Healthy
Conditions
Brief summary
The main objective of this trial is to assess single dose drug exposure of several newly developed formulation prototypes of Nintedanib compared to Ofev® following oral administration.
Interventions
DRUGOfev®
Ofev®
DRUGNintedanib formulation 1
Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2).
DRUGNintedanib formulation 2
Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2).
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male subjects (Caucasian and Black only) according to the investigator's assessment, based on a complete medical history including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiograms (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) and absolute body weight of at least 65 kg. * Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation. * Non-smokers for at least 6 months. * Subjects who are sexually active must use with their partner, highly effective contraception from the time of administration of trial medication until 30 days after administration of trial medication. Adequate methods are: * Condoms plus use of hormonal contraception by the female partner that started at least 2 months prior to administration of trial medication (e.g., implants, injectables, combined oral or vaginal contraceptives, intrauterine device) or; * Condoms plus surgical sterilization (vasectomy at least 1 year prior to enrolment) or; * Condoms plus surgically sterilised partner (including hysterectomy) or; * Condoms plus intrauterine device or; * Condoms plus partner of non-childbearing potential (including homosexual men). Subjects are required to use condoms to prevent unintended exposure of the partner (both, male and female) to the study drug via seminal fluid. Male subjects should use a condom throughout the study and for 30 days after last Investigational Medicinal Product (IMP) administration. Alternatively, true abstinence is acceptable when it is in line with the subject's preferred and usual lifestyle. If a subject is usually not sexually active but becomes active with their partner, they must comply with the contraceptive requirements detailed above. Male subjects should not donate sperm for the duration of the study and for at least 30 days after last IMP administration. Male subjects with pregnant or lactating partners are allowed.
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 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. * Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results. * Liver enzymes (Aspartate amino transferase (AST) and Alanine amino transferase (ALT)) above upper limit of normal at the screening examination. * Any evidence of a concomitant disease assessed as clinically relevant by the investigator. * Clinically significant gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, dermatological or hormonal disorders. Subjects with Gilbert's syndrome are not permitted. * Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair). Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 Extrapolated to Infinity Which Includes Also the Second Nintedanib (Ofev®) Dose of the Day (AUC₀-∞) | Within 3 hours (h) prior and 1, 2, 3, 4, 6, 8, 10, 12, 13 (except MR1, MR2), 14, 15, 16, 17 (except R), 18, 20, 22, 24, 34, 48, 58, and 72 h after administration. | The area under the concentration-time curve over the time interval from 0 \[first dose\] extrapolated to infinity (AUC₀-∞) was analyzed in 3 different formulations of Nintedanib (MR1, MR2 and Ofev®) and in two cohorts: * Cohort 1: Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2), * Cohort 2: Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2), and each compared to the reference (R) treatment: Nintedanib formulation 3: Ofev® capsules. The adjusted geometric least squares mean and adjusted geometric standard error were calculated by an analysis of variance (ANOVA) model on the logarithmic scale. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC₀-tz) | Within 3 hours (h) prior and 1, 2, 3, 4, 6, 8, 10, 12, 13 (except MR1, MR2), 14, 15, 16, 17 (except R), 18, 20, 22, 24, 34, 48, 58, and 72 h after administration. | The area under the concentration-time curve over the time interval from 0 to the last quantifiable data point (AUC₀-tz) was analyzed in 3 different formulations of Nintedanib (MR1, MR2 and Ofev®) and in two cohorts: * Cohort 1: Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2), * Cohort 2: Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2), and each compared to the reference (R) treatment: Nintedanib formulation 3: Ofev® capsules. The adjusted geometric least squares mean and adjusted geometric standard error were calculated by an analysis of variance (ANOVA) model on the logarithmic scale. |
