Primary objective- To explore the pharmacodynamic effects of topically applied IMQ (in combination with or without TS) - To identify dose-response relationship of topically applied IMQ Secondary objective- To assess safety and tolerability of…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To explore the pharmacodynamic effects of topically applied imiquimod and to
identify dose-response relationship.
Secondary outcome
To assess safety and tolerability of topically applied imiquimod
Background summary
The skin is the largest organ of the human body, accounting for approximately
16% of the total body weight. It plays critical roles in immunologic
surveillance, protection from infection, thermal regulation, and tactile
sensation. Dysfunction of the skin can lead to inflammatory skin disorders,
such as atopic dermatitis and psoriasis. Pharmacological challenges have been
used previously to induce local inflammatory reactions on the skin, with the
purpose to develop models to mimic skin diseases temporarily for application in
drug development programs. However, fully characterized suitable challenge
models are not yet available.
Aldara 5% ® is a topical cream containing 50 mg/g imiquimod (IMQ). IMQ is an
imidazoquinolone which is a class of immunomodulatory drugs. It mobilizes
several cytokines with antiviral and tumoricidal properties. This cytokine
recruitment occurs because of a highly intricate process involving the innate
and adaptive immune response through cell surface receptors named toll-like
receptors (TLRs) located on macrophages, Langerhans cells, and dendritic cells.
TLR activation also causes a host of secondary effects on the molecular and
cellular levels that are not yet fully understood. The predominant antitumor
mechanism of imiquimod is specific binding to TLR-7 and TLR-8, activating the
central transcription factor, nuclear factor-kB and inducing 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). According to literature all
cytokine elevations and local effects are reversible.
IMQ is registered for various indications including basal cell carcinoma (BCC),
actinic keratosis (AK) and genital and peri-anal warts. Topical administration
of IMQ appears to be safe and reasonable tolerated with local skin reactions as
main adverse events. Although, psoriasis exacerbations in psoriasis patients
using IMQ were described previously. This not only occurred at treatment site,
but also generalized. Topical IMQ on mice showed higher expression of IL-17
producing gamma-delta (**)-cells at untreated dermis, suggesting memory cells
can travel to distant skin and accelerate secondary IL-17 driven response,
which can lead to psoriasis exacerbation.
The overall aim of this study is the development of a challenge model to
temporarily induce skin inflammation and to enable future application as
proof-of-pharmacology or drug profiling in in drug developmental programs.
A recent study on healthy volunteers explored the biochemical effects of IMQ
application compared to tape stripping (TS). A significant up-regulation in
mRNAs encoding for interferon type I response was found for each treatment with
more pronounced effect after TS. However, no assessment of IMQ in combination
with TS was performed. Furthermore, relevant other pharmacodynamics and safety
endpoints were omitted.
This challenge study is intended to explore the pharmacodynamic effects of
topically applied IMQ and IMQ in combination with TS by means of biophysical,
biochemical, imaging, clinical and patient-recorded parameters. Furthermore
dose-response relationship will be identified and safety / tolerability will be
assessed.
Study objective
Primary objective
- To explore the pharmacodynamic effects of topically applied IMQ (in
combination with or without TS)
- To identify dose-response relationship of topically applied IMQ
Secondary objective
- To assess safety and tolerability of topically applied IMQ
Study design
This is a randomized, open-label, vehicle-controlled, parallel, dose-ranging
study.
Intervention
Application of imiquimod under occlusion
Study burden and risks
For this study, volunteers will visit the clinic 4 times, with one overnight
stay period of 4 days. During visit both non-invasive and invasive examination
will be performed. Some of the non-invasive assessments include blood pressure
measurements, ECGs, photography of the skin, questionnaires and skun function
measurements. Invasive assessments include blood samples and skin punch
biopsies. In total, 4 blood samples will be taken and 6 skin punch biopsies.
The risks associated with the topical application of IMQ have been identified
in healthy volunteers as well as patients with various indications for
treatment, such as BCC, AK and genital warts. Treatment appears to be safe and
well-tolerated, with local skin reactions including erythema, edema, vesicles,
erosions/ulcerations, weeping/exudate, flaking/skaling/dryness and
scabbing/crusting as main side effect. Since psoriasis exacerbations due to IMQ
treatment have been described, psoriasis patients as well as patients with
other auto-immune diseases and skin diseases are excluded to participate in
this study to minimize potential risk(s). Furthermore, because of the potential
systemic effects, IMQs mechanism of action will be explored not only at the
treated skin surface, but also at a distant untreated dermal site and in venous
blood (PBMCs). Adverse events due to the possible systemic effects have not
been described and due to the topical route of administration with a very
limited area of administration in this study (0,018% BSA) systemic effects are
not expected. Therefore we assess the risks as acceptable for the subjects to
participate in the study.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
* Healthy male subjects, 18 to 45 years of age, inclusive
* Body mass index (BMI) between 18 and 30 kg/m2, inclusive, and with a minimum weight of 50 kg
* Fitzpatrick Skin type I-II (Caucasian type)
* Able to participate and willing to give written informed consent and to comply with the study restrictions.
Exclusion criteria
1. Any disease associated with immune system impairment, including auto-immune diseases, HIV and transplantation patients.
2. Family history of psoriasis
3. History of pathological scar formation (keloid, hypertrophic scar)
4. Have any current and / or recurrent pathologically, clinical significant relevant skin condition.
5. Previous use of imiquimod / resiquimod / gardiquimod
6. Known hypersensitivity to the investigational drug, comparative drug, drugs of the same class, or any of their excipients.
7. Requirement of immunosuppressive or immunomodulatory medication within 30 days prior to enrollment or planned to use during the course of the study.
8. 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
9. Tanning due to sunbathing, excessive sun exposure or a tanning booth within 3 weeks of enrollment.
10. Participation in an investigational drug or device study within 3 months prior to screening or more than 4 times a year.
11. Loss or donation of blood over 500 mL within three months prior to screening.
12. 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.
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 | EUCTR2016-000331-41-NL |
| CCMO | NL56586.056.16 |