Healthy
Conditions
Brief summary
This trial will be conducted to further evaluate, in a controlled setting, potential cardiac effects of an anticipated therapeutic and supra-therapeutic dose of BI 409306 under resting and exercise conditions. Since the drug is being developed in part for a disease with an expectedly high number of elderly (AD), the characterization of cardiac safety of BI 409306 is considered to be important for the development of this compound. This trial will be conducted to further evaluate, in a controlled setting, potential cardiac effects of an anticipated therapeutic and supra-therapeutic dose of BI 409306 under resting and exercise conditions. Since the drug is being developed in part for a disease with an expectedly high number of elderly (AD), the characterization of cardiac safety of BI 409306 is considered to be important for the development of this compound.
Interventions
DRUGBI 409306
high dose, single dose, oral administration
DRUGPlacebo
single dose, oral administration
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
\- Healthy males according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests. * Age of 18 to 45 years (incl.) * BMI of 18.5 to 29.9 kg/m2 (incl.) * Waist-to-height ratio less than 0.5 * Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation * Ready and able to use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the subject information.
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) is deviating from normal and judged as clinically relevant by the investigator * Repeated measurement of * Systolic blood pressure less than 90 mm Hg or more than140 mmHg * Diastolic blood pressure less than 50 mm Hg or more than 90 mmHg * Pulse rate less than 45 bpm or more than 90 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease judged as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the PK of the trial medication (except appendectomy and 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) * Intake of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication * Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial or that might prolong the QT/QTc interval * Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication * Smoker (unless the subject quit smoking for at least 30 days prior to screening) * Alcohol abuse (consumption of more than 30 g per day) * Drug abuse or positive drug screening * Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial * Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial * Inability to comply with dietary regimen of 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 Torsades 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 considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study * Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active suicidal thought, active suicidal thought with method, active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent) * Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behaviour). In addition, the following trial-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Slope of the Placebo-corrected Change From Baseline of Heart Rate at Rest and Plasma Concentration Between 0 to 10 Hours | Baseline and up to 10 hours | Slope of the placebo-corrected change from baseline in resting heart rate (ΔΔHR) vs. plasma concentration of BI 409306, as assessed from 0 to 10 hours (h) after intake of trial medication. The predicted mean value (90% CI) of ΔΔHR at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table. Primary analysis excluded measurement with missing values. Patients with available data were included. |
| Maximum Difference to Placebo of the Change From Baseline in Heart Rate at Rest Between 0 to 4 Hours, Per 50 mg Dose Group | Baseline and up to 4 hours | For 50 mg dose, the maximal difference in the change from baseline in resting HR for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in heart rate at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note Not Calculated represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 1 hour. Predicted mean changes from baseline (90% Cis) are shown in the measured value table. |
| Maximum Difference to Placebo of the Change From Baseline in Heart Rate at Rest Between 0 to 4 Hours, Per 200 mg Dose Group | Baseline and up to 4 hours | For 200 mg dose, the maximal difference in the change from baseline in resting HR for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in heart rate at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note Not Calculated represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 1 hour. Predicted mean changes from baseline (90% Cis) are shown in the measured value table. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Slope of the Placebo-corrected Maximum Heart Rate During Exercise vs. Plasma Concentration of BI 409306 | 20 minutes and 2 hours 20 minutes after drug intake | Slope of the placebo-corrected maximum heart rate during exercise vs. plasma concentration of BI 409306. Patients with available data were included. Exercise testing was completed before gMean Cmax was reached for BI 409306 200 mg arm. The predicted mean value (90% CI) at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table. |
