Vascular Function and Biomarker Assessments in Healthy Volunteers and in Patients With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the vascular function and biomarkers in healthy volunteers and type 2 diabetic patients.

Detailed Description
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The present interventional study will be performed in 3 groups of healthy volunteers of different ages and in type 2 diabetic patients without an investigational medicinal product administrated.

Official Title
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Target Involvement and Exploratory Biomarkers Investigations in Healthy Volunteers and in Patients With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Other
* Drug: Other


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers: Age [18 -30], [50-59] and [60-70] years Male and female healthy volunteers, except with skin types 5 and 6 Body weight ≥ 50 kg and BMI between [18.0 -28.0] kg/m^2 inclusive Non or ex-smokers (defined as someone who completely stopped smoking for at least 1 month before the beginning of this study) No clinically relevant findings in the medical history and physical examination, especially with regards to cardiovascular system, lung, liver and renal function Normal blood and urine laboratory tests Patients with type 2 diabetes (T2D) mellitus: Male and female patients, except with skin types 5 and 6 Age [50 - 70] years BMI ≤35 kg/m2 T2D patients (according to American Diabetes Association (ADA) criteria i.e. HbA1c > 6.5% or fasting plasma glucose > 126 mg/dL (7.00 mmol/L) or 2-hour glucose ≥ 200mg/dL (11.1mmol/L) after 75g oral glucose or glucose ≥200mg/dL (11.1mmol/L) at any time on two separate occasions (historic values and/or at selection) Currently treated with Standards of Medical Care in T2D at stable doses for at least 3 months Antihypertensive drugs allowed except beta-blockers and calcium antagonists Non or ex-smokers (defined as someone who completely stopped smoking for at least 1 month before the beginning of this study) Non inclusion Criteria: Healthy volunteers: Unlikely to co-operate in the study, Participation in another interventional study, including last study drug intake, at the same time or within the 3 months preceding the selection visit; participation in non-interventional registries or epidemiological studies is allowed, Deprived of his freedom by administrative or court order or under guardianship, History or evidence of acute or chronic abuse of alcohol consumption of> 21 alcohol units per week for males and >14 units per week for females (1 alcohol unit = 100 mL of 12% wine; = 30 mL of 40% spirits; = 250 mL of 6% beer), Positive alcohol breath test, Positive cotinine test, Known or suspected to be drug-dependent, Positive result in urinary screening for drug abuse, Pregnancy, breastfeeding or lactating, Regular use of prescribed and non-prescribed drugs in the last 60 days before the day of investigations into the study except hormonal contraception (e.g. pill or hormonal intrauterine device (IUD) or hormonal implants or Nuva Ring) (if applicable), Any drug intake of prescribed or non-prescribed drugs including over-counter drugs (except acetaminophen), herbal remedies or nutritional supplements such as multivitamins in the 2 weeks before the day of investigations unless the investigator deems this drug intake to be irrelevant for the purpose of this study and that can be temporarily suspended, Intake of dipyridamol (contraindicated with adenosine infusion) Known hypersensitivity to adenosine injection, Any acute or chronic illness or clinically relevant findings (i.e. liver, kidney, cardiovascular diseases) in the selection visit examinations, Patients with type II diabetes mellitus (T2D): Unlikely to co-operate in the study, Participation in another interventional study, including last study drug intake, at the same time or within the 3 months preceding the selection visit; participation in non-interventional registries or epidemiological studies is allowed, Deprived of his freedom by administrative or court order or under guardianship, Unwilling to allow his or her primary care practitioner to be notified of participation in the study and for information on a participant's medical history to be obtained from the general practitioner, History or evidence of acute or chronic abuse of alcohol consumption of> 21 alcohol units per week for males and >14 units per week for females (1 alcohol unit = 100 mL of 12% wine; = 30 mL of 40% spirits; = 250 mL of 6% beer), Positive alcohol breath test, Positive cotinine test, Known or suspected to be drug-dependent, Positive result in urinary screening for drug abuse, Pregnancy, breastfeeding or lactating, Intake of dipyridamol (contraindicated with adenosine infusion) Known hypersensitivity to adenosine injection, Any acute or chronic illness or clinically relevant findings (i.e. liver,kidney, cardiovascular diseases) in the selection visit examinations.