Relative Bioavailability of Two Different Formulations of Nerandomilast and Investigation of the Food Effect on New Formulation Following Oral Administration in Healthy Adult Male and Female Subjects (an Open-label, Randomised, Single-dose, Three-way Crossover Trial)
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All trials for Healthy All trials of Nerandomilast 18 mg - adult formulation All trials of Nerandomilast 1 mg - paediatric formulation
-Summary
The main objective of this trial is to investigate two different formulations of nerandomilast and the effect of food on the pharmacokinetics of the new formulation following oral administration.
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+Arms and interventions
| Arm | Type | Interventions | Description |
|---|
| Nerandomilast (18 mg) in treatment sequence R-T1-T2 | Experimental | Drug: Nerandomilast 18 mg - adult formulation; Drug: Nerandomilast 1 mg - paediatric formulation | Participants first received a single oral dose of 1 tablet of 18 milligrams (mg) nerandomilast adult formulation in the fasted state (Reference treatment, R), followed by a single oral dose of 18 tablets of 1 mg nerandomilast pediatric formulation in the fasted state (Treatment, T1), and then 18 tablets of 1 mg of nerandomilast pediatric formulation in the fed state as a single oral dose (Treatment, T2).
Treatments were separated by a wash-out period of at least 7 days and treatments were taken with 240 mL of water after an overnight fast of at least 10 hours (hrs) for R and T1, or after a high-fat, high-calorie breakfast for T2. |
| Nerandomilast (18 mg) in treatment sequence T1-T2-R | Experimental | Drug: Nerandomilast 18 mg - adult formulation; Drug: Nerandomilast 1 mg - paediatric formulation | Participants first received a single oral dose of 18 tablets of 1 mg nerandomilast pediatric formulation in the fasted state (T1), followed by a single oral dose of 18 tablets of 1 mg nerandomilast pediatric formulation in the fed state (T2), and then a single oral dose of 18 mg of nerandomilast adult formulation in the fasted state (R).
Treatments were separated by a wash-out period of at least 7 days and treatments were taken with 240 mL of water after an overnight fast of at least 10 hrs for R and T1, or after a high-fat, high-calorie breakfast for T2. |
| Nerandomilast (18 mg) in treatment sequence T2-R-T1 | Experimental | Drug: Nerandomilast 18 mg - adult formulation; Drug: Nerandomilast 1 mg - paediatric formulation | Participants first received a single oral dose of 18 tablets of 1 mg nerandomilast pediatric formulation in the fed state (T2), followed by a single oral dose of 18 mg of nerandomilast adult formulation in the fasted state (R), and then a single oral dose of 18 tablets of 1 mg nerandomilast pediatric formulation in the fasted state (T1).
Treatments were separated by a wash-out period of at least 7 days and treatments were taken with 240 mL of water after an overnight fast of at least 10 hrs for R and T1, or after a high-fat, high-calorie breakfast for T2. |
- Nerandomilast 18 mg - adult formulation (Drug), also known as BI 1015550, JASCAYD®: BI 1015550, oral tablet
- Nerandomilast 1 mg - paediatric formulation (Drug), also known as BI 1015550, JASCAYD®: BI 1015550, oral tablet
+Outcome measures
Primary outcomes
- AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T1 vs Reference R [Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.]: AUC0-tz (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 to the last quantifiable data point) for Treatment T1 vs Reference R is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% confidence interval (CI).
- AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T2 vs T1 [Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.]: AUC0-tz (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 to the last quantifiable data point) for Treatment T2 vs T1 is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI.
- Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T1 vs Reference R [Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.]: Cmax (maximum measured concentration of nerandomilast in plasma) for Treatment T1 vs Reference R is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI.
- Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T2 vs T1 [Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.]: Cmax (maximum measured concentration of nerandomilast in plasma) for Treatment T2 vs T1 is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI.
Secondary outcomes
- AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T1 vs Reference R [Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.]: AUC0-∞ (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 extrapolated to infinity) for Treatment T1 vs Reference R is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI.
- AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T2 vs T1 [Within 3 hours (hrs) before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 58, 72, and 96 hrs after drug administration. For dosing after 58hrs, a tolerance of +/- 2 hrs was allowed.]: AUC0-∞ (area under the concentration-time curve of nerandomilast in plasma over the time interval from 0 extrapolated to infinity) for Treatment T2 vs T1 is reported. Geometric least square mean (adjusted geometric mean) and standard error (adjusted geometric standard error) were calculated using an analysis of variance (ANOVA) model on the logarithmic scale restricted to the data of interest for each comparison. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the effect 'subjects within sequences' as random and the other effects of sequence, period and treatment were considered as fixed. These quantities were then back-transformed to the original scale to provide the point estimate and the 90% CI.
+Eligibility
Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers
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 55 years (inclusive)
* Body mass index (BMI) 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 Further inclusion criteria apply.
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 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 Further exclusion criteria apply.
