Primary Objectives- To evaluate disease-related characteristics and biomarkers in patients with CLE compared to healthy volunteers. Secondary Objectives- To evaluate the variability of the selected biomarkers between patients - To investigate the…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tolerability / safety endpoints
Part A: not applicable.
Part B safety and tolerability upon topical IMQ challenge will be assessed in
the following endpoints:
- Application site assessment (LIGS), including Erythema grading scale
- Vital signs (HR, BP)
- Body temperature
- Patient-reported outcomes (itch, pain)
Observational and pharmacodynamic endpoints
- Skin suction blisters (cells and micro-environment proteomics)
- Skin punch biopsies
o Histology
o RNA-sequencing
- Imaging:
o Laser Speckle Contrast Imaging* (microcirculation)
o Antera 3D multispectral imaging* (3D skin morphology, erythema, haemoglobin
level)
o Optical Coherence Tomography* (skin morphology, epidermal thickness, blood
perfusion)
o AquaFlux and GPSkin Barrier Pro-1* (trans-epidermal water loss, stratum
corneum hydration)
o 2D photography*
- Tape stripping (lipidomics, OLINK)*
- Skin swabs (microbiome)*
- Faecal microbiota*
- Laboratory (blood):
o IFN signature
o Ex vivo imiquimod
o Cytokines
o Complement
o Autoantibodies
- Patient reported outcomes (DLQI, 5D-itch, NRS itch and pain, sleeplessness)*
- Patient satisfaction of imaging and non-imaging tools/interventions*
Endpoints marked with *** denote non-invasive assessments.
Secondary outcome
N/A
Background summary
Cutaneous lupus erythematosus (CLE) is an autoimmune disease that can occur
isolated to the skin or as a manifestation of Systemic Lupus Erythematosus
(SLE) (Stannard and Kahlenberg, 2016). Subtypes of CLE, which differ in lesion
morphology and histopathology, include acute cutaneous LE (ACLE), subacute
cutaneous LE (SCLE), intermittent cutaneous LE (ICLE) i.e., lupus tumidus (LET)
and chronic cutaneous LE (CCLE). CCLE can be further subdivided into various
subtypes including (but not limited to) cutaneous discoid LE (CDLE) and LE
profundus (LEP).
The pathogenesis and pathophysiology of CLE are not fully understood. The
current concept regarding the onset of the disease comprises a genetic
background predisposing to CLE triggered by factors such as UV light, what
leads to cellular stress and eventually to the release of DNA components in
keratinocytes (Fetter et al., 2022). Activation of both Toll-like receptor
(TLR)-dependent and TLR-independent inflammatory signalling cascades leads to
increased expression of several cytokines, in particular type I interferon
(IFN). Type I interferon mediates increased expression of proinflammatory
chemokines via the JAK-STAT pathway, leading to recruitment of immune cells,
release of cytokines and a chronic reactivation of innate immune pathways.
Findings on the pathogenesis of the disease have led to the development of
several targeted therapies that are currently being investigated in clinical
trials. However, blockage of one important pathway might not suffice for
decreasing disease activity given the limited efficacy of selective IFN
antibodies in clinical trials (Kalunian et al., 2016), (Khamashta et al., 2016)
(Werth et al., 2017).
Given the complex and heterogeneous character of the disease, identification,
and development of specific biomarkers for diagnosis, disease subtyping,
disease severity, and treatment response in CLE is challenging. Only few
biomarkers for CLE have been validated and widely incorporated into clinical
practice (Zhu et al., 2021). Type I interferon-inducible proteins can be
potentially used to assess disease severity of SCLE and CDLE (Braunstein et
al., 2013). Furthermore, low complement in CLE patients may be related to poor
prognosis and increased risk of developing systemic disease (Vera et al., 2010)
(Vera et al., 2010).
In this study, we aim to further characterize CLE by using a deep phenotyping
approach. The study consists of an observational (part A) and interventional
(part B) part in CLE patients and healthy volunteers. The main objective is to
characterize objectively measured disease characteristics and detect novel
biomarkers for CLE(-subtypes). To specifically study the role of TLR7
activation in the pathophysiology of the various clinical subtypes of CLE, an
ex vivo (part A) and in vivo (part B) immune challenge with imiquimod will be
performed.
Study objective
Primary Objectives
- To evaluate disease-related characteristics and biomarkers in patients with
CLE compared to healthy volunteers.
