Assessment of Exposure of BI 409306 in Cerebrospinal Fluid (CSF) Relative to Plasma as Well as to Evaluation of the Effect of Different Doses of BI 409306 on the cGMP (Cyclic Guanosine Monophosphate) Levels in CSF in Healthy Male Volunteers

• BI 409306 (Drug): Film-coated tablet
• Placebo (Drug): Film-coated tablet

Primary outcomes

• Ratio of Cmax of BI 409306 in CSF Compared to Plasma [Pharmacokinetic samples were collected within 2 hours before and up to up to 24 hours after BI 409306 administration (please refer the description for the time frame in detail).]: Ratio of Cmax (maximum measured concentration) of BI 409306 in Cerebrospinal fluid (CSF) compared to plasma is presented. Ratio was calculated as: Cmax of BI 409306 in CSF/ Cmax of BI 409306 in plasma. Time frame: Blood: Within 2:00 hours (h):minutes (min) before dosing and 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00 and 24:00 h:min after dosing. CSF: Within 2:00 hours (h):minutes (min) before dosing and 0:00, 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00 and 24:00 h:min after dosing.
• Maximum Change From Baseline of cGMP in CSF Calculated as Ratio (Emax) [Within 2:00 hours (h):minutes (min) before dosing and 0:00, 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00 and 24:00 h:min after dosing.]: The maximum change from baseline of cyclic guanosine monophosphate (cGMP) in cerebrospinal fluid (CSF) was calculated as: exp(ln(cGMPmax) - ln(cGMP0)), where cGMP0 is the baseline cGMP value per subject (mean of the two pre-dose measurements) and cGMPmax is the maximal cGMP value per subject measured after drug intake.
• Maximum Relative Change From Baseline of cGMP in CSF [Within 2:00 hours (h):minutes(min) before dosing and 0:00, 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00h, 4:00, 6:00, 8:00h, 10:00, 12:00, 14:00 and 24:00 h:min after dosing.]: Maximum relative change from baseline of cyclic guanosine monophosphate (cGMP) in cerebrospinal fluid (CSF) is presented. Maximum relative change from baseline was calculated as: (cGMPmax - cGMP0)/ cGMP0, where cGMPmax is the maximum measured concentration of cGMP after dosing of BI 409306 and cGMP0 is cGMP concentration at baseline.
• Maximum (Absolute) Change From Baseline of cGMP Concentration in CSF [Within 2:00 hours (h):minutes (min) before dosing and 0:00, 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00 and 24:00 h:min after dosing.]: Maximum (absolute) change from baseline of cyclic guanosine monophosphate (cGMP) concentration in cerebrospinal fluid (CSF) is presented. The maximum (absolute) change from baseline in cGMP concentration was calculated as: maximum measured concentration of cGMP after dosing of BI 409306 (cGMPmax) - cGMP concentration at baseline (cGMP0).

Secondary outcomes

• Maximum Measured Concentration of BI 409306 in Plasma and CSF (Cmax) [Pharmacokinetic samples were collected within 2 hours before and up to up to 24 hours after BI 409306 administration (please refer the description for the time frame in detail).]: Maximum measured concentration of BI 409306 in plasma and CSF (cerebrospinal fluid) (Cmax) is reported. Time frame: Blood: Within 2:00 hours (h): minutes (min) before dosing and 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00 and 24:00 h:min after dosing CSF: Within 2:00 hours (h):minutes (min before dosing and 0:00, 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00 and 24:00 h:min after dosing
• Time From Dosing to Maximum Measured BI 409306 Concentration in Plasma and CSF (Tmax) [Pharmacokinetic samples were collected within 2 hours before and up to up to 24 hours after BI 409306 administration (please refer the description for the time frame in detail).]: Time from dosing to maximum measured BI 409306 concentration in plasma and CSF (cerebrospinal fluid) (tmax) is reported. Time frame: Blood: Within 2:00 hours (h):minutes (min) before dosing and 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00, and 24:00 h:min after dosing. CSF: Within 2:00 hours (h):minutes (min) before dosing and 0:00, 0:10 , 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00 and 24:00 h:min after dosing.
• Maximum Measured cGMP Concentration in CSF (Cmax) [Within 2:00 hours (h): minutes (min) before dosing and 0:00, 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00 and 24:00 h:min after dosing.]: Maximum measured cyclic guanosine monophosphate (cGMP) concentration in cerebrospinal fluid (CSF) (Cmax) is reported.
• Time From Dosing to Maximum Measured cGMP Concentration in CSF (Tmax) [Within 2:00 hours (h):minutes (min) before dosing and 0:00, 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00 and 24:00 h:min after dosing.]: Time from dosing to maximum measured cyclic guanosine monophosphate (cGMP) concentration in cerebrospinal fluid (CSF) (tmax) is reported.

