Atopic dermatitis (AD) is a chronic or chronic recurring inflammatory skin disorder. Patients suffer from eczema and often severe pruritus on the affected skin, as well as from frequent complications and secondary infections. Next to a genetically predetermined defect in epidermal barrier function and vegetative dysfunction, AD arises from an upregulation of Th2-modified immune responses inducing increased IgE-antibody production, cytokine secretion and subsequently, local inflammation. Although standard therapies of AD, modern topical corticosteroids, show a better ratio of therapeutic effects to side effects, they retain a moderate acceptance due to their non-specific action, strict compliance requirements and possible adverse effects. As a newer alternative, calcineurin inhibitors show fewer side effects but raise concerns regarding long term risks including the possibility of skin carcinogenicity. Therefore, medical need remains for novel therapies for this major public health problem, directed in particular at specific early disease-causing mechanisms and/or molecular targets, with an improved efficacy, safety and compliance. Novel therapeutic strategies for the treatment of chronic inflammatory diseases by targeting early disease-causing mechanisms are a promising approach for the treatment of AD. The transcription factor GATA-3 represents the key regulatory factor of Th2-driven immune responses. It is indispensable for the differentiation and activation of Th2 cells; it integrates Th2 signals and induces Th2 cytokine expression. The investigational product SB011 contains the DNAzyme hgd40 that targets GATA-3. By cleaving GATA-3 mRNA hgd40 reduces specific cytokine production and thereby reduces key features of allergic airway inflammation. DNAzymes are completely generated by chemical synthesis and can be produced under Good Manufacturing Practice (GMP) controlled conditions. The DNAzymes are not biological drugs, i.e. they are not generated by use of any living organism including cell culture or bacteria. The molecules are highly water-soluble and will be applied as a water/oil/water (W/O/W) formulation since multiple emulsions have been shown to protect the active ingredient from degradation on the skin and have penetration enhancing properties in comparison to other carrier systems. This proof-of-concept study will evaluate the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the topical formulation SB011 containing 2 % hgd40 twice daily (BID) in patients with mild to moderate atopic eczema.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
25
Treatment will be performed BID on 14 consecutive days and one single last application at the site on Day 15 (29 applications in total). Two preferably disseminated and contralateral, comparable lesional treatment areas of approximately 50 cm2 each and located on arms, legs, chest, stomach or neck will be chosen. All patients will perform treatment with both formulation SB011 containing 2% hgd40 and the active ingredient-free vehicle. Comparison of the IMPs will be performed intraindividually. Approximately 5 mg/cm2 (250 μl) of SB011 (2% hgd40) and the vehicle will be applied to the respective treatment areas. The time between the two applications should include min. 8 hours and max. 16 hours. Patients compliance will be controlled by weighing of the IMPs at each visit. On day 1 the application of the IMPs will be demonstrated to the patients at the clinical site. The first treatment as well as the morning treatment on Days 3, 5, 8, 12, and 15 will be carried out at the clinical site
Treatment will be performed BID on 14 consecutive days and one single last application at the site on Day 15 (29 applications in total). Two preferably disseminated and contralateral, comparable lesional treatment areas of approximately 50 cm2 each and located on arms, legs, chest, stomach or neck will be chosen. All patients will perform treatment with both formulation SB011 containing 2% hgd40 and the active ingredient-free vehicle. Comparison of the IMPs will be performed intraindividually. Approximately 5 mg/cm2 (250 μl) of SB011 (2% hgd40) and the vehicle will be applied to the respective treatment areas. The time between the two applications should include min. 8 hours and max. 16 hours. Patients compliance will be controlled by weighing of the IMPs at each visit. On day 1 the application of the IMPs will be demonstrated to the patients at the clinical site. The first treatment as well as the morning treatment on Days 3, 5, 8, 12, and 15 will be carried out at the clinical site
Division for Immunodermatology and Allergy Research Clinic for Dermatology, Allergy and Venereology Hannover Medical School
Hanover, Germany
Change of local SCORing atopic dermatitis (SCORAD) from baseline to Day 15.
The following parameters are included in scoring: A: the extent of the involved body area; B: the intensity of the criteria erythema, edema/papulation, oozing/crusts, excoriations,lichenification and dryness, whereby dryness is evaluated on uninvolved areas; C: the subjective symptoms of pruritus at application areas and sleep loss evaluated on a visual analogue scale from 0 to 10 (average for the last three days or nights) and added. The intensity of each of the criteria erythema, edema/papulation, oozing/crusts, excoriations, lichenification and dryness will be graded according to the following 4 point scale: 0 = absent 1. = mild 2. = moderate 3. = severe Each single parameter for SCORAD calculation will be documented on a source document. The SCORAD will be calculated according to the formula A/5 + 7B/2 + C and documented in the source documents and the CRF.
Time frame: On baseline (day 1) and on day 15 (Last day after 2 Weeks IMP administration)
The change from baseline in modified local SCORAD
Time frame: On Days 3, 5, 8, and 12
Modified local SCORAD
The intensity of each of the criteria will be graded according to the following 4 point scale and documented in the CRF: 0 = absent 1. = mild 2. = moderate 3. = severe
Time frame: on Days 1, 3, 5, 8, 12, and 15
Change from baseline in transepidermal water loss (TEWL)
Time frame: On Days 3, 5, 8, 12, and 15
TEWL on Days 1, 3, 5, 8, 12, and 15
Time frame: Days 1, 3, 5, 8, 12, and 15
Subjective assessment of pruritus using a 10-point rating scale
Subjective assessment of pruritus at test sites on Days 1, 3, 5, 8, 12, and 15 using a 10-point rating scale.
Time frame: Days 1, 3, 5, 8, 12, and 15
Subjective efficacy assessment on Days 3, 5, 8, 12 and 15
The efficacy of the IMPs will be assessed in each test area by asking the patients using the following 5-point rating scale: The answer of the patients will be documented in the CRF. 0 = no activity 1. = poor 2. = fair 3. = good 4. = excellent
Time frame: Days 3, 5, 8, 12 and 15
Subjective dermal tolerability assessment using a 5-point rating scale on Days 3, 5, 8, 12 and 15
The dermal tolerability of the IMPs will be assessed in each test area by asking the patients using the following 5-point rating scale: The answer of the patients will be documented in the CRF. 0 = no activity 1. = poor 2. = fair 3. = good 4. = excellent
Time frame: Days 3, 5, 8, 12 and 15
Pharmacokinetic outcome measure
The pharmacokinetic endpoints are the hgd40 levels on Days 1 (pre-dose and 1, 2, 4 and 6 h post-dose) and 15 (pre-dose and 1, 2, 4 and 6 h post-dose and 24 h post-dose to Day 15).
Time frame: Day 1 and Day 15
Physical examination of the skin and Vital signs
Time frame: Screening period and day 16
Adverse Events
Time frame: Including the whole screening period and the experimental phase day -14 to day 16
Standard Safety laboratory
Including serology, IgE \[immunoglobulin E\] and sx1 test at screening
Time frame: Screening period + on days 1, 5 and 16 in the Treatment period
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