Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of the Topical Formulation SB011 Applied to Lesional Skin in Patients With Atopic Eczema

NCT ID: NCT02079688

Last Updated: 2017-01-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-02-28
• Study Completion Date: 2017-01-31

Brief Summary

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.

Conditions

Mild to Moderate Atopic Dermatitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

SB011, 2 % (Water/Oil/Water) emulsion of hgd40

All patients will perform treatment with formulation SB011 containing 2 % hgd40 and the active ingredient-free vehicle. The comparison of the IMPs will be performed intraindividually.

Comparison and random assignment of treatments to two distinct treatment areas (area 1, area 2).

IMP SB011: Topical application of approximately 5 mg/cm2 (250 μl) per treatment area (50 cm2) twice daily on 14 consecutive days, one single last application at the site on Day 15 (29 treatments) daily dosage: Approximately 10 mg hgd40 total dosage: Approximately 145 mg hgd40

Group Type: EXPERIMENTAL

SB011, 2 % (Water/Oil/Water) emulsion of hgd40

Intervention Type: DRUG

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

Multiple W/O/W formulation, active ingredient-free vehicle

All patients will perform treatment with formulation SB011 containing 2 % hgd40 and the active ingredient-free vehicle. The comparison of the IMPs will be performed intraindividually.

Comparison and random assignment of treatments to two distinct treatment areas (Area 1, Area 2).

Vehicle: Topical application of approximately 5 mg/cm2 (250 μl) per treatment area (50 cm2) twice daily on 14 consecutive days, one single last application at the site on Day 15 (29 treatments)

Group Type: PLACEBO_COMPARATOR

Multiple W/O/W formulation, active ingredient-free vehicle

Intervention Type: DRUG

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

Interventions

SB011, 2 % (Water/Oil/Water) emulsion of hgd40

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

Intervention Type: DRUG

Multiple W/O/W formulation, active ingredient-free vehicle

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

Intervention Type: DRUG

Other Intervention Names

Active drug substance is hgd40

Eligibility Criteria

Inclusion Criteria

• Patient oral and written informed consent
• Adult Caucasian patients (male and female) aged 18-69 years (both included);
• Patients smoking ≤ 10 cigarettes/day
• Patient has confirmed diagnosis of atopic dermatitis using the diagnostic features as described by Hanifin and Rajka, initial diagnosis made at least 12 weeks before first treatment;
• SCORAD (12) between 20 and 50 (mild to moderate atopic dermatitis);
• Two comparable lesional areas of approximately 50 cm2 each (difference in modified local SCORAD not greater than 2) on the arms, legs, chest, stomach or neck (distance between the lesions at least 5 cm), clinical condition of atopic eczema mild to moderate defined by a modified local SCORAD between 7 and 10 with 2 parameters scored at least 2 one being the erythema score;
• Patient has to have an increased total IgE;
• Patient has to have an increased specific IgE of at least 1 of the sx1 allergens with CAP classification II [>0.7 KU/l];
• Erythema score from modified local SCORAD for both lesional areas of at least 2;
• TEWL in the lesional areas at least 12 g/m²h, TEWL value differences ≤ 30 % are allowed between both lesional areas (related to the higher TEWL value);
• Except for atopic diseases or asthma like atopic dermatitis or allergic rhinitis assessed as healthy based on a screening examination including medical history, physical examination of the skin, vital signs, and clinical laboratory results;
• The male patient must agree:
• to use two methods of contraception in combination with his female partner, if she is of childbearing potential (At least one of the contraception methods must be a barrier contraception method)
• The female patient must agree:
• to use two methods of contraception in combination with her male partner, if she is of childbearing potential;

Exclusion Criteria

• History of allergic reactions to any active or inactive component of the IMP;
• Presence of clinically significant diseases other than asthma or atopic diseases (cardiovascular, renal, hepatic, gastrointestinal, haematological, neurological, genitourinary, autoimmune, endocrine, metabolic, etc.) which in the opinion of the investigator, influence the results of the trial or the patient's ability to take part in it;
• Inherent or acquired immune deficiency, immune deficiency in consequence of drug use;
• Immune mediated diseases;
• Suntan, hyperpigmentation or tattoos in the test fields;
• Dark-skinned persons whose skin colour prevents ready assessment of skin reactions;
• Systemic bacterial or mycotic as well as severe viral systemic infections;
• Severe systemic other disease;
• Patients with a resting heart rate <50 and >100 bpm, systolic blood pressure <100 and >150 mmHg, diastolic blood pressure <60 and >95 mmHg;
• UV-therapy within 6 weeks before first treatment and during the trial;
• History or current evidence of a malignant tumour (an excised basal cell carcinoma distant from target lesion with at least 14 days after surgery will be allowed);
• Clinically relevant abnormalities in serology, clinical chemical, haematological or in any other laboratory variables;
• Chronic or acute infections (a small lesion of non-treated onychomycosis will be allowed in the opinion of the investigator);
• Pregnancy or nursing
• Signs of secondary infections on the lesions to be treated;
• History of previous administration of SB011 or any other registered or investigational oligonucleotide-based drug;
• History or presence of alcohol or drug abuse;
• Consumption of alcohol within 48 h before administration of IMPs and during the trial;
• Use of any medication (including over-the-counter medication such as herbal products) except allowed concomitant medication within 2 weeks (for biologics: 6 months, for systemic treatment of atopic dermatitis 4 weeks) before administration of the IMPs or within <10 times the elimination half-life of the respective drug, or the duration of the pharmacodynamics effect, whatever is longer, or anticipated concomitant medication during the treatment period (exception: asthma may be found in patients with AD, therefore the continuation of inhalative treatment with corticosteroids in patients with asthma accompanying AD that began at least four weeks prior to randomisation will be allowed; dose limited: ≤ 300 μg/d fluticasone propionate or equivalent);
• Treatment with known cytochrome P450 enzyme inducing or inhibiting agents (St. John's Wort ("Johanniskraut"), barbiturates, phenothiazines, cimetidine, ketoconazole) within 30 days before administration of the IMPs or during the trial;
• Consumption of grapefruit, grapefruit juice within 14 days prior to the IMP administration or during the trial;
• Need for additional skin care products in the treatment area(s);
• Use of skin care products with anti-septic components during the last four weeks before first treatment and during the trial or anti-septic textiles with contact to the target lesions;
• Proneness to orthostatic dysregulation, faintings, or blackouts;
• Planned donation of germ cells, blood, organs, bone marrow during the course of the trial or within 6 months thereafter;
• Participation in another clinical trial with an investigational drug or device within the last 3 months. For biologics, the minimum exclusion period is at least 6 months or the time of duration of the pharmacodynamics effect or 10 times the half-life of the respective drug whatever is longer before inclusion in this trial;
• Lack of ability or willingness to give informed consent;
• Anticipated non-availability for trial visits/procedures;
• Anticipated lack of willingness or inability to cooperate adequately;
• Close affiliation with the investigators (e.g. a close relative) or with persons working at bioskin GmbH or with persons working at the study site or with employees of sterna biologicals GmbH & Co. KG;
• Vulnerable patients (e.g., persons kept in detention)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 69 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sterna Biologicals GmbH & Co. KG

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Thomas Werfel, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Division for Immunodermatology and Allergy Research Clinic for Dermatology, Allergy and Venereology Hannover Medical School

Locations

Division for Immunodermatology and Allergy Research Clinic for Dermatology, Allergy and Venereology Hannover Medical School

Hanover, , Germany

Countries

Germany

Other Identifiers

SB011/02/2013

Identifier Type: -

Identifier Source: org_study_id