Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of BI 653048 BS H3PO4 Capsule Assessing Endotoxin-induced Inflammatory Response in Healthy Male Subjects

NCT02224105 | Completed Phase 1

• 1 other identifier: 1262.9
• Study Type: interventional
• Target: 56
• Locations: 0 countries
• Sites: N/A

Brief Summary

The general aim of the current study was to investigate the safety and tolerability, and pharmacodynamics (endotoxin-induced inflammatory response of a single intravenous bolus administration of 2 ng/kg body weight Escherichia coli lipopolysaccharide (LPS)) of BI 653048 BS H3PO4 capsules in healthy male subjects following oral administration of multiple rising doses of 25 mg to 200 mg over three days compared to the active comparator prednisolone and placebo. Pharmacodynamics were assessed by investigating the influence of LPS administration on inflammatory parameters. More specifically, it was evaluated whether and to what extent the symptoms induced by LPS challenge can be attenuated by ascending BI 653048 BS H3PO4 doses using prednisolone as positive control and placebo as negative control. A secondary objective was the exploration of pharmacokinetics of BI 653048 BS, the investigation of other pharmacodynamic parameters (biomarker) and of the tolerability of LPS.

Conditions

Healthy

Outcome Measures

Primary Outcomes (7)

• Number of subjects with adverse events

  up to 37 days

• Number of subjects with clinically significant findings in vital signs

  blood pressure, pulse rate and body temperature

  up to day 15

• Number of subjects with clinically significant findings in 12-lead electrocardiogram (ECG)

  up to day 15

• Number of subjects with clinically significant findings in laboratory tests

  up to day 15

• Assessment of tolerability by investigator on a 4-point scale

  up to day 15

• Maximum measured concentration of the biomarker level in plasma (Emax)

  up to 96 hours after first drug administration

• Area under the concentration-time curve of the biomarker in plasma over the time interval from 0 to the last measurable time point of the dose (AUEC)

  up to 96 hours after first drug administration

Secondary Outcomes (13)

• Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss)

  up to 96 hours after first drug administration

• Time from dosing to maximum measured concentration of the analyte at steady state (tmax,ss)

  up to 96 hours after first drug administration

• Area under the concentration-time curve of the analyte in the plasma over the time interval from 0 to the last measurable time point of the dose at steady state (AUC0-tz,ss)

  up to 96 hours after first drug administration

• Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity at steady state (AUC0-∞,ss)

  up to 96 hours after first drug administration

• Percentage of the AUC0-∞ that is obtained by extrapolation at steady state (%AUCtz-∞,ss)

  up to 96 hours after first drug administration

Study Arms (4)

BI 653048 BS

EXPERIMENTAL

escalating doses

Drug: BI 653048 BS; Drug: sodium chloride infusion; Drug: endotoxin escherichia coli (E. coli) lipopolysaccharide (LPS)

Prednisolone low

ACTIVE COMPARATOR

Drug: Prednisolone low; Drug: sodium chloride infusion; Drug: endotoxin escherichia coli (E. coli) lipopolysaccharide (LPS)

Prednisolone high

ACTIVE COMPARATOR

Drug: Prednisolone high; Drug: sodium chloride infusion; Drug: endotoxin escherichia coli (E. coli) lipopolysaccharide (LPS)

Placebo

PLACEBO COMPARATOR

Drug: Placebo; Drug: sodium chloride infusion; Drug: endotoxin escherichia coli (E. coli) lipopolysaccharide (LPS)

Interventions

BI 653048 BS DRUG

BI 653048 BS

Prednisolone low DRUG

Prednisolone low

Prednisolone high DRUG

Prednisolone high

Placebo DRUG

Placebo

sodium chloride infusion DRUG

BI 653048 BS; Placebo; Prednisolone high; Prednisolone low

endotoxin escherichia coli (E. coli) lipopolysaccharide (LPS) DRUG

BI 653048 BS; Placebo; Prednisolone high; Prednisolone low

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy males according to the following criteria:
• Based upon a complete medical history, including the physical examination, vital signs (blood pressure, pulse rate and body temperature), 12-lead ECG, clinical laboratory tests
• Age ≥18 and Age ≤50 years
• Body mass index (BMI) ≥18.5 and BMI ≤29.9 kg/m2
• Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and the local legislation

You may not qualify if:

• Any finding of the medical examination (including blood pressure, pulse rate, orthostatic test, body temperature and ECG) deviating from normal and of clinical relevance
• Any evidence of a clinically relevant concomitant disease
• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
• Surgery of the gastrointestinal tract (except appendectomy)
• Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
• History of relevant orthostatic hypotension, fainting spells or blackouts
• Chronic or relevant acute infections
• History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
• Intake of drugs with a long half-life (\>24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial
• Use of drugs which might reasonably influence the results of the trial or that prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial
• Participation in another trial with an investigational drug within 30 days prior to administration or during the trial
• Smoker (\>10 cigarettes or \>3 cigars or \>3 pipes/day)
• Inability to refrain from smoking for 1 day prior to first drug administration until discharge from the study site
• Alcohol abuse (more than 60 g/day)
• Drug abuse

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Related Publications (1)

• Harcken C, Scholl P, Nabozny G, Thomson D, Bianchi D. Clinical profile of the functionally selective glucocorticoid receptor agonist BI 653048 in healthy male subjects. Expert Opin Investig Drugs. 2019 May;28(5):489-496. doi: 10.1080/13543784.2019.1599859. Epub 2019 Apr 9.

  PMID: 30908082 DERIVED

MeSH Terms

Interventions

BI 653048 BS H3PO4; endotoxin, Escherichia coli; Lipopolysaccharides

Intervention Hierarchy (Ancestors)

Glycoconjugates; Carbohydrates; Polysaccharides, Bacterial; Polysaccharides; Lipids; Antigens, Bacterial; Antigens; Biological Factors; Endotoxins; Bacterial Toxins; Toxins, Biological

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 21, 2014
• First Posted: August 25, 2014
• Study Start: March 1, 2010
• Primary Completion: May 1, 2010
• Last Updated: August 25, 2014

Record last verified: 2014-08