| Slope of Placebo-corrected Change From Baseline of Time Between Start of the Q Wave and End of the T Wave in an ECG Corrected for Heart Rate Using the Fridericia Correction Formula (QTcF) at Rest and Plasma Concentration Between 0 to 10 Hours | Baseline and up to 10 hours | Slope of placebo-corrected change from baseline in resting Fridericia correction formula QTcF vs. plasma concentration of BI 409306, as assessed from 0 to 10 h after intake of trial medication. The predicted mean value (90% CI) of ΔΔQTcF at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table. Patients with available data were included. |
| Slope of the Placebo Corrected Change From Maximum Heart Rate 1 and 5 Minutes After End of Exercise and Plasma Concentration | 20 minutes and 2 hours 20 minutes after drug intake | Slope of the placebo-corrected difference between maximum heart rate (HR) during exercise and recovery HR at 1 and 5 minutes (min) after the end of exercise vs. plasma concentration of BI 409306. The note Not Calculated represents that the plasma concentrations 1 min after the end of exercise did not reach gMean Cmax for the perticular arm. Patients with available data were included. The predicted mean value (90% CI) at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table. |
| Maximum Difference to Placebo of the Change From Baseline of QTcF at Rest to Placebo Between 0 to 4 Hours, Per 50 mg Dose Group | Baseline and up to 4 hours | For 50 mg dose, the maximal difference in the change from baseline in resting Fridericia correction formula QTcF for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in resting QTcF at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note Not Calculated represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 20 minutes. The predicted mean changes from baseline (90% Cis) are shown in the measured value table. |
| Maximum Difference to Placebo of the Change From Baseline of QTcF at Rest to Placebo Between 0 to 4 Hours, Per 200 mg Dose Group | Baseline and up to 4 hours | For 200 mg dose, the maximal difference in the change from baseline in resting Fridericia correction formula QTcF for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in resting QTcF at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note Not Calculated represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 20 minutes. The predicted mean changes from baseline (90% Cis) are shown in the measured value table. |
Countries
Germany
Participant flow
Recruitment details
Actual number of subjects enrolled in fact represents entered / randomized subjects due to the study set up.
Pre-assignment details
Screening included informed consent, physical examination, vital signs, Holter Electrocardiogram (ECG), ECG, laboratory, demographics, medical history, Columbia Suicide Severity Rating Scale, cardiopulmonary exercise, concomitant therapy, review of inclusion/exclusion criteria. Subjects genotyped as CYP2C19 poor metabolizers were not to be treated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo /50 mg/ 200 mg of BI 409306 Participants first received matching Placebo 250 mg, after a separation phase of at least 6 days, they then received BI 409306 50 mg with 200 mg matching placebo, again after a separation phase of at least 6 days, they received BI 409306 200 mg with 50 mg matching placebo film-coated tablets. Every treatment is given oral as 2 single doses (with wash-out phase of approximately 48 hours) with 240 mL of water after a standardized light breakfast on Day 1 and Day 3. | 4 |
| Placebo /200 mg/ 50 mg of BI 409306 Participants first received matching Placebo 250 mg, after a separation phase of at least 6 days, they then received BI 409306 200 mg with 50 mg matching placebo, again after a separation phase of at least 6 days, they received BI 409306 50 mg with 200 mg matching placebo film-coated tablets. Every treatment is given oral as 2 single doses (with wash-out phase of approximately 48 hours) with 240 mL of water after a standardized light breakfast on Day 1 and Day 3. | 3 |
| 50 mg / Placebo / 200 mg of BI 409306 Participants first received BI 409306 50 mg with 200 mg matching placebo, after a separation phase of at least 6 days, they then received matching Placebo 250 mg, again after a separation phase of at least 6 days, they received BI 409306 200 mg with 50 mg matching placebo film-coated tablets. Every treatment is given oral as 2 single doses (with wash-out phase of approximately 48 hours) with 240 mL of water after a standardized light breakfast on Day 1 and Day 3. | 2 |