| Maximum Measured Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Within the 24h Dosing Interval (Cmax) | Within 3 hours (h) prior and 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 13.0 (except MR1, MR2), 14.0, 15.0, 16.0, 17.0 (except R), 18.0, 20.0, 22.0, 24.0, 34.0, 48.0, 58.0, and 72 h after administration | The maximum measured concentration in plasma was analyzed in 3 different formulations of Nintedanib (MR1, MR2 and Ofev®) and in two cohorts: * Cohort 1: Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2), * Cohort 2: Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2), and each compared to the reference (R) treatment: Nintedanib formulation 3: Ofev® capsules. The adjusted geometric least squares mean and adjusted geometric standard error were calculated by an analysis of variance (ANOVA) model on the logarithmic scale. |
| Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma 24 Hours After the First Dose (C₂₄) | Within 3 hours (h) prior and 1, 2, 3, 4, 6, 8, 10, 12, 13 (except MR1, MR2), 14, 15, 16, 17 (except R), 18, 20, 22, 24, 34, 48, 58, and 72 h after administration. | The measured concentration in plasma 24 hours after first administration was analyzed in 3 different formulations of Nintedanib (MR1, MR2 and Ofev®) and in two cohorts: * Cohort 1: Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2), * Cohort 2: Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2), and each compared to the reference (R) treatment: Nintedanib formulation 3: Ofev® capsules. The adjusted geometric least squares mean and adjusted geometric standard error were calculated by an analysis of variance (ANOVA) model on the logarithmic scale. |
Countries
United Kingdom
Participant flow
Recruitment details
This trial was a randomised, open-label, crossover, single-dose (once daily \[qd\] for test and twice daily \[bid\] for reference treatment) study in up to 3 parts; trial part 1: 2 parallel groups (Cohort 1, Cohort 2), each a randomised three-period crossover; trial part 2 (optional): one group of randomised three-period crossover; trial part 3 (optional): one group of randomised two-period crossover. Parts 2 and 3 were not performed. The trial was stopped as per protocol during trial part 1.
Pre-assignment details
Only participants that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All participants were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all participants was adhered to throughout the trial conduct. Rescue medication was allowed for all participants as required.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: R | MR1-1 | MR1-2 In this arm participants were treated at 3 treatment visits (= 3 treatment periods). There was a washout period of at least 14 days between each treatment visit, i.e. the morning dose in the preceding treatment period and the morning dose in the following treatment period were separated by at least 14 days.
Treatments:
* First: R, a low oral dose of Ofev® capsule bid with 240 milliliter (ml) of water after a light breakfast and dinner, respectively;
* Second: MR1-1, a single medium oral dose of Nintedanib MR1-1 tablet with 240 ml water in the morning after a light breakfast;
* Third: MR1-2, a single medium oral dose of Nintedanib MR1-2 tablet with 240 ml water in the morning after a light breakfast.
Abbreviations:
R=Reference=Ofev® capsules, MR1-1=Monolithic Nintedanib Modified Release Prototype 1 Tablet, MR1-2=Monolithic Nintedanib Modified Release Prototype 2 Tablet. | 3 |
| Cohort 1: MR1-2 | R | MR1-1 In this arm participants were treated at 3 treatment visits (= 3 treatment periods). There was a washout period of at least 14 days between each treatment visit, i.e. the morning dose in the preceding treatment period and the morning dose in the following treatment period were separated by at least 14 days.
Treatments:
* First: MR1-2, a single medium oral dose of Nintedanib MR1-2 tablet with 240 ml water in the morning after a light breakfast;
* Second: R, a low oral dose of Ofev® capsule bid with 240 ml of water after a light breakfast and dinner, respectively;
* Third: MR1-1, a single medium oral dose of Nintedanib MR1-1 tablet with 240 ml water in the morning after a light breakfast. | 2 |
| Cohort 1: MR1-1 | MR1-2 | R In this arm participants were treated at 3 treatment visits (= 3 treatment periods). There was a washout period of at least 14 days between each treatment visit, i.e. the morning dose in the preceding treatment period and the morning dose in the following treatment period were separated by at least 14 days.
