Safety, Tolerability, and Pharmacokinetics of Orally Inhaled DNAzyme Solution for Nebulisation in Healthy Male Subjects

NCT01470911 | Completed Phase 1 DMC

• 2 other identifiers: SB010/01/20112011-002916-10
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

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 principle hgd40 of the investigational medicinal product 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 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 solution directly in their synthesized form. The current study will evaluate the safety and tolerability of increasing single doses of inhaled SB010 in healthy male subjects.

Conditions

Asthma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Limiting dose of inhaled ascending single dose of SB010.

  Safety will be monitored as adverse events, vital signs, clinical chemistry, haematology, urinalysis, electrocardiogram, pulmonary function testing, body temperature, overall tolerability.

  Study period 4 days, follow up visit 12±2 days, end of study day 60±4 days; maximum of 78 days for a particular subject.

Secondary Outcomes (4)

• Number of participants with any dose-limiting adverse effects.

  Study period 4 days, follow up visit 12±2 days, end of study day 60±4 days; maximum of 78 days for a particular subject.

• Maximum tolerated dose.

  Study period 4 days, follow up visit 12±2 days, end of study day 60±4 days; maximum of 78 days for a particular subject.

• Single-dose plasma concentration of hgd40 over time after inhalation of SB010.

  Day 1 to 4 of the study.

• Feasibility of the inhalative technique.

  Day 1.

Study Arms (2)

SB010

EXPERIMENTAL

The drug SB010 is administered in phosphate-buffered saline solution, inhaled via a controlled breathing system over a 5 to 10 min.

Drug: SB010

Placebo

PLACEBO COMPARATOR

The placebo (phosphate-buffered saline) is administered as a solution inhaled via a controlled breathing system over a 5 to 10 min.

Drug: Placebo

Interventions

SB010 DRUG

Six ascending dose groups (DG) are planned, with a total of 48 subjects. DG 1 and 2 will consist of n=6 subjects (n=3 receiving SB010, n=3 placebo). The following DG will consist of n=9 subjects (n=6 receiving SB010, n=3 placebo). The number of subjects to be exposed to active compound will be limited on a particular study day. Subjects of a particular DG will be divided into subgroups and exposed to the drug on different days. In DG 1 and 2, the time interval between the two administrations of the first subgroup will be at least 2 hours. In DG 3-6, the time interval between two subsequent administrations will be at least 1 hour. Dose level (DL) 1: 0.4 mg hgd40/2 mL; DL 2: 2 mg hgd40/2 mL; DL 3: 5 mg hgd40/2 mL; DL 4: 10 mg hgd40/2 mL; DL 5: 20 mg hgd40/2 mL; DL 6: 40 mg hgd40/2 mL.

SB010

Placebo DRUG

Six ascending dose groups (DG) are planned, with a total of 48 subjects. DG 1 and 2 will consist of n=6 subjects (n=3 receiving SB010, n=3 placebo). The following DG will consist of n=9 subjects (n=6 receiving SB010, n=3 placebo). The number of subjects to be exposed to active compound will be limited on a particular study day. Subjects of a particular DG will be divided into subgroups and exposed to the drug on different days. In DG 1 and 2, the time interval between the two administrations of the first subgroup will be at least 2 hours. In DG 3-6, the time interval between two subsequent administrations will be at least 1 hour.

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Written consent to participation in the trial prior to trial start and any trial-related procedure.
• Healthy male Caucasian subject - healthy based on a screening examination including medical history, without clinically relevant pathologies, physical examination, vital signs, ECG assessment, pulmonary function testing, and clinical laboratory results.
• Body weight according to a body mass index (BMI) between 18 and 29 kg/m2 (inclusive); body weight between 60 and 90 kg.
• Non-smokers or ex-smokers (stopped smoking for at least 5 years prior to start of the clinical study).
• Ability to inhale in an appropriate manner.

You may not qualify if:

• History or current evidence of clinically relevant allergies or idiosyncrasy to any drug or food.
• History of allergic reactions to any active or inactive component of the study medication.
• History or current evidence of any clinically relevant pulmonary, cardiovascular, hepatic, renal, gastrointestinal, haematological, endocrinological, metabolic, neurological, or psychiatric disease within the last 2 years.
• ECG abnormalities of clinical relevance (e.g., QTc according to Bazett's ³440 ms, PR ³210 ms; or QRS ³120 ms).
• Subjects with a resting heart rate \<50 bpm, systolic blood pressure \<100 mmHg, diastolic blood pressure \<60 mmHg.
• Proneness to orthostatic dysregulation, fainting, or blackouts.
• History or presence of any malignancy except for basalioma.
• Abnormalities in clinical chemical or haematologic variables considered medically relevant by the investigator.
• Chronic or acute infections.
• Positive results in any of the following virology tests: human immunodeficiency virus (HIV) antibodies and antigen, Anti-hepatitis B-core antibody, hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus antibody.
• Positive drug screen.
• History of previous administration of any registered or investigational oligonucleotide-based drug.
• History or presence of alcohol or drug abuse.
• Treatment with any known enzyme inducing or inhibiting agents (e.g., St. John's Wort (Johanniskraut), barbiturates, phenothiazines, cimetidine, ketoconazole, etc.) within 30 days before administration of IMP or during the trial.
• Use of any medication (including over-the-counter medication, herbal products) except allowed concomitant medication within 2 weeks (for biologics: 6 months) before administration of IMP or within \<10 times the elimination half-life of the respective drug, or the duration of the pharmacodynamic effect, whatever is longer.

Sponsors & Collaborators

• Sterna Biologicals GmbH & Co. KG: lead

Study Sites (1)

CRS Clinical Research Services Mannheim GmbH

Mannheim, 68167, Germany

Location

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

• Wolfgang Timmer, MD

  CRS-Mannheim GmbH, Germany

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• 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: October 31, 2011
• First Posted: November 11, 2011
• Study Start: November 1, 2011
• Primary Completion: December 1, 2011
• Study Completion: December 1, 2011
• Last Updated: November 22, 2012

Record last verified: 2012-11

Locations

DE (1)