Safety and Efficacy of Linagliptin (BI 1356) as Monotherapy or in Combination in Type 2 DM

Study Overview
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Brief Summary
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The objective of the current study is to investigate the safety and tolerability of BI 1356 (5 mg / once daily) given for 78 weeks in different modalities of treatment. The treatment modalities are determined by the treatment in the blinded trial in which every patient was included previously as BI 1356 in monotherapy (patients in 1218.16 trial), BI 1356 in combination with pioglitazone (patients in 1218.15 trial), BI 1356 added to metformin background (patients in 1218.17 trial) or BI 1356 added to a background therapy of metformin in combination with a sulphonylurea (patients in 1218.18 study)

Official Title
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A 78 Week Open Label Extension to Trials Assessing the Safety and Efficacy of BI 1356 (5 mg) as Monotherapy or in Combination With Other Antidiabetic Medications in Type 2 Diabetic Patients.

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: linagliptine 5 mg
* Drug: linagliptine 5 mg and pioglitazone 30 mg


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed and dated written informed consent in accordance with the GCP and local legislation. Patients completing the entire treatment period as a double blind trial whether or not they have been treated with rescue medication. Exclusion criteria: Patients who meet one or more of the withdrawal criteria of the treatment period of the previous trial. Pre-menopausal women (last menstruation =< 1 year prior to signing 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. Acceptable methods of birth control include transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, true sexual abstinence (when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of birth control) and vasectomised partners. No exception will be made. Alcohol abuse within the 3 months prior to informed consent that would interfere with trial participation. Drug abuse which, in the opinion of the investigator, would interfere with trial participation. Any other clinical condition which, in the opinion of the investigator, would not allow safe completion of the protocol and safe administration of the trial medication.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 82 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: linagliptin 5 mg<br>open label | Drug: linagliptine 5 mg<br>* safety and efficacy of linagliptine 5 mg open label<br>|
| Experimental: linagliptin 5 mg and pioglitazone 30 mg<br>open label | Drug: linagliptine 5 mg and pioglitazone 30 mg<br>* efficacy and safety of the combination linagliptine and pioglitazone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Patients With Adverse Events (AEs) | This includes any AEs detected during routine physical examination and electrocardiogram (ECG) procedures. | 78 weeks | 
| Frequency of Patients With Investigator-defined Hypoglycaemic Adverse Events |  | 78 weeks | 
| Frequency of Patients With Significant Adverse Events Based on Standardised MedDRA Query (SMQ) | As significant adverse events are considered: renal Aes (SMQ 'acute renal failure'), hypersensitivity reactions ('anaphylactic reactions' and 'angioedema'), hepatic Aes ('hepatitis, non-infectious', 'hepatic failure, fibrosis, cirrhosis and other liver damage-related conditions', 'liver-related investigations, signs and symptoms', 'cholestasis and jaundice of hepatic origin'), severe cutaneous adverse reactions ('severe cutaneous adverse reaction'), pancreatitis ('acute pancreatitis', 'chronic pancreatitis''). | 78 weeks | 
| Frequency of Patients With Adjudication of Cardiac and Cerebrovascular Events | Patients reported with cardiac and cerebrovascular events qualified for adjudication by the Clinical Event Committee (CEC) | 78 weeks | 
| Number of Patients With Abnormalities in Vital Signs | Vital sign abnormalities (any abnormalities found during PE or ECG are reported with adverse events) | 78 weeks | 
| Number of Patients With Abnormalities in Haematology: Eosinophils | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than or equal to 10%. | 78 weeks | 
| Number of Patients With Abnormalities in Haematology: Haemoglobin | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value less than or equal to 11.5 g/dL for male and as a value less than or equal to 9.5 g/dL for female patients. | 78 weeks | 
| Number of Patients With Abnormalities in Haematology: Haematocrit | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value less than or equal to 32%. | 78 weeks | 
| Number of Patients With Abnormalities in Haematology: Red Blood Cell Count | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value less than 3 * 10^12/L. | 78 weeks | 
| Number of Patients With Abnormalities in Haematology: White Blood Cell Count | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value less than 3 * 10^9/L (decrease) or a value greater than 20.1 * 10^9/L (increase). | 78 weeks | 
| Number of Patients With Abnormalities in Haematology: Platelets | For this laboratory parameter, a possibly clinically significant abnormality is defined as value less than or equal to 75 * 10^9/L (decrease) or a value greater than or equal to 700 * 10^9/L (increase). | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Potassium | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value less than 3 mmol/L (decrease) or a value greater than 5.8 mmol/L (increase). | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Uric Acid | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than 11 mg/dL for male and as a value greater than 10 mg/dL for female patients. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Triglycerides | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than 300 mg/dL. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Amylase | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than 1.5 times the upper limit of normal (ULN). | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: γ-Glutamyl-transferase (GGT) | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than or equal to 3 times the ULN. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Creatinine | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than or equal to 1.5 mg/dL. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Creatinine Kinase | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than or equal to 3 times the ULN. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Phosphate | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value less than 0.7 mmol/L (decrease) or a value greater than 1.7 mmol/L (increase). | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Calcium | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value less than 1.8 mmol/L (decrease) or a value greater than 3 mmol/L (increase). | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Sodium | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value less than 130 mmol/L (decrease) or a value greater than 160 mmol/L (increase). | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Alanine Transaminase (ALT) | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than or equal to 3 times the ULN. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Aspartate Transaminase (AST) | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than or equal to 3 times the ULN. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Glucose | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value less than 54 mg/dL. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Bilirubin | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than or equal to 2 mg/dL. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Alkaline Phosphatase (AP) | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than or equal to 2 times the ULN. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Albumin | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value less than 2.5 g/dL. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Lactate Dehydrogenase (LDH) | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than or equal to 3 times the ULN. | 78 weeks | 
| Number of Patients With Abnormalities in Clinical Chemistry: Cholesterol | For this laboratory parameter, a possibly clinically significant abnormality is defined as a value greater than 300 mg/dL. | 78 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c From Baseline to Week 6 |  | Baseline and week 6 | 
| Change in HbA1c From Baseline to Week 18 |  | Baseline and week 18 | 
| Change in HbA1c From Baseline to Week 30 |  | Baseline and week 30 | 
| Change in HbA1c From Baseline to Week 42 |  | Baseline and week 42 | 
| Change in HbA1c From Baseline to Week 54 |  | Baseline and week 54 | 
| Change in HbA1c From Baseline to Week 66 |  | Baseline and week 66 | 
| Change in HbA1c From Baseline to Week 78 |  | Baseline and week 78 | 
| Number of Patients With HbA1c<7.0% Over Time |  | 78 weeks | 
| Number of Patients With HbA1c<6.5% Over Time |  | 78 weeks | 
| Number of Patients With Lowered HbA1c by at Least 0.5% Over Time |  | 78 weeks | 
| Change in FPG From Baseline to Week 6 |  | Baseline and week 6 | 
| Change in FPG From Baseline to Week 18 |  | Baseline and week 18 | 
| Change in FPG From Baseline to Week 30 |  | Baseline and week 30 | 
| Change in FPG From Baseline to Week 42 |  | Baseline and week 42 | 
| Change in FPG From Baseline to Week 54 |  | Baseline and week 54 | 
| Change in FPG From Baseline to Week 66 |  | Baseline and week 66 | 
| Change in FPG From Baseline to Week 78 |  | Baseline and week 78 |