+Posted results
Participant flow
| Milestone | Nerandomilast (18 mg) in Treatment Sequence R-T1-T2 | Nerandomilast (18 mg) in Treatment Sequence T1-T2-R | Nerandomilast (18 mg) in Treatment Sequence T2-R-T1 |
|---|
| Started | 5 | 5 | 5 |
| Completed | 5 | 5 | 5 |
| Not completed | 0 | 0 | 0 |
Outcome results
- AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T1 vs Reference R (Primary), Geometric least squares mean, hours*nanomoles/Liter (h·nmol/L): Nerandomilast 18 mg Pediatric (Ped) Fasted State (Treatment T1) 2732.81 +/- NA; Nerandomilast 18 mg Adult Fasted State (Reference R) 2647.2 +/- NA
- AUC0-tz (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) for Treatment T2 vs T1 (Primary), Geometric least squares mean, hours*nanomoles/Liter (h·nmol/L): Nerandomilast 18 mg Ped Fed State (Treatment T2) 2611.55 +/- NA; Nerandomilast 18 mg Ped Fasted State (Treatment T1) 2732.81 +/- NA
- Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T1 vs Reference R (Primary), Geometric least squares mean, nanomoles/Liter (nmol/L): Nerandomilast 18 mg Ped Fasted State (Treatment T1) 501.74 +/- NA; Nerandomilast 18 mg Adult Fasted State (Reference R) 480.85 +/- NA
- Cmax (Maximum Measured Concentration of Nerandomilast in Plasma) for Treatment T2 vs T1 (Primary), Geometric least squares mean, nanomoles/Liter (nmol/L): Nerandomilast 18 mg Ped Fed State (Treatment T2) 344.76 +/- NA; Nerandomilast 18 mg Ped Fasted State (Treatment T1) 501.74 +/- NA
- AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T1 vs Reference R (Secondary), Geometric least squares mean, hours*nanomoles/Liter (h·nmol/L): Nerandomilast 18 mg Pediatric (Ped) Fasted State (Treatment T1) 2748.78 +/- NA; Nerandomilast 18 mg Adult Fasted State (Reference R) 2667.20 +/- NA
- AUC0-∞ (Area Under the Concentration-time Curve of Nerandomilast in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Treatment T2 vs T1 (Secondary), Geometric least squares mean, hours*nanomoles/Liter (h·nmol/L): Nerandomilast 18 mg Ped Fed State (Treatment T2) 2631.39 +/- NA; Nerandomilast 18 mg Ped Fasted State (Treatment T1) 2748.78 +/- NA
Adverse events
Time frame: Adverse events: From intake of trial medication till end of the residual effect period (REP), up to 7 days for each treatment. All-Cause Mortality: Up to 7 days (REP) for each treatment (R, T1, T2), then follow-up (13 days), up to a total of 34 days.
| Arm | Deaths | Serious adverse events | Other adverse events |
|---|
| Nerandomilast 18 mg Adult Fasted State (Reference R) | 0/14 (0.0%) | 0/14 (0.0%) | 6/14 (42.9%) |
| Nerandomilast 18 mg Ped Fasted State (Treatment T1) | 0/15 (0.0%) | 0/15 (0.0%) | 11/15 (73.3%) |
| Nerandomilast 18 mg Ped Fed State (Treatment T2) | 0/15 (0.0%) | 0/15 (0.0%) | 7/15 (46.7%) |
Other adverse events by term
| Term | Organ system | Nerandomilast 18 mg Adult Fasted State (Reference R) | Nerandomilast 18 mg Ped Fasted State (Treatment T1) | Nerandomilast 18 mg Ped Fed State (Treatment T2) |
|---|
| Abdominal distension | Gastrointestinal disorders | 0/14 | 2/15 | 1/15 |
| Constipation | Gastrointestinal disorders | 1/14 | 0/15 | 0/15 |
| Nausea | Gastrointestinal disorders | 2/14 | 2/15 | 2/15 |
| Vomiting | Gastrointestinal disorders | 0/14 | 0/15 | 2/15 |
| Fatigue | General disorders | 1/14 | 0/15 | 0/15 |
| Peripheral swelling | General disorders | 0/14 | 0/15 | 1/15 |
| Nasopharyngitis | Infections and infestations | 0/14 | 1/15 | 0/15 |
| Contusion | Injury, poisoning and procedural complications | 0/14 | 1/15 | 0/15 |
| Muscle spasms | Musculoskeletal and connective tissue disorders | 0/14 | 1/15 | 0/15 |
| Myalgia | Musculoskeletal and connective tissue disorders | 1/14 | 0/15 | 0/15 |
| Neck pain | Musculoskeletal and connective tissue disorders | 0/14 | 1/15 | 0/15 |
| Pain in extremity | Musculoskeletal and connective tissue disorders | 1/14 | 2/15 | 0/15 |
| Dizziness | Nervous system disorders | 2/14 | 0/15 | 0/15 |
| Headache | Nervous system disorders | 4/14 | 7/15 | 6/15 |
| Paraesthesia | Nervous system disorders | 0/14 | 1/15 | 0/15 |
| Presyncope | Nervous system disorders | 0/14 | 0/15 | 1/15 |
| Somnolence | Nervous system disorders | 0/14 | 1/15 | 0/15 |
| Dysmenorrhoea | Reproductive system and breast disorders | 1/14 | 0/15 | 0/15 |
| Skin lesion | Skin and subcutaneous tissue disorders | 0/14 | 2/15 | 0/15 |
| Haematoma | Vascular disorders | 0/14 | 0/15 | 1/15 |
+Locations (1)
| Facility | City | Country | Status |
|---|
| Humanpharmakologisches Zentrum Biberach | Biberach | Germany | |
+Study documents