A Study in Healthy Men to Test How the Body Takes up and Tolerates Different Doses of BI 474121, and Whether it Makes a Difference if BI 474121 is Taken as a Tablet or a Drink.

A Randomised, Single-blind, Placebo-controlled Trial to Investigate Safety, Tolerability, and Pharmacokinetics of Single Rising Oral Doses of BI 474121 Administered as Oral Solution and Tablets to Healthy Male Subjects (SRD Part), and a Randomised, Open-label, Single-dose, Three-way Cross-over Bioavailability Comparison of BI 474121 as Tablet Versus Oral Solution and Tablet With and Without Food (BA Part)

The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics (PK) of BI 474121 in healthy male subjects following oral administration of single rising doses.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Placebo tablet; Drug: Placebo solution; Drug: BI 474121 oral solution; Drug: BI 474121 tablet

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Biberach, Germany, 88397
    • Humanpharmakologisches Zentrum Biberach

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria:

• Healthy male subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (Blood pressure (BP), Pulse rate (PR)), 12- lead Electrocardiogram (ECG), and clinical laboratory tests
• Age of 18 to 45 years (inclusive)
• Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive)
• Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation

Exclusion criteria:

• Any finding in the medical examination (including Blood pressure (BP), Pulse rate (PR) or Electrocardiogram (ECG)) deviating from normal and assessed as clinically relevant by the investigator
• Repeated measurement of systolic blood pressure outside the range of 100 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate 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
• 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 stroke), and other relevant neurological or psychiatric disorders
• History of relevant orthostatic hypotension, fainting spells, or blackouts
• Chronic or relevant acute infections
• History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients)
• Use of drugs within 30 days of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause QT/QTc interval prolongation)
• Intake of an investigational drug in another clinical trial within 60 days of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administered
• Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
• Inability to refrain from smoking on specified trial days
• Alcohol abuse (consumption of more than 24 g per day)
• Drug abuse or positive drug screening
• Blood donation of more than 100 mL within 30 days of planned administration of trial medication or intended blood donation during the trial
• Intention to perform excessive physical activities within one week prior to the administration of trial medication or during the trial
• Inability to comply with the dietary regimen of the trial site
• A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms or any other relevant ECG finding at screening)
• A history of additional risk factors for Torsade de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome)
• Subject is assessed as unsuitable for inclusion by the investigator, for instance, because the subject is not considered able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study
• Male subjects with WOCBP partner who are unwilling to use a highly effective method of birth control from time point of administration of trial medication until 30 days thereafter.

Highly effective methods of birth control are:

• Male subject is sexually abstinent
• Male subjects is vasectomised (vasectomy at least 1 year prior to enrolment), plus condom in male subject
• Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
• Use of progestogen-only hormonal contraception by female partner that inhibits ovulation (only injectables or implants), plus condom in male subject
• Use of combined (estrogen and progestogen containing) hormonal contraception by female partner that prevents ovulation (oral, intravaginal or transdermal), plus condom in male subject
• Female partner is surgically sterilised (including hysterectomy)

• Female partner is postmenopausal, defined as no menses for 1 year without an alternative medical cause (in questionable cases a blood sample with FSH above 40 U/L and estradiol below 30 ng/L is confirmatory) Sperm donation is not allowed from the time point of drug administration until 30 days thereafter.

  • ALT (alanine transaminase), AST (aspartate transaminase), or serum creatinine exceed upper limit of normal range at screening, confirmed by a repeat test
  • Orthostatic hypotension during orthostatic testing at Day -3, that the investigator considers to be of clinical relevance (only applicable for Single-rising dose (SRD) part).
  • During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 infection.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

