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

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

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

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Other; Drug: Other

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Neu-Ulm, Germany, 89231
    • Nuvisan GmBH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Healthy volunteers aged of 18-30 years	Drug: Other; 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.; Drug: Other; 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.
Other: Healthy volunteers aged of 50-59 years	Drug: Other; 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.; Drug: Other; 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.
Other: Healthy volunteers aged of 60-70 years	Drug: Other; 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.; Drug: Other; 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.
Other: Type 2 diabetic patients aged of 50-70 years	Drug: Other; 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.; Drug: Other; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institut de Recherches Internationales Servier
• Collaborators: ADIR, a Servier Group company
• Investigators: Principal Investigator: Denis Strugala, Dr, Nuvisan GmBH

Publications and helpful links

Helpful Links

• Results summary

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2017
• Primary Completion (Actual): September 15, 2018
• Study Completion (Actual): September 15, 2018

Study Registration Dates

• First Submitted: January 27, 2021
• First Submitted That Met QC Criteria: February 4, 2021
• First Posted (Actual): February 9, 2021

Study Record Updates

• Last Update Posted (Actual): July 25, 2024
• Last Update Submitted That Met QC Criteria: July 24, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Healthy volunteers; Cardiovascular disease; Phase 1; Type 2 diabetes mellitus; Vascular function; Coronary flow reserve; Clinical translational exploratory study; Target involvement; Exploratory biomarkers; Biopterins; Cutaneous blood flow
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: CL1-RTCMP-001; 2017-000045-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

• IPD Sharing Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• IPD Sharing Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Study Data/Documents

1. Individual Participant Data Set
2. Study Protocol
3. Statistical Analysis Plan
4. Informed Consent Form
5. Clinical Study Report
6. Study-level clinical trial data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No