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Trial record 5 of 7 for:    DNAzyme

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

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ClinicalTrials.gov Identifier: NCT02079688
Recruitment Status : Completed
First Posted : March 6, 2014
Last Update Posted : January 13, 2017
Sponsor:
Information provided by (Responsible Party):
Sterna Biologicals GmbH & Co. KG

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.


Condition or disease Intervention/treatment Phase
Mild to Moderate Atopic Dermatitis Drug: SB011, 2 % (Water/Oil/Water) emulsion of hgd40 Drug: Multiple W/O/W formulation, active ingredient-free vehicle Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase IIa, Single-centre, Randomised, Vehicle Controlled, Double-blind Trial for Assessment of Efficacy, Safety and Tolerability of the Topical Formulation SB011 Containing a Human GATA-3 Specific DNAzyme and of Systemic Absorption of hgd40 Following Application to Lesional Skin in Patients With Atopic Eczema
Study Start Date : February 2014
Actual Primary Completion Date : November 2016
Actual Study Completion Date : January 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Eczema

Arm Intervention/treatment
Experimental: 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

Drug: 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

Other Name: Active drug substance is hgd40

Placebo Comparator: 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)

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





Primary Outcome Measures :
  1. Change of local SCORing atopic dermatitis (SCORAD) from baseline to Day 15. [ Time Frame: On baseline (day 1) and on day 15 (Last day after 2 Weeks IMP administration) ]

    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.


Secondary Outcome Measures :
  1. The change from baseline in modified local SCORAD [ Time Frame: On Days 3, 5, 8, and 12 ]
  2. Modified local SCORAD [ Time Frame: on Days 1, 3, 5, 8, 12, and 15 ]

    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

  3. Change from baseline in transepidermal water loss (TEWL) [ Time Frame: On Days 3, 5, 8, 12, and 15 ]
  4. TEWL on Days 1, 3, 5, 8, 12, and 15 [ Time Frame: Days 1, 3, 5, 8, 12, and 15 ]
  5. Subjective assessment of pruritus using a 10-point rating scale [ Time Frame: Days 1, 3, 5, 8, 12, and 15 ]
    Subjective assessment of pruritus at test sites on Days 1, 3, 5, 8, 12, and 15 using a 10-point rating scale.

  6. Subjective efficacy assessment on Days 3, 5, 8, 12 and 15 [ Time Frame: 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

  7. Subjective dermal tolerability assessment using a 5-point rating scale on Days 3, 5, 8, 12 and 15 [ Time Frame: 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

  8. Pharmacokinetic outcome measure [ Time Frame: Day 1 and Day 15 ]
    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).

  9. Physical examination of the skin and Vital signs [ Time Frame: Screening period and day 16 ]
  10. Adverse Events [ Time Frame: Including the whole screening period and the experimental phase day -14 to day 16 ]
  11. Standard Safety laboratory [ Time Frame: Screening period + on days 1, 5 and 16 in the Treatment period ]
    Including serology, IgE [immunoglobulin E] and sx1 test at screening



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Ages Eligible for Study:   18 Years to 69 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02079688


Locations
Germany
Division for Immunodermatology and Allergy Research Clinic for Dermatology, Allergy and Venereology Hannover Medical School
Hannover, Germany, 30625
Sponsors and Collaborators
Sterna Biologicals GmbH & Co. KG
Investigators
Principal Investigator: Thomas Werfel, Prof. Dr. Division for Immunodermatology and Allergy Research Clinic for Dermatology, Allergy and Venereology Hannover Medical School

Responsible Party: Sterna Biologicals GmbH & Co. KG
ClinicalTrials.gov Identifier: NCT02079688     History of Changes
Other Study ID Numbers: SB011/02/2013
First Posted: March 6, 2014    Key Record Dates
Last Update Posted: January 13, 2017
Last Verified: January 2017

Keywords provided by Sterna Biologicals GmbH & Co. KG:
Antisense oligonucleotide
atopic eczema
atopic dermatitis
Phase II
Transcription factor GATA-3
dermal application
Proof-of-Concept

Additional relevant MeSH terms:
Dermatitis
Dermatitis, Atopic
Eczema
Skin Diseases
Skin Diseases, Genetic
Genetic Diseases, Inborn
Skin Diseases, Eczematous
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases