Safety, Efficacy, PK, and PD Characteristics of Orally Inhaled SB010 in Male Patients With Mild Asthma (Multiple Dose)

NCT01743768 | Completed Phase 2 DMC

• 2 other identifiers: SB010/04/20122012-003570-77
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 7

Brief Summary

Asthma is a chronic inflammatory bronchial disorder with three distinct components: airway hyper-responsiveness (respiratory hypersensitivity), airway inflammation, and intermittent airway obstruction. One of the characteristics of the disease is an inflammatory reaction of the immune system caused by cytokine production. A substantial number of asthma patients do not satisfactorily respond to steroid therapy and consequently have an unmet medical need for novel targeted therapies with improved specificity, tolerability, 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 asthma. The transcription factor GATA-3 plays a key role in mediating the asthmatic immune response and has been shown to be necessary and sufficient for the production of cytokines interleukin (IL)-4, IL-5, and IL-13. The active drug substance of the investigational medicinal product SB010 is hgd40. SB010 belongs to a new class of antisense oligonucleotide therapeutics, the 10-23 DNA (deoxyribonucleic acid)zymes (antisense oligonucleotide). DNAzymes are catalytically active nucleic acids that cleave complementary RNA (ribonucleic acid) molecules. By cleaving GATA-3 mRNA, hgd40 reduces specific cytokine production and thereby reduces key features of allergic airway inflammation. DNAzymes are generated completely 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 solution directly in their synthesized form. This proof-of-concept study will evaluate the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple doses of inhaled SB010 in male patients with mild asthma.

Conditions

Asthma

Keywords

Antisense oligonucleotide; Asthma; Healthy subjects; Phase 1; Transcription factor GATA-3; Oral inhalation

Outcome Measures

Primary Outcomes (1)

• Change in late phase response after allergen challenge (AC), following multiple doses of inhaled SB010

  After 28 days of treatment with SB010 or placebo, patients will undergo allergen bronchoprovocation \[allergen challenge (AC)\]. The results from AC on Day 28 will be compared to results obtained on Enrolment (Day -1). Allergen for AC will be selected based on skin prick test performed at Screening. The dose of selected allergen will be determined based on skin prick dilution test. After the AC, serial spirometry will be used to assess the influence of inhaled SB010 on the area under the Forced Expiratory Volume in 1 second (FEV1) curve during the late asthma response (LAR, 4 - 7 hours); measurement time points will be at 4, 5, 6, and 7 hours after AC. The spirometric parameters FEV1 and forced vital capacity (FVC), obtained during pulmonary function testing, will be used to derive the primary efficacy variable AUC4-7 FEV1.

  Day -1 and Day 28 (monitoring for 7 h after AC).

Secondary Outcomes (5)

• Number of patients with adverse events after multiple doses of inhaled SB010

  Screening examination (Day -56 to -14 before first drug administration); Study period (Day 1 to 28); Follow-up visit (Day 88±4); Maximum of 149 days for a particular subject.

• Number of patients with changes in vital signs after multiple doses of inhaled SB010

  Screening examination (Day -56 to -14 before first drug administration); Study period (Day 1 to 28); Follow-up visit (Day 88±4); Maximum of 149 days for a particular subject.

• Number of patients with changes in electrocardiogram (ECG) after multiple doses of inhaled SB010

  Screening examination (Day -56 to -14 before first drug administration); Study period (Day 1 to 28); Follow-up visit (Day 88±4); Maximum of 149 days for a particular subject.

• Number of patients with changes in safety laboratory tests after multiple doses of inhaled SB010

  Screening examination (Day -56 to -14 before first drug administration); Study period (Day 1 to 28); Follow-up visit (Day 88±4); Maximum of 149 days for a particular subject.

• Number of patients with changes in spirometry laboratory tests (FEV1, FVC) after multiple doses of inhaled SB010

  Screening examination (Day -56 to -14 before first drug administration); Study period (Day 1 to 28); Follow-up visit (Day 88±4); Maximum of 149 days for a particular subject.

Other Outcomes (12)

• Area under the FEV1 curve during early phase response (0 - 3 hours) after allergen challenge (AC)

  Screening (Day -54 to -15); Enrolment (Day -1); Study period (Day 28).

• Allergen-induced airway responsiveness (PC20 methacholine)

  Screening (Day -56 to -17); Baseline (Day 0); Endpoint assessment (Day 29).

• Fractionated exhaled nitric oxide (FeNO)

  Enrolment (Day -1); Baseline (Day 0); Study period (Day 1, 13±1, 28); Endpoint assessment (Day 29); Follow-up assessment (Day 88±4).

Study Arms (2)

SB010

EXPERIMENTAL

The drug will be administered in phosphate-buffered saline solution, inhaled over 5 - 10 min, using inhalation device. Administered dose: 10 mg hgd40 in 2 mL solution (5.0 mg/mL). Initial dose on Day 1 (single-dose PK profile); once daily dose for 28 consecutive days (Days 1 to 28); last inhalation on Day 28 (steady state PK profile).

Drug: SB010

Placebo

PLACEBO COMPARATOR

The placebo (phosphate-buffered saline) is administered as a solution, inhaled over 5 - 10 min, using inhalation device. Initial dose on Day 1 (single-dose PK profile); once daily dose for 28 consecutive days (Days 1 to 28); last inhalation on Day 28 (steady state PK profile).