| 50 mg / 200 mg / Placebo of BI 409306 Participants first received BI 409306 50 mg with 200 mg matching placebo, after a separation phase of at least 6 days, they then received BI 409306 200 mg with 50 mg matching placebo, again after a separation phase of at least 6 days, they received matching Placebo 250 mg film-coated tablets. Every treatment is given oral as 2 single doses (with wash-out phase of approximately 48 hours) with 240 mL of water after a standardized light breakfast on Day 1 and Day 3. | 3 |
| 200 mg / Placebo / 50 mg of BI 409306 Participants first received BI 409306 200 mg with 50 mg matching placebo, after a separation phase of at least 6 days, they then received matching Placebo 250 mg, again after a separation phase of at least 6 days, they received BI 409306 50 mg with 200 mg matching placebo film-coated tablets. Every treatment is given oral as 2 single doses (with wash-out phase of approximately 48 hours) with 240 mL of water after a standardized light breakfast on Day 1 and Day 3. | 4 |
| 200 mg / 50 mg / Placebo of BI 409306 Participants first received BI 409306 200 mg with 50 mg matching placebo, after a separation phase of at least 6 days, they then received BI 409306 50 mg with 200 mg matching placebo, again after a separation phase of at least 6 days, they received matching Placebo 250 mg film-coated tablets. Every treatment is given oral as 2 single doses (with wash-out phase of approximately 48 hours) with 240 mL of water after a standardized light breakfast on Day 1 and Day 3. | 4 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo /50 mg/ 200 mg of BI 409306 | Placebo /200 mg/ 50 mg of BI 409306 | 50 mg / Placebo / 200 mg of BI 409306 | 50 mg / 200 mg / Placebo of BI 409306 | 200 mg / Placebo / 50 mg of BI 409306 | 200 mg / 50 mg / Placebo of BI 409306 | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 28.8 Years STANDARD_DEVIATION 10.9 | 36.0 Years STANDARD_DEVIATION 9.2 | 31.0 Years STANDARD_DEVIATION 5.7 | 28.0 Years STANDARD_DEVIATION 3 | 30.3 Years STANDARD_DEVIATION 8.2 | 37.8 Years STANDARD_DEVIATION 9.5 | 32.1 Years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 4 Participants | 19 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 20 | 1 / 20 | 0 / 20 | 1 / 19 | 9 / 19 | 7 / 19 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 19 | 0 / 19 | 0 / 19 |
Outcome results
Primary
Maximum Difference to Placebo of the Change From Baseline in Heart Rate at Rest Between 0 to 4 Hours, Per 200 mg Dose Group
For 200 mg dose, the maximal difference in the change from baseline in resting HR for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in heart rate at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note Not Calculated represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 1 hour. Predicted mean changes from baseline (90% Cis) are shown in the measured value table.
Time frame: Baseline and up to 4 hours
Population: The electrocardiogram analysis set (ECGS) consisted of all subjects in the treated set who had at least 1 baseline and 1 post-baseline assessment (measured at rest) in 1 treatment period for at least 1 ECG interval endpoint. The ECGS was used for all ECG analyses except for those assessing the relationship between plasma concentration and ECG variables. Patients in the treatment groups are not mutually exclusive.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BI 409306 50 mg Under Resting Conditions | Maximum Difference to Placebo of the Change From Baseline in Heart Rate at Rest Between 0 to 4 Hours, Per 200 mg Dose Group | 5.85 beats/min | Standard Error 1.35 |
| BI 409306 200 mg Under Resting Conditions | Maximum Difference to Placebo of the Change From Baseline in Heart Rate at Rest Between 0 to 4 Hours, Per 200 mg Dose Group | 0.92 beats/min | Standard Error 1.33 |
Comparison: The a repeated measures model included 'period baseline', 'subject baseline' (defined as the arithmetic mean of the 2 period baselines), 'treatment', 'baseline\*time' interaction, 'treatment\*time' interaction and 'time' as fixed effects and subject as random effect (Primary analysis).90% CI: [1.69, 8.16]
Primary
Maximum Difference to Placebo of the Change From Baseline in Heart Rate at Rest Between 0 to 4 Hours, Per 50 mg Dose Group
For 50 mg dose, the maximal difference in the change from baseline in resting HR for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in heart rate at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note Not Calculated represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 1 hour. Predicted mean changes from baseline (90% Cis) are shown in the measured value table.
