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出境医 / 临床实验 / Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses (HCIR)
Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses (HCIR)
Study Description
Brief Summary:
People with Type 1 diabetes (T1DM), type 2 diabetes (T2DM) and healthy volunteers will undergo a hypoglycaemic clamp to to investigate the effect of hypoglycaemia on cardiovascular and inflammatory responses.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Hypoglycemia Inflammatory Response Diabetes Mellitus, Type 1 Diabetes Mellitus, Type 2 | Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp | Not Applicable |
Detailed Description:
Objectives: The overall aim of the present study is to investigate the effect of hypoglycaemia on cardiovascular and inflammatory responses, molecular mechanisms and epigenetic profiles in various groups of people with diabetes type 1, type 2 and healthy volunteers.
Study design: Intervention study
Intervention: All subjects will undergo a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp (nadir 2.8 mmol/L), during and after which blood and urine will be sampled for further examination for up to one week.
Study Design
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 110 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Masking Description: | All subjects will undergo a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp (nadir 2.8 mmol/L), during and after which blood and urine will be sampled for further examination for up to one week. |
| Primary Purpose: | Diagnostic |
| Official Title: | Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses in Patients With Diabetes Mellitus Type 1, Type 2 and Healthy Volunteers |
| Actual Study Start Date : | August 12, 2019 |
| Actual Primary Completion Date : | March 31, 2021 |
| Actual Study Completion Date : | March 31, 2021 |
Arms and Interventions
| Arm | Intervention/treatment |
|---|---|
|
Active Comparator: T1DM poor glycaemic control
patients with type 1 diabetes and poor glycaemic control (HbA1c >8% / >64 mmol/mol will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
|
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Name: hypoglycaemic clamp
|
|
Active Comparator: T1DM impaired awareness
patients with type 1 diabetes and impaired awareness of hypoglycaemia will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
|
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Name: hypoglycaemic clamp
|
|
Active Comparator: T1DM Normal awareness
patients with type 1 diabetes and normal awareness of hypoglycaemia will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
|
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Name: hypoglycaemic clamp
|
|
Active Comparator: T2DM + Insulin
patients with type 2 diabetes with insulin treatment for at least 1 year will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
|
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Name: hypoglycaemic clamp
|
|
Active Comparator: Healthy control T2DM
healthy controls without diabetes and age, gender and BMI matched with diabetes type 2 participants will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
|
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Name: hypoglycaemic clamp
|
|
Active Comparator: Healthy control T1DM
Healthy controls without diabetes and age, gender and BMI matched with diabetes type 1 participants will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
|
Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Name: hypoglycaemic clamp
|
Outcome Measures
Primary Outcome Measures :
- Inflammatory responses of hypoglycaemia by measuring the cytokine production of isolated monocytes using ELISA [ Time Frame: 1.5 year ]Cytokine production (TNF-alfa, IL-6, IL-10 and IL-1β) of isolated and stimulated monocytes
Secondary Outcome Measures :
- Atherogenic responses of (recurrent) hypoglycaemia using foam cell formation. [ Time Frame: 1.5 year ]Measurement of Ox-LDL uptake by measuring intracellular apolipoproteine B
- Metabolomics profile of each group [ Time Frame: 1.5 year ]Un-targeted metabolomics and identification of metabolites based on exact mass using metabolomics library
- Epigenetic modifications [ Time Frame: 1.5 year ]Epigenetic modifications due to hypoglycaemia in the promoter regions of the pro-inflammatory cytokines in monocytes
- Cardiac function responses to hypoglycaemia using echocardiography [ Time Frame: 1.5 year ]Cardiac function responses to hypoglycaemia using echocardiography
- Cognitive function responses to hypoglycaemia using cognitive function tests (TAP, PASAT) [ Time Frame: 1.5 year ]Amount of correct answers
- Oxidative stress responses using oxidative stress marker [ Time Frame: 1.5 year ]Excretion of guanine nucleosides in urine (ng/mL)
Eligibility Criteria
| Ages Eligible for Study: | 18 Years to 80 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
Criteria
Inclusion Criteria:
Overall inclusion criteria
- Ability to provide written informed consent
- Must be able to speak and read Danish (for Hillerød-site) and Dutch (for Nijmegen-site)
- Insulin treatment according to basal-bolus insulin regimen (injections or insulin pump) (except for group 5)
- Body-Mass Index: 19-40 kg/m2
- Age ≥18 years, ≤ 80 years
- Blood pressure: <140/90 mmHg
- Duration of diabetes > 1 year (except for group 5)
- HbA1c < 100 mmol/mol
Group specific
- Group 1: HbA1c >64 mmol/mol
- Group 2: impaired awareness of hypoglycaemia (IAH) as assessed by a score of ≥3 on the modified Clarke questionnaire, ≥4 on the Gold questionnaire and a positive score on the Pedersen-Bjergaard questionnaire.
- Group 3: normal awareness of hypoglycaemia (NAH) as assessed by a score of <3 on the modified Clarke questionnaire, <4 on the Gold questionnaire and a negative score on the Pedersen-Bjergaard.
