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
DRUGBI 1015550
Participants received two formulations of nerandomilast separated by a washout period
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
two-way crossover
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* 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 * Age of 18 to 50 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) * Signed and dated written informed consent in accordance with International Council for Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial * Female subject who meets any of the following criteria for a highly effective contraception from at least 30 days before the first administration of trial medication until 7 days after last administration Highly effective methods of contraception include: * Use of oral hormonal contraception that prevents ovulation, plus condom * Use of combined (estrogen and progestogen-containing) hormonal contraception that prevents ovulation (intravaginal or transdermal) * Use of progestogen-only hormonal contraception that inhibits ovulation (only injectables or implants) * Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) * Sexually abstinent is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. * Bilateral tubal occlusion \- Women not of childbearing potential (WNOCBP) include: * Permanently surgically sterilised (including hysterectomy, bilateral oophorectomy and bilateral salpingectomy) * Postmenopausal, defined as no menses for 1 year without an alternative medical cause (in questionable cases a blood sample with levels of follicle stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory) WNOCBP are not required to use any methods of contraception. For in vitro fertilization (IVF) and in foreign countries, female subjects should not participate in egg donation and male subjects should not participate in sperm donation from the first study drug administration, for the duration of the study and for at least 7 days after the last study drug 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 millimetre(s) 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 * 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 behaviour * 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 (hrs) prior to and at 15minutes (min), 30min, 45min, 1hrs, 1:15hrs, 1:30hrs, 1:45hrs, 2hrs, 2:30hrs, 3hrs, 3:30hrs, 4hrs, 6hrs, 8hrs, 12hrs, 24hrs, 34hrs, 48hrs, 58hrs, 72hrs, 96hrs, 120hrs, and 144hrs after nerandomilast intake. | Area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. The statistical model applied was an analysis of variance (ANOVA), with 'subjects within sequence' as a random effect and 'sequence,' 'period,' and 'treatment' as fixed effects. |
| Maximum Measured Concentration of Nerandomilast in Plasma (Cmax) | Within 3 hours (hrs) prior to and at 15minutes (min), 30min, 45min, 1hrs, 1:15hrs, 1:30hrs, 1:45hrs, 2hrs, 2:30hrs, 3hrs, 3:30hrs, 4hrs, 6hrs, 8hrs, 12hrs, 24hrs, 34hrs, 48hrs, 58hrs, 72hrs, 96hrs, 120hrs, and 144hrs after nerandomilast intake. | Maximum measured concentration of nerandomilast in plasma (Cmax) is presented. The statistical model applied was an analysis of variance (ANOVA), with 'subjects within sequence' as a random effect and 'sequence,' 'period,' and 'treatment' as fixed effects. |
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 (hrs) prior to and at 15minutes (min), 30min, 45min, 1hrs, 1:15hrs, 1:30hrs, 1:45hrs, 2hrs, 2:30hrs, 3hrs, 3:30hrs, 4hrs, 6hrs, 8hrs, 12hrs, 24hrs, 34hrs, 48hrs, 58hrs, 72hrs, 96hrs, 120hrs, and 144hrs after nerandomilast intake. | Area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented. The statistical model applied was an analysis of variance (ANOVA), with 'subjects within sequence' as a random effect and 'sequence,' 'period,' and 'treatment' as fixed effects. |
Countries
Germany
Participant flow
Recruitment details
The open-label, randomised, single-dose, two-way crossover study aimed to assess the bioequivalence of the BI 1015550 low dose Formulation C2 and the BI 1015550 low dose Formulation C1 (Phase 3 formulation) following oral administration in healthy subjects.
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 |
|---|---|
| BI 1015550 Formulation C1 (Reference, R) Then BI 1015550 Formulation C2 (Test, T) For this two period crossover study arm, participants received treatment in the following order:
Participants received a single oral dose of nerandomilast (BI 1015550), a low dose film coated tablet (formulation C1, titanium dioxide \[TiO2\]-containing phase III formulation, reference (R)) with 240 mL water after an overnight fast of at least 10 h (period 1).
Participants received a single oral dose of nerandomilast (BI 10105550), a low dose film coated tablet (formulation C2, titanium dioxide \[TiO2\] free, test (T)) with 240 mL water after an overnight fast of at least 10 h (period 2).
In between the treatment periods, participants went through a washout period of 10 days. | 32 |
| BI 1015550 Formulation C2 (Test, T) Then BI 1015550 Formulation C1 (Reference, R) For this two period crossover study arm, participants received treatment in the following order:
Participants received a single oral dose of nerandomilast (BI 10105550), a low dose film coated tablet (formulation C2, titanium dioxide \[TiO2\] free, test (T)) with 240 mL water after an overnight fast of at least 10 h (period 1).
Participants received a single oral dose of nerandomilast (BI 1015550), a low dose film coated tablet (formulation C1, titanium dioxide \[TiO2\]-containing phase III formulation, reference (R)) with 240 mL water after an overnight fast of at least 10 h (period 2).
