Primary Objectives* To assess the pharmacodynamic effects of systemic prednisolone on the LPS- or IMQ-induced inflammatory response* To assess safety & tolerability of intradermal LPS and topical IMQ in combination with prednisoloneSecondary…
ID
Source
Brief title
Condition
- Skin and subcutaneous tissue disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tolerability / safety endpoints
* Adverse events (AEs)
* Vital signs
* 12-leads ECGs
* Local tolerance (erythema grading scale, numeric rating scale (NRS) pruritus
and pain)
Pharmacodynamic endpoints
Non-invasive measures:
* Perfusion by Laser speckle contrast imaging (LSCI)
* Erythema by Antera 3D camera
* Erythema by clinical evaluation (erythema grading scale)
* Optical Coherence Topography (OCT) (part A only)
* 2D photography by ATBM for photo documentation only (part A only)
Invasive measures:
* Suction blister exudates, including but not limited to
o Cytokines and chemokines
o Flow cytometry (for example: neutrophils, monocytes/macrophages, CD4+
lymphocytes, CD8+ lymphocytes, CD56+ lymphocytes, CD1c dendritic cells)
* Skin punch biopsies
o Local biomarkers, may include but is not limited to,: IL-8, IFN-*, IL-1*,
IFN-*, MXA, MX1, IL-6, IL-10, CCL20 and HBD-2
o Immunohistochemistry: CD1a, HLADR, CD8+, CD4+, CD14+, CD11c complement
factors, iNOS, Gasdermin, IRAK4
o Histology (HE)
* Ex vivo blood assay
o Ex vivo cytokine release assay (imiquimod, part A only)
o Ex vivo cytokine release assay (LPS, part B only)
o Ex vivo NET assay (Part B only)
Secondary outcome
N.A.
Background summary
Inflammation is a response to damaged tissue and/or pathogens resulting in a
release of cytokines and subsequent cellular activation. Although inflammation
is in principle a healthy process, in some cases an excessive and/or poorly
regulated inflammatory response can be harmful to the host, which is the case
in many inflammatory disorders.
Toll-like receptors belong to the family of pattern recognition receptors
(PRRs). These highly conserved receptors recognize pathogen-associated
molecular patterns (PAMPs) and danger associated molecular patterns (DAMPs).
Upon recognition PRRs induce the activation of a strong inflammatory response
and thereby kick starting the innate immune response. Toll-like receptor 7
(TLR7) is an intracellular, endosomal TLR and is able to recognize single
stranded (ss)RNA from viruses and the class of imidazoquinolone drugs such as
imiquimod (IMQ). Toll-like receptor 4 (TLR4) is a transmembrane TLR to
recognize lipopolysaccharide (LPS), a large molecule found on the outer
membrane of Gram-negative bacteria. Activation of TLR4 or TLR7 leads to the
activation of the central transcription factor, nuclear factor-kB and induces
secretion of pro inflammatory cytokines such as tumor necrosis factor alpha
(TNF-*), interferon gamma (IFN-*), IFN-*, interleukin(IL)-6, IL-1a, IL-1b,
IL-8, IL-12, IL-17, IL-22, IL-23 granulocyte macrophage colony-stimulating
factor and granulocyte colony-stimulating factor (innate immunity). All
cytokine elevations and local effects have been reported to be reversible.
Imiquimod (a TLR7 agonist) has shown to exhibit tumoricidal and anti-viral
effects both in vitro and in vivo (Hanna et al, 2016). Aldara (imiquimod 5%)
cream is an immune response modifier for topical administration and is
currently on the market for (pre)malignant and HPV-induced skin lesions (see
SPC Aldara).
Study objective
Primary Objectives
* To assess the pharmacodynamic effects of systemic prednisolone on the LPS- or
IMQ-induced inflammatory response
* To assess safety & tolerability of intradermal LPS and topical IMQ in
combination with prednisolone
Secondary Objectives
* To explore pharmacodynamic biomarkers determined in blister exudate compared
to skin punch biopsies in LPS or IMQ-induced inflammation.