Time frame: Baseline and up to 4 hours
Population: The electrocardiogram analysis set (ECGS) consisted of all subjects in the treated set who had at least 1 baseline and 1 post-baseline assessment (measured at rest) in 1 treatment period for at least 1 ECG interval endpoint. The ECGS was used for all ECG analyses except for those assessing the relationship between plasma concentration and ECG variables. Patients in the treatment groups are not mutually exclusive.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BI 409306 50 mg Under Resting Conditions | Maximum Difference to Placebo of the Change From Baseline in Heart Rate at Rest Between 0 to 4 Hours, Per 50 mg Dose Group | 4.33 beats/min | Standard Error 1.33 |
| BI 409306 200 mg Under Resting Conditions | Maximum Difference to Placebo of the Change From Baseline in Heart Rate at Rest Between 0 to 4 Hours, Per 50 mg Dose Group | 0.48 beats/min | Standard Error 1.28 |
Comparison: The a repeated measures model included 'period baseline', 'subject baseline' (defined as the arithmetic mean of the 2 period baselines), 'treatment', 'baseline\*time' interaction, 'treatment\*time' interaction and 'time' as fixed effects and subject as random effect (Primary analysis).90% CI: [0.73, 6.97]
Primary
Slope of the Placebo-corrected Change From Baseline of Heart Rate at Rest and Plasma Concentration Between 0 to 10 Hours
Slope of the placebo-corrected change from baseline in resting heart rate (ΔΔHR) vs. plasma concentration of BI 409306, as assessed from 0 to 10 hours (h) after intake of trial medication. The predicted mean value (90% CI) of ΔΔHR at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table. Primary analysis excluded measurement with missing values. Patients with available data were included.
Time frame: Baseline and up to 10 hours
Population: The pharmacokinetics electrocardiogram set (PKECGS) included all subjects from the electrocardiogram (ECG) set (all subjects in the treated set who had at least 1 baseline and 1 post-baseline assessment in 1 treatment period for at least 1 ECG interval endpoint) who provided at least 1 valid drug plasma concentration and a corresponding ECG or oxygen variable in any period. Patients in the treatment groups are not mutually exclusive.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| BI 409306 50 mg Under Resting Conditions | Slope of the Placebo-corrected Change From Baseline of Heart Rate at Rest and Plasma Concentration Between 0 to 10 Hours | 0.80 beats/min |
| BI 409306 200 mg Under Resting Conditions | Slope of the Placebo-corrected Change From Baseline of Heart Rate at Rest and Plasma Concentration Between 0 to 10 Hours | 5.46 beats/min |
Comparison: The regression model with response variable placebo-corrected HR change from baseline (ddHR) and independent variable Plasma concentration includes a fixed slope effect as well as random intercept and slope estimates for each subject. (Primary analysis).95% CI: [0.0012, 0.0046]
Secondary
Maximum Difference to Placebo of the Change From Baseline of QTcF at Rest to Placebo Between 0 to 4 Hours, Per 200 mg Dose Group
For 200 mg dose, the maximal difference in the change from baseline in resting Fridericia correction formula QTcF for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in resting QTcF at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note Not Calculated represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 20 minutes. The predicted mean changes from baseline (90% Cis) are shown in the measured value table.
