Establishing Cardiovascular Biomarkers to Define Preferred Lantus® Use

Study Overview
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Brief Summary
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The aim of this study is to observe changes in cardiovascular biomarkers during treatment with Lantus in patients with Type 2 Diabetes mellitus.

Detailed Description
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Phase IV Indication: Diabetes mellitus Type 2 Primary objective: To compare fasting intact proinsulin secretion at the beginning and after a 24 week treatment period. - Secondary objectives: To evaluate changes in the parameters insulin, glucose, intact proinsulin (after a glucose challenge), hsCRP, adiponectin, MMP-9, HbA1c, weight after 24 weeks of treatment. To investigate the changes of glucose, intact proinsulin, hsCRP, adiponectin, HbA1c weight between visit 2 (baseline), visit 6 (12 weeks) and visit 8 (final visit after 24 weeks). To investigate the number of patients with normal values for parameters hsCRP, adiponectin, and intact proinsulin after 24 weeks of treatment (responder rates). -Primary efficacy variable: Fasting intact proinsulin concentration at timepoint Visit 2 (Baseline) and Visit 8 (after 24 week treatment) -Secondary efficacy variables: All secondary parameters will be assessed after 24 weeks of treatment and compared versus baseline assessment. Weight hsCRP Adiponectin MMP-9 OGTT parameters (insulin, intact proinsulin, glucose at time point 0, 60 and 120 minutes after 24 weeks HOMA-IR score HbA1c Additionally the following parameters will be assessed at visit 6 and will be compared with visit 2 and visit 8: Weight hsCRP Adiponectin Fasting intact Proinsulin Glucose HbA1c Safety Variables: Adverse Events Hypoglycaemic events Medication/Dosage: Insulin glargine, dose individually adapted to reach treatment goal (FBG ≤ 100 mg/dL)NPH Insulin, dose individually adapted to reach treatment goal (FBG ≤ 100 mg/dL)Insulin glulisine, dose individually adapted to reach treatment goal (FBG ≤ 100 mg/dL)Human Insulin, dose individually adapted to reach treatment goal (FBG ≤ 100 mg/dL) -Study Duration: Duration of study participation for one patient is approximately 26 weeks. Overall total duration of the study is approximately 10 months. Design: This is a randomized in four arms, open-label, multi-center study. Population Patients with Type 2 Diabetes mellitus, Sample Size n = 60 (15 per arm)

Official Title
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Establishing Cardiovascular Biomarkers to Define Preferred Lantus® Use.

