Primary* To immunologically characterize imiquimod-induced inflammation after 7-day exposure of healthy skin;* To evaluate local complement activation/depositions after a prolonged topical imiquimod challenge;* To evaluate systemic activation of…
ID
Source
Brief title
Condition
- Immune disorders NEC
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Cytokines and immune cells in skin biopsies
* Local complement factors in skin biopsies
* Complement factors and activation markers in blood samples
Secondary outcome
* Perfusion by LSCI
* Erythema by Antera 3D and clinical evaluation
Background summary
Inflammation is a response to damaged tissue and/or pathogens resulting in
cellular activation and a release of cytokines. Although inflammation is in
principle a physiological 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).
Detection of PAMPs by mediators of innate immunity brings multiple components
of immunity into play, including the complement system. One part of the
complement system is a collection of proteins (C5-C9) that, when activated,
form aggregates that punch holes in the cell membranes of targeted microbes,
killing the cells by lysis. The complement system also includes serum
glycoproteins that, when activated, promote uptake of microorganisms by
phagocytes (opsonization). As such, the complement system is a first line of
defence for fighting pathogens and clearing apoptotic cells. However, when
hyperactivated, it is a driver of a variety of autoimmune and inflammatory
diseases, making it an interesting target for drug development. An in vivo
complement activation model would be of great benefit for clinical evaluation
of the pharmacological activity of novel complement-targeting investigational
compounds, but such a model is not readily available.
Study objective
Primary
* To immunologically characterize imiquimod-induced inflammation after 7-day
exposure of healthy skin;
* To evaluate local complement activation/depositions after a prolonged topical
imiquimod challenge;
* To evaluate systemic activation of complement after imiquimod challenge
Secondary
* To characterize the clinical response to prolonged imiquimod challenge over a
7-day imiquimod treatment period;
Study design
This is a single-center, inflammatory challenge study in healthy volunteers, to
evaluate immune cell and complement activation by prolonged exposure to
imiquimod. 10 volunteers will receive imiquimod as a challenge agent on
tape-stripped skin, followed by serial biopsies of the challenge sites.In
addition, one area will treated with imiquimod for 7 days and only be followed
non-invasively over time (local perfusion and erythema).
Intervention
ALDARA 5% cream
Study burden and risks
Aldara 5% ®, on the market since 1997, is a topical cream containing 50 mg/g
imiquimod. Aldara has been registered for various indications including basal
cell carcinoma, actinic keratosis and genital and peri-anal warts. Please refer
to the summary of product characteristics (SPC) in D2 for additional
non-clinical and clinical information. CHDR has run multiple topical imiquimod
challenge studies over the last 3 years, without any safety concerns. In these
studies, imiquimod was applied at a dosage of 5 mg (100 mg Aldara®), with a
maximum of 15 mg imiquimod (CHDR1430) and 60 mg (CHDR1631) a day for 2 or 3
consecutive days. In this study, imiquimod will be applied for 7 consecutive
days. Five (5) areas per subject will be treated with imiquimod on the back.
Although CHDR does not have experience yet with 7 day treatment of IMQ, studies
in cancer patients have shown that 7 day treatment (both once daily and twice
daily) or even 12 weeks treatment (once daily or 5 times a week) are well
tolerated. In the treatment of Lentigo Maligna, imiquimod is applied daily for
12 consecutive weeks. Nevertheless, there are some potential skin reactions
including erythema, oedema, vesicles, erosions/ulcerations, weeping/exudate,
flaking/scaling/dryness and scabbing/crusting. Because CHDR does not have
previous experience with application of imiquimod for 7 consecutive days,
possible skin reactions should be monitored carefully during treatment. Daily
skin examination by a trained physician will take place to mitigate the risk of
severe skin reactions. If signs of ulcerations appear, imiquimod treatment will
be terminated immediately. Any local inflammation induced by imiquimod is
expected to resolve after termination of the treatment, without long-term
effects.
Since psoriasis exacerbations due to imiquimod treatment have been described,
psoriasis patients as well as patients with other autoimmune diseases and skin
diseases are excluded to participate in this study to minimize potential
risk(s).
Skin punch biopsies
Since complement deposition can only be assessed histologically, skin biopsies
are indispensable in this study. Biopsies will be taken in a minimally invasive
manner. Since the diameter is only 4 mm no surgical sutures are necessary.
Subjects with a dark skin type (Fitzpatrick IV * VI) have a higher risk for the
development of hypertrophic scars or keloids, and will therefore not be
included in this trial.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Healthy male and 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 minimum weight of 50 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. History of pathological scar formation (keloid, hypertrophic scar) or
keloids or surgical scars in the target treatment area that in the opinion of
the investigator, would limit or interfere with dosing and/or measurement in
the trial;
2. Diagnosed with psoriasis or family history of psoriasis
3. History of skin cancer (basal cell carcinoma, squamous cell carcinoma,
melanoma);
4. Have any current and / or recurrent clinically significant skin condition at
the treatment area (e.g. atopic dermatitis); including tattoos;
5. Using immunosuppressive or immunomodulatory medication within 30 days prior
to enrolment or planned to use during the course of the study;
6. 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;
7. Participation in an investigational drug or device study within 3 months
prior to screening or more than 4 times a year;
8. Loss or donation of blood over 500 mL within three months prior to screening
or donation of plasma within 14 days of screening;
9. 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;
10. Any vaccination within 30 days prior to initial IMQ dosing or planned
during the course of the study with exception of vaccination for SARS-CoV-2;
11. Vaccination for SARS-CoV-2 within 14 days prior to initial IMQ dosing, or
planned during the course of the study;
12. Chronic infection with HIV, hepatitis B (HBV) or hepatitis C (HCV). A
positive HBV surface antigen (HBsAg) test at screening excludes a subject;
13. A history of ongoing, chronic or recurrent infectious disease;
14. Current smoker and/or regular user of other nicotine-containing products
(e.g., patches);
15. History of or current drug or substance abuse considered significant by the
PI (or medically qualified designee), including a positive urine drug screen.
16. Previous use of Aldara (imiquimod cream) 3 months prior to the baseline
visit;
17. Volunteers with clinically relevant infections
18. Hypersensitivity for dermatological marker at screening
19. Tanning due to sunbathing, excessive sun exposure or a tanning both within
3 weeks of enrollment.
20. Pregnant, a positive pregnancy test, intending to become pregnant, or
breastfeeding
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-005429-26-NL |
| CCMO | NL79321.056.21 |