Linagliptin in Combination With Metformin in Treatment Naive Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control

Study Overview
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Brief Summary
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The aim of this study is to investigate the impact of the combination therapy of linagliptin and metformin at submaximal doses in reduction of Glycosylated haemoglobin (HbA1c) and metformin pre-specified gastro-intestinal (GI) side effects in treatment naive patients of with type 2 diabetes mellitus.

Official Title
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A Randomised, Double-blind, Double-dummy, Active-comparator Controlled Study Investigating the Efficacy and Safety of Linagliptin Co-administered With Metformin QD at Evening Time Versus Metformin BID Over 14 Weeks in Treatment Naive Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: metformin placebo
* Drug: linagliptin placebo
* Drug: metformin
* Drug: metformin
* Drug: linagliptin


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 naive, defined as absence of any oral antidiabetic therapy or insulin for 12 weeks prior to randomization Glycosylated haemoglobin A1c (HbA1c) >/= 7.0% (53 mmol/mol) to </= 10.0% (86 mmol/mol) at visit 1 (screening); Age>/=18 and </=80 years at visit 1(screening); Body Mass Index (BMI)</= 45kg/m2 at visit 1 (screening); Signed and dated written informed consent by date of visit 1 in accordance with Good Clinical Practice (GCP) and local legislation Exclusion criteria: Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (13.3mmol/L) after an overnight fast during screening/placebo run-in and confirmed by a second measurement (Not on the same day); Treatment with any oral antidiabetic drug or insulin within 12 weeks prior to randomization Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris),stroke or Transient ischemia attack (TIA) within 3 months prior to informed consent; Indication of liver disease/Impaired hepatic function, defined by serum levels of either Aspartate aminotransferase (ALT or SGPT), alanine aminotransferase (AST or SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at visit 1 and/or run-in phase, Impaired renal function, defined as eGFR< 60ml/min (moderate or severe renal impairment, modification of diet in renal disease (MDRD) formula) as determined during screening or at run-in phase Bariatric surgery within the past two years and other gastrointestinal surgeries that induced chronic malabsorption Medical history of Cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years Blood dyscrasia or any other disorders causing haemolysis or unstable Red Blood Cell (eg. malaria, babesiosis, haemolytic anemia) Known history of pancreatitis and chronic pancreatitis Contraindications to metformin according to the local label Treatment with anti-obesity drugs 3 months 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 Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except T2DM Pre-menopausal women (last menstruation less than 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 and do not agree to submit to periodic pregnancy testing during participation in the trial or who do not agree to continue contraception for at least 30 days after the last dose of study drug. Acceptable methods of birth control include tubal ligation, transdermal patch, intra-uterine devices/systems(IUDs/IUSs), oral, implantable, or injectable contraceptives, complete sexual abstinence (if acceptable by local authorities), double barrier method and vasectomized partner. Alcohol or drug abuse within 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 Participation in another trial with application of any investigational drug within 30 days prior to informed consent Any other clinical condition that would jeopardize patients safety while participating in this trial

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: linagliptin + metformin<br>patients to receive linagliptin +metformin QD | Drug: metformin<br>* metformin tablets 500 mg<br>Drug: linagliptin<br>* linagliptin tablets 5mg<br>|
| Active Comparator: metformin<br>patients to receive metformin BID | Drug: metformin placebo<br>* metformin placebo tablets 500mg<br>Drug: linagliptin placebo<br>* linagliptin placebo tablets 5mg<br>Drug: metformin<br>* metformin tablets 500mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) After 14 Weeks Treatment | Adjusted mean change in HbA1c from baseline at Week 14 was analysed using an ANCOVA model. The Model included treatment and continuous baseline HbA1c. | Baseline and 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <7.0% After 14 Weeks of Treatment, on no Occurrence of Moderate or Severe Gastrointestinal (GI) Side Effects During 14 Weeks of Treatment | The proportion of patients who achieved all the targets in a composite endpoint (HbA1c below 7.0% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe gastrointestinal (GI) side effects of metformin, as assessed by the investigators during 14 weeks of treatment) | 14 weeks | 
| Occurence of Metformin Pre-specified Moderate to Severe GI Side Effects Assessed by Investigators During 14 Weeks of Treatment | Proportion of patients who experienced at least one metformin pre-specified moderate or severe GI side effect during 14 weeks | 14 weeks | 
| Change From Baseline in Fasting Plasma Glucose (FPG) After 14 Weeks of Treatment | Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline fasting plasma glucose. | Baseline and 14 weeks | 
| Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment | Patients could experience multiple events, therefore, multiple answers were possible for each patient. | 14 weeks | 
| Metformin Pre-specified GI Symptom Intensity Score Assessed by Patients During 14 Weeks of Treatment | The intensity of the GI side effects was also assessed by the patients using VAS scaled from 0 to 10; higher scores indicate more severe events. Means are adjusted by treatment and continuous baseline HbA1c. | 14 weeks | 
| Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <6.5% After 14 Weeks of Treatment, and no Occurrence of Moderate or Severe Metformin Pre-specified GI Side Effects Assessed by Investigators | The proportion of patients who achieved all the targets in a composite endpoint (HbA1c below 6.5% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment). | 14 weeks | 
| Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) | The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.5% after 14 weeks of treatment). | 14 weeks | 
| Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) | The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.8% after 14 weeks of treatment). | 14 weeks | 
| Composite Endpoint of Occurence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) and no Occurence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by the Investigators During 14 Weeks | The proportion of patients who achieved all the targets in a composite endpoint (HbA1c lowered by at least 0.5% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment). | 14 weeks | 
| Change From Baseline in Body Weight by Visit at Week 14 | Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline weight | Baseline and 14 weeks | 
| Composite Endpoint of Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) and no Occurrence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by Investigators During 14 Weeks | The proportion of patients who achieved all the targets in a composite endpoint (HbA1c lowered by at least 0.8% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment). | 14 weeks | 
| Change From Baseline in HbA1c Over Time | Means are adjusted by treatment and continuous baseline HbA1c | Baseline, 2 weeks and 8 weeks |