Linagliptin Add-on to Insulin Background Therapy

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of linagliptin compared to placebo when added on to insulin therapy alone or in combination with metformin in Chinese patients with type 2 diabetes mellitus with insufficient glycaemic control

Official Title
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A Phase III, Randomised, Double-blind, Placebo-controlled, Parallel Group, Efficacy and Safety Study of Linagliptin, Administered Orally Once Daily, in Combination With Insulin Therapy for 24 Weeks in Chinese Type 2 Diabetes Mellitus Patients With Insufficient Glycaemic Control

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: placebo
* Drug: linagliptin
* Drug: background therapy


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of type 2 diabetes mellitus prior to informed consent. Chinese male or female patients who are pre-treated with insulin alone or in combination with metformin: With maximum insulin dose of <= 1 unit/kg/day. Acceptable basal insulins could be insulin glargin, insulin detemir or NPH (neutral protamin hagedorn) insulin with duration of action up to 24 h; acceptable pre-mixed insulins could be preparations with 25/75 or 30/70 ratio, with once or twice daily posology only. The total insulin dose should not be changed by more than 10% of the baseline value within the 12 weeks prior to randomisation (Visit 3). Both human insulin & insulin analogue are accepted. If the patient is taking metformin, stable dose (at least 1500 mg daily) must be maintained for at least 12 weeks without dose adjustments prior to randomisation (Visit 3). HbA1c fulfills the following criteria: >= 7.5 % to <= 10.0 % at Visit 1. Age >= 18 years at Visit 1. BMI <= 45 kg/m2 (Body Mass Index) at Visit 1. Women of childbearing potential must be ready and able to use highly effective methods of birth control per ICH (International Conference on Harmonisation) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Signed and dated written informed consent by date of Visit 1 in accordance with ICH-GCP (Good Clinical Practice) and local legislation Exclusion criteria: Uncontrolled hyperglycaemic with a glucose level >240 mg/dl (>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day). Any other antidiabetic drug within 3 months prior to informed consent except those defined as background treatment via inclusion criterion 2. Acute coronary syndrome (non-STEMI (ST Segment Elevation Myocardial Infarction), STEMI and unstable angina pectoris), stroke or TIA (Transient ischemic attack) within 3 months prior to informed consent. Indication of liver disease, defined by serum levels of either ALT (Alanine aminotransferase) (SGPT (serum glutamic pyruvate transaminase )), AST (Aspartate aminotransferase) (SGOT (serum glutamic-oxaloacetic transaminase)), or alkaline phosphatase above 3 × upper limit of normal (ULN (upper limit of normal)) as determined during screening and/or run-in phase. Any contraindications to metformin according to the local label for those patients that enter the study with metformin therapy as provided in ISF (Investigator Site File). Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years. Blood dyscrasias or any disorders causing hemolysis or unstable Red Blood Cell (e.g. malaria, babesiosis, haemolytic anemia). Known hypersensitivity or allergy to the investigational product or its recipients. 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 (Type 2 diabetes mellitus). Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 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. Participation in another trial with an investigational drug within 2 months prior to informed consent or previous enrolment in this trial. Any other clinical condition that would jeopardize patient's safety while participating in this clinical trial in the opinion of the investigator.

Ages Eligible for Study
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Minimum Age: 18 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<br> | Drug: linagliptin<br> <br> Drug: background therapy<br>* insulin with or without metformin<br>|
| Placebo Comparator: Placebo<br> | Drug: placebo<br> <br> Drug: background therapy<br>* insulin with or without metformin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) After 24 Weeks of Treatment | Percentage change from baseline, that is, [[(HbA1c after 24 weeks of treatment) - (HbA1c at baseline)] / (HbA1c at baseline)] *100%, where baseline refers to the last observation prior to the start of randomised study drug, including the observation prior to the placebo run-in. | Baseline and week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks of Treatment | Change from baseline in Fasting plasma glucose (FPG) after 24 weeks of treatment. | Baseline and week 24 | 
| Change From Baseline in 2-hour (2-h) Postprandial Plasma Glucose (PPG) After 24 Weeks of Treatment | Change from baseline in 2-hour (2-h) postprandial plasma glucose (PPG) after 24 weeks of treatment. | Baseline and week 24 | 
| Percentage of Participants With HbA1c on Treatment <7.0 Percentage (%) After 24 Weeks of Treatment | Percentage of participants with HbA1c on treatment <7.0 percentage (%) after 24 weeks of treatment. Participants with baseline HbA1c <7.0% were excluded from the analysis. | 24 weeks | 
| Percentage of Participants With HbA1c on Treatment < 6.5% After 24 Weeks of Treatment | Percentage of participants with HbA1c on treatment < 6.5% after 24 weeks of treatment. Participants with baseline HbA1c <6.5% were excluded from the analysis. | 24 weeks | 
| Percentage of Participants With HbA1c Lowering by at Least 0.5% After 24 Weeks of Treatment | Percentage of participants with HbA1c lowering by at least 0.5% after 24 weeks of treatment. | 24 weeks | 
| Percentage of Participants With Any Investigator-defined Hypoglycaemic Adverse Event (AE) With Plasma Glucose (PG) ≤70 mg/dL | Incidence of investigator-reported hypoglycaemic events confirmed by a measured blood glucose ≤70 mg/dL (≤3.9 Millimoles Per Litre (mmol/L)). Severe hypoglycaemic AE = hypoglycaemic event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. | 24 weeks | 
| Percentage of Participants With Any Severe Hypoglycaemic AE | Incidence of severe hypoglycaemic events (requiring active assistance by another person, or fatal). Severe hypoglycaemic AE = hypoglycaemic event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. | 24 weeks |