Role of Adrenaline in in the Inflammatory Response in Diabetes (RAID)

• ClinicalTrials.gov Identifier: NCT05990933
• Recruitment Status: Not yet recruiting
• First Posted: August 14, 2023
• Last Update Posted: August 14, 2023
• Sponsor: Cees Tack
• Information provided by (Responsible Party): Cees Tack, Radboud University Medical Center

Study Description

Brief Summary:

The primary aim of the present study is to study the effect of adrenaline administration on inflammatory parameters (e.g. leukocyte phenotype, cytokines, inflammatory proteins). Secondary objectives consist of the effect of adrenaline on atherogenic parameters.

• All participants will receive intravenous infusion of adrenaline for an hour
• We will draw blood at 7 time points, not including screening
• Participants will be asked to return for a total of 4 times

Researchers will compare 2 groups, healthy individuals versus people with diabetes type 1 to see if the inflammatory reaction to adrenaline differs between these two groups.

Condition or disease	Intervention/treatment	Phase
Inflammatory Response; Diabetes type1; Hypoglycemia	Drug: Adrenaline	Not Applicable

Detailed Description:

Objective: The primary aim of the present study is to study the effect of adrenaline administration on inflammatory parameters (e.g. leukocyte phenotype, cytokines, inflammatory proteins). Secondary objectives consist of the effect of adrenaline on atherogenic parameters.

Potentially eligible adult ( 16 - 75 years) participants will be recruited from the diabetes clinic at the department of internal medicine from the Radboud University Medical Center. Healthy participants will be recruited through social media and other advertisements. Researchers will recruit a total of 30 individuals, i.e. 15 healthy participants and 15 people with type 1 diabetes. Participants with type 1 diabetes will be equipped with a blinded continuous glucose monitoring device (CGM) during the test, which will measure interstitial glucose levels for a total of 10 days.

Intervention: All participants will receive intravenous infusion of adrenaline at a rate of 0.04ug/kg/min for 1 hour. We will draw blood at baseline, 30 minutes, 60 minutes, 180 minutes, 24 hours 72 hours and a week after start of infusion. The blood samples will be used for phenotyping of the innate immune system and measuring inflammatory and atherogenic parameters. Throughout the infusion, vital parameters will be monitored.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: All participants will receive intravenous infusion of adrenaline at a rate of 0.04ug/kg/min for 1 hour. We will draw blood at baseline, 30 minutes, 60 minutes, 180 minutes, 24 hours 72 and a week after start of infusion. These samples will be used for phenotyping of the innate immune system and measuring inflammatory and atherogenic parameters. Throughout the infusion vital parameters will be monitored.
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Role of Adrenaline in the Inflammatory Response in People With Diabetes Mellitus Type 1, and Healthy Individuals
• Estimated Study Start Date: September 2023
• Estimated Primary Completion Date: October 2024
• Estimated Study Completion Date: October 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: People with type 1 diabetes; The participants with type 1 diabetes will receive an intravenous infusion of adrenaline at a rate of 0.04ug/kg/min for 1 hour.	Drug: Adrenaline; Adrenaline infusion at a rate of 0.04ug/kg/min for 1 hour administered intravenously.; Other Name: Adrenaline infusion
Active Comparator: Healthy individuals; The participants without type 1 diabetes will receive an intravenous infusion of adrenaline at a rate of 0.04ug/kg/min for 1 hour.	Drug: Adrenaline; Adrenaline infusion at a rate of 0.04ug/kg/min for 1 hour administered intravenously.; Other Name: Adrenaline infusion

Outcome Measures

Primary Outcome Measures :

1. Monocyte count [ Time Frame: Change from baseline compared to after 1 hour ]
   The amount of monocytes following 60 minutes of adrenaline infusion compared to baseline to asses the adrenaline effect on the inflammatory response.

Secondary Outcome Measures :