Secondary Objectives
- To evaluate the variability of the selected biomarkers between patients
- To investigate the immune response of CLE patients following a (local) ex
vivo and in vivo imiquimod skin challenge compared to healthy volunteers.
Study design
This is a single-center, two-part, exploratory study in CLE patients and
healthy volunteers. For part A, up to 30 patients with subacute cutaneous lupus
erythematosus (SCLE), chronic discoid cutaneous lupus erythematosus (CDLE) or
lupus tumidus (LET) (at least 6 per subtype) will be included. Patients will be
recruited from multiple centers. As a comparison, 10 healthy volunteers
(age-matched) will be included. Healthy volunteers and CLE patients will visit
CHDR two times in total for part A: a screening visit and Day 1 visit. All
healthy volunteers will be enrolled in part B and patients with the diagnosis
CDLE can be enrolled in part B. In part B, patients and healthy volunteers will
visit CHDR for 6 visits: a screening visit, Day 1-4, and an EOS visit.
Intervention
Aldara 5% is a cream containing the active ingredient imiquimod (50 mg/g).
Imiquimod is registered for various indications including the treatment of
basal cell carcinoma, actinic keratosis, and perianal warts. Imiquimod is also
broadly used as pharmacological challenge agent to induce a transient mild to
moderate fully reversible skin inflammation. In part A of this study, blood
from CLE patients and healthy volunteers will be drawn and stimulated (ex vivo)
with imiquimod. In part B of this study, imiquimod will be applied by trained
medical staff on two areas of non-lesional skin of CLE patients and healthy
volunteers. A dosage of 5 mg IMQ (100 mg Aldara®) per treatment site will be
applied using 12mm Finn Chambers, for 2 consecutive days under occlusion
Study burden and risks
The overall aim of this study is to evaluate objectively measured disease
related characteristics to comprehensively characterize patients with CLE
compared to healthy volunteers.
No medical benefit can be expected for the participants during both part A and
B of this study.
Albeit all study procedures are considered minimal invasive, participants can
experience pain and/or haematoma and in rare cases local infection during and
after a skin punch biopsy and/or venepuncture. Both biopsies and suction
blisters can possibly leave a lasting mark on the skin, therefore healthy
subjects with a history of hypertrophic scarring or keloid will be excluded.
Topical application of IMQ in healthy volunteers will result in mild to
moderate skin inflammation, which heals spontaneously. In CLE patients,
application of IMQ can induce a CLE(-like) skin lesion. However, it will be
applied locally on a small skin area (using a Finn chamber of 12mm) and for a
short period of time (2 applications in 48h). The skin area*s where the IMQ was
applied on Day 1 in part B will be checked prior to the next planned IMQ
administration, to determine if the IMQ application can continue. Next to this,
it will be determined on an individual basis if CDLE-patients can participate
in part B. In case of occurrence of a persistent skin lesion after IMQ
application, patients will be followed up until the lesion is resolved
completely.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
Eligible healthy volunteers must meet all the following inclusion criteria at
screening:
1. Signed informed consent prior to any study-mandated procedure.
2. Male or female subjects, 18 years of age or older at the time of signing
informed consent; in general, stable good health as per judgement of the
investigator based upon the results of a medical history, physical examination,
vital signs, ECG, and laboratory assessments performed at screening. Repeated
laboratory testing may be performed at the discretion of the clinical
investigator.
3. Body mass index (BMI) > 18.0 and < 32.0 kg/m2.
4. Fitzpatrick skin type I-III (Caucasian).
5. Subjects and their partners of childbearing potential must use effective
contraception for the
duration of the study.
6. No clinically significant skin disease as judged by the investigator.
7. No history of hypertrophic scarring or keloid.
8. Subject is willing to refrain from application of any topical product (e.g.,
ointments, cream or washing lotions) on the target lesion(s) 24 hours prior to
every study visit day.
9. Subject has the ability to communicate well with the investigator in the
Dutch language and is willing to comply with the study requirements.
Eligible CLE patients must meet all the following inclusion criteria at
screening:
1. Signed informed consent prior to any study-mandated procedure.
2. Male or female CLE patients, 18 years of age or older at the time of signing
informed consent; in general, stable good health as per judgement of the
investigator based upon the results of a medical history, physical examination,
vital signs, ECG, and laboratory assessments performed at screening. Repeated
laboratory testing may be performed at the discretion of the clinical
investigators.
3. Body mass index (BMI) > 18.0 and < 35.0 kg/m2.
4. Only applicable for CDLE patients who will also participate in part B:
Fitzpatrick skin type I-III (Caucasian).