Sex: Male, ages: 21 Years to 50 Years, accepts healthy volunteers

Inclusion criteria:

1. Healthy males according to the following criteria:

   Based upon a complete medical history, including the physical examination, vital signs after 10 minutes in supine position (blood pressure (BP), pulse rate (PR)), body temperature (BT)), 12-lead electrocardiogram (ECG)), clinical laboratory tests
2. Age =21 and Age =50 years
3. Body Mass Index (BMI) =18.5 and BMI =29.9 kg/m2
4. Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and the local legislation

Exclusion criteria:

1. Any finding of the medical examination (including BP, PR and ECG) deviating from normal and considered by the investigator as clinical relevant
2. Abnormal values for Prothrombin Time (PT), (Activated Partial Thromboplastin Time (aPTT) and thrombocytes considered by the investigator as clinically relevant
3. Any evidence of a clinically relevant concomitant disease
4. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
5. Surgery of the gastrointestinal tract (except appendectomy)
6. Diseases of the central nervous system (included but not limited to any kind of seizures, stroke or psychiatric disorders)
7. History of relevant orthostatic hypotension, fainting spells or blackouts.
8. Chronic or relevant acute infections
9. History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
10. Intake of drugs with a long half-life (> 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration
11. 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
12. Participation in another trial with an investigational drug within two months prior to administration or during the trial
13. Smoker, who consume more than 5 cigarettes per day
14. Inability to refrain from smoking on trial days
15. Alcohol abuse (more than 20 g/day): 2 units/day (14 units/week)
16. Drug abuse
17. Blood donation (more than 100 mL within four weeks prior to administration or during the trial)
18. Excessive physical activities (within one week prior to administration or during the trial)
19. Any laboratory value outside the reference range that is of clinical relevance
20. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTcF interval >450 ms)
21. Inability to understand and to comply with protocol requirements and restrictions and dietary regimen of trial site
22. of additional risk factors for Torsades de points (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
23. Male subjects who do not agree to minimize the risk of female partners becoming pregnant from the first dosing day until three month after the study completion. Acceptable methods of contraception comprises barrier contraception and a medically accepted contraceptive method for the female (intra-uterine device with spermicide, hormonal contraceptive since at least two months)

Participant flow

Outcome results

• Ratio of Cmax of BI 409306 in CSF Compared to Plasma (Primary), Geometric mean, Ratio: BI 409306 25mg 0.267 +/- 18.40; BI 409306 50 mg 0.244 +/- 15.80; BI 409306 100 mg 0.294 +/- 42.80; BI 409306 200 mg 0.335 +/- 5.74 (p 1.0000)
• Maximum Change From Baseline of cGMP in CSF Calculated as Ratio (Emax) (Primary), Geometric mean, ratio: BI 409306 25mg NA +/- NA; BI 409306 50 mg NA +/- NA; BI 409306 100 mg NA +/- NA; BI 409306 200 mg NA +/- NA; Placebo NA +/- NA
• Maximum Relative Change From Baseline of cGMP in CSF (Primary), Least squares mean, Ratio: BI 409306 25mg 1.166 +/- 0.714; BI 409306 50 mg 1.329 +/- 0.716; BI 409306 100 mg 2.247 +/- 0.713; BI 409306 200 mg 4.973 +/- 0.738; Placebo 0.910 +/- 0.737
• Maximum (Absolute) Change From Baseline of cGMP Concentration in CSF (Primary), Least squares mean, nanomole/Liter: BI 409306 25mg 2.299 +/- 0.825; BI 409306 50 mg 3.451 +/- 0.827; BI 409306 100 mg 5.239 +/- 0.824; BI 409306 200 mg 9.089 +/- 0.852; Placebo 0.748 +/- 0.852
• Maximum Measured Concentration of BI 409306 in Plasma and CSF (Cmax) (Secondary), Geometric mean, nanomole/Liter (nmol/L): BI 409306 25mg 46.9 +/- 84.3; BI 409306 50 mg 183 +/- 51.3; BI 409306 100 mg 271 +/- 39.7; BI 409306 200 mg 902 +/- 36.3
• Time From Dosing to Maximum Measured BI 409306 Concentration in Plasma and CSF (Tmax) (Secondary), Median, hour: BI 409306 25mg 2.00 (2.00 to 3.00); BI 409306 50 mg 2.00 (1.00 to 2.00); BI 409306 100 mg 1.75 (1.50 to 3.00); BI 409306 200 mg 1.50 (0.767 to 2.02)
• Maximum Measured cGMP Concentration in CSF (Cmax) (Secondary), Mean, nanomole/Liter (nmol/L): BI 409306 25mg 5.96 +/- 3.31; BI 409306 50 mg 6.32 +/- 2.91; BI 409306 100 mg 8.80 +/- 3.44; BI 409306 200 mg 11.2 +/- 3.09; Placebo 5.36 +/- 1.11
• Time From Dosing to Maximum Measured cGMP Concentration in CSF (Tmax) (Secondary), Median, hour: BI 409306 25mg 5.00 (0.50 to 10.0); BI 409306 50 mg 2.50 (1.65 to 3.00); BI 409306 100 mg 3.52 (3.00 to 4.00); BI 409306 200 mg 2.00 (2.00 to 4.00); Placebo 16.00 (0.50 to 24.00)

Adverse events

Time frame: From first drug administration until end of the trial, ie., up to 17 days

Other adverse events by term

• Boehringer Ingelheim, Study chair, Boehringer Ingelheim