1. Leukocyte count [ Time Frame: Change from baseline at day 30, 60 and 180 minutes 1, day 3 and day 7 after adrenaline infusion ]
   Measurement of the amount of leukocytes
2. Leukocyte phenotype [ Time Frame: Change from baseline at day 30, 60 and 180 minutes 1, day 3 and day 7 after adrenaline infusion ]
   Measuring several phenotypes by using a pre-defined panel of interest with flow-cytometry ( e.g. NK-cells, granulocytes)
3. Pro-inflammatory proteins [ Time Frame: Change from baseline at day 30, 60 and 180 minutes 1, day 3 and day 7 after adrenaline infusion ]
   Pro-inflammatory proteins using Olink Proteomics AB inflammation panel with 92 circulating inflammatory proteins ( e.g. EN-rage, FIT3L)
4. Inflammation plasma parameters [ Time Frame: Change from baseline at 30, 60 and 180 minutes day 1, day 3 and day 7 after adrenaline infusion ]
   Inflammatory plasma protein using ELISA, ( e.g high sensitive-crp)
5. Atherogenic parameters [ Time Frame: Change from baseline at 30, 60 and 180 minutes day 1, day 3 and day 7 after adrenaline infusion ]
   Atherogenic parameters using ELISA method including but not limited to, VCAM-1, ICAM-1, E-Selectin, P-selectin, PAI-1, Plasma Endothelin
6. Insulin [ Time Frame: Change from baseline at, 60 and 180 minutes ]
   Plasma levels of insulin
7. Adrenaline [ Time Frame: Change from baseline at 30, 60 and 180 minutes ]
   Plasma levels of adrenaline
8. Noradrenaline [ Time Frame: Change from baseline at 30, 60 and 180 minutes ]
   Plasma levels of noradrenaline
9. Glucose variability [ Time Frame: 2 weeks ]
   Glucose variability measured by the blinded continuous glucose monitor including but not limited to, measuring time within range, amount of hypoglycaemic events, amount of hyperglycaemic events.
10. Ex vivo cytokines [ Time Frame: Change from baseline at 30, 60 and 180 minutes, day 1, day 3 and day 7 after adrenaline infusion ]
    Ex vivo production of pro- and anti-inflammatory cytokines and chemokines after ex vivo stimulation of isolated monocytes, including TNF-α, IL-6, IL-10 and IL-1β.
11. Distribution of monocyte subset [ Time Frame: Change from baseline at 30, 60 and 180 minutes, day 1, day 3 and day 7 after adrenaline infusion ]
    Distribution of pro- and anti-inflammatory monocyte subsets using FACS (Fluorescence-activated Cell Sorting)

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 75 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Overall inclusion criteria:

• Ability to provide written informed consent
• Body-Mass Index: 19-30kg/m2
• Age ≥16 years, ≤ 75 years
• Blood pressure: <140/90 mmHg
• Non-smoking
• Electrocardiogram not showing any serious arrythmia's (PVC's and PAC's accepted)

Diabetes group specific criteria:

• Insulin treatment according to basal-bolus insulin regimen (injections or insulin pump)
• Duration of diabetes > 1 year
• HbA1c < 100 mmol/mol,

Exclusion Criteria:

• - Any event of cardiovascular disease in the past 5 years (e.g. myocardial infarction, stroke, heart failure, symptomatic peripheral arterial disease)
• Pregnancy or breastfeeding or unwillingness to undertake measures for birth control
• Epilepsy,
• Current treatment with Alpha or beta blockers ( doxazosin, propranolol)
• History of panic disorders
• History of Arrhythmias
• Use of immune-modifying drugs or antibiotics
• Use of tricyclic antidepressants or MAO inhibitors
• Use of statins (e.g. stop statins >2 weeks before performing blood sampling.
• Any infection with systemic symptoms in past 2 weeks
• Previous vaccination in the past 2 weeks
• Proliferative retinopathy
• Nephropathy with an estimated glomerular filtration rate (by MDRD) ˂60ml/min/1.73m2
• Overt impaired hypoglycaemic awareness assed by the Clarke Questionnaire 4 or higher

Contacts and Locations

Contacts

Contact: Ilyas Mustafajev, MD; +31683358037; ilyas.mustafajev@radboudumc.nl

Contact: Rick Meijer, MD. PHD; rick.meijer@radboudumc.nl

Locations

Netherlands

Radboud UMC

Nijmegen, Gelderland, Netherlands, 6525GA

Contact: Ilyas Mustafajev, MD +31683358037 ilyas.mustafajev@radboudumc.nl

Sponsors and Collaborators

Cees Tack

Investigators

• Principal Investigator: Cees Tack, MD. PHD.; Radboud University Medical Center (Radboudumc)

More Information

• Responsible Party: Cees Tack, Prof. Dr., Radboud University Medical Center
• ClinicalTrials.gov Identifier: NCT05990933
• Other Study ID Numbers: 114664
• First Posted: August 14, 2023
• Last Update Posted: August 14, 2023
• Last Verified: August 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: WE will share the study protocol using a data respository accesible through the research team on demand. Starting around 6 months after publication.
• Supporting Materials: Study Protocol
• Time Frame: 6 months after publication
• Access Criteria: The coordinating researcher will review acces requests. Seeing as the data are all anonimised acces will be granted for additional research in the field of inflammation or diabetes.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Diabetes Mellitus; Hypoglycemia; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Epinephrine; Racepinephrine; Epinephryl borate; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Adrenergic beta-Agonists; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Asthmatic Agents; Respiratory System Agents; Mydriatics; Sympathomimetics; Vasoconstrictor Agents