Primary objectives• To evaluate complement activation after topical imiquimod challenge• To evaluate complement activation after local UV-B challenge
ID
Source
Brief title
Condition
- Immune disorders NEC
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Complement factors in skin biopsies following imiquimod challenge
• Complement factors in skin biopsies following UV-B challenge
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 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).
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
defense for fighting pathogens and clearing apoptotic cells. However, when
hyperactivated, it is a driver of a variety of autoimmune and inflammatory
diseases. Investigational products are under development for regulation of
complement, preferably directly to diseased tissues without long-term systemic
blockade, minimizing the risk of serious infections and other complications. An
in vivo complement activation model would be of great benefit for the early
clinical evaluation of the pharmacological activity of novel
complement-targeting investigational compounds, but such a model is not readily
available. The current study will evaluate the capacity of 2 common and
clinically well-characterized innate immune triggers (UV-B and imiquimod) to
drive complement activation in vivo.
Imiquimod is an imidazoquinolone drug acting as TLR7 agonist, exhibiting
tumoricidal and anti-viral effects both in vitro and in vivo (Hanna et al,
2016). Aldara® (imiquimod 5%) cream is on the market for treatment of
(pre)malignant and HPV-induced skin lesions (see SPC Aldara). CHDR has
extensive experience with the topical imiquimod challenge model in which
repeated exposure of tape-stripped skin to Aldara results in the development of
psoriasis-like inflammatory lesions. The UV-B *sun burn* model is an
inflammatory pain model in which erythema is induced on the skin by radiating
the skin with UV-B light in a well-controlled and reproducible manner. UV-B
exposure drives an increase in skin perfusion, followed by infiltration of
immune cells increase into the skin. CHDR has applied this model frequently in
the field of inflammatory pain studies.
In this study, we aim to evaluate complement activation after local imiquimod
and UV-B exposure in healthy volunteers. Readouts will be based on non-invasive
measures (local erythema, perfusion, temperature) and invasive measures (IHC
and mRNA analysis of skin punch biopsies, for cytokines/chemokines, immune
cells, and complement factors).
Study objective
Primary objectives
• To evaluate complement activation after topical imiquimod challenge
• To evaluate complement activation after local UV-B challenge
Study design
This is a single-centre, two-part inflammatory challenge study in healthy
volunteers, to evaluate complement activation by imiquimod and UV-B in two
parallel groups of healthy volunteers. In the first study part, two cohorts of
5 volunteers will undergo a topical UV-B or imiquimod challenge, accompanied by
non-invasive imaging and serial biopsies of the challenge sites. In the second
study part, one of both challenges may be repeated in a group of 5 additional
volunteers to confirm the outcomes of the first study part, and optimize the
timing of assessments, if necessary.
Intervention
Imiquimod
Aldara 5% is a cream containing the active ingredient imiquimod (50 mg/g). In
general use, maximum application duration is up to 16 weeks with 3-5
applications per week depending on the indication (see SPC). A dosage of 5 mg
imiquimod (100 mg Aldara®) per treatment site will be applied, for 3 days.
UV-B
As part of the screening assessments, the subject*s Fitzpatrick skin photo type
is determined (type I - VI). The subject is first exposed to 6 different doses
of UV-B, to determine the Minimal Erythemic Dose (MED) expressed in J/cm2,
using the six different slots of the UV-B lamp. Twenty-four hours (± 2 hours)
after the exposure of the 6 doses, the erythemic response of the skin to UV-B
is assessed by two observers. The MED is determined visually, by observing
which dose produces the first clearly discernible erythema. On the treatment
days, the subject*s skin is exposed to two minimal erythema doses (2MED) of
UV-B.
Study burden and risks
Aldara / imiquimod
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 (SmPC) in D2 for additional
non-clinical and clinical information. Treatment with imiquimod appears to be
safe and reasonably tolerated. Nevertheless, there are some potential skin
reactions including erythema, oedema, vesicles, erosions/ulcerations,
weeping/exudate, flaking/scaling/dryness and scabbing/crusting. Therefore,
possible skin reactions should be monitored carefully during treatment. 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). CHDR has run multiple topical imiquimod challenge studies over the
last 3 years, without any safety concerns. Imiquimod exposure in this study
will be within the normal therapeutic range, at a limited duration.
UV-B
UV irradiation from sunlight is associated with an increased incidence of skin
cancer. UV irradiation contains a spectrum of wavelengths with UV-B being one
of the risk factors for skin cancer. The UV-B wavelength range used in this
study is the narrow band (NB) range 310-315nm, which is also used for
phototherapy of skin conditions such as psoriasis. In general, UV-B
phototherapy is a very safe treatment modality [Lee, 2005]. In a large study
aiming to define the long*term carcinogenic risk of NB*UV-B treatment in
humans, no significant association was found between NB*UV-B treatment and
basal or squamous cell carcinomas, or melanoma [Hearn, 2008]. Participants with
pre-existing risk factor for skin cancer will be excluded.
The UV-B test may induce post-inflammatory hyperpigmentation (PIH) in some
cases [Siebenga, 2019]. Typically, at centres performing the UV-B inflammatory
test, 3xMED (Minimum Erythemal Dose) of UV-B irradiation is applied to induce
sensitisation, however, long-lasting PIH has been associated with 3xMED. As
risk mitigation, participants with Fitzpatrick skin type IV, V or VI will be
excluded. Dose of UV irradiation will be at 2 x MED. The potential occurrence
of hyperpigmentation will be carefully monitored. Before study participation,
study participants will be thoroughly informed the potential risk of PIH at the
UV irradiation sites. CHDR has run multiple UV-B challenge studies over the
last 10 years, without any safety concerns.
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 3 mm no stitching is necessary.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Healthy male subjects, 18 to 65 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, coagulation, 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. History of skin cancer (basal cell carcinoma, squamous cell carcinoma,
melanoma);
3. Have any current and / or recurrent clinically significant skin condition at
the treatment area (i.e. atopic dermatitis); including tattoos;
4. History or presence of post-inflammatory hyperpigmentation.
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. Chronic infection with HIV, hepatitis B (HBV) or hepatitis C (HCV). A
positive HBV surface antigen (HBsAg) test at screening excludes a subject;
11. A history of ongoing, chronic or recurrent infectious disease;
12. Current smoker and/or regular user of other nicotine-containing products
(e.g., patches);
13. History of or current drug or substance abuse considered significant by the
PI (or medically qualified designee), including a positive urine drug screen.
14. Previous use of Aldara (IMIQUIMOD cream) 3 weeks prior to the baseline
visit;
15. Tanning due to sunbathing, excessive sun exposure or a tanning booth within
3 weeks of enrollment.
16. A minimal erythema dose (MED) higher than 355 mJ/cm2 at screening.
Applicable for the participants in the UVB-MITT population only.
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 | EUCTR2020-005595-35-NL |
| CCMO | NL76227.056.20 |