Treatments:
* First: MR1-1, a single medium oral dose of Nintedanib MR1-1 tablet with 240 ml water in the morning after a light breakfast;
* Second: MR1-2, a single medium oral dose of Nintedanib MR1-2 tablet with 240 ml water in the morning after a light breakfast;
* Third: R, a low oral dose of Ofev® capsule bid with 240 ml of water after a light breakfast and dinner, respectively. | 2 |
| Cohort 2: R | MR2-1 | MR2-2 In this arm participants were treated at 3 treatment visits (= 3 treatment periods). There was a washout period of at least 14 days between each treatment visit, i.e. the morning dose in the preceding treatment period and the morning dose in the following treatment period were separated by at least 14 days.
Treatments:
* First: R, a low oral dose of Ofev® capsule bid with 240 ml of water after a light breakfast and dinner, respectively;
* Second: MR2-1, a single medium oral dose of Nintedanib MR2-1 tablet with 240 ml water in the morning after a light breakfast;
* Third: MR2-2, a single medium oral dose of Nintedanib MR2-2 tablet with 240 ml water in the morning after a light breakfast.
Abbreviations:
R=Reference=Ofev® capsules, MR2-1=Polyox Nintedanib Modified Release Prototype 1 Tablet, MR2-2=Polyox Nintedanib Modified Release Prototype 2 Tablet. | 5 |
| Cohort 2: MR2-2 | R | MR2-1 In this arm participants were treated at 3 treatment visits (= 3 treatment periods). There was a washout period of at least 14 days between each treatment visit, i.e. the morning dose in the preceding treatment period and the morning dose in the following treatment period were separated by at least 14 days.
Treatments:
* First: MR2-2, a single medium oral dose of Nintedanib MR2-2 tablet with 240 ml water in the morning after a light breakfast;
* Second: R, a low oral dose of Ofev® capsule bid with 240 ml of water after a light breakfast and dinner, respectively;
* Third: MR2-1, a single medium oral dose of Nintedanib MR2-1 tablet with 240 ml water in the morning after a light breakfast. | 5 |
| Cohort 2: MR2-1 | MR2-2 | R In this arm participants were treated at 3 treatment visits (= 3 treatment periods). There was a washout period of at least 14 days between each treatment visit, i.e. the morning dose in the preceding treatment period and the morning dose in the following treatment period were separated by at least 14 days.
Treatments:
* First: MR2-1, a single medium oral dose of Nintedanib MR2-1 tablet with 240 ml water in the morning after a light breakfast;
* Second: MR2-2, a single medium oral dose of Nintedanib MR2-2 tablet with 240 ml water in the morning after a light breakfast;
* Third: R, a low oral dose of Ofev® capsule bid with 240 ml of water after a light breakfast and dinner, respectively. | 4 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 3 | Not treated because of an adverse event | 0 | 1 | 0 | 0 | 0 | 0 |
| Washout Period 2 | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: R | MR1-1 | MR1-2 | Cohort 1: MR1-2 | R | MR1-1 | Cohort 1: MR1-1 | MR1-2 | R | Cohort 2: R | MR2-1 | MR2-2 | Cohort 2: MR2-2 | R | MR2-1 | Cohort 2: MR2-1 | MR2-2 | R | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 42.7 Years STANDARD_DEVIATION 16.2 | 36.5 Years STANDARD_DEVIATION 20.5 | 44.5 Years STANDARD_DEVIATION 7.8 | 35.8 Years STANDARD_DEVIATION 8.6 | 32.2 Years STANDARD_DEVIATION 9.2 | 34.5 Years STANDARD_DEVIATION 11.6 | 36.6 Years STANDARD_DEVIATION 10.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 2 Participants | 5 Participants | 5 Participants | 4 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 1 Participants | 5 Participants | 4 Participants | 4 Participants | 19 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 2 Participants | 5 Participants | 5 Participants | 4 Participants | 21 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 14 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 3 / 7 | 1 / 6 | 0 / 6 | 4 / 14 | 4 / 14 | 3 / 14 |
| serious Total, serious adverse events | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 Extrapolated to Infinity Which Includes Also the Second Nintedanib (Ofev®) Dose of the Day (AUC₀-∞)
The area under the concentration-time curve over the time interval from 0 \[first dose\] extrapolated to infinity (AUC₀-∞) was analyzed in 3 different formulations of Nintedanib (MR1, MR2 and Ofev®) and in two cohorts: * Cohort 1: Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2), * Cohort 2: Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2), and each compared to the reference (R) treatment: Nintedanib formulation 3: Ofev® capsules. The adjusted geometric least squares mean and adjusted geometric standard error were calculated by an analysis of variance (ANOVA) model on the logarithmic scale.
