Healthy
Conditions
Brief summary
The main objective is to investigate the effect of food on the pharmacokinetics of BI 1015550 Formulation C2.
Interventions
DRUGBI 1015550
Participants received a single 18 mg Nerandomilast Formulation C2 film-coated tablet either after an overnight fast of at least 10 hours or following a high-fat, high-calorie meal.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
: * Healthy male or female 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 50 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 kg/m\^2 (inclusive) * Signed and dated written informed consent in accordance with International Conference of Harmonization-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial * Female subject who meets the criteria defined in the protocol for a highly effective contraception from at least 30 days before the first administration of trial medication until 7 days after last administration
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 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 betas per minute (bpm) at screening * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance, in particular, hepatic parameters (Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total bilirubin) or renal parameters (creatinine) exceeding the upper limit of normal (ULN) at screening * 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 including but not limited to depression and suicidal behavior * History of relevant orthostatic hypotension, fainting spells, or blackouts Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) (AUC0-tz) | Within 3 hours before Nerandomilast administration and at 0:15, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 3:30, 4:00, 6:00, 8:00, 11:00, 12:00, 24:00, 34:00, 48:00, 58:00, 72:00, 96:00, 120:00, and 144:00 hours after administration. | Area under the concentration-time curve of Nerandomilast in plasma over the time interval from 0 to the last quantifiable data point is presented. Geometric least square mean (adjusted geometric mean) and geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. These quantities will then be back-transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. This model will include effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. |
| Maximum Measured Concentration of Nerandomilast in Plasma (Cmax) | Within 3 hours before Nerandomilast administration and at 0:15, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 3:30, 4:00, 6:00, 8:00, 11:00, 12:00, 24:00, 34:00, 48:00, 58:00, 72:00, 96:00, 120:00, and 144:00 hours after administration. | Maximum measured concentration of Nerandomilast in plasma (Cmax) is presented. Geometric least square mean (adjusted geometric mean) and geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. These quantities will then be back-transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. This model will include effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours before Nerandomilast administration and at 0:15, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 3:30, 4:00, 6:00, 8:00, 11:00, 12:00, 24:00, 34:00, 48:00, 58:00, 72:00, 96:00, 120:00, and 144:00 hours after administration. | Area under the concentration-time curve of Nerandomilast in plasma over the time interval from 0 extrapolated to infinity is presented. Geometric least square mean (adjusted geometric mean) and geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. These quantities will then be back-transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. This model will include effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. |
Countries
Germany
Participant flow
Recruitment details
This open-label, single-dose, 2-period, 2-sequence crossover trial investigated how food affects the pharmacokinetics of an 18 mg nerandomilast tablet (Formulation C2). Subjects received nerandomilast in a fasting (Reference (R)) and fed (Test (T)) state with a minimum 10-day washout period in between and were randomized to the sequences R-T or T-R.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Nerandomilast Fasted State (Reference (R))/Nerandomilast Fed State Test (T) Nerandomilast fasted state Reference (R)/Nerandomilast fed state Test (T)
Two period crossover separated by a wash-out of at least 10 days:
Period 1: Participants received one 18 mg Nerandomilast Formulation C2 film-coated tablet following an overnight fast of at least 10 hours.
Period 2: Participants received one 18 mg Nerandomilast Formulation C2 film-coated tablet following a high fat/high calorie meal. | 9 |
| Nerandomilast Fed State (Test (T))/Nerandomilast Fasted State (Reference (R)) Nerandomilast fed state Test (T)/Nerandomilast fasted state Reference (R)
Two period crossover separated by a wash-out of at least 10 days:
Period 1: Participants received one 18 mg Nerandomilast Formulation C2 film-coated tablet following a high fat/high calorie meal.
