Study to Compare the Efficacy and Safety of Administration of the Fix Dose Combination of Linagliptin Plus Metformin in Drug naïve Type 2 Patients

Study Overview
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Brief Summary
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Reduced factorial design study with 24 week randomized treatment of initial combination therapy with linagliptin and metformin in T2DM patients

Official Title
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A Phase III Randomised, Double-blind, Double-dummy, Parallel Group Study to Compare the Efficacy and Safety of Twice Daily Administration of the Fix Dose Combination of Linagliptin 2.5 mg + Metformin 500 mg, or of Linagliptin 2.5 mg + Metformin 1000 mg, With the Individual Components of Metformin (500 mg or 1000 mg, Twice Daily), and Linagliptin (5.0 mg, Once Daily) Over 24 Weeks in Treatment naïve Type 2 Diabetic Patients With Insufficient Glycaemic Control

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: linagliptin2.5mg/metformin1000mg
* Drug: linagliptin2.5mg/metformin1000mg
* Drug: linagliptin 5mg
* Drug: Metformin 500mg
* Drug: linagliptin2.5mg/metformin500mg
* Drug: linagliptin2.5mg/metformin500mg
* Drug: linagliptin 5mg
* Drug: Metformin 1000mg


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of Type 2 diabetes mellitus(T2DM) prior to informed consent Male and female patients on diet and exercise regimen who are drug-naïve Glycosylated haemoglobin A1c (HbA1c) at V1a >/=7.5 %<11% for main group and HbA1c >/= 11.0 % for the additional parallel group Age >/= 18 and </= 80 years at Visit 1a (Screening) Body Mass Index(BMI)</ = 40 kg/m2 at Visit 1a (Screening) Signed and dated written informed consent by date of Visit 1a in accordance with good clinical practice(GCP) and local legislation Exclusion criteria: Uncontrolled hyperglycaemia required for rescue medication during placebo run-in phase In main group, the patients with investigational medicinal product(IMP) compliance < 80 % or >120 % during 2 weeks placebo run in period Acute coronary syndrome stroke or Transient ischaemic attack (TIA) within 3 months prior to randomisation Impaired hepatic function, defined by serum levels of either Alanine aminotransferase(ALT) ,Aspartate aminotransferase(AST), or alkaline phosphatase (AP) above 3 x upper limit of normal (ULN) ,or total bilirubin above 1.5 x ULN as determined at Visit 1a Known hypersensitivity or allergy to linagliptin or its excipients or metformin or placebo Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at the time of screening Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake in the opinion of the investigator. Concurrent participation in another clinical trial or any investigational therapy within thirty days prior to signing the consent form or during the trial. Pre-menopausal women (last menstruation </= 1 year prior to informed consent) who are nursing or pregnant or 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 study Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent. Renal failure or renal impairment at Visit 1a (screening) with an Estimated Glomerular Filtration Rate(eGFR) < 60 ml/min Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption Dehydration by clinical judgement of the investigator Clinical detected unstable or acute congestive heart failure Acute or chronic metabolic acidosis (present in patient history) Hereditary galactose intolerance Known history of pancreatitis and chronic pancreatitis Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within last 5 years. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial at the discretion of investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: linagliptin2.5mg / metformin500mg BID<br>patient to receive a tablet containing linagliptin 2.5mg and metformin 500mg BID | Drug: linagliptin 5mg<br>* linagliptin 5mg once daily<br>Drug: Metformin 500mg<br>* Metformin 500mg BID<br>|
| Experimental: linagliptin2.5mg / metformin1000mg BID<br>patient to receive a tablet containing linagliptin 2.5mg and metformin 1000mg BID | Drug: linagliptin 5mg<br>* linagliptin 5mg once daily<br>Drug: Metformin 1000mg<br>* Metformin 1000mg BID<br>|
| Active Comparator: metformin 500mg BID<br>patient to receive a tablet containing metformin 500mg BID | Drug: linagliptin2.5mg/metformin500mg<br>* linagliptin2.5mg/metformin500mg BID<br>|
| Active Comparator: metformin 1000mg BID<br>patient to receive a tablet containing metformin 1000mg BID | Drug: linagliptin2.5mg/metformin1000mg<br>* linagliptin2.5mg/metformin1000mg BID<br>|
| Active Comparator: linagliptin 5 mg QD<br>patient to receive a tablet containing linagliptin 5mg once daily | Drug: linagliptin2.5mg/metformin1000mg<br>* linagliptin2.5mg/metformin1000mg BID<br>Drug: linagliptin2.5mg/metformin500mg<br>* linagliptin2.5mg/metformin500mg BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group - FAS (OC) | The change from baseline in HbA1c after 24 weeks of treatment in main group. Only subjects from the FAS with measured HbA1c values (observed cases [OC]) were considered. The mean was adjusted by treatment, baseline HbA1c, week and treatment*week. The sensitivity analysis was added as the primary analysis failed with borderline results. | Baseline and week 24 | 
| The Change From Baseline in HbA1c After 12 Weeks of Treatment in APG | The change from baseline in HbA1c after 12 weeks of treatment in additional parallel group (APG) The mean was adjusted by baseline HbA1c and treatment group. | Baseline and week 12 | 
| The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group | The change from baseline in HbA1c after 24 weeks of treatment in main group. The mean was adjusted by baseline HbA1c and treatment group. | Baseline and week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Frequency of Patients With Use of Rescue Therapy During 24 Week Treatment Period in Main Group | The frequency of patients with use of rescue therapy during 24 week treatment period in main group. For this analysis the main group contrast 'Metformin 1000mg BID, Linagliptin 2.5mg / Metformin 1000mg BID' could not be analysed due to lack of events in the Metformin 1000mg BID group. | From baseline until week 24 | 
| The Frequency of Patients With Use of Rescue Therapy During 12 Week Treatment Period in APG | The Frequency of Patients With Use of Rescue Therapy During 12 Week Treatment Period in APG. | From baseline until week 12 | 
| The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 24 Weeks of Treatment in Main Group | The occurrence of treat to target efficacy response in terms of HbA1c < 7.0 % after 24 weeks of treatment in main group. | Week 24 (after first drug administration) | 
| The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 12 Weeks of Treatment in APG | The occurrence of treat to target efficacy response in terms of HbA1c < 7.0 % after 12 weeks of treatment in APG. | Week 12 (after first drug administration) | 
| The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 24 Weeks of Treatment in Main Group | The occurrence of treat to target efficacy response in terms of HbA1c < 6.5% after 24 weeks of treatment in main group. | Week 24 (after first drug administration) | 
| The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 12 Weeks of Treatment in APG | The occurrence of treat to target efficacy response in terms of HbA1c < 6.5% after 12 weeks of treatment in APG. | Week 12 (after first drug administration) | 
| The Occurrence of Relative Efficacy Response in Main Group | The occurrence of relative efficacy response (HbA1c lowering by at least 0.5% after 24 weeks of treatment) in main group | From baseline until week 24 | 
| The Occurrence of Relative Efficacy Response in APG | The Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 12 Weeks of Treatment) in APG | From baseline until week 12 | 
| The Change in Fasting Plasma Glucose (FPG) From Baseline After 24 Weeks of Treatment in Main Group | The change in fasting plasma glucose (FPG) from baseline after 24 weeks of treatment in main group. Adjusted mean: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group. | Baseline and week 24 | 
| The Change in Fasting Plasma Glucose (FPG) From Baseline After 12 Weeks of Treatment in APG | The Change in Fasting Plasma Glucose (FPG) From Baseline After 12 Weeks of Treatment in APG. Adjusted mean: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group. | Baseline and week 12 |