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

NCT02079688 | Completed Phase 2 DMC

• 1 other identifier: SB011/02/2013
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

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

Keywords

Antisense oligonucleotide; atopic eczema; atopic dermatitis; Phase II; Transcription factor GATA-3; dermal application; Proof-of-Concept

Outcome Measures

Primary Outcomes (1)

• 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.

  On baseline (day 1) and on day 15 (Last day after 2 Weeks IMP administration)

Secondary Outcomes (11)

• The change from baseline in modified local SCORAD

  On Days 3, 5, 8, and 12

• Modified local SCORAD

  on Days 1, 3, 5, 8, 12, and 15

• Change from baseline in transepidermal water loss (TEWL)

  On Days 3, 5, 8, 12, and 15

• TEWL on Days 1, 3, 5, 8, 12, and 15

  Days 1, 3, 5, 8, 12, and 15

• Subjective assessment of pruritus using a 10-point rating scale

  Days 1, 3, 5, 8, 12, and 15

Study Arms (2)

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

EXPERIMENTAL

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

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

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

PLACEBO COMPARATOR

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)

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

Interventions

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

Also known as: Active drug substance is hgd40

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

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

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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;

Sponsors & Collaborators

• Sterna Biologicals GmbH & Co. KG: lead

Study Sites (1)

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

Hanover, 30625, Germany

Location

MeSH Terms

Conditions

Dermatitis, Atopic

Condition Hierarchy (Ancestors)

Skin Diseases, Genetic; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Dermatitis; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Eczematous; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Officials

• Thomas Werfel, Prof. Dr.

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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 4, 2014
• First Posted: March 6, 2014
• Study Start: February 1, 2014
• Primary Completion: November 1, 2016
• Study Completion: January 1, 2017
• Last Updated: January 13, 2017

Record last verified: 2017-01

Locations

DE (1)