Healthy
Conditions
Brief summary
The main objective of this trial is to establish the bioequivalence of the BI 1015550 Formulation C2 (Test, T) and the BI 1015550 Formulation C1 (Reference, R), following a single oral dose administration.
Interventions
DRUGNerandomilast
One dose of Formulation C2 (Test treatment - T) administered with approximately 240 mL of water after an overnight fast of at least 10 h. After drug administration, subjects additionally fasted for 4 h.
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
1. Healthy male or female subject 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 2. Age of 18 to 50 years (inclusive) 3. Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) 4. Signed and dated written informed consent in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial Further inclusion criteria apply.
Exclusion criteria
1. Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator 2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 millimetre of mercury (mmHg), diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 beats per minute (bpm) at screening 3. 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 4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator 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 h prior to drug administration, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 34, 48, 58, 72, 96, 120, 144 h after drug administration. | Area under the concentration-time curve of nerandomilast (R-BI 1015550) in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: subjects within sequences as random effect, sequence, period and treatment as fixed effects. These quantities were then back-transformed to the original scale. |
| Maximum Measured Concentration of Nerandomilast in Plasma (Cmax) | Within 3 h prior to drug administration, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 34, 48, 58, 72, 96, 120, 144 h after drug administration. | Maximum measured concentration of nerandomilast (R-BI 1015550) in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: subjects within sequences as random effect, sequence, period and treatment as fixed effects. These quantities were then back-transformed to the original scale. |
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 h prior to drug administration, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 34, 48, 58, 72, 96, 120, 144 h after drug administration. | Area under the concentration-time curve of nerandomilast (R-BI 1015550) in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: subjects within sequences as random effect, sequence, period and treatment as fixed effects. These quantities were then back-transformed to the original scale. |
Countries
Germany
Participant flow
Recruitment details
This was a open-label, randomised, single-dose, two-way crossover trial in healthy subjects to compare the test treatment (T - nerandomilast \[BI 1015550\] Formulation C2) to the reference treatment (R - nerandomilast Formulation C1, as the phase 3 formulation). Subjects were randomly allocated to the 2 treatment sequences (T-R or R-T), and there was a washout period of at least 10 days between the administration of each treatment.
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. Screening procedures also included physical examination, check of vital signs, electrocardiogram, safety laboratory, demographics, relevant medical history, concomitant therapy. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Test Treatment (T), Then Reference Treatment (R): T-R Healthy subjects were administered one tablet of nerandomilast (Formulation C2) (Test treatment - T). After a washout period of at least 10 days, subjects were administered one tablet of nerandomilast (Formulation C1 - phase 3 formulation) (Reference treatment - R).
Both treatments were administered orally with approximately 240 milliliters (mL) of water after an overnight fast of at least 10 hours (h). After drug administration, subjects additionally fasted for 4 h. | 32 |
| Reference Treatment (R), Then Test Treatment (T): R-T Healthy subjects were administered one tablet of nerandomilast (Formulation C1 - phase 3 formulation) (Reference treatment - R). After a washout period of at least 10 days, subjects were administered one tablet of nerandomilast (Formulation C2) (Test treatment - T).
Both treatments were administered orally with approximately 240 mL of water after an overnight fast of at least 10 h. After drug administration, subjects additionally fasted for 4 h. | 32 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout period | Non-compliance from subject with trial procedures | 1 | 0 |
| Washout period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Reference Treatment (R), Then Test Treatment (T): R-T | Total | Test Treatment (T), Then Reference Treatment (R): T-R |
|---|---|---|---|
| Age, Continuous | 35.0 Years STANDARD_DEVIATION 8.3 | 35.5 Years STANDARD_DEVIATION 8.3 | 36.1 Years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 61 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 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 | 32 Participants | 60 Participants | 28 Participants |
| Sex: Female, Male Female | 14 Participants | 31 Participants | 17 Participants |
| Sex: Female, Male Male | 18 Participants | 33 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 63 |
| other Total, other adverse events | 5 / 59 | 2 / 63 |
| serious Total, serious adverse events | 0 / 59 | 0 / 63 |
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 (R-BI 1015550) in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: subjects within sequences as random effect, sequence, period and treatment as fixed effects. These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug administration, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 34, 48, 58, 72, 96, 120, 144 h after drug administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): includes all subjects in the TS who provided at least 1 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 they contributed only 1 PK parameter value for 1 period to the statistical assessment. Only participants with available PK data are included in the analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Test treatment (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) | 2275.77 hour*nanomole/Liter (h*nmol/L) |
| Reference treatment (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) | 2166.70 hour*nanomole/Liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: subjects within sequences as random effect, sequence, period and treatment as fixed effects. These quantities were then back-transformed to the original scale.90% CI: [99.07, 111.36]
Primary
Maximum Measured Concentration of Nerandomilast in Plasma (Cmax)
Maximum measured concentration of nerandomilast (R-BI 1015550) in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: subjects within sequences as random effect, sequence, period and treatment as fixed effects. These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug administration, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 34, 48, 58, 72, 96, 120, 144 h after drug administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): includes all subjects in the TS who provided at least 1 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 they contributed only 1 PK parameter value for 1 period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Test treatment (T) | Maximum Measured Concentration of Nerandomilast in Plasma (Cmax) | 417.47 nanomole/Liter (nmol/L) |
| Reference treatment (R) | Maximum Measured Concentration of Nerandomilast in Plasma (Cmax) | 368.38 nanomole/Liter (nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: subjects within sequences as random effect, sequence, period and treatment as fixed effects. These quantities were then back-transformed to the original scale.90% CI: [102.7, 125.05]
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 (R-BI 1015550) in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: subjects within sequences as random effect, sequence, period and treatment as fixed effects. These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug administration, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 34, 48, 58, 72, 96, 120, 144 h after drug administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): includes all subjects in the TS who provided at least 1 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 they contributed only 1 PK parameter value for 1 period to the statistical assessment. Only participants with available PK data are included in the analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Test treatment (T) | Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2298.06 hour*nanomole/Liter (h*nmol/L) |
| Reference treatment (R) | Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2189.77 hour*nanomole/Liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: subjects within sequences as random effect, sequence, period and treatment as fixed effects. These quantities were then back-transformed to the original scale.90% CI: [99.1, 111.14]