Time frame: Baseline and up to 4 hours
Population: The electrocardiogram analysis set (ECGS) consisted of all subjects in the treated set who had at least 1 baseline and 1 post-baseline assessment (measured at rest) in 1 treatment period for at least 1 ECG interval endpoint. The ECGS was used for all ECG analyses except for those assessing the relationship between plasma concentration and ECG variables. Patients in the treatment groups are not mutually exclusive.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BI 409306 50 mg Under Resting Conditions | Maximum Difference to Placebo of the Change From Baseline of QTcF at Rest to Placebo Between 0 to 4 Hours, Per 200 mg Dose Group | 11.01 milliseconds (msec) | Standard Error 1.42 |
| BI 409306 200 mg Under Resting Conditions | Maximum Difference to Placebo of the Change From Baseline of QTcF at Rest to Placebo Between 0 to 4 Hours, Per 200 mg Dose Group | 6.28 milliseconds (msec) | Standard Error 1.38 |
Comparison: The a repeated measures model included 'period baseline', 'subject baseline' (defined as the arithmetic mean of the 2 period baselines), 'treatment', 'baseline\*time' interaction, 'treatment\*time' interaction and 'time' as fixed effects and subject as random effect (Primary analysis).90% CI: [1.34, 8.13]
Secondary
Maximum Difference to Placebo of the Change From Baseline of QTcF at Rest to Placebo Between 0 to 4 Hours, Per 50 mg Dose Group
For 50 mg dose, the maximal difference in the change from baseline in resting Fridericia correction formula QTcF for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in resting QTcF at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note Not Calculated represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 20 minutes. The predicted mean changes from baseline (90% Cis) are shown in the measured value table.
Time frame: Baseline and up to 4 hours
Population: The electrocardiogram analysis set (ECGS) consisted of all subjects in the treated set who had at least 1 baseline and 1 post-baseline assessment (measured at rest) in 1 treatment period for at least 1 ECG interval endpoint. The ECGS was used for all ECG analyses except for those assessing the relationship between plasma concentration and ECG variables. Patients in the treatment groups are not mutually exclusive.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BI 409306 50 mg Under Resting Conditions | Maximum Difference to Placebo of the Change From Baseline of QTcF at Rest to Placebo Between 0 to 4 Hours, Per 50 mg Dose Group | 10.76 milliseconds (msec) | Standard Error 1.39 |
| BI 409306 200 mg Under Resting Conditions | Maximum Difference to Placebo of the Change From Baseline of QTcF at Rest to Placebo Between 0 to 4 Hours, Per 50 mg Dose Group | 6.22 milliseconds (msec) | Standard Error 1.37 |
Comparison: The a repeated measures model included 'period baseline', 'subject baseline' (defined as the arithmetic mean of the 2 period baselines), 'treatment', 'baseline\*time' interaction, 'treatment\*time' interaction and 'time' as fixed effects and subject as random effect (Primary analysis).90% CI: [3.39, 5.7]
Secondary
Slope of Placebo-corrected Change From Baseline of Time Between Start of the Q Wave and End of the T Wave in an ECG Corrected for Heart Rate Using the Fridericia Correction Formula (QTcF) at Rest and Plasma Concentration Between 0 to 10 Hours
Slope of placebo-corrected change from baseline in resting Fridericia correction formula QTcF vs. plasma concentration of BI 409306, as assessed from 0 to 10 h after intake of trial medication. The predicted mean value (90% CI) of ΔΔQTcF at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table. Patients with available data were included.