Study design
A placebo controlled, interventional study to assess the anti-inflammatory
effects oral prednisolone in an LPS or IMQ skin challenge model in healthy
volunteers.
In part A of this study, IMQ will be applied on a tape-stripped skin area on
the upper back in combination with oral administration of prednisolone.
In part B of this study subjects will receive a two day pretreatment with oral
prednisolone (0.25mg/kg BID) or placebo. At day 1 subjects will receive either
two or four intradermal LPS injections on the volar forearm (10ng LPS per
injection)
Intervention
Part A ; Imiquimod and Prednisolone
Part B ; LPS and Prednisolone (or placebo)
Study burden and risks
The overall aim of this study is to evaluate the anti-inflammatory and
immunomodulatory properties of oral prednisolone in an LPS and IMQ skin
challenge model in healthy volunteers. Prednisolone is known for the side
effects when used in a high dose for a longer period, however in this study
this product is only used for a limited amount of days (up to 4 days) and
therefore no lasting effects are likely to occur. We refer to the SPC in D of
the submission dossier for more information. No medical benefit can be expected
from this study for the participating subjects.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Healthy male or female subjects (part B males only), 18 to 45 years of age,
inclusive. Healthy status is defined by absence of evidence of any active or
chronic disease following a detailed medical and surgical history, a complete
physical examination including vital signs, 12-lead ECG, hematology, blood
chemistry, blood serology and urinalysis. In the case of uncertain or
questionable results, tests performed during screening may be repeated before
randomization to confirm eligibility or judged to be clinically irrelevant for
healthy subjects;
2. Body mass index (BMI) between 18 and 30 kg/m2 and a maximum weight of 100
kg, inclusive;
3. Fitzpatrick skin type I-III (Caucasian);
4. Subjects and their partners of childbearing potential must use effective
contraception for the duration of the study;
5. Able and willing to give written informed consent and to comply with the
study restrictions.
Exclusion criteria
Eligible subjects must meet none of the following exclusion criteria at
screening:
1. Any vaccination within the last 3 months; COVID19 vaccination is allowed up
until 4 weeks prior to the first prednisolone/placebo dosing, and from 2 weeks
after the last prednisolone/placebo dosing.
2. Family history of psoriasis;
3. History of pathological scar formation (keloid, hypertrophic scar);
4. Have any current and / or recurrent pathologically, clinical significant
skin condition at the treatment area (i.e. atopic dermatitis); including tattoos
5. Previous use of Aldara (IMQ cream) 3 weeks prior to the baseline visit (part
A only)
6. Known hypersensitivity to the (non)investigational drug, drugs of the same
class, or any of their excipients;
7. Hypersensitivity for dermatological marker at screening;
8. Requirement of immunosuppressive or immunomodulatory medication within 30
days prior to enrollment or planned to use during the course of the study;
9. Use of topical medication (prescription or over-the-counter [OTC]) within 30
days of study drug administration, or less than 5 half-lives (whichever is
longer) in local treatment area
10. Tanning due to sunbathing, excessive sun exposure or a tanning booth within
3 weeks of enrollment;
11. Participation in an investigational drug or device study within 3 months
prior to screening or more than 4 times a year.
12. Loss or donation of blood over 500 mL within three months prior to
screening (part A and B), or donation of plasma within 14 days of screening
(part B only)
13. Any (medical) condition that would, in the opinion of the investigator,
potentially compromise the safety or compliance of the patient or may preclude
the patient*s successful completion of the clinical trial.
14. Latent Diabetes Mellitus
15. Volunteers with clinically relevant infections
16. Current smoker and/or regular user of other nicotine-containing products
(e.g., patches); or positive urine cotinine test at screening (part B only)
17. History of or current drug or substance abuse considered significant by
the PI (or medically qualified designee), including a positive urine drug
screen.
18. Subjects that test positive for a SARS-CoV-2 infection
19. Subjects with a BMI > 30 and/or cardiovascular, respiratory or immune
system disorders
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003567-21-NL |
| CCMO | NL71422.056.19 |
| OMON | NL-OMON28349 |