Healthy
Conditions
Brief summary
BI 1810631 trial formulation 1 (TF1) is currently used in clinical trials, but is planned to be replaced by another formulation (principle) in future clinical trials and on the market. This trial intends to bridge pharmacokinetics (PK) between the two formulation principles. For this, relative bioavailability of TF1 and new formulation (NF) is assessed. Moreover the trial intends to inform on the effect of food and of the proton pump inhibitor rabeprazole on the PK of BI 1810631 after administration as NF in order to inform management of food and concomitant medications.
Interventions
DRUGBI 1810631 - trial formulation 1 (TF1)
BI 1810631 - trial formulation 1 (TF1)
DRUGBI 1810631 - new formulation (NF)
BI 1810631 - new formulation (NF)
DRUGRabeprazole sodium
Rabeprazole sodium
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
4-way crossover
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male 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 45 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 weight divided by height squared (kg/m2) (inclusive) * Signed and dated written informed consent in accordance with International Council on Harmonisation - Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial
Exclusion criteria
* Any finding in the medical examination (including blood pressure (BP), pulse rate (PR) or electrocardiogram (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 of mercury (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 * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * 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 * History of relevant orthostatic hypotension, fainting spells, or blackouts * further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours prior and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 46, 70, 94 and 118 hours after BI 1810631 administration. | The area under the concentration-time curve of BI 1810631 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) was reported. Unit of geometric coefficient of variation (gCV) is %. |
| Maximum Measured Concentration of BI 1810631 in Plasma (Cmax) | Within 3 hours prior and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 46, 70, 94 and 118 hours after BI 1810631 administration. | The maximum measured concentration of BI 1810631 in plasma (Cmax) was reported. Unit of geometric coefficient of variation (gCV) is %. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours prior and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 46, 70, 94 and 118 hours after BI 1810631 administration. | The area under the concentration-time curve of BI 1810631 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) was reported. Unit of geometric coefficient of variation (gCV) is %. |
Countries
Germany
Participant flow
Recruitment details
This study was to investigate the relative bioavailability of 2 different BI 1810631 oral formulations (trial formulation 1 \[TF1\], Reference \[R\] and new formulation \[NF\], Test 1 \[T1\]) under fasting conditions; BI 1810631 NF under fasting (T1) and fed (T2) conditions; BI 1810631 NF given alone (T1) and together with the proton pump inhibitor rabeprazole (T3) under fasting conditions.
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 |
|---|---|
| Treatment Sequence 1: R - T1 - T2 - T3 The treatment sequence R-T1-T2-T3 was administered. The treatments were separated by a washout interval of at least 14 days between BI 1810631 administrations.
Reference (R): 30 mg BI 1810631 as trial formulation 1 (TF1) were administered orally as single dose once on Day 1 of respective period under fasted condition.
Test 1 (T1): 30 mg BI 1810631 as new formulation (NF) were administered orally as single dose once on Day 1 of respective period under fasted condition.
T2: 30 mg BI 1810631 as NF were administered orally as single dose once on Day 1 of respective period under fed condition.
T3: 2 gastroresistant tablets of 20 mg Pariet® (rabeprazole; 40 mg per dose) were administered orally once daily over Day -4 to Day 1 (5 days in total) of respective period; 30 mg BI 1810631 as NF were administered orally as single dose once on Day 1 of respective period under fasted condition. | 3 |
| Treatment Sequence 2: T1 - T3 - R - T2 The treatment sequence T1 - T3 - R - T2 was administered. The treatments were separated by a washout interval of at least 14 days between BI 1810631 administrations.
Reference (R): 30 mg BI 1810631 as trial formulation 1 (TF1) were administered orally as single dose once on Day 1 of respective period under fasted condition.
Test 1 (T1): 30 mg BI 1810631 as new formulation (NF) were administered orally as single dose once on Day 1 of respective period under fasted condition.
T2: 30 mg BI 1810631 as NF were administered orally as single dose once on Day 1 of respective period under fed condition.
T3: 2 gastroresistant tablets of 20 mg Pariet® (rabeprazole; 40 mg per dose) were administered orally once daily over Day -4 to Day 1 (5 days in total) of respective period; 30 mg BI 1810631 as NF were administered orally as single dose once on Day 1 of respective period under fasted condition. | 4 |
| Treatment Sequence 3: T2 - R - T3 - T1 The treatment sequence T2 - R - T3 - T1 was administered. The treatments were separated by a washout interval of at least 14 days between BI 1810631 administrations.
Reference (R): 30 mg BI 1810631 as trial formulation 1 (TF1) were administered orally as single dose once on Day 1 of respective period under fasted condition.
Test 1 (T1): 30 mg BI 1810631 as new formulation (NF) were administered orally as single dose once on Day 1 of respective period under fasted condition.
T2: 30 mg BI 1810631 as NF were administered orally as single dose once on Day 1 of respective period under fed condition.
