Human Insulin Analogs: Evaluation of Inflammatory mRNA Expression of Macrophages and Endothelial Function of Short-acting Insulin - HERMES Pilot Study

Study Overview
=================
Brief Summary
-----------------
The planned HERMES study is to investigate and compare the effects of Insulin Glulisine, Insulin Aspart and regular human insulin on postprandial nitrotyrosine concentrations and several clinical and laboratory markers of postprandial endothelial cell function, sub-clinical inflammation and cardiovascular risk in patients with type 2 DM. The primary parameter in this study are the postprandial changes in the nitrotyrosine concentrations, a biomarker for oxidative stress. As vascular data on Insulin Glulisine vs. Insulin Aspart are missing, it is not possible to calculate sample size and statistical power. Therefore the goal of the HERMES-Pilot-Study is to generate preliminary data for statistical considerations and estimations on the probability of success of HERMES.

Official Title
-----------------
Human Insulin Analogs: Evaluation of Inflammatory mRNA Expression of Macrophages and Endothelial Function of Short-acting Insulin - HERMES Pilot Study

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Insulin glulisine
* Drug: Insulin aspart
* Drug: Regular human insulin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Type 2 diabetes mellitus Stable BOT (basal oral therapy) with Insulin Glargine + ≥ 2 OHA (oral hypoglycemic agents except for TZD) for a minimum of three months before entering the study HbA1c ≤ 8.5% Age between 30 and 75 years inclusively Body mass index ≤ 40 kg/m2 Patient consents that his/her family physician will be informed of trial participation Exclusion Criteria: Type 1 diabetes mellitus Unspecific infection or inflammation (hsCRP >10mg/L in POC test) Use of thiazolidinediones within the last 3 months prior to study start Retinopathy, hepatic or renal dysfunction or clinically relevant other major diseases History of drug or alcohol abuse within the last five years prior to screening 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 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 Lack of compliance or other similar reason that, according to investigator, precludes satisfactory participation in the study

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin Glulisine: bolus injections before each main meal<br>Patients are already on an Insulin Glargine therapy when they start and will them after randomization receive additionally Insulin Glulisine bolus injections before each of the main meals. | Drug: Insulin glulisine<br>* Dosage will be pro re nata. Patients should aim an blood glucose level of 2h ppBG ≤ 135 mg/dL.<br>* Other names: Apidra;|
| Active Comparator: Insulin Aspart: bolus injections before each main meal<br>Patients are already on an Insulin Glargine ± metformin therapy when they start the start and will them after randomization receive additionally Insulin Aspart bolus injections before each of the main meals. | Drug: Insulin aspart<br>* Dosage will be pro re nata. Patients should aim an blood glucose level of 2h ppBG ≤ 135 mg/dL.<br>* Other names: NovoRapid;|
| Active Comparator: Regular human insulin:bolus injections before each main meal<br>Patients are already on an Insulin Glargine ± metformin therapy when they start the start and will them after randomization receive additionally regular human insulin bolus injections before each of the main meals. | Drug: Regular human insulin<br>* Dosage will be pro re nata. Patients should aim an blood glucose level of 2h ppBG ≤ 135 mg/dL.<br>* Other names: InsumanRapid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nitrotyrosine | The difference in the percent increase of the oxidative stress biomarker nitrotyrosine after stimulation with a standardized meal | Baseline, after 10 weeks, after 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skin blood flow | Change in skin blood flow during stimulation by a standardized meal | Baseline, after 10 weeks, after 24 weeks | 
| mRNA expression of proinflammatory cytokines (MAPK/eNOS, adiponectin, hsCRP, MMP-9) | Biomarkers of sub-clinical inflammation and cardiovascular risk: Change in Macrophage activation, MAPK/eNOS production levels, adiponectin and hsCRP (after test meal) from baseline to endpoint | Baseline, after 10 weeks, after 24 weeks | 
| Insulin | Change in Insulin and the ratio from baseline to endpoint | Baseline, after 10 weeks, after 24 weeks | 
| HbA1c | Blood glucose control: Change during test meal, HbA1c and FBG from baseline to endpoint | Baseline, after 10 weeks, after 24 weeks | 
| Fasting blood glucose | Blood glucose control: Change during test meal, HbA1c and FBG from baseline to endpoint | Baseline, after 10 weeks, after 24 weeks | 
| Hypoglycemic events | Incidence of hypoglycemia from baseline to endpoint | Baseline, after 10 weeks, after 24 weeks | 
| intact Proinsulin | Change in intact Proinsulin and the ratio from baseline to endpoint | Baseline, after 10 weeks, after 24 weeks |