Period 2: Participants received one 18 mg Nerandomilast Formulation C2 film-coated tablet following an overnight fast of at least 10 hours. | 9 |
| Total | 18 |
Baseline characteristics
| Characteristic | Nerandomilast Fed State (Test (T))/Nerandomilast Fasted State (Reference (R)) | Total | Nerandomilast Fasted State (Reference (R))/Nerandomilast Fed State Test (T) |
|---|---|---|---|
| Age, Continuous | 38.0 Years STANDARD_DEVIATION 6.5 | 39.5 Years STANDARD_DEVIATION 6.8 | 41.0 Years STANDARD_DEVIATION 7.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 17 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 18 Participants | 9 Participants |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 8 / 18 | 7 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 |
Outcome results
Primary
Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) (AUC0-tz)
Area under the concentration-time curve of Nerandomilast in plasma over the time interval from 0 to the last quantifiable data point is presented. Geometric least square mean (adjusted geometric mean) and geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. These quantities will then be back-transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. This model will include effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment.
Time frame: Within 3 hours before Nerandomilast administration and at 0:15, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 3:30, 4:00, 6:00, 8:00, 11:00, 12:00, 24:00, 34:00, 48:00, 58:00, 72:00, 96:00, 120:00, and 144:00 hours after administration.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nerandomilast fasted state (Reference (R)) | Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) (AUC0-tz) | 2225.20 hour*nanomol/Liter (h*nmol/L) |
| Nerandomilast fed state (Test (T)) | Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) (AUC0-tz) | 2563.65 hour*nanomol/Liter (h*nmol/L) |
Comparison: Relative bioavailability of Nerandomilast administered in fed state (Test) compared with Nerandomilast administered in fasted state (Reference) was estimated by the ratios of the gMeans (Test/Reference). Their corresponding 2-sided 90% confidence intervals (CIs) were provided. This method corresponds to 2 one-sided t-test procedures, each at the 5% significance level.90% CI: [106.55, 124.58]
Primary
Maximum Measured Concentration of Nerandomilast in Plasma (Cmax)
Maximum measured concentration of Nerandomilast in plasma (Cmax) is presented. Geometric least square mean (adjusted geometric mean) and geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. These quantities will then be back-transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. This model will include effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment.
Time frame: Within 3 hours before Nerandomilast administration and at 0:15, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 3:30, 4:00, 6:00, 8:00, 11:00, 12:00, 24:00, 34:00, 48:00, 58:00, 72:00, 96:00, 120:00, and 144:00 hours after administration.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nerandomilast fasted state (Reference (R)) | Maximum Measured Concentration of Nerandomilast in Plasma (Cmax) | 412.88 nanomol/Liter (nmol/L) |
| Nerandomilast fed state (Test (T)) | Maximum Measured Concentration of Nerandomilast in Plasma (Cmax) | 354.35 nanomol/Liter (nmol/L) |
Comparison: Relative bioavailability of Nerandomilast administered in fed state (Test) compared with Nerandomilast administered in fasted state (Reference) was estimated by the ratios of the gMeans (Test/Reference). Their corresponding 2-sided 90% confidence intervals (CIs) were provided. This method corresponds to 2 one-sided t-test procedures, each at the 5% significance level.90% CI: [68.8, 107.06]
Secondary
Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of Nerandomilast in plasma over the time interval from 0 extrapolated to infinity is presented. Geometric least square mean (adjusted geometric mean) and geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. These quantities will then be back-transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. This model will include effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment.
Time frame: Within 3 hours before Nerandomilast administration and at 0:15, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 3:30, 4:00, 6:00, 8:00, 11:00, 12:00, 24:00, 34:00, 48:00, 58:00, 72:00, 96:00, 120:00, and 144:00 hours after administration.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nerandomilast fasted state (Reference (R)) | Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2240.58 hour*nanomol/Liter (h*nmol/L) |
| Nerandomilast fed state (Test (T)) | Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2578.16 hour*nanomol/Liter (h*nmol/L) |
Comparison: Relative bioavailability of Nerandomilast administered in fed state (Test) compared with Nerandomilast administered in fasted state (Reference) was estimated by the ratios of the gMeans (Test/Reference). Their corresponding 2-sided 90% confidence intervals (CIs) were provided. This method corresponds to 2 one-sided t-test procedures, each at the 5% significance level.90% CI: [106.38, 124.46]