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Safety, tolerability, and pharmacokinetics of single rising intravenous doses of BI 765845 in healthy male Japanese subjects (single-blind, randomised, placebo-controlled, parallel group design)

A study in healthy Japanese men to test how well different doses of BI 765845 are tolerated

32

A total of 32 subjects were entered into the trial and received a single i.v. dose of trial medication (BI 765845 or placebo) as planned. All subjects except 1 (in the placebo group) completed the planned observation time according to the CTP; this subject discontinued the trial due to lost to follow-up. All subjects completed the planned treatment. No important protocol deviations were reported. All subjects were male and Asian. No subjects were of Hispanic/Latino ethnicity. The mean age was 29.1 years (standard deviation [SD]: 8.5; range: 19 to 45). The mean BMI was 21.4 kg/m2 (SD: 1.5; range: 19.3 to 24.4). No relevant medical history or baseline conditions were reported for any of the subjects.

A total of 32 subjects were entered into the trial and received a single i.v. dose of trial medication (BI 765845 or placebo) as planned. All subjects except 1 (in the placebo group) completed the planned observation time according to the CTP; this subject discontinued the trial due to lost to follow-up. All subjects completed the planned treatment. No important protocol deviations were reported.

No investigator-defined drug-related TEAEs were reported in this trial. No deaths, serious AEs (SAEs), AEs leading to discontinuation of trial drug, protocol-specified AESIs, or other significant AEs (according to ICH E3) were reported. During the follow-up period, there were 15 AEs reported in 12 patients. One of these AEs was reported as drug-related. All follow-up AEs were reported as resolved by the end of the trial. Possible clinically significant abnormalities in safety laboratory tests (excluding subjects with possible clinically significant abnormalities at screening or baseline) were reported in 5 out of 8 subjects treated with placebo and in 13 out of 24 subjects treated with BI 765845. Overall, 3 possible clinically significant abnormalities were reported as follow-up AEs. None of the findings in the laboratory safety data were reported as TEAEs. There were no clinically relevant trends. The evaluation of vital signs showed no clinically relevant findings. Regarding the ECG evaluations, no notable findings were reported and no subjects were reported with new-onset findings. The results of the descriptive exposure-response analyses of BI 765845_acb serum concentrations and changes from baseline in QTcF and HR indicated no relationship between BI 765845_acb serum concentrations and changes from baseline in either ECG parameter.

The primary endpoint The primary safety endpoint of the trial was the percentage of subjects treated with the investigational drug who experienced investigator-defined drug-related TEAEs. No investigator-defined drug-related TEAEs were reported in this trial. No deaths, serious AEs (SAEs), AEs leading to discontinuation of trial drug, protocol-specified AESIs, or other significant AEs (according to ICH E3) were reported. During the follow-up period, there were 15 AEs reported in 12 patients. One of these AEs was reported as drug-related. All follow-up AEs were reported as resolved by the end of the trial. Possible clinically significant abnormalities in safety laboratory tests (excluding subjects with possible clinically significant abnormalities at screening or baseline) were reported in 5 out of 8 subjects treated with placebo and in 13 out of 24 subjects treated with BI 765845. Overall, 3 possible clinically significant abnormalities were reported as follow-up AEs. None of the findings in the laboratory safety data were reported as TEAEs. There were no clinically relevant trends. The evaluation of vital signs showed no clinically relevant findings. Regarding the ECG evaluations, no notable findings were reported and no subjects were reported with new-onset findings. The results of the descriptive exposure-response analyses of BI 765845_acb serum concentrations and changes from baseline in QTcF and HR indicated no relationship between BI 765845_acb serum concentrations and changes from baseline in either ECG parameter. Secondary endpoints Secondary and further PK endpoints were calculated for the endogenous MYDGF-corrected concentrations of BI 765845 (analyte BI 765845_acb, which represents the BI 765845 concentration minus 10.0 ng/mL for each time point). Following a single 1-h i.v. infusion of BI 765845, Cmax was reached at the end of the 1-h infusion, with a median time from dosing to the maximum measured concentration (tmax) of 0.983 h across dose groups, followed by a quick decrease of BI 765845 concentrations in a multi-exponential manner until reaching endogenous concentration levels. Geometric mean Cmax and Area under the concentration-time curve of the analyte in serum over the time interval from 0 extrapolated to infinity increased with increasing dose. Based on the statistical power model, dose proportionality can be assumed for a restricted dose range for the PK parameters Cmax, Area under the concentration-time curve of the analyte in serum over the time interval from 0 extrapolated to infinity, and AUC0-tz.

Single dose of BI 765845 administered as an i.v. infusion were safe and well tolerated by healthy male Japanese subjects. Based on visual inspection, it is considered that exposure increased in a nearly dose proportional manner in the entire dose of BI 765845. All evaluable subjects in this trial were ADA negative, which is consistent with the results of study 1478-0001, suggesting a low risk of immunogenicity.

Yes

Researchers can refer to https://trials.boehringer-ingelheim.com/ to request access to raw data from our clinical studies.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031230092

Kutsunai Mitsuru

Boehringer Ingelheim

2-1-1, Osaki, Shinagawa-ku, Tokyo

medchiken.jp@boehringer-ingelheim.com

Kawahara Shizuko

Boehringer Ingelheim

2-1-1, Osaki, Shinagawa-ku, Tokyo

+81-120-189-779

medchiken.jp@boehringer-ingelheim.com

Complete

June. 26, 2023

Interventional

randomized controlled trial

single blind

placebo control

parallel assignment

treatment purpose

Healthy male subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests
Japanese ethnicity
Age of 18 to 45 years (inclusive)
BMI of 18.5 to 24.9 kg/m2 (inclusive)
Signed and dated written informed consent in accordance with ICH-Good Clinical Practice (GCP) and local legislation prior to admission to the trial

Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator
Repeated measurement of systolic BP outside the range of 90 to 140 mmHg, diastolic BP outside the range of 50 to 90 mmHg, or PR outside the range of 50 to 90 bpm
Any laboratory value outside the reference range that the investigator considers to be of clinical relevance
Any evidence of a concomitant disease assessed as clinically relevant by the investigator
Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders (including any history of cardiovascular diseases such as atherosclerosis, previous myocardial infarction or angina pectoris)
Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
Diseases of the central nervous system (including but not limited to any kind of seizures or history of stroke), and other relevant neurological or psychiatric disorders

Male

ST segment-elevation myocardial infarction (STEMI)

single rising doses of investigational products BI 765845

Occurrence of any treatment-emergent adverse event assessed as drug-related by the investigator.

June. 05, 2023

none