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HypoglycemiaHCIRNCT03976271

Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses

A study testing hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp in people with Hypoglycemia and Inflammatory Response, run by Radboud University Medical Center at 2 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 80 yearsHealthy volunteers can take part
What is being tested?
hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
Could I receive a placebo?
No, everyone receives an active treatment
How many people
110 participants
Where
2 sitesin 2 countries
Study dates
12 Aug 2019to 31 Mar 2021
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • - 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)
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  • 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

Trial locations and contacts

2 sites in 2 countries.

2 sites in 2 countries

Denmark1 site

  • Nordsjællands University Hospital

    Hillerød, Nordsjaelland, 3400

Other trials in Denmark

Netherlands1 site

  • Radboudumc

    Nijmegen, Gelderland, 6525 GA

Other trials in Netherlands

About this study

Official title: Consequences of Hypoglycaemia on Cardiovascular and Inflammatory Responses in Patients With Diabetes Mellitus Type 1, Type 2 and Healthy Volunteers

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.

Read the 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.

Being tested
hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
Medical subject headings
Hypoglycemia, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • hyperinsulinemic normoglycaemic-hypoglycaemic glucose clampProcedure or surgery

    Also called hypoglycaemic 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.

Study groups in NCT03976271
Study groupRoleWhat they receive
T1DM poor glycaemic controlActive comparatorpatients with type 1 diabetes and poor glycaemic control (HbA1c >8% / >64 mmol/mol will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
Receives: Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
T1DM impaired awarenessActive comparatorpatients with type 1 diabetes and impaired awareness of hypoglycaemia will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
Receives: Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
T1DM Normal awarenessActive comparatorpatients with type 1 diabetes and normal awareness of hypoglycaemia will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
Receives: Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
T2DM + InsulinActive comparatorpatients with type 2 diabetes with insulin treatment for at least 1 year will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
Receives: Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
Healthy control T2DMActive comparatorhealthy controls without diabetes and age, gender and BMI matched with diabetes type 2 participants will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
Receives: Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
Healthy control T1DMActive comparatorHealthy controls without diabetes and age, gender and BMI matched with diabetes type 1 participants will undergo hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp
Receives: Procedure: hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Inflammatory responses of hypoglycaemia by measuring the cytokine production of isolated monocytes using ELISA

    Cytokine production (TNF-alfa, IL-6, IL-10 and IL-1β) of isolated and stimulated monocytes

    Measured: 1.5 year

Secondary outcomes (6)

  1. Atherogenic responses of (recurrent) hypoglycaemia using foam cell formation.

    Measurement of Ox-LDL uptake by measuring intracellular apolipoproteine B

    Measured: 1.5 year

  2. Metabolomics profile of each group

    Un-targeted metabolomics and identification of metabolites based on exact mass using metabolomics library

    Measured: 1.5 year

  3. Epigenetic modifications

    Epigenetic modifications due to hypoglycaemia in the promoter regions of the pro-inflammatory cytokines in monocytes

    Measured: 1.5 year

  4. Cardiac function responses to hypoglycaemia using echocardiography

    Cardiac function responses to hypoglycaemia using echocardiography

    Measured: 1.5 year

  5. Cognitive function responses to hypoglycaemia using cognitive function tests (TAP, PASAT)

    Amount of correct answers

    Measured: 1.5 year

  6. Oxidative stress responses using oxidative stress marker

    Excretion of guanine nucleosides in urine (ng/mL)

    Measured: 1.5 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Jun 2019
  2. Study start12 Aug 2019
  3. Primary completion31 Mar 2021
  4. Study completion31 Mar 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Diagnosis
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
110 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03976271
Sponsor's protocol ID
HCIR
Acronym
HCIR
Status last verified
Mar 2021
First submitted
8 Nov 2018
Last updated
12 May 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: No IPD sharing plan necessary

Publications

  • Ajie M, van Heck JIP, Verhulst CEM, Fabricius TW, Hendriksz MS, McCrimmon RJ, Pedersen-Bjergaard U, de Galan B, Stienstra R, Tack CJ. Real-life hypoglycaemia partially blunts the inflammatory response to experimental hypoglycaemia in people with type 1 diabetes. Diabetes Obes Metab. 2024 Sep;26(9):3696-3704. doi: 10.1111/dom.15712. Epub 2024 Jun 20.

    PubMed 38899554

  • Verhulst CEM, van Heck JIP, Fabricius TW, Stienstra R, Teerenstra S, McCrimmon RJ, Tack CJ, Pedersen-Bjergaard U, de Galan BE; Hypo-RESOLVE consortium. The impact of prior exposure to hypoglycaemia on the inflammatory response to a subsequent hypoglycaemic episode. Cardiovasc Diabetol. 2024 Feb 8;23(1):55. doi: 10.1186/s12933-023-02095-w.

    PubMed 38331900

  • Verhulst CEM, van Heck JIP, Fabricius TW, Stienstra R, Teerenstra S, McCrimmon RJ, Tack CJ, Pedersen-Bjergaard U, de Galan BE; Hypo-RESOLVE consortium. Hypoglycaemia induces a sustained pro-inflammatory response in people with type 1 diabetes and healthy controls. Diabetes Obes Metab. 2023 Nov;25(11):3114-3124. doi: 10.1111/dom.15205. Epub 2023 Jul 24.

    PubMed 37485887

  • Verhulst CEM, Fabricius TW, Nefs G, Kessels RPC, Pouwer F, Teerenstra S, Tack CJ, Broadley MM, Kristensen PL, McCrimmon RJ, Heller S, Evans ML, Pedersen-Bjergaard U, de Galan BE. Consistent Effects of Hypoglycemia on Cognitive Function in People With or Without Diabetes. Diabetes Care. 2022 Sep 1;45(9):2103-2110. doi: 10.2337/dc21-2502.

    PubMed 35876660

Questions about this trial

What is this clinical trial studying?

A study testing hyperinsulinemic normoglycaemic-hypoglycaemic glucose clamp in people with Hypoglycemia and Inflammatory Response, run by Radboud University Medical Center at 2 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 May 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Denmark, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Inflammatory responses of hypoglycaemia by measuring the cytokine production of isolated monocytes using ELISA (time frame: 1.5 year). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03976271, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 May 2021.

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