Healthy
Conditions
Brief summary
The main objective of this trial is to establish the bioequivalence of zongertinib tablet from manufacturer 1 (Test, T) compared with zongertinib tablet from manufacturer 2 (reference, R) following oral administration.
Interventions
DRUGZongertinib manufacturer 1
Zongertinib
DRUGZongertinib manufacturer 2
Zongertinib
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) * BMI (Body mass index) 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 * Either male subject, or female subject who meet any of the following criteria for a highly effective contraception from at least 30 days before the first administration of trial medication until 30 days after trial completion: * Use of progestogen-only hormonal contraception that inhibits ovulation (only injectables or implants), plus condom * Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) * Sexually abstinent * A vasectomised sexual partner who received medical assessment of the surgical success (documented absence of sperm) and provided that partner is the sole sexual partner of the trial participant * Surgically sterilised (including hysterectomy or bilateral tubular occlusion) * 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)
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 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 Zongertinib in Plasma Over the Time Interval From 0 to 72h (AUC0-72h) | Within 3 hours prior to and 0.50, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours after administration of zongertinib Test Treatment and zongertinib Reference Treatment. | Area under the concentration-time curve of zongertinib in plasma over the time interval from 0 to 72h (AUC0-72h) is reported. Geometric least squares mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance model (ANOVA) on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included 'subjects within sequences' as a random effect, and sequence, period and treatment as fixed. These quantities were then back transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. |
| Maximum Measured Concentration of Zongertinib in Plasma (Cmax) | Within 3 hours prior to and 0.50, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours after administration of zongertinib Test Treatment and zongertinib Reference Treatment. | Maximum measured concentration of zongertinib in plasma (Cmax) is reported. Geometric least squares mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance model (ANOVA) on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included 'subjects within sequences' as a random effect, and sequence, period and treatment as fixed. These quantities were then back transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Dosing to Maximum Measured Concentration of Zongertinib in Plasma (Tmax) | Within 3 hours prior to and 0.50, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours after administration of zongertinib Test Treatment and zongertinib Reference Treatment. | Time from dosing to maximum measured concentration of zongertinib in plasma (tmax) is reported. |
Countries
Germany
Participant flow
Recruitment details
This was an open-label, randomised, single-dose, two-period and two-sequence crossover trial in healthy male and female subjects to compare a test treatment (T) to a reference treatment (R). The test and reference treatments comprised 60 mg zongertinib tablet manufactured by two different manufacturers. Subjects were randomly allocated to the two treatment sequences, namely T-R or R-T (i.e. all subjects received both treatments), with a washout period of at least 14 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 |
|---|---|
| First Zongertinib Test, Then Zongertinib Reference (T-R) Participants were administered during Period 1 on Day 1 a single oral dose of 60 milligrams (mg) of zongertinib film-coated tablet produced by Manufacturer 1 (Test treatment, T) with 240 milliliters (ml) of water following an overnight fast of at least 10 hours (hrs).
Following a washout period of at least 14 days, participants were administered a single oral dose of 60 mg of zongertinib produced by Manufacturer 2 (Reference treatment, R) with 240 mL of water after an overnight fast of at least 10 hrs. | 28 |
| First Zongertinib Reference, Then Zongertinib Test (R-T) Participants were administered during Period 1 on Day 1 a single oral dose of 60 mg of zongertinib film-coated tablet produced by Manufacturer 2 (Reference treatment, R) with 240 ml of water following an overnight fast of at least 10 hrs.
Following a washout period of at least 14 days, participants were administered a single oral dose of 60 mg of zongertinib produced by Manufacturer 1 (Test treatment, T) with 240 mL of water after an overnight fast of at least 10 hrs. | 28 |
| Total | 56 |
Baseline characteristics
| Characteristic | First Zongertinib Reference, Then Zongertinib Test (R-T) | Total | First Zongertinib Test, Then Zongertinib Reference (T-R) |
|---|---|---|---|
| Age, Continuous | 31.7 Years STANDARD_DEVIATION 7.7 | 32.1 Years STANDARD_DEVIATION 8.3 | 32.5 Years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 54 Participants | 27 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 | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 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 | 26 Participants | 53 Participants | 27 Participants |
| Sex: Female, Male Female | 10 Participants | 18 Participants | 8 Participants |
| Sex: Female, Male Male | 18 Participants | 38 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 56 |
| other Total, other adverse events | 13 / 56 | 13 / 56 |
| serious Total, serious adverse events | 0 / 56 | 0 / 56 |
Outcome results
Primary
Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to 72h (AUC0-72h)
Area under the concentration-time curve of zongertinib in plasma over the time interval from 0 to 72h (AUC0-72h) is reported. Geometric least squares mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance model (ANOVA) on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included 'subjects within sequences' as a random effect, and sequence, period and treatment as fixed. These quantities were then back transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint.
Time frame: Within 3 hours prior to and 0.50, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours after administration of zongertinib Test Treatment and zongertinib Reference Treatment.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least 1 primary or secondary PK endpoint and were 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) |
|---|---|---|
| Zongertinib Test Treatment (T) | Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to 72h (AUC0-72h) | 13448.03 hours*nanomole/Liter (h·nmol/L) |
| Zongertinib Reference Treatment (R) | Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to 72h (AUC0-72h) | 13463.07 hours*nanomole/Liter (h·nmol/L) |
Comparison: PK endpoints were back transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. The model included effects accounting for variation in sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the others were considered as fixed. Confidence intervals were calculated based on the residual error from the ANOVA.p-value: <0.000190% CI: [97.08, 102.78]ANOVA
Primary
Maximum Measured Concentration of Zongertinib in Plasma (Cmax)
Maximum measured concentration of zongertinib in plasma (Cmax) is reported. Geometric least squares mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance model (ANOVA) on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included 'subjects within sequences' as a random effect, and sequence, period and treatment as fixed. These quantities were then back transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint.
Time frame: Within 3 hours prior to and 0.50, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours after administration of zongertinib Test Treatment and zongertinib Reference Treatment.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least 1 primary or secondary PK endpoint and were 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) |
|---|---|---|
| Zongertinib Test Treatment (T) | Maximum Measured Concentration of Zongertinib in Plasma (Cmax) | 1135.49 nanomole/Liter (nmol/L) |
| Zongertinib Reference Treatment (R) | Maximum Measured Concentration of Zongertinib in Plasma (Cmax) | 1126.11 nanomole/Liter (nmol/L) |
Comparison: PK endpoints were back transformed to the original scale to provide the point estimate and 90% confidence intervals (CIs) for each endpoint. The model included effects accounting for variation in sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the others were considered as fixed. Confidence intervals were calculated based on the residual error from the ANOVA.p-value: <0.000190% CI: [96.43, 105.44]ANOVA
Secondary
Time From Dosing to Maximum Measured Concentration of Zongertinib in Plasma (Tmax)
Time from dosing to maximum measured concentration of zongertinib in plasma (tmax) is reported.
Time frame: Within 3 hours prior to and 0.50, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours after administration of zongertinib Test Treatment and zongertinib Reference Treatment.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least 1 primary or secondary PK endpoint and were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zongertinib Test Treatment (T) | Time From Dosing to Maximum Measured Concentration of Zongertinib in Plasma (Tmax) | 2.50 hours (h) |
| Zongertinib Reference Treatment (R) | Time From Dosing to Maximum Measured Concentration of Zongertinib in Plasma (Tmax) | 2.01 hours (h) |