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ID
Source
Brief title
Health condition
Dermatological challenge model, skin inflammation model
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)
• 2D photography by ATBM for photo documentation only
lnvasive measures:
• Suction blister exudates, including but not limited to
o Cytokines and chemokines
o Flow cytometry (neutrophils, monocytes/macrophages, CD4+ lymphocytes, CD8+ lymphocytes, CD56+ lymphocytes, CDlc dendritic cells)
• Skin punch biopsies
o Local biomarkers, including but not limited to: lL-8, IFN-α, lL-1β, IFN-ɣ, MXA, MX1, lL-6, lL-10, CCL20 and HBD-2
o lmmunohistochemistry:CD1a, HLADR, CD8+, CD4+, CD14+, CD11c
o Histology (HE)
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). The agonistic activity of IMQ on the TLR7 receptor causes activation of the central transcription factor, nuclear factor-kB and inducing secretion of pro inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-ɣ), IFN-α, 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 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). The safety and efficacy of imiquimod in immunosuppressed patients have not been established.
Study objective
Primary Objectives
• To assess the pharmacodynamic effects of prednisolone on the IMQ-induced inflammatory response
• To assess safety & tolerability of topical IMQ in combination with prednisolone
Secondary Objectives
• To explore pharmacodynamic biomarkers determined in blister exudate compared to skin punch biopsies in IMQ-induced inflammation
Study design
Baseline till EOS
Intervention
lmiquimod and Prednisolone
Inclusion criteria
1. Healthy male or female subjects, 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-II (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
1. Any vaccination within the last 3 months;
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);
5. Previous use of Aldara (IMQ cream) 3 weeks prior to the baseline visit
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
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
Design
Recruitment
IPD sharing statement
Plan description
Followed up by the following (possibly more current) registration
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| NTR-new | NL8391 |
| CCMO | NL71422.056.19 |
| OMON | NL-OMON55304 |