T3: 2 gastroresistant tablets of 20 mg Pariet® (rabeprazole; 40 mg per dose) were administered orally once daily over Day -4 to Day 1 (5 days in total) of respective period; 30 mg BI 1810631 as NF were administered orally as single dose once on Day 1 of respective period under fasted condition. | 3 |
| Treatment Sequence 4: T3 - T2 - T1 - R The treatment sequence T3 - T2 - T1 - R was administered. The treatments were separated by a washout interval of at least 14 days between BI 1810631 administrations.
Reference (R): 30 mg BI 1810631 as trial formulation 1 (TF1) were administered orally as single dose once on Day 1 of respective period under fasted condition.
Test 1 (T1): 30 mg BI 1810631 as new formulation (NF) were administered orally as single dose once on Day 1 of respective period under fasted condition.
T2: 30 mg BI 1810631 as NF were administered orally as single dose once on Day 1 of respective period under fed condition.
T3: 2 gastroresistant tablets of 20 mg Pariet® (rabeprazole; 40 mg per dose) were administered orally once daily over Day -4 to Day 1 (5 days in total) of respective period; 30 mg BI 1810631 as NF were administered orally as single dose once on Day 1 of respective period under fasted condition. | 3 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Washout Period 1 | Not attend visit | 1 | 0 | 0 | 0 |
| Washout Period 2 | Adverse Event | 1 | 0 | 0 | 0 |
| Washout Period 3 | Adverse Event | 0 | 1 | 0 | 0 |
| Washout Period 3 | Not attend visit | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Treatment Sequence 1: R - T1 - T2 - T3 | Treatment Sequence 2: T1 - T3 - R - T2 | Treatment Sequence 3: T2 - R - T3 - T1 | Treatment Sequence 4: T3 - T2 - T1 - R | Total |
|---|---|---|---|---|---|
| Age, Continuous | 37.7 Years STANDARD_DEVIATION 7 | 33.5 Years STANDARD_DEVIATION 3.1 | 34.7 Years STANDARD_DEVIATION 8.5 | 34.0 Years STANDARD_DEVIATION 7.2 | 34.8 Years STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 12 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 13 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 9 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 4 / 12 | 1 / 12 | 4 / 9 | 2 / 11 | 4 / 11 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 9 | 0 / 11 | 0 / 11 |
Outcome results
Primary
Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
The area under the concentration-time curve of BI 1810631 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) was reported. Unit of geometric coefficient of variation (gCV) is %.
Time frame: Within 3 hours prior and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 46, 70, 94 and 118 hours after BI 1810631 administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): this set included all subjects in the treated set who provided at least 1 PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| TF1 Fasted (R) | Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 4240 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 52.7 |
| NF Fasted (T1) | Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 5680 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 18.8 |
| NF Fed (T2) | Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 4060 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 13.7 |
| NF Fasted + Rabeprazole (T3) | Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 5410 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 27.6 |
90% CI: [99.7, 183.6]
90% CI: [67.6, 81.6]
90% CI: [85.8, 110]
Primary
Maximum Measured Concentration of BI 1810631 in Plasma (Cmax)
The maximum measured concentration of BI 1810631 in plasma (Cmax) was reported. Unit of geometric coefficient of variation (gCV) is %.
Time frame: Within 3 hours prior and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 46, 70, 94 and 118 hours after BI 1810631 administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): this set included all subjects in the treated set who provided at least 1 PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| TF1 Fasted (R) | Maximum Measured Concentration of BI 1810631 in Plasma (Cmax) | 291 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 93.1 |
| NF Fasted (T1) | Maximum Measured Concentration of BI 1810631 in Plasma (Cmax) | 399 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 37.3 |
| NF Fed (T2) | Maximum Measured Concentration of BI 1810631 in Plasma (Cmax) | 208 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 31.4 |
| NF Fasted + Rabeprazole (T3) | Maximum Measured Concentration of BI 1810631 in Plasma (Cmax) | 327 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 34.2 |
90% CI: [87.7, 221.3]
90% CI: [40.5, 70.8]
90% CI: [66.8, 113.2]
Secondary
Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
The area under the concentration-time curve of BI 1810631 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) was reported. Unit of geometric coefficient of variation (gCV) is %.
Time frame: Within 3 hours prior and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 46, 70, 94 and 118 hours after BI 1810631 administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): this set included all subjects in the treated set who provided at least 1 PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| TF1 Fasted (R) | Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 4550 hour * nanomole / Liter (h * nmol/L) | Geometric Coefficient of Variation 52.7 |
| NF Fasted (T1) | Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 5980 hour * nanomole / Liter (h * nmol/L) | Geometric Coefficient of Variation 19.2 |
| NF Fed (T2) | Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 4310 hour * nanomole / Liter (h * nmol/L) | Geometric Coefficient of Variation 14.2 |
| NF Fasted + Rabeprazole (T3) | Area Under the Concentration-time Curve of BI 1810631 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 5660 hour * nanomole / Liter (h * nmol/L) | Geometric Coefficient of Variation 28.8 |
90% CI: [96.2, 173.4]
90% CI: [68.6, 81.7]
90% CI: [85.3, 110.2]