Drug: Placebo

Interventions

SB010 DRUG

Treatment group (n=19), receiving the active drug substance.

Also known as: Active drug substance is hgd40

SB010

Placebo DRUG

Treatment group (n=19), receiving placebo.

Also known as: Phosphate-buffered saline

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Adult male Caucasian patients aged ≥ 18 and ≤ 60 years.
• Clinical diagnosis of mild asthma (according to GINA guidelines 2008 update) for at least 6 months prior to screening. No concomitant asthma treatment. except inhaled short-acting bronchodilators.
• Screening FEV1 value of FEV1 ≥ 70 % of the predicted normal value (ECSC) after a wash out of at least 6 hours for inhaled short-acting bronchodilators,
• Patient must demonstrate sufficient induced sputum production.
• Positive skin prick test (skin reactivity) to common aeroallergens (e.g. animal epithelia, dust mite).
• Patient must demonstrate positive allergen-induced early- and late-phase airway bronchoconstriction.
• At all timepoints before AC and MCh, patients must show FEV1 not below 65 % predicted.
• Presence of sputum eosinophils either before or after screening allergen challenge (first or second induced sputum).
• Patient has been informed both verbally and in writing about the objectives of the clinical trial, the methods, the anticipated benefits and potential risks and the discomfort to which he may be exposed, and has given written consent to participation in the trial prior to trial start and any trial-related procedure.
• Patient is able to understand and give written informed consent and has signed a written informed consent form approved by the Investigator's Research Ethics Board.
• Non-smokers or ex-smokers who had stopped smoking for at least 1 year prior to start of the clinical study with \< 10 pack years.
• Ability to inhale in an appropriate manner (patients will be trained to inhale from the AKITA2 APIXNEB® device with a placebo medication at the screening visit).
• Only men who do not want to father children for six months after the last dose of SB010 will be included into this study.

You may not qualify if:

• Presence of clinically significant diseases other than asthma (cardiovascular, renal, hepatic, gastrointestinal, haematological, neurological, genitourinary, autoimmune, endocrine, metabolic, etc.), which, in the opinion of the investigator, may either put the patient at risk because of participation in the trial, or diseases which may influence the results of the study or the patient's ability to take part in it.
• Presence of relevant pulmonary diseases or history of thoracic surgery, such as:
• known active tuberculosis,
• History of interstitial lung or pulmonary thromboembolic disease,
• Pulmonary resection during the past 12 months,
• History of status asthmaticus,
• History of bronchiectasis secondary to respiratory diseases (e.g. cystic fibrosis, Kartagener's syndrome, etc.),
• History of chronic bronchitis, emphysema, allergic bronchopulmonary aspergillosis or respiratory infection within the 4 preceding weeks of the first morning IMP administration.
• Patients on concomitant treatments, except for inhaled short-acting bronchodilators as judged by the investigator.
• Use of short-acting ß2-agonists 6 hours before study visits 2, 3, 4, 5, 11, and 12.
• Hospitalisation or emergency room treatment for acute asthma in the 6 months prior to screening, between screening and the start of the treatment period.
• Intubation (ever) or hospitalisation for longer than 24 hours for the management of an asthma exacerbation within the preceding 6 months of the screening visit.
• History or current evidence of clinically relevant allergies or idiosyncrasy to drugs.
• History of allergic reactions to any active or inactive ingredients of the nebuliser solution.
• ECG abnormalities of clinical relevance.

Sponsors & Collaborators

• Sterna Biologicals GmbH & Co. KG: lead

Study Sites (7)

Charité Research Organisation GmbH

Berlin, D-10117, Germany

Location

Clinical Research Centre RespiratoryMedicine (IKF)

Frankfurt, D-60596, Germany

Location

Inamed GmbH

Gauting, D-82131, Germany

Location

Pulmonary Research Institute (PRI)

Großhansdorf, D-22927, Germany

Location

Clinical Airway Research Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM)

Hanover, D-30625, Germany

Location

Johannes Gutenberg University Medical Clinic III for Hematology, Oncology and Pneumology

Mainz, D-55131, Germany

Location

insaf - Respiratory Research Institute GmbH

Wiesbaden, D-65187, Germany

Location

Related Publications (1)

• Krug N, Hohlfeld JM, Kirsten AM, Kornmann O, Beeh KM, Kappeler D, Korn S, Ignatenko S, Timmer W, Rogon C, Zeitvogel J, Zhang N, Bille J, Homburg U, Turowska A, Bachert C, Werfel T, Buhl R, Renz J, Garn H, Renz H. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med. 2015 May 21;372(21):1987-95. doi: 10.1056/NEJMoa1411776. Epub 2015 May 17.

  PMID: 25981191 DERIVED

MeSH Terms

Conditions

Asthma

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Officials

• Norbert Krug, Prof MD

  Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: November 28, 2012
• First Posted: December 6, 2012
• Study Start: December 1, 2012
• Primary Completion: November 1, 2013
• Study Completion: December 1, 2013
• Last Updated: May 20, 2015

Record last verified: 2014-03

Locations

DE (7)