5. Subjects and their partners of childbearing potential must use effective
contraception for the
duration of the study.
6. Patient has the ability to communicate well with the investigator in the
Dutch language and is willing to comply with the study requirements.
7. Subject is willing to refrain from application of any topical product (e.g.,
ointments, cream or washing lotions) on the target lesion(s) 24 hours prior to
every study visit day.
8. Participants must have a diagnosis of SCLE, CDLE or LET that fulfils the
following:
• Confirmed CLE diagnosis by clinicopathological correlation.
• At least one CLE skin lesion of at least 3x3 cm suitable as assessed by the
investigator for measurements performed in the study.
• Location of the lesion(s) selected for biopsy outside the face (possible are
e.g., neck, chest, back, limbs, scalp, ear etc.).
• Receiving one of the following systemic treatments for CLE and SLE (if
applicable) (stable for a minimum of 8 weeks) with or without use of local
therapy:
o None
o Hydroxychloroquine
o Prednisolone
o Methotrexate
o Mycophenate mofetil
o A combination of the abovementioned treatments
• An overall CLE Disease Area and Severity Index Activity (CLASI-A) Score >=3
without counting any diffuse alopecia or oral ulcers.
Exclusion criteria
Eligible healthy volunteers must meet none of the following exclusion criteria
at screening:
1. (History of) immunological abnormality (e.g., immune suppression) that may
interfere with study objectives, in the opinion of the investigator.
2. Have any current and/or recurrent clinically significant skin condition,
including tattoos.
3. Antibiotic use, operation, or clinically significatn intervention by
surgeon/dentist within one month before Day 1.
4. Positive hepatitis B surface antigen (HbsAg), hepatitis C antibody (HCV ab),
or human immunodeficiency virus antibody (HIB ab) at screening.
5. Participation in an investigational drug study within 3 months prior to
screening or more than 4 times a year.
6. Loss or donation of blood over 500mL within three months prior to screening.
7. Subject is willing to refrain from the use of any medication within 28 days
prior to Day 1, if the investigator judges it may interfere with the study
objectives.
8. History of alcohol abuse or consumption exceeding 5 standard drinks per day
on average within 3 months of screening.
9. Positive urine test for drugs or history of abuse at screening. Urine drug
test may be repeated at the discretion of the investigator.
10. Pregnant, a positive pregnancy test, intending to become pregnant during
the study conduct, or breastfeeding.
11. (A history of) any clinically significant medical condition, factor or
abnormality that might interfere with study conduct or interpretation, as
judged by the investigator.
12. Previous use of Aldara (imiquimod cream) 3 months prior to the Day 1 visit
in part B.
13. Any active or chronic and/or uncontrolled condition that, in the opinion of
the investigator, may influence study conduct or interpretation.
14. Increased risk of delirium based on the delirium screening (meaning that at
least one of the delirium risk questions was answered with *yes* at the
screening visit, only applicable for participants > 70 years old).
Eligible CLE patients must meet none of the abovementioned and following
exclusion criteria at screening:
1. Presence of a relevant skin infection or disease in the target areas other
than the observational disease (CLE), inclusively, but not limited to atopic
dermatitis, psoriasis vulgaris and dermatomycosis.
2. Having received treatments for CLE or any other disease within the following
intervals prior to Day 1:
a. <2 weeks for topical treatment, e.g., corticosteroids at target area(s)
b. <6 weeks for systemic therapy with immunosuppressive agents (other than the
permitted systemic treatments with stable use for a minimum of 8 weeks)
c. <12 weeks for biologics
d. <8 weeks procedure or surgery in or close to the target areas
e. <3 months for chemotherapeutical treatment
3. Presence of severe lupus-associated renal disease.
4. Presence of antiphospholipid syndrome.
5. Active or unstable lupus-associated neuropsychiatric disease.
6. Severe organ SLE manifestation(s) (e.g., active myocarditis) or unstable
disease as judged by the investigator.
7. Diagnosis of systemic lupus erythematosus (SLE) according to the EULAR-ACR
criteria (2019) or substantial indication for systemic involvement (part B
only).
8. Low complement (C3 and/or C4) levels at screening (< ULN) (Part B only).
9. Positive ANA and anti-dsDNA and/or anti-SM at screening (Part B only).
Design
Recruitment
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 |
|---|---|
| CCMO | NL84645.056.23 |