In between the treatment periods, participants went through a washout period of 10 days. | 32 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout period | Adverse Event | 2 | 0 |
| Washout period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | BI 1015550 Formulation C2 (Test, T) Then BI 1015550 Formulation C1 (Reference, R) | Total | BI 1015550 Formulation C1 (Reference, R) Then BI 1015550 Formulation C2 (Test, T) |
|---|---|---|---|
| Age, Continuous | 35.5 Years STANDARD_DEVIATION 8.8 | 34.6 Years STANDARD_DEVIATION 8.5 | 33.7 Years STANDARD_DEVIATION 8.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 62 Participants | 30 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 | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 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 | 31 Participants | 60 Participants | 29 Participants |
| Sex: Female, Male Female | 15 Participants | 21 Participants | 6 Participants |
| Sex: Female, Male Male | 17 Participants | 43 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 0 / 61 |
| other Total, other adverse events | 15 / 64 | 10 / 61 |
| serious Total, serious adverse events | 0 / 64 | 0 / 61 |
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 (AUC0-tz) is presented. The statistical model applied was an analysis of variance (ANOVA), with 'subjects within sequence' as a random effect and 'sequence,' 'period,' and 'treatment' as fixed effects.
Time frame: Within 3 hours (hrs) prior to and at 15minutes (min), 30min, 45min, 1hrs, 1:15hrs, 1:30hrs, 1:45hrs, 2hrs, 2:30hrs, 3hrs, 3:30hrs, 4hrs, 6hrs, 8hrs, 12hrs, 24hrs, 34hrs, 48hrs, 58hrs, 72hrs, 96hrs, 120hrs, and 144hrs after nerandomilast intake.
Population: Pharmacokinetic parameter analysis set (PKS): included all subjects in the treated set (TS) who provided at least one pharmacokinetic (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.~Participants in both arms are not mutually exclusive.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1015550 Formulation C1 (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) | 1270.92 hours*nanomole/Liter (hrs*nmol/L) |
| BI 1015550 Formulation C2 (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) | 1320.24 hours*nanomole/Liter (hrs*nmol/L) |
Comparison: The statistical model applied was an analysis of variance (ANOVA), with 'subjects within sequence' as a random effect and 'sequence,' 'period,' and 'treatment' as fixed effects.90% CI: [101.08, 106.75]
Primary
Maximum Measured Concentration of Nerandomilast in Plasma (Cmax)
Maximum measured concentration of nerandomilast in plasma (Cmax) is presented. The statistical model applied was an analysis of variance (ANOVA), with 'subjects within sequence' as a random effect and 'sequence,' 'period,' and 'treatment' as fixed effects.
Time frame: Within 3 hours (hrs) prior to and at 15minutes (min), 30min, 45min, 1hrs, 1:15hrs, 1:30hrs, 1:45hrs, 2hrs, 2:30hrs, 3hrs, 3:30hrs, 4hrs, 6hrs, 8hrs, 12hrs, 24hrs, 34hrs, 48hrs, 58hrs, 72hrs, 96hrs, 120hrs, and 144hrs after nerandomilast intake.
Population: Pharmacokinetic parameter analysis set (PKS): included all subjects in the treated set (TS) who provided at least one pharmacokinetic (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.~Participants in both arms are not mutually exclusive.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1015550 Formulation C1 (Reference, R) | Maximum Measured Concentration of Nerandomilast in Plasma (Cmax) | 218.84 nanomole/Liter (nmol/L) |
| BI 1015550 Formulation C2 (Test, T) | Maximum Measured Concentration of Nerandomilast in Plasma (Cmax) | 230.48 nanomole/Liter (nmol/L) |
Comparison: The statistical model applied was an analysis of variance (ANOVA), with 'subjects within sequence' as a random effect and 'sequence,' 'period,' and 'treatment' as fixed effects.90% CI: [100.83, 110.01]
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 (AUC0-∞) is presented. The statistical model applied was an analysis of variance (ANOVA), with 'subjects within sequence' as a random effect and 'sequence,' 'period,' and 'treatment' as fixed effects.
Time frame: Within 3 hours (hrs) prior to and at 15minutes (min), 30min, 45min, 1hrs, 1:15hrs, 1:30hrs, 1:45hrs, 2hrs, 2:30hrs, 3hrs, 3:30hrs, 4hrs, 6hrs, 8hrs, 12hrs, 24hrs, 34hrs, 48hrs, 58hrs, 72hrs, 96hrs, 120hrs, and 144hrs after nerandomilast intake.
Population: Pharmacokinetic parameter analysis set (PKS): included all subjects in the treated set (TS) who provided at least one pharmacokinetic (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.~Participants in both arms are not mutually exclusive.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1015550 Formulation C1 (Reference, R) | Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 1284.94 hours*nanomole/Liter (hrs*nmol/L) |
| BI 1015550 Formulation C2 (Test, T) | Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 1333.23 hours*nanomole/Liter (hrs*nmol/L) |
Comparison: The statistical model applied was an analysis of variance (ANOVA), with 'subjects within sequence' as a random effect and 'sequence,' 'period,' and 'treatment' as fixed effects.90% CI: [100.95, 106.65]