Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BI 653048 BS H3PO4 Capsule Multiple Rising Doses in Healthy Male Volunteers

Study Overview
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Brief Summary
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The objectives of the trial were to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of BI 653048 BS H3PO4 compared with prednisolone.

Official Title
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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics (Biomarkers) of BI 653048 BS H3PO4 Capsule Formulation Administered as Multiple Doses of 25 mg to 200 mg qd for 10 Days. A Randomised, Double-blind Within Dose Groups, Placebo-controlled, Multiple Rising Dose Trial With Open-label Active Comparator

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 653048 BS H3PO4
* Drug: Prednisolone low dose
* Drug: Prednisolone high dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subjects based on a complete medical history, physical examination, vital signs (blood pressure and pulse rate), 12-lead ECG, and clinical laboratory tests Age of 18 to 50 years Body mass index (BMI) of 18.5 to 29.9 kg/m2 Signed and dated written informed consent in accordance with Good Clinical Practice and the local legislation Exclusion Criteria: Any clinically relevant deviation from normal in the medical examination including blood pressure, pulse rate, and ECG 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), psychiatric disorders, or neurological disorders History of relevant orthostatic hypotension, fainting spells, or blackouts Chronic or relevant acute infections History of relevant allergy or hypersensitivity (including allergy to drug or its excipients) Intake of drugs with a long half-life (>24 h) within at least 1 month or less than 10 half-lives of the respective drug before first treatment with study drug or during trial Use of drugs which might reasonably influence the results of the trial or which prolong the QT/QTc interval within 10 days before first treatment with study drug or during trial Participation in another trial with an investigational drug within 30 days before first treatment with study drug or during trial Smoker (more than 10 cigarettes, 3 cigars, or 3 pipes per day) Inability to refrain from smoking beginning from 1 day before first treatment with study drug until discharge from the clinical unit Alcohol abuse (more than 60 grams per day) Drug abuse Blood donation of more than 100 mL within 4 weeks before first treatment with study drug or during trial Excessive physical activities within 1 week before first treatment with study drug or during trial Any laboratory value outside the reference range and of clinical relevance Inability to comply with dietary regimen of trial site A marked baseline prolongation of the QT/QTc interval (e.g. QTc intervals that are repeatedly longer than 450 ms) A history of additional risk factors for torsades de points (e.g. heart failure, hypokalaemia, or family history of Long QT syndrome

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 653048 BS H3PO4<br>dose escalation | Drug: BI 653048 BS H3PO4<br> <br> |
| Active Comparator: Prednisolone low dose<br> | Drug: Prednisolone low dose<br> <br> |
| Active Comparator: Prednisolone high dose<br> | Drug: Prednisolone high dose<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events |  | up to day 14 | 
| Number of patients with clinically significant findings in vital signs | blood pressure, pulse rate, body temperature, orthostatic test | up to 10 days after last drug administration | 
| Number of patients with clinically significant findings in ECG |  | up to 10 days after last drug administration | 
| Number of patients with clinically significant findings in laboratory tests |  | up to 10 days after last drug administration | 
| Assessment of tolerability by the investigator on a four-point scale |  | up to 10 days after last drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum measured concentration of the analyte in plasma at different time points (Cmax) |  | up to day 13 | 
| time from dosing to maximum measured concentration of the analyte at different time points (tmax) |  | up to day 13 | 
| Area under the concentration-time curve of the analyte in the plasma over time interval from 0 to the last measurable time point of the dose at different time points (AUC0-tz) |  | up to day 13 | 
| Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity at different time points (AUC0-∞) |  | up to day 13 | 
| Percentage of the AUC0-∞ that is obtained by extrapolation at different time points (%AUCtz-∞) |  | up to day 13 | 
| Terminal phase elimination rate constant at different time points (λz) |  | up to day 13 | 
| Mean residence time of the analyte in the body after oral administration at different time points (MRTpo) |  | up to day 13 | 
| Terminal phase elimination half life at different time points (t1/2) |  | up to day 13 | 
| Apparent clearance of the analyte in plasma following extravascular administration at steady state (CL/Fss) |  | up to day 13 | 
| Apparent volume of distribution during the terminal phase λz following an extravascular dose at steady state (Vz/Fss) |  | up to day 13 | 
| Minimum plasma concentration at steady state (Cmin,ss) |  | up to day 13 | 
| Dose-normalized Cmax at steady state (Cmax/Dss) |  | up to day 13 | 
| Dose-normalised AUC0-∞ at steady state (AUC0-∞/Dss) |  | up to day 13 | 
| Accumulation index of the analyte when comparing AUCτ (RA,AUCτ) |  | up to day 13 | 
| Accumulation index of the analyte when comparing Cmax (RA,Cmax) |  | up to day 13 | 
| Linearity index (LI) |  | up to day 13 | 
| Amount of analyte excreted in urine unchanged from t1 to t2 interval at different time points (Aet1-t2) |  | up to day 11 | 
| Renal clearance of the unchanged analyte at different time points (CLr) |  | up to day 11 | 
| Area under the serum biomarker concentration-time curve after the Nth dose (AUECN) |  | up to day 13 | 
| Area under the baseline (before dose level) but above serum biomarker concentration-time curve after the Nth dose (AUECbelow_base) |  | up to day 13 | 
| Minimum measured serum concentration of the biomarkers after the Nth dose (Emin,N) |  | up to day 13 | 
| Maximum measured serum concentration of the biomarkers after the Nth dose (Emax,N) |  | up to day 13 | 
| Serum biomarker concentration after the (N-1)th dose but before the Nth dose (Epre,N) |  | up to day 13 | 
| Measured value of the biomarkers in biological matrix at the set time point after Nth dose (EN) |  | up to day 13 | 
| Oral glucose insulin sensitivity (OGIS) index |  | up to day 13 | 
| Homeostasis model assessment (HOMA) value |  | up to day 13 |