- Group 4: Insulin treatment for at least 1 year
- Group 5/6: HbA1c <42 mmol/mol
Exclusion Criteria:
- - Severe medical or psychological conditions interfering with the perception of hypoglycaemia other than IAH such as brain injuries, epilepsy, a major cardiovascular disease event or anxiety disorders
- Use of immune-modifying drugs or antibiotics
- Treatment with glucose-modifying (other than insulin, SGLT-2 inhibitors and metformin) agents (e.g. prednisolon)
- Use of anti-depressive drugs
- Pregnancy or breastfeeding or unwillingness to undertake measures for birth control
- Use of statins (e.g. stop statins >2 weeks before performing blood sampling. This can be safely done in the context of primary prevention)
- Any event of cardiovascular disease in the past 5 years (e.g. myocardial infarction, stroke, heart failure, symptomatic peripheral arterial disease)
- Auto-inflammatory or auto-immune diseases
- Any infection in past three months
- Previous vaccination in the past three months
- Laser coagulation for proliferative retinopathy in the past six months
- Proliferative retinopathy
- Diabetic nephropathy as reflected by an albumin-creatinine ratio ˃ 30 mg/gor an estimated glomerular filtration rate (by MDRD) ˂60ml/min/1.73m2
- History of pancreatitis (acute or chronic) or pancreatic cancer
Contacts and Locations
Locations
| Denmark | |
| Nordsjællands University Hospital | |
| Hillerød, Nordsjaelland, Denmark, 3400 | |
| Netherlands | |
| Radboudumc | |
| Nijmegen, Gelderland, Netherlands, 6525 GA | |
Sponsors and Collaborators
Radboud University
Rigshospitalet, Denmark
Investigators
| Principal Investigator: | Bastiaan E de Galan, MD, PhD | Radboud University | |
| Principal Investigator: | Ulrik Pedersen-Bjergaard, MD, PhD | Nordsjællands University Hospital |
| Tracking Information | |||||||
|---|---|---|---|---|---|---|---|
| First Submitted Date ICMJE | November 8, 2018 | ||||||
| First Posted Date ICMJE | June 6, 2019 | ||||||
| Last Update Posted Date | May 12, 2021 | ||||||
| Actual Study Start Date ICMJE | August 12, 2019 | ||||||
| Actual Primary Completion Date | March 31, 2021 (Final data collection date for primary outcome measure) | ||||||
| Current Primary Outcome Measures ICMJE |
Inflammatory responses of hypoglycaemia by measuring the cytokine production of isolated monocytes using ELISA [ Time Frame: 1.5 year ] Cytokine production (TNF-alfa, IL-6, IL-10 and IL-1β) of isolated and stimulated monocytes
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| Original Primary Outcome Measures ICMJE | Same as current | ||||||
| Change History | |||||||
| Current Secondary Outcome Measures ICMJE |
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||||
| Descriptive Information | |||||||
| Brief Title ICMJE | Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses | ||||||
| Official Title ICMJE | Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses in Patients With Diabetes Mellitus Type 1, Type 2 and Healthy Volunteers | ||||||
| Brief Summary | People with Type 1 diabetes (T1DM), type 2 diabetes (T2DM) and healthy volunteers will undergo a hypoglycaemic clamp to to investigate the effect of hypoglycaemia on cardiovascular and inflammatory responses. | ||||||
| Detailed Description |
Objectives: The overall aim of the present study is to investigate the effect of hypoglycaemia on cardiovascular and inflammatory responses, molecular mechanisms and epigenetic profiles in various groups of people with diabetes type 1, type 2 and healthy volunteers. Study design: Intervention study Intervention: All subjects will undergo a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp (nadir 2.8 mmol/L), during and after which blood and urine will be sampled for further examination for up to one week. |
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| Study Type ICMJE | Interventional | ||||||
| Study Phase ICMJE | Not Applicable | ||||||
| Study Design ICMJE | Allocation: Non-Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Masking Description: All subjects will undergo a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp (nadir 2.8 mmol/L), during and after which blood and urine will be sampled for further examination for up to one week. Primary Purpose: Diagnostic
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| Condition ICMJE |
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| Intervention ICMJE | Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
For this study, a hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp will be conducted to investigate the effect of hypoglycaemia. This means that subjects will receive an intravenous insulin infusion, at a continuous rate of 60 mU∙m-2∙min-1, as well as glucose 20% w/w intravenously at a variable rate, adjusted by arterial plasma glucose levels, measured at 5 minute intervals.
Other Name: hypoglycaemic clamp
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| Study Arms ICMJE |
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| Publications * | Not Provided | ||||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||||
| Recruitment Status ICMJE | Completed | ||||||
| Actual Enrollment ICMJE |
110 | ||||||
| Original Estimated Enrollment ICMJE |
112 | ||||||
| Actual Study Completion Date ICMJE | March 31, 2021 | ||||||
| Actual Primary Completion Date | March 31, 2021 (Final data collection date for primary outcome measure) | ||||||
| Eligibility Criteria ICMJE |
Inclusion Criteria: Overall inclusion criteria
Group specific
Exclusion Criteria:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years to 80 Years (Adult, Older Adult) | ||||||
| Accepts Healthy Volunteers ICMJE | Yes | ||||||
| Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||||
| Listed Location Countries ICMJE | Denmark, Netherlands | ||||||
| Removed Location Countries | |||||||
| Administrative Information | |||||||
| NCT Number ICMJE | NCT03976271 | ||||||
| Other Study ID Numbers ICMJE | HCIR | ||||||
| Has Data Monitoring Committee | Yes | ||||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | Radboud University | ||||||
| Study Sponsor ICMJE | Radboud University | ||||||
| Collaborators ICMJE | Rigshospitalet, Denmark | ||||||
| Investigators ICMJE |
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| PRS Account | Radboud University | ||||||
| Verification Date | March 2021 | ||||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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