Safety, Tolerability and Pharmacokinetics of BI 653048 H3PO4 Oral Drinking Solution in Healthy Male Volunteers

Safety, Tolerability and Pharmacokinetics of BI 653048 H3PO4 Oral Drinking Solution in Healthy Male Volunteers (Dose Range: 0.1 mg - 1500 mg). A Singleblind (Within Dose Groups), Randomised, Placebo-controlled Within Dose Groups, Single Rising Dose Phase I Study

• Investigation of safety and tolerability of BI 653048 H3PO4 following the administration of single rising doses of an aqueous solution in healthy male subjects
• Pharmacokinetic and pharmacodynamic characteristics of BI 653048, including the investigation of dose proportionality
• Investigation of relative bioavailability of capsules versus aqueous solution

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Placebo; Drug: BI 653048 H3PO4 solution; Drug: BI 653048 H3PO4 low dose capsule; Drug: BI 653048 H3PO4 high dose capsule

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy males according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), clinical laboratory tests
• Age ≥21 years and ≤50 years
• Body Mass Index (BMI) ≥18.5 kg/m2 and BMI ≤29.9 kg/m2
• Signed and dated written informed consent prior to admission to the trial in accordance with Good Clinical Practice (GCP) and the local legislation

Exclusion Criteria:

• Any finding of the medical examination (including BP, PR 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 h) 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 2 months prior to administration or during the trial
• Smoker (>10 cigarettes or >3 cigars or >3 pipes/day)
• Inability to refrain from smoking on trial days
• Alcohol abuse (more than 60 g/day)
• Drug abuse
• Blood donation (more than 100 mL within 4 weeks prior to administration or during the trial)
• Excessive physical activities (within 1 week prior to administration or during the trial)
• Any laboratory value outside the reference range that was of clinical relevance
• Inability to comply with dietary regimen of trial site
• A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms)
• A history of additional risk factors for Torsades des Pointes (e.g., heart failure, hypokalaemia, family history of Long QT Syndrome)
• Not willing to use adequate contraception (condom use plus another form of contraception e.g., spermicide, oral contraceptive taken by female partner, sterilisation, intrauterine device) during the whole trial period from the time of the first intake of trial drug until 3 months after the last intake

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo
Experimental: BI 653048 H3PO4 solution; single rising doses	Drug: BI 653048 H3PO4 solution
Experimental: BI 653048 H3PO4 low dose capsule	Drug: BI 653048 H3PO4 low dose capsule
Experimental: BI 653048 H3PO4 high dose capsule	Drug: BI 653048 H3PO4 high dose capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with clinically significant findings in vital signs	blood pressure (BP), pulse rate (PR) respiratory rate (RR), oral body temperature (T), orthostatic test	up to 10 days after drug administration
Number of patients with clinically significant findings in ECG		up to 10 days after drug administration
Number of patients with clinically significant findings in laboratory tests		up to 10 days after drug administration
Number of patients with adverse events		up to 10 days after drug administration
Assessment of tolerability performed by the investigator on a four-point scale		up to 10 days after drug administration

Secondary Outcome Measures

Outcome Measure	Time Frame
Cmax (maximum measured concentration of the analyte in plasma)	up to 72 hours after drug administration
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point)	up to 72 hours after drug administration
t1/2 (terminal half-life of the analyte in plasma)	up to 72 hours after drug administration
Vz/F (apparent volume of distribution during the terminal phase λz following an extravascular dose)	up to 72 hours after drug administration
tmax (time from dosing to maximum measured concentration)	up to 72 hours after drug administration
AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity)	up to 72 hours after drug administration
λz (terminal rate constant in plasma)	up to 72 hours after drug administration
CL/F (total/apparent clearance of the analyte in plasma after extravascular administration)	up to 72 hours after drug administration
%AUCtz-∞ (the percentage of the AUC0-∞ that is obtained by extrapolation)	up to 72 hours after drug administration
AUCt1-t2 (Area under the concentration-time curve of the analyte in plasma over the time interval t1 to t2)	up to 72 hours after drug administration
MRTp.o. (mean residence time of the analyte in the body after oral administration)	up to 72 hours after drug administration
Aet1-t2 (amount of analyte eliminated in urine from the time point t1 to time point t2)	up to 48 hours after drug administration
fet1-t2 (fraction of analyte eliminated in urine from time point t1 to time point t2)	up to 48 hours after drug administration
CLR,t1-t2 (renal clearance of the analyte from the time point t1 until the time point t2)	up to 48 hours after drug administration
Dose-normalised Cmax	up to 72 hours after drug administration
Dose-normalized AUC0-∞	up to 72 hours after drug administration
Emax (maximum measured concentration of the biomarker in blood or serum)	up to 72 hours after drug administration
Emin (minimum measured concentration of the biomarker in blood or serum)	up to 72 hours after drug administration
Tmin (time from dosing to minimum measured concentration of the biomarker)	up to 72 hours after drug administration
Tmax (time from dosing to maximum measured concentration of the biomarker)	up to 72 hours after drug administration
AUECt1-t2 (area under the concentration-time curve of the biomarker in the blood over the time interval from t1 to t2)	up to 72 hours after drug administration
AUECbelow_base (area under the baseline corrected concentration-time curve of the biomarker)	up to 72 hours after drug administration
AUECabove_base (area above the baseline corrected concentration-time curve of the biomarker)	up to 72 hours after drug administration
Expression of glucocorticoid responsive genes	up to 72 hours after drug administration

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): June 1, 2009

Study Registration Dates

• First Submitted: August 14, 2014
• First Submitted That Met QC Criteria: August 14, 2014
• First Posted (Estimate): August 15, 2014

Study Record Updates

• Last Update Posted (Estimate): August 15, 2014
• Last Update Submitted That Met QC Criteria: August 14, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Other Study ID Numbers: 1262.1