A Study in Healthy Men to Test How Different Doses of BI 474121 Are Taken up and How They Influence the Amount of a Molecular Messenger (cGMP) in the Spinal Fluid

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Placebo; Drug: 10 milligram (mg) BI 474121; Drug: 40 milligram (mg) BI 474121; Drug: 2.5 milligram (mg) BI 474121; Drug: 20 milligram (mg) BI 474121

• Registration Number: NCT04672954
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

The main objectives of this trial are:

* To evaluate the effect of BI 474121 on cyclic guanosine monophosphate (cGMP) levels in cerebrospinal fluid (CSF)

* To assess the exposure of BI 474121 in CSF relative to plasma

* To determine the exposure effect relationship in CSF with different oral doses of BI 474121

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2020-12-14
• Study First Submitted QC: 2020-12-14
• Study First Posted: 2020-12-17
• Study Start: 2021-01-07
• Primary Completion: 2021-07-01
• Study Completion: 2021-07-01
• Status Verified: 2023-07
• Results First Submitted: 2023-07-31
• Results First Submitted QC: 2023-07-31
• Last Update Submitted: 2023-07-31
• Results First Posted: 2024-03-08
• Last Update Posted: 2024-03-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 24

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 65 years (inclusive)
• 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

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Exclusion Criteria

• 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 blood pressure outside the range of 90 to 150 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 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 assessed as clinically relevant by the investigator
• 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
• Further exclusion criteria apply

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo matching to 10 mg BI 474121 administered as uncoated tablets with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 1: randomised, placebo-controlled, single-blind.
10 milligram (mg) BI 474121	10 milligram (mg) BI 474121	10 mg BI 474121 administered as uncoated tablets (1 x 10 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 3 of the study: randomised, open-label.
40 milligram (mg) BI 474121	40 milligram (mg) BI 474121	40 mg BI 474121 administered as uncoated tablets (4 x 10 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 2 of the study: non-randomised, open-label.
2.5 milligram (mg) BI 474121	2.5 milligram (mg) BI 474121	2.5 mg BI 474121 administered as uncoated tablets (1 x 2.5 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 3 of the study: randomised, open-label.
20 milligram (mg) BI 474121	20 milligram (mg) BI 474121	20 mg BI 474121 administered as uncoated tablets (2 x 10 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 1 of the study: randomised, placebo-controlled, single-blind.

Primary Outcome Measures

Name	Time	Method
Maximum Exposure-related Change From Baseline (Calculated as Ratio) of Cyclic Guanosine Monophosphate (cGMP) in Cerebrospinal Fluid (CSF)	Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration.	Maximum exposure-related change from baseline (calculated as ratio) of cyclic guanosine monophosphate (cGMP) in Cerebrospinal fluid (CSF). In subjects treated with BI 474121 this is the maximum cGMP value measured within 1 hour (h) prior and 4 h post BI 474121 Maximum measured concentration (Cmax) in CSF. For subjects treated with placebo, this is the maximum cGMP value measured within 1 h prior to and 4 h after the median BI 474121 tmax (time from (last) dosing to the maximum measured concentration of the analyte) in CSF of the BI 474121 treated subjects. Baseline cGMP concentration was calculated as the arithmetic mean of all pre-dose measurements above Lower limit of quantification (LLOQ) obtained in that subject. The maximum exposure-related change from baseline in cGMP in CSF was explored using an analysis of covariance (ANCOVA) model on the logarithmic scale. Maximum exposure related cGMP: Ratio \[maximum cGMP / baseline cGMP\].
Maximum Measured Concentration (Cmax) Ratio of BI 474121 in Cerebrospinal Fluid (CSF) Compared to Plasma	Up to 72 hours, see endpoint description for detailed sampling scheme.	Maximum measured concentration (Cmax) ratio of BI 474121 in CSF compared to plasma. Mixed effects model: random effect 'subject nested within treatment', fixed effect, treatment, substance and their interaction' (for estimation of overall group effect the model was run without interaction term). Cmax was log transformed (natural logarithm) prior to fitting the model. Difference between expected means for log(CSF)- log(plasma) was estimated by difference in the corresponding least square means (point estimate) and two-sided 90% CI based on the t-distribution were computed. Quantities were back-transformed to the original scale to give an point estimator and interval estimate. Ratio = CSF (T) / plasma (R).; Plasma: Within 3 hours (h) before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 34, 48 and 72 h following drug administration.; CSF: Within approximately 2, 1, and 0.17 h before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 h following drug administration.

Secondary Outcome Measures

Name	Time	Method
Maximum Measured Concentration (Cmax) of BI 474121 in Plasma	Within 3 hours before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 34, 48 and 72 hours following drug administration.	Maximum measured concentration (Cmax) of BI 474121 in plasma.
Maximum Measured Exposure-related cGMP Concentration in Cerebrospinal Fluid (CSF)	Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration.	Maximum measured exposure-related cGMP concentration in CSF. In subjects treated with BI 474121 this is the maximum cGMP value measured within 1 hour (h) prior and 4 h post BI 474121 Maximum measured concentration (Cmax) in CSF. For subjects treated with placebo, this is the maximum cGMP value measured within 1 h prior to and 4 h after the median BI 474121 tmax (time from (last) dosing to the maximum measured concentration of the analyte) in CSF of the BI 474121 treated subjects.
Maximum Measured Concentration (Cmax) of BI 474121 in Cerebrospinal Fluid (CSF)	Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration.	Maximum measured concentration (Cmax) of BI 474121 in Cerebrospinal fluid (CSF).
Time From Dosing to Maximum Measured BI 474121 Concentrations in Plasma (Tmax)	Within 3 hours before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 34, 48 and 72 hours following drug administration.	Time from dosing to maximum measured BI 474121 concentrations in plasma (tmax).
Time From Dosing to Maximum Measured BI 474121 Concentrations in CSF (Tmax)	Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration.	Time from dosing to maximum measured BI 474121 concentrations in CSF (tmax).

Trial Locations

Locations (1)

Centre Human Drug Research; 🇳🇱 Leiden, Netherlands