15

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: SRD: Placebo matching BI 474121 oral solution (OS); This arm comprises all placebo treated participants of the single rising dose (SRD) part treated with an oral solution (placebo treated participants of the two lowest dose group (DG)s). Participants receiving placebo were equally distributed across dose groups. A single dose of BI 474121 matching placebo powder for oral solution was administered after an overnight fast together with 240 milliliter (mL) of water to participants who were in a standing position.	Drug: Placebo solution; Placebo solution
Placebo Comparator: SRD: Placebo matching BI 474121 tablet (T); This arm comprises all placebo treated participants of the SRD part treated with a tablet (placebo treated participants of the five upper DGs). Participants receiving placebo were equally distributed across dose groups. A single dose of BI 474121 matching placebo tablet was administered after an overnight fast together with 240 mL of water to subjects who were in a standing position.	Drug: Placebo tablet; Placebo tablet
Experimental: SRD: 0.25 milligram (mg) BI 474121 - OS; A single dose of 0.25 mg BI 474121 was solved in 0.5 mL of water and was administered after an overnight fast together with 240 mL of water to participants who were in a standing position.	Drug: BI 474121 oral solution; BI 474121 oral solution
Experimental: SRD: 1 mg BI 474121 - OS; A single dose of 1 mg BI 474121 was solved in 2mL of water and was administered after an overnight fast together with 240 mL of water to participants who were in a standing position.	Drug: BI 474121 oral solution; BI 474121 oral solution
Experimental: SRD: 2.5 mg BI 474121 - T; A single dose of 2.5 mg BI 474121 was administered as 1 uncoated 2.5 mg tablet after an overnight fast together with 240 mL of water to participants who were in a standing position.	Drug: BI 474121 tablet; BI 474121 tablet
Experimental: SRD: 5 mg BI 474121 - T; A single dose of 5.0 mg BI 474121 was administered as 2 uncoated 2.5 mg tablets after an overnight fast together with 240 mL of water to participants who were in a standing position.	Drug: BI 474121 tablet; BI 474121 tablet
Experimental: SRD: 10 mg BI 474121 - T; A single dose of 10.0 mg BI 474121 was administered as 1 uncoated 10.0 mg tablet after an overnight fast together with 240 mL of water to participants who were in a standing position.	Drug: BI 474121 tablet; BI 474121 tablet
Experimental: SRD: 20 mg BI 474121 - T; A single dose of 20.0 mg BI 474121 was administered as 2 uncoated 10.0 mg tablets after an overnight fast together with 240 mL of water to participants who were in a standing position.	Drug: BI 474121 tablet; BI 474121 tablet
Experimental: SRD: 40 mg BI 474121 - T; A single dose of 40.0 mg BI 474121 was administered as 4 uncoated 10.0 mg tablets after an overnight fast together with 240 mL of water to participants who were in a standing position.	Drug: BI 474121 tablet; BI 474121 tablet
Experimental: BA: BI 474121 10 mg as: OS fasted (Reference (R)) / T fasted (T2) / T fed (T1); Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (Reference (R)), in period 2 as 1 uncoated tablet with 240 mL of water after an overnight fast (Test 2 (T2)) and in period 3 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (Test 1 (T1)). Between periods was a wash-out period of at least 7 days.	Drug: BI 474121 oral solution; BI 474121 oral solution; Drug: BI 474121 tablet; BI 474121 tablet
Experimental: BA: BI 474121 10 mg as: R / T1 / T2; Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R), in period 2 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1) and in period 3 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2). Between periods was a wash-out period of at least 7 days.	Drug: BI 474121 oral solution; BI 474121 oral solution; Drug: BI 474121 tablet; BI 474121 tablet
Experimental: BA: BI 474121 10mg as: T2 / R / T1; Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2), in period 2 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R) and in period 3 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1). Between periods was a wash-out period of at least 7 days.	Drug: BI 474121 oral solution; BI 474121 oral solution; Drug: BI 474121 tablet; BI 474121 tablet
Experimental: BA: BI 474121 10mg as: T2 / T1 / R; Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2), in period 2 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1) and in period 3 as oral solution solved in 20 mL water with 240 mL of water after an overnight fast (R). Between periods was a wash-out period of at least 7 days.	Drug: BI 474121 oral solution; BI 474121 oral solution; Drug: BI 474121 tablet; BI 474121 tablet
Experimental: BA: BI 474121 10mg: T1 / R / T2; Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1), in period 2 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R) and in period 3 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2). Between periods was a wash-out period of at least 7 days.	Drug: BI 474121 oral solution; BI 474121 oral solution; Drug: BI 474121 tablet; BI 474121 tablet
Experimental: BA: BI 474121 10mg: T1 / T2 / R; Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1), in period 2 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2) and in period 3 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R). Between periods was a wash-out period of at least 7 days.	Drug: BI 474121 oral solution; BI 474121 oral solution; Drug: BI 474121 tablet; BI 474121 tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events.	For assessment of safety and tolerability of BI 474121 the percentage of participants with drug-related adverse events (AE) was calculated. All AEs occurring between first drug intake till 7 days after last drug intake were assigned to the randomised treatment.	From drug administration until 7 days after drug administration, 7 days.
Bioavailability (BA): Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz).	Area under the concentration-time curve of BI 474121 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) was analyzed after single dose administration of BI 474121 as: an oral solution in fasted conditions (reference treatment), an uncoated tablet in fed conditions (treatment 1) and an uncoated tablet in fasted conditions (treatment 2). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis.	Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration.
BA: Maximum Measured Concentration of BI 474121 in Plasma (Cmax )	Maximum measured concentration of of BI 474121 in plasma (Cmax). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis.	Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SRD: Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz).	Area under the concentration-time curve of BI 474121 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) was analyzed after single dose administration of BI 474121. The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis.	Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration.
SRD: Maximum Measured Concentration of of BI 474121 in Plasma (Cmax).	Maximum measured concentration of of BI 474121 in plasma (Cmax). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis.	Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration.
BA: Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞).	Area under the concentration-time curve of BI 474121 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis.	Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2020
• Primary Completion (Actual): March 25, 2021
• Study Completion (Actual): March 25, 2021

Study Registration Dates

• First Submitted: December 10, 2019
• First Submitted That Met QC Criteria: December 10, 2019
• First Posted (Actual): December 11, 2019

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pharmaceutical Solutions
• Other Study ID Numbers: 1411-0001; 2019-002358-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents. Exceptions might apply, e.g. studies in products where Boehringer Ingelheim is not the license holder; studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; studies conducted in a single center or targeting rare diseases (in case of low number of patients and therefore limitations with anonymization). For more details refer to: https:// www.mystudywindow.com/msw/datatransparency

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No