Effect of different drugs on the immune response during inflammation: the DEDICATE-LPS study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Stichting Radboud University Medical Center

Participant type

Healthy volunteers

Age range

18-64 years

Gender

Male

Therapeutic area

Phenomena and Processes [G] - Immune system processes [G12]

Trial duration

24 Oct 2024 → ongoing

Decision date (initial)

2024-05-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

1. To determine the immunomodulatory effects of dexamethasone, tocilizumab and anakinra in healthy volunteers undergoing repeated experimental human endotoxemia.

Secondary objectives 13

1. To determine the effects of dexamethasone, tocilizumab and anakinra on the development of systemic immunoparalysis as reflected by other mediators.
2. Determining the effects of dexamethasone, tocilizumab and anakinra on the acute systemic inflammatory response
3. Determining the effects of LPS-induced inflammation, dexamethasone, tocilizumab and anakinra on transcriptome profiles of circulating leukocytes.
4. Determining the effects of dexamethasone, tocilizumab and anakinra on ex vivo cytokine production and endotoxin tolerance of leukocytes.
5. Determining the effects of dexamethasone, tocilizumab and anakinra on plasmatic coagulation
6. Determining the pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood during LPS-induced inflammation.
7. Determining the effects of LPS administration as well as dexamethasone, tocilizumab and anakinra on salivary cytokine levels
8. Determining the relationship between systemic and salivary cytokine responses.
9. Determining the effects of LPS-induced inflammation, dexamethasone, tocilizumab and anakinra on transcriptome profiles of cells in saliva.
10. Determining the kinetics of blood nitric oxide concentrations during exercise, stress, and systemic inflammation
11. Safety
12. Determining the long-term effects of LPS administration, dexamethasone, tocilizumab and anakinra on DNA methylation.
13. Determining the long-term effects of LPS administration, dexamethasone, tocilizumab and anakinra on immunological parameters

Conditions and MedDRA coding

Inflammatory response following human endotoxemia in healthy volunteers

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Male subjects aged ≥18 and ≤35 years
2. Body mass index (BMI) ≥18 and ≤30 kg/m2
3. Healthy (as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram and routine clinical laboratory parameters)
4. Able to comprehend and sign the Information letter and Informed Consent (IC) prior to enrolment in the study.

Exclusion criteria 22

1. Use of any prescription medication or over-the-counter non-steroidal anti-inflammatory drugs
2. History of psychiatric disorders
3. Thrombocytopenia (<150*109/mL) or anaemia (<8.0 mmol/L)
4. History, signs or symptoms of cardiovascular disease (in particular: Prone to vagal collapse; History of atrial or ventricular arrhythmia; Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrio-ventricular block or a complete left bundle branch block; Hypertension (defined as RR systolic > 160 or RR diastolic > 90 mmHg); Hypotension (defined as RR systolic < 100 or RR diastolic < 50 mmHg))
5. Renal impairment (defined as plasma creatinine >120 μmol/L)
6. Liver enzyme abnormalities (above 2x the upper limit of normal)
7. Signs of infection (CRP > 20 mg/L, white blood cells > 12x109/L or < 4x109/L)
8. Clinically significant acute illness, including infections or trauma, within 1 month prior to the first LPS challenge
9. Previous (participation in a study with) endotoxin (LPS) administration
10. Participation in an experimental intervention or drug trial within 3 months prior to the first LPS challenge
11. Any vaccination or blood donation within 1 month prior to the first LPS challenge
12. Known anaphylaxis or hypersensitivity to any (non-)investigational products or their excipients
13. Recent hospital admission or surgery with general anaesthesia within 3 months prior to the first LPS challenge
14. Use of recreational drugs within 2 weeks prior to the first LPS challenge
15. Suspected of not being able to comply with the trial protocol
16. Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study
17. History or signs of severe atopic syndrome (asthma, rhinitis with medication and/or eczema)
18. History of any disease associated with immune deficiency
19. History of cancer in the last 5 years (excluding localised skin cancer or carcinoma in situ)
20. History or signs of haematological disease
21. History or signs of thromboembolic disorders
22. History of peptic / gastric ulcer disease

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The effects of dexamethasone, tocilizumab and anakinra on the development of immunoparalysis in a repeated endotoxemia model in humans, reflected by between-group differences in plasma TNF concentrations upon the second LPS challenge.

Secondary endpoints 22

1. Between-group differences in plasma cytokine concentrations during the second LPS challenge (e.g. IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40).
2. Between-group differences in the log2-fold change of the Area Under the Curves (AUCs) of plasma cytokine concentrations (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40) during the first and second LPS challenges.
3. Between-group differences in other plasma inflammatory proteins upon the second LPS challenge, as measured by the Olink Target 96 inflammation panel (92 protein biomarkers).
4. Between-group differences in the log2-fold change of peak plasma concentrations of other inflammatory proteins, as measured by the Olink Target 96 inflammation panel (92 protein biomarkers), during the first and second LPS challenges.
5. Between-group differences in mHLA-DR during the first and second LPS challenge.
6. Between-group differences in plasma cytokine concentrations during the first LPS challenge (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40).
7. Between-group differences in other plasma inflammatory proteins upon the first LPS challenge, as measured by the Olink Target 96 inflammation panel (92 protein biomarkers).
8. Between-group differences in blood pressure, heart rate, temperature and symptom scores during the first LPS challenge.
9. Within and between-group differences in blood leukocyte single cell and/or bulk mRNA profiles/transcriptomic pathways upon both LPS challenges.
10. Within and between-group differences in cytokine production of whole blood cultures.
11. Within and between-group differences in plasmatic coagulation parameters.
12. Pharmacokinetic measurements (concentrations, Cmax, Tmax, AUCs, Kel and t1/2) of dexamethasone, anakinra and tocilizumab in blood upon both LPS challenges.
13. Within and between-group differences in cytokine concentrations in saliva fluid during both LPS challenges (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10).
14. Correlation between cytokines in plasma and saliva during systemic inflammation upon both LPS challenges.
15. Within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells in saliva upon both LPS challenges.
16. Correlation of blood nitric oxide concentrations between exercise, stress and systemic inflammation.
17. Number of adverse events related to the use of dexamethasone, tocilizumab and anakinra.
18. Within and -between-group differences in DNA methylation profiles after 3, 6 and 12 months.
19. Within and -between-group differences in plasma cytokine concentrations (e.g. IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40) after 3, 6 and 12 months.
20. Within and -between -group differences in other plasma inflammatory proteins after 3, 6 and 12 months, as measured by the Olink Target 96 inflammation panel (92 protein biomarkers).
21. Within and between-group differences in blood leukocyte single cell and/or bulk mRNA profiles/transcriptomic pathways after 3, 6 and 12 months.
22. Within and between-group differences in cytokine production of whole blood cultures after 3, 6 and 12 months.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Stichting Radboud University Medical Center

Sponsor organisation

Stichting Radboud University Medical Center

Address

Geert Grooteplein Zuid 10

City

Nijmegen

Postcode

6525 GA

Country

Netherlands

Scientific contact point

Organisation

Stichting Radboud University Medical Center

Contact name

Peter Pickkers

Public contact point

Organisation

Stichting Radboud University Medical Center

Contact name

Peter Pickkers

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications