Healthy
Conditions
Brief summary
The main objective of this trial is to investigate two different formulations of nerandomilast and the effect of food on the pharmacokinetics of the new formulation following oral administration.
Interventions
BI 1015550, oral tablet
DRUGNerandomilast 1 mg - paediatric formulation
BI 1015550, oral tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 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 55 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 kg/m² (inclusive) * Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial Further inclusion criteria apply.
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 45 to 90 beats per minute (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 Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T1 vs Reference R | Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed. | AUC0-tz (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 to the last quantifiable data point) for Treatment T1 vs Reference R is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% confidence interval (CI). |
| AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T2 vs T1 | Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed. | AUC0-tz (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 to the last quantifiable data point) for Treatment T2 vs T1 is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI. |
| Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T1 vs Reference R | Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed. | Cmax (maximum measured concentration of nerandomilast in plasma) for Treatment T1 vs Reference R is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI. |
| Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T2 vs T1 | Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed. | Cmax (maximum measured concentration of nerandomilast in plasma) for Treatment T2 vs T1 is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T1 vs Reference R | Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed. | AUC0-∞ (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 extrapolated to infinity) for Treatment T1 vs Reference R is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI. |
| AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T2 vs T1 | Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed. | AUC0-∞ (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 extrapolated to infinity) for Treatment T2 vs T1 is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI. |
Countries
Germany
Participant flow
Recruitment details
This trial was an open-label, single dose, 3-way crossover design. Subjects were randomly allocated to one of 3 treatment sequences. Each subject participated in 3 treatment periods, receiving a single dose in each, with a washout period of at least 7 days between treatments.
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 (18 mg) in Treatment Sequence R-T1-T2 Participants first received a single oral dose of 1 tablet of 18 milligrams (mg) nerandomilast adult formulation in the fasted state (Reference treatment, R), followed by a single oral dose of 18 tablets of 1 mg nerandomilast pediatric formulation in the fasted state (Treatment, T1), and then 18 tablets of 1 mg of nerandomilast pediatric formulation in the fed state as a single oral dose (Treatment, T2).
Treatments were separated by a wash-out period of at least 7 days and treatments were taken with 240 mL of water after an overnight fast of at least 10 hours (hrs) for R and T1, or after a high-fat, high-calorie breakfast for T2. | 5 |
| Nerandomilast (18 mg) in Treatment Sequence T1-T2-R Participants first received a single oral dose of 18 tablets of 1 mg nerandomilast pediatric formulation in the fasted state (T1), followed by a single oral dose of 18 tablets of 1 mg nerandomilast pediatric formulation in the fed state (T2), and then a single oral dose of 18 mg of nerandomilast adult formulation in the fasted state (R).
Treatments were separated by a wash-out period of at least 7 days and treatments were taken with 240 mL of water after an overnight fast of at least 10 hrs for R and T1, or after a high-fat, high-calorie breakfast for T2. | 5 |
| Nerandomilast (18 mg) in Treatment Sequence T2-R-T1 Participants first received a single oral dose of 18 tablets of 1 mg nerandomilast pediatric formulation in the fed state (T2), followed by a single oral dose of 18 mg of nerandomilast adult formulation in the fasted state (R), and then a single oral dose of 18 tablets of 1 mg nerandomilast pediatric formulation in the fasted state (T1).
Treatments were separated by a wash-out period of at least 7 days and treatments were taken with 240 mL of water after an overnight fast of at least 10 hrs for R and T1, or after a high-fat, high-calorie breakfast for T2. | 5 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Washout Period 1 (7 days) | Adverse Event | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Nerandomilast (18 mg) in Treatment Sequence R-T1-T2 | Nerandomilast (18 mg) in Treatment Sequence T1-T2-R | Nerandomilast (18 mg) in Treatment Sequence T2-R-T1 | Total |
|---|---|---|---|---|
| Age, Continuous | 40.2 Years STANDARD_DEVIATION 10.5 | 37.8 Years STANDARD_DEVIATION 10.1 | 39.8 Years STANDARD_DEVIATION 8.6 | 39.3 Years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 5 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 5 Participants | 15 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 6 / 14 | 11 / 15 | 7 / 15 |
| serious Total, serious adverse events | 0 / 14 | 0 / 15 | 0 / 15 |
Outcome results
Primary
AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T1 vs Reference R
AUC0-tz (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 to the last quantifiable data point) for Treatment T1 vs Reference R is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% confidence interval (CI).
Time frame: Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided 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. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment. Only participants with available data were analyzed.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nerandomilast 18 mg Pediatric (Ped) Fasted State (Treatment T1) | AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T1 vs Reference R | 2732.81 hours*nanomoles/Liter (h·nmol/L) |
| Nerandomilast 18 mg Adult Fasted State (Reference R) | AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T1 vs Reference R | 2647.2 hours*nanomoles/Liter (h·nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale.90% CI: [97.31, 109.52]
Primary
AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T2 vs T1
AUC0-tz (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 to the last quantifiable data point) for Treatment T2 vs T1 is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI.
Time frame: Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided 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. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nerandomilast 18 mg Pediatric (Ped) Fasted State (Treatment T1) | AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T2 vs T1 | 2611.55 hours*nanomoles/Liter (h·nmol/L) |
| Nerandomilast 18 mg Adult Fasted State (Reference R) | AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T2 vs T1 | 2732.81 hours*nanomoles/Liter (h·nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale.90% CI: [89.37, 102.18]
Primary
Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T1 vs Reference R
Cmax (maximum measured concentration of nerandomilast in plasma) for Treatment T1 vs Reference R is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI.
Time frame: Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided 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. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment. Only participants with available data were analyzed.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nerandomilast 18 mg Pediatric (Ped) Fasted State (Treatment T1) | Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T1 vs Reference R | 501.74 nanomoles/Liter (nmol/L) |
| Nerandomilast 18 mg Adult Fasted State (Reference R) | Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T1 vs Reference R | 480.85 nanomoles/Liter (nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale.90% CI: [91, 119.65]
Primary
Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T2 vs T1
Cmax (maximum measured concentration of nerandomilast in plasma) for Treatment T2 vs T1 is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI.
Time frame: Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided 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. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nerandomilast 18 mg Pediatric (Ped) Fasted State (Treatment T1) | Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T2 vs T1 | 344.76 nanomoles/Liter (nmol/L) |
| Nerandomilast 18 mg Adult Fasted State (Reference R) | Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T2 vs T1 | 501.74 nanomoles/Liter (nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale.90% CI: [61.23, 77.11]
Secondary
AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T1 vs Reference R
AUC0-∞ (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 extrapolated to infinity) for Treatment T1 vs Reference R is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI.
Time frame: Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided 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. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment. Only participants with available data were analyzed.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nerandomilast 18 mg Pediatric (Ped) Fasted State (Treatment T1) | AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T1 vs Reference R | 2748.78 hours*nanomoles/Liter (h·nmol/L) |
| Nerandomilast 18 mg Adult Fasted State (Reference R) | AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T1 vs Reference R | 2667.20 hours*nanomoles/Liter (h·nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale.90% CI: [97.22, 109.25]
Secondary
AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T2 vs T1
AUC0-∞ (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 extrapolated to infinity) for Treatment T2 vs T1 is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI.
Time frame: Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided 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. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nerandomilast 18 mg Pediatric (Ped) Fasted State (Treatment T1) | AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T2 vs T1 | 2631.39 hours*nanomoles/Liter (h·nmol/L) |
| Nerandomilast 18 mg Adult Fasted State (Reference R) | AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T2 vs T1 | 2748.78 hours*nanomoles/Liter (h·nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale.90% CI: [89.47, 102.42]