Conditions
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Insulin-requiring Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: nph insulin
* Drug: human insulin
* Drug: Insulin Glargine
* Drug: Insulin glulisine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Give written informed consent. Patient consents that his/her family physician/diabetologist will be informed of trial participation Type-2 diabetes mellitus ≥ 1 year of diagnosis (male and female) Experienced in self blood glucose measurement for ≥ 3 months. HbA1c ≤ 9% and >6,5% BMI > 30 kg/m² Age ≥ 18 years Waist circumference > 88 cm (female) and > 102 cm (male) NPH insulin treatment plus 1 or 2 OAD (except TZD) Exclusion Criteria: History of drug or alcohol abuse within the last five years prior to screening Anamnestic history of hypersensitivity to the study drugs (or any component of the study drug) or to drugs with similar chemical structures History of severe or multiple allergies Treatment with any other investigational drug within 3 months prior to screening Progressive fatal disease History of significant cardiovascular, respiratory, gastrointestinal, hepatic (ALAT and/or ASAT > 3 times the normal reference range), renal (creatinine > 1.3 mg/dl in women and >1.6 mg/dl in men), neurological, psychiatric and/or hematological disease as judged by the investigator Pregnant or lactating women Sexually active women of childbearing potential not consistently and correctly practicing birth control by implants, injectables, combined oral contraceptives, hormonal intrauterine devices (IUDs), sexual abstinence or vasectomized partner Treatment with GLP1-analog or Thiazolidinediones (TZD) hsCRP > 10 mg/l (by rapid test at screening visit). Lack of compliance or other similar reason that, according to investigator, precludes satisfactory participation in the study Type 1 Diabetes mellitus Patients already treated with intensified conventional insulin therapy.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: NPH insulin + insulin glulisine<br>Patients will be randomized to be treated with NPH insulin + Insulin Glulisine for 24 weeks. | Drug: nph insulin<br>* Dosage will be pro re nata. Patients should aim an blood glucose level of ≤ 100 mg/dL.<br>* Other names: Insuman Basal;Drug: Insulin glulisine<br>* Dosage will be pro re nata. Patients should aim an blood glucose level of ≤ 100 mg/dL. Insulin glulisine: bolus injections before each main meal<br>* Other names: Apidra;|
| Active Comparator: NPH insulin + human insulin<br>Patients will be randomized to be treated with NPH insulin + human insulin for 24 weeks. | Drug: human insulin<br>* Dosage will be pro re nata. Patients should aim an blood glucose level of ≤ 100 mg/dL. human insulin: bolus injections before each main meal<br>* Other names: Insuman Rapid;|
| Experimental: Insulin glargine + insulin glulisine<br>Patients will be randomized to be treated with insulin glargine + insulin glulisine for 24 weeks. | Drug: Insulin Glargine<br>* Dosage will be pro re nata. Patients should aim an blood glucose level of ≤ 100 mg/dL.<br>* Other names: Lantus;Drug: Insulin glulisine<br>* Dosage will be pro re nata. Patients should aim an blood glucose level of ≤ 100 mg/dL. Insulin glulisine: bolus injections before each main meal<br>* Other names: Apidra;|
| Experimental: Insulin Glargine + Human insulin<br>Patients will be randomized to be treated with insulin glargine + human insulin for 24 weeks. | Drug: human insulin<br>* Dosage will be pro re nata. Patients should aim an blood glucose level of ≤ 100 mg/dL. human insulin: bolus injections before each main meal<br>* Other names: Insuman Rapid;Drug: Insulin Glargine<br>* Dosage will be pro re nata. Patients should aim an blood glucose level of ≤ 100 mg/dL.<br>* Other names: Lantus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Intact Proinsulin | The difference of fasting intact proinsulin after 24 weeks of treatment compared to baseline. | Change from baseline at 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight | To evaluate the changes of weight after 24 weeks of treatment compared to baseline. | Baseline and after 24 weeks of treatment. | 
| hsCRP | To evaluate changes of hsCRP after 24 weeks of treatment compared to baseline. | Baseline and after 24 weeks of treatment. | 
| Adiponectin | To evaluate changes of adiponectin after 24 weeks of treatment compared to baseline. | Baseline and after 24 weeks of treatment. | 
| MMP-9 | To evaluate changes of MMP-9 after 24 weeks of treatment compared to baseline. | Baseline and after 24 weeks of treatment. | 
| OGTT parameters (insulin, intact proinsulin, glucose at time point 0, 60 and 120 minutes after 24 weeks | To evaluate changes of OGTT parameters (insulin, intact proinsulin, glucose at time point 0, 60 and 120 minutes) after 24 weeks of treatment compared to baseline. | Baseline and after 24 weeks of treatment. | 
| HOMA-IR score | To evaluate changes of HOMA-IR score after 24 weeks of treatment compared to baseline. | Baseline and after 24 weeks of treatment. | 
| HbA1c | To evaluate changes of HbA1C after 24 weeks of treatment compared to baseline. | Baseline and after 24 weeks of treatment. | 
| Weight | To evaluate changes of weight after 12 weeks of treatment compared to baseline and compared to 24 weeks. | After 12 weeks of treatment compared to baseline and to 24 weeks of treatment. | 
| hsCRP | To evaluate changes of hsCRP after 12 weeks of treatment compared to baseline and compared to 24 weeks. | After 12 weeks of treatment compared to baseline and to 24 weeks of treatment. | 
| Adiponectin | To evaluate changes of adiponectin after 12 weeks of treatment compared to baseline and compared to 24 weeks. | After 12 weeks of treatment compared to baseline and to 24 weeks of treatment. | 
| Fasting intact Proinsulin | To evaluate changes of fasting intact proinsulin after 12 weeks of treatment compared to baseline and compared to 24 weeks. | After 12 weeks of treatment compared to baseline and to 24 weeks of treatment. | 
| Glucose | To evaluate changes of Glucose after 12 weeks of treatment compared to baseline and compared to 24 weeks. | After 12 weeks of treatment compared to baseline and to 24 weeks of treatment. | 
| HbA1c | To evaluate changes of HbA1c after 12 weeks of treatment compared to baseline and compared to 24 weeks. | After 12 weeks of treatment compared to baseline and to 24 weeks of treatment. | 
| Responder rate | To investigate the number of patients with normal values for parameters hsCRP, adiponectin, and intact proinsulin after 24 weeks of treatment (responder rates). | After 24 weeks of treatment compared to baseline. | 
| Hypoglycemic events. | Hypoglycemic events defined as blood glucose below 63 mg/dl. | Baseline up to 24 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes mellitus, NPH insulin, Insulin Glargine, cardiovascular biomarkers, hsCRP, adiponectin, intact proinsulin, cardiovascular risk