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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: empagliflozin 10 mg + linagliptin 5 mg
* Drug: empagliflozin 10 mg
* Drug: empagliflozin 25 mg + linagliptin 5 mg
* Drug: empagliflozin 25 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 |