Time frame: Baseline and up to 10 hours
Population: The pharmacokinetics electrocardiogram set (PKECGS) included all subjects from the electrocardiogram set (ECGS) who provided at least 1 valid drug plasma concentration and a corresponding ECG or oxygen variable in any period. Patients in the treatment groups are not mutually exclusive.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| BI 409306 50 mg Under Resting Conditions | Slope of Placebo-corrected Change From Baseline of Time Between Start of the Q Wave and End of the T Wave in an ECG Corrected for Heart Rate Using the Fridericia Correction Formula (QTcF) at Rest and Plasma Concentration Between 0 to 10 Hours | 0.37 milliseconds (msec) |
| BI 409306 200 mg Under Resting Conditions | Slope of Placebo-corrected Change From Baseline of Time Between Start of the Q Wave and End of the T Wave in an ECG Corrected for Heart Rate Using the Fridericia Correction Formula (QTcF) at Rest and Plasma Concentration Between 0 to 10 Hours | 2.09 milliseconds (msec) |
Comparison: The regression model with response variable placebo-corrected QTcF change from baseline (ddQTcF) and independent variable. Plasma concentration includes a fixed slope effect as well as random intercept and slope estimates for each subject (Primary analysis). The covariance structure is No diagonal Factor Analytic FA0(2).95% CI: [-0.0009, 0.003]
Secondary
Slope of the Placebo Corrected Change From Maximum Heart Rate 1 and 5 Minutes After End of Exercise and Plasma Concentration
Slope of the placebo-corrected difference between maximum heart rate (HR) during exercise and recovery HR at 1 and 5 minutes (min) after the end of exercise vs. plasma concentration of BI 409306. The note Not Calculated represents that the plasma concentrations 1 min after the end of exercise did not reach gMean Cmax for the perticular arm. Patients with available data were included. The predicted mean value (90% CI) at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table.
Time frame: 20 minutes and 2 hours 20 minutes after drug intake
Population: The pharmacokinetics electrocardiogram set (PKECGS) included all subjects from the ECGS who provided at least 1 valid drug plasma concentration and a corresponding ECG or oxygen variable in any period. Patients in the treatment groups were not mutually exclusive.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| BI 409306 50 mg Under Resting Conditions | Slope of the Placebo Corrected Change From Maximum Heart Rate 1 and 5 Minutes After End of Exercise and Plasma Concentration | Primary analysis - 1 minute after exercise | 2.14 beats/min |
| BI 409306 50 mg Under Resting Conditions | Slope of the Placebo Corrected Change From Maximum Heart Rate 1 and 5 Minutes After End of Exercise and Plasma Concentration | Primary analysis - 5 minutes after exercise | 0.58 beats/min |
| BI 409306 200 mg Under Resting Conditions | Slope of the Placebo Corrected Change From Maximum Heart Rate 1 and 5 Minutes After End of Exercise and Plasma Concentration | Primary analysis - 1 minute after exercise | NA beats/min |
| BI 409306 200 mg Under Resting Conditions | Slope of the Placebo Corrected Change From Maximum Heart Rate 1 and 5 Minutes After End of Exercise and Plasma Concentration | Primary analysis - 5 minutes after exercise | -4.79 beats/min |
Comparison: The regression model with response variable placebo-corrected change from max HR to recovery HR (ddHR) and independent variable Plasma concentration includes a fixed slope effect as well as random intercept estimates for each subject (Primary analysis).95% CI: [-0.0036, 0.0008]
Comparison: The regression model with response variable placebo-corrected change from max HR to recovery HR (ddHR) and independent variable Plasma concentration includes a fixed slope effect as well as random intercept estimates for each subject (Primary analysis).95% CI: [-0.0052, -0.0007]
Secondary
Slope of the Placebo-corrected Maximum Heart Rate During Exercise vs. Plasma Concentration of BI 409306
Slope of the placebo-corrected maximum heart rate during exercise vs. plasma concentration of BI 409306. Patients with available data were included. Exercise testing was completed before gMean Cmax was reached for BI 409306 200 mg arm. The predicted mean value (90% CI) at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table.
Time frame: 20 minutes and 2 hours 20 minutes after drug intake
Population: The pharmacokinetics electrocardiogram set (PKECGS) included all subjects from the ECGS who provided at least 1 valid drug plasma concentration and a corresponding ECG or oxygen variable in any period. Patients in the treatment groups are not mutually exclusive.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| BI 409306 50 mg Under Resting Conditions | Slope of the Placebo-corrected Maximum Heart Rate During Exercise vs. Plasma Concentration of BI 409306 | 2.97 beats/min |
Comparison: The regression model with response variable placebo-corrected max HR (dHR) and independent variable Plasma concentration includes a fixed slope effect as well as random intercept and slope estimates for each subject. (Primary analysis)95% CI: [0.0032, 0.0076]