflozin placebo + linagliptin placebo low dose
Matching placebo empagliflozin + linagliptin
• Empagliflozin + linagliptin low dose
tablet
• Linagliptin placebo
Matching placebo linagliptin
• Empagliflozin + linagliptin high dose
tablet
• Empa + lina highdose placebo

Locations

Country	Name	City	State
Japan	Nagoya Kyoritsu Hospital	Aichi, Nagoya
Japan	Kashiwa City Hospital	Chiba, Kashiwa
Japan	Otabe internal medicine clinic	Fukuoka, Fukuoka
Japan	Nakamura Cardiovascular Clinic	Fukuoka, Itoshima
Japan	Tanaka I.M. Clinic, Fukuoka, I.M.	Fukuoka, Kurume
Japan	Seino I.M. Clinic, Fukushima, I.M.	Fukushima, Koriyama
Japan	Hiraoka Naika Clinic, Hiroshima, I.M.	Hiroshima, Hiroshima
Japan	Matsuda Cardiovascular Clinic	Hokkaido, Sapporo
Japan	Mita Internal Medicine Cardiology Clinic	Hokkaido, Sapporo
Japan	Miyanosawa Clinic of Internal Medicine and Cardiology	Hokkaido, Sapporo
Japan	Teine Keijinkai Clinic	Hokkaido, Sapporo
Japan	Itabashi Diabetic medicine and Dermatology Clinic	Ibaraki, Koga
Japan	Nakakinen Clinic	Ibaraki, Naka
Japan	Kubota Clinic	Kanagawa, Kawasaki
Japan	Kitasato University Hospital	Kanagawa, Sagamihara
Japan	H.E.C Science Clinic	Kanagawa, Yokohama
Japan	Medical Corporation Hayashi Katagihara Clinic	Kyoto, Kyoto
Japan	Rakuwakai Otowa Hospital	Kyoto, Kyoto
Japan	Yoshimasa Diabetes & Endocrine Clinic	Kyoto, Kyoto
Japan	Gibo Hepatology Clinic, Nagano, Digestive Tract I.M.	Nagano, Matsumoto
Japan	Miyamoto Naika Clinic, Nagano, I.M.	Nagano, Matsumoto
Japan	Takekawa Clinic, Osaka, I.M.	Osaka, Higashi-Osaka
Japan	Kinugawa Cardiovascular Internal Medicine clinic	Osaka, Osaka
Japan	Medical Corporation Koseikai Fukuda Naika Clinic	Osaka, Osaka
Japan	Nakaoka Clinic	Osaka, Osaka
Japan	Sato Hospital	Osaka, Osaka
Japan	OCROM Clinic	Osaka, Suita
Japan	Miyauchi Medical Center	Osaka, Takatsuki
Japan	Medical Corporation Shinseikai Mashiba Clinic	Saitama, Hanno
Japan	Asano Clinic	Saitama, Kawagoe
Japan	Medical Corporation Fusa Shimizu Clinic Fusa	Saitama, Saitama
Japan	Ogino Clinic	Saitama, Tokorozawa
Japan	Kanda Clinic	Tokyo, Chiyoda-ku
Japan	Fukuwa Clinic	Tokyo, Chuo-ku
Japan	Tokyo-Eki Center-building Clinic	Tokyo, Chuo-ku
Japan	Myojin Tou Clinic	Tokyo, Hachioji
Japan	Sawai Medical Clinic	Tokyo, Koto-ku
Japan	Mishuku Hospital	Tokyo, Meguro-ku
Japan	Toshiba General Hospital	Tokyo, Shinagawa-ku
Japan	ToCROM Clinic	Tokyo, Shinjuku-ku

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Eli Lilly and Company

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change of Glycosylated Haemoglobin A1c (Glycosylated Haemoglobin A1c After 24 Weeks of Double-blind Treatment From Baseline)	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.	Baseline and 24 week
Secondary	Change in HbA1c From Week 28 at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Only)	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.	28 Week (pre up-titration) and 52 Week
Secondary	Change in HbA1c From Baseline at Week 52 (All Empagliflozin Versus All Placebo)	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.	Baseline and 52 week
Secondary	Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus Linagliptin 5 mg + Placebo 25 mg)	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.	Baseline and 52 week
Secondary	Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus All Placebo)	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.	Baseline and 52 week

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