Time frame: Within 3 hours (h) prior and 1, 2, 3, 4, 6, 8, 10, 12, 13 (except MR1, MR2), 14, 15, 16, 17 (except R), 18, 20, 22, 24, 34, 48, 58, and 72 h after administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Only subjects with available PK data were included in this analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1: Reference (R) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 Extrapolated to Infinity Which Includes Also the Second Nintedanib (Ofev®) Dose of the Day (AUC₀-∞) | 359.80 Hours times nanogram per milliliter |
| Cohort 1: Test Treatment 1 (MR1-1) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 Extrapolated to Infinity Which Includes Also the Second Nintedanib (Ofev®) Dose of the Day (AUC₀-∞) | 60.04 Hours times nanogram per milliliter |
| Cohort 1: Test Treatment 2 (MR1-2) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 Extrapolated to Infinity Which Includes Also the Second Nintedanib (Ofev®) Dose of the Day (AUC₀-∞) | 48.72 Hours times nanogram per milliliter |
| Cohort 2: Reference (R) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 Extrapolated to Infinity Which Includes Also the Second Nintedanib (Ofev®) Dose of the Day (AUC₀-∞) | 241.32 Hours times nanogram per milliliter |
| Cohort 2: Test Treatment 1 (MR2-1) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 Extrapolated to Infinity Which Includes Also the Second Nintedanib (Ofev®) Dose of the Day (AUC₀-∞) | 100.88 Hours times nanogram per milliliter |
| Cohort 2: Test Treatment 2 (MR2-2) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 Extrapolated to Infinity Which Includes Also the Second Nintedanib (Ofev®) Dose of the Day (AUC₀-∞) | 103.55 Hours times nanogram per milliliter |
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [7.28, 38.24]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [8.1, 22.64]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [34.24, 51.04]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [34.9, 52.76]
Secondary
Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC₀-tz)
The area under the concentration-time curve over the time interval from 0 to the last quantifiable data point (AUC₀-tz) was analyzed in 3 different formulations of Nintedanib (MR1, MR2 and Ofev®) and in two cohorts: * Cohort 1: Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2), * Cohort 2: Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2), and each compared to the reference (R) treatment: Nintedanib formulation 3: Ofev® capsules. The adjusted geometric least squares mean and adjusted geometric standard error were calculated by an analysis of variance (ANOVA) model on the logarithmic scale.
Time frame: Within 3 hours (h) prior and 1, 2, 3, 4, 6, 8, 10, 12, 13 (except MR1, MR2), 14, 15, 16, 17 (except R), 18, 20, 22, 24, 34, 48, 58, and 72 h after administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Only subjects with available PK data were included in this analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1: Reference (R) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC₀-tz) | 326.48 Hours times nanogram per milliliter |
| Cohort 1: Test Treatment 1 (MR1-1) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC₀-tz) | 30.54 Hours times nanogram per milliliter |
| Cohort 1: Test Treatment 2 (MR1-2) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC₀-tz) | 40.51 Hours times nanogram per milliliter |
| Cohort 2: Reference (R) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC₀-tz) | 226.69 Hours times nanogram per milliliter |
| Cohort 2: Test Treatment 1 (MR2-1) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC₀-tz) | 85.91 Hours times nanogram per milliliter |
| Cohort 2: Test Treatment 2 (MR2-2) | Area Under the Concentration-time Curve of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC₀-tz) | 81.35 Hours times nanogram per milliliter |
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [5.91, 14.8]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [7.93, 19.43]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [29.25, 49.11]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [27.66, 46.55]
Secondary
Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma 24 Hours After the First Dose (C₂₄)
The measured concentration in plasma 24 hours after first administration was analyzed in 3 different formulations of Nintedanib (MR1, MR2 and Ofev®) and in two cohorts: * Cohort 1: Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2), * Cohort 2: Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2), and each compared to the reference (R) treatment: Nintedanib formulation 3: Ofev® capsules. The adjusted geometric least squares mean and adjusted geometric standard error were calculated by an analysis of variance (ANOVA) model on the logarithmic scale.