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Healthy volunteers aged of 18-30 years<br> | Drug: Other<br>* Healthy volunteers will be selected within 3 weeks before inclusion (Day 0). The investigations will be performed on 2 days (Day 1 (D1) and Day 2 (D2)): vascular endothelial function assessment and blood collection for biomarker investigation on Day 1 and Case Report Form (CFR) on Day 2. Then, subjects will be discharged at the end of the last investigation day (Day 2). All the participants have received two pharmacological agents (NIMP) : Acetylcholine : administered subcutaneously (by iontophoresis) to assess maximal vascular endothelial function. Adenosine : administered intravenously during MRI for the measurement of CFR.<br>|
| Other: Healthy volunteers aged of 50-59 years<br> | Drug: Other<br>* Healthy volunteers will be selected within 3 weeks before inclusion (Day 0). The investigations will be performed on 2 days (Day 1 (D1) and Day 2 (D2)): vascular endothelial function assessment and blood collection for biomarker investigation on Day 1 and Case Report Form (CFR) on Day 2. Then, subjects will be discharged at the end of the last investigation day (Day 2). All the participants have received two pharmacological agents (NIMP) : Acetylcholine : administered subcutaneously (by iontophoresis) to assess maximal vascular endothelial function. Adenosine : administered intravenously during MRI for the measurement of CFR.<br>|
| Other: Healthy volunteers aged of 60-70 years<br> | Drug: Other<br>* Healthy volunteers will be selected within 3 weeks before inclusion (Day 0). The investigations will be performed on 2 days (Day 1 (D1) and Day 2 (D2)): vascular endothelial function assessment and blood collection for biomarker investigation on Day 1 and Case Report Form (CFR) on Day 2. Then, subjects will be discharged at the end of the last investigation day (Day 2). All the participants have received two pharmacological agents (NIMP) : Acetylcholine : administered subcutaneously (by iontophoresis) to assess maximal vascular endothelial function. Adenosine : administered intravenously during MRI for the measurement of CFR.<br>|
| Other: Type 2 diabetic patients aged of 50-70 years<br> | Drug: Other<br>* Type 2 diabetic patients will be selected within 3 weeks before inclusion (Day 0). The investigations will be performed on 2 days (Day 1 (D1) and Day 2 (D2)): vascular endothelial function assessment and blood collection for biomarker investigation on Day 1 and CFR on Day 2. Then, subjects will be discharged at the end of the last investigation day (Day 2). All the participants have received two pharmacological agents (NIMP): Acetylcholine : administered subcutaneously (by iontophoresis) to assess maximal vascular endothelial function. Adenosine : administered intravenously during MRI for the measurement of CFR.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Guanylate triphosphate cyclohydrolase (GTP-CH) investigations | Plasma/platelet levels of Dihydrobiopterin (BAH)/Tetrahydrobiopterin (BH4), Cyclic guanosine monophosphate (cGMP) | Day 1 | 
| Guanylate triphosphate cyclohydrolase (GTP-CH) investigations | Blood flow changes for vascular endothelial function | Day 1 | 
| Guanylate triphosphate cyclohydrolase (GTP-CH) investigations | Coronary flow reserve | Day 2 | 
| Guanylate triphosphate cyclohydrolase (GTP-CH) investigations | Genomic market (blood) DNA and/or RNA characteristics of genes such as GTP Cyclohydrolase 1 (GCH) | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Occurence of any adverse events | Through study completion, 3.5 weeks | 
| Blood pressure supine | Relevant abnormalities on supine blood pressure | Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus, Phase 1, Healthy volunteers, Clinical translational exploratory study, Target involvement, Exploratory biomarkers, Cardiovascular disease, Vascular function, Coronary flow reserve, Biopterins, Cutaneous blood flow