Time frame: Within 3 hours (h) prior and 1, 2, 3, 4, 6, 8, 10, 12, 13 (except MR1, MR2), 14, 15, 16, 17 (except R), 18, 20, 22, 24, 34, 48, 58, and 72 h after administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Only subjects with available PK data were included in this analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1: Reference (R) | Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma 24 Hours After the First Dose (C₂₄) | 5.48 Nanogram per milliliter |
| Cohort 1: Test Treatment 1 (MR1-1) | Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma 24 Hours After the First Dose (C₂₄) | 0.66 Nanogram per milliliter |
| Cohort 1: Test Treatment 2 (MR1-2) | Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma 24 Hours After the First Dose (C₂₄) | 0.77 Nanogram per milliliter |
| Cohort 2: Reference (R) | Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma 24 Hours After the First Dose (C₂₄) | 4.10 Nanogram per milliliter |
| Cohort 2: Test Treatment 1 (MR2-1) | Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma 24 Hours After the First Dose (C₂₄) | 1.32 Nanogram per milliliter |
| Cohort 2: Test Treatment 2 (MR2-2) | Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma 24 Hours After the First Dose (C₂₄) | 1.29 Nanogram per milliliter |
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [8.88, 16.11]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [10.59, 18.46]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [26.46, 39.01]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [25.71, 38.3]
Secondary
Maximum Measured Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Within the 24h Dosing Interval (Cmax)
The maximum measured concentration in plasma was analyzed in 3 different formulations of Nintedanib (MR1, MR2 and Ofev®) and in two cohorts: * Cohort 1: Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2), * Cohort 2: Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2), and each compared to the reference (R) treatment: Nintedanib formulation 3: Ofev® capsules. The adjusted geometric least squares mean and adjusted geometric standard error were calculated by an analysis of variance (ANOVA) model on the logarithmic scale.
Time frame: Within 3 hours (h) prior and 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 13.0 (except MR1, MR2), 14.0, 15.0, 16.0, 17.0 (except R), 18.0, 20.0, 22.0, 24.0, 34.0, 48.0, 58.0, and 72 h after administration
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Only subjects with available PK data were included in this analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1: Reference (R) | Maximum Measured Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Within the 24h Dosing Interval (Cmax) | 32.02 Nanogram per milliliter |
| Cohort 1: Test Treatment 1 (MR1-1) | Maximum Measured Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Within the 24h Dosing Interval (Cmax) | 3.87 Nanogram per milliliter |
| Cohort 1: Test Treatment 2 (MR1-2) | Maximum Measured Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Within the 24h Dosing Interval (Cmax) | 7.66 Nanogram per milliliter |
| Cohort 2: Reference (R) | Maximum Measured Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Within the 24h Dosing Interval (Cmax) | 17.55 Nanogram per milliliter |
| Cohort 2: Test Treatment 1 (MR2-1) | Maximum Measured Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Within the 24h Dosing Interval (Cmax) | 12.03 Nanogram per milliliter |
| Cohort 2: Test Treatment 2 (MR2-2) | Maximum Measured Concentration of 3 Different Formulations of Nintedanib (MR1, MR2 and Ofev®) in Plasma Within the 24h Dosing Interval (Cmax) | 11.73 Nanogram per milliliter |
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [6.73, 21.71]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [13.51, 42.42]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [50.07, 93.86]
Comparison: Analysis of Variance (ANOVA) model (logarithmic scale) with the effects: sequence, subjects within sequences, period, and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [48.77, 91.64]