Healthy
Conditions
Brief summary
The primary objective of this trial is to investigate the relative bioavailability of rosuvastatin when given alone (Reference treatment, R) compared to when given together with one of the three different doses of metformin (10 mg, Test treatment 1 (T1); 50 mg (T2); 500 mg (T3)) or one of the two doses of furosemide (1 mg (T4); 5 mg (T5)).
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male subjects according to the investigators assessment, based on a complete medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests 2. Age of 18 to 55 years (incl.) 3. BMI of 18.5 to 29.9 kg/m2 (incl.) 4. Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation
Exclusion criteria
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from normal and judged as clinically relevant by the investigator 2. 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 bpm 3. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance 4. Any evidence of a concomitant disease judged as clinically relevant by the investigator 5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders 6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair) 7. Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders 8. History of relevant orthostatic hypotension, fainting spells, or blackouts 9. Chronic or relevant acute infections 10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients) 11. Intake of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication 12. Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial 13. Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication 14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) 15. Inability to refrain from smoking on specified trial days 16. Alcohol abuse (consumption of more than 30 g per day) 17. Drug abuse or positive drug screening 18. Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial 19. Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial 20. Inability to comply with dietary regimen of trial site 21. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study In addition, the following trial-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve of Rosuvastatin From 0 to the Last Quantifiable Data Point (AUC0-tz) | Blood sampling within 3 hours (h) prior to the study drug administration, at the time of administration (0:00) and 30 minutes, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11h, 12h, 24h, 34h, and 48h thereafter. | This outcome measure presents the area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). |
| Maximum Concentration of Rosuvastatin (Cmax) | Blood sampling within 3 hours (h) prior to the study drug administration, at the time of administration (0:00) and 30 minutes, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11h, 12h, 24h, 34h, and 48h thereafter. | This outcome measure presents the maximum measured concentration of rosuvastatin in plasma (Cmax). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC0-∞) | Blood sampling within 3 hours (h) prior to the study drug administration, at the time of administration (0:00) and 30 minutes, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11h, 12h, 24h, 34h, and 48h thereafter. | This outcome measure presents area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). |
Countries
Germany
Participant flow
Recruitment details
All subjects were screened for eligibility to participate in the study. No run-in or wash-out period was conducted, since the trial was conducted in healthy subjects, that were not expected to take medications regularly. Actual number of subjects enrolled in fact represents randomized subjects due to the study set up.
Pre-assignment details
All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (T) 1-T3-Reference (REF)-T5-T2-T4 The subjects received test treatment 1 (T1) which is 10 milligram (mg) metformin hydrochloride (oral solution, brand name: MetfoLiquid GeriaSan) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor) followed by test treatment 3 (T3) which is 500mg metformin hydrochloride together with REF followed by REF alone followed by test treatment 5 (T5) which is 5 mg furosemide (oral solution, brand name: Lasix liquidum) together with REF followed by test treatment 2 (T2) which is 50 mg of metformin hydrochloride together with REF followed by test treatment 4 (T4) which is 1mg of furosemide together with REF. Trial medication was administered as a single oral dose in the fasted state in each treatment period. The six single dose treatment periods were separated from each other by a wash-out period of at least 6 days between the drug administrations. | 3 |
| T2-REF-T4-T1-T5-T3 The subjects received T2, followed by REF alone, followed by T4, followed by T1, followed by T5 and followed by T3. Trial medication was administered as a single oral dose in the fasted state in each treatment period. The six single dose treatment periods were separated from each other by a wash-out period of at least 6 days between the drug administrations. | 3 |
| T3-T5-T1-T4-REF-T2 The subjects received T3, followed by T5, followed by T1, followed by T4, followed by REF alone and followed by T2. Trial medication was administered as a single oral dose in the fasted state in each treatment period. The six single dose treatment periods were separated from each other by a wash-out period of at least 6 days between the drug administrations. | 3 |
| T4-T2-T5-REF-T3-T1 The subjects received T4, followed by T2, followed by T5, followed by REF alone, followed by T3 and followed by T1. Trial medication was administered as a single oral dose in the fasted state in each treatment period. The six single dose treatment periods were separated from each other by a wash-out period of at least 6 days between the drug administrations. | 3 |
| T5-T4-T3-T2-T1-REF The subjects received T5, followed by T4, followed by T3, followed by T2, followed by T1 and followed by REF alone. Trial medication was administered as a single oral dose in the fasted state in each treatment period. The six single dose treatment periods were separated from each other by a wash-out period of at least 6 days between the drug administrations. | 3 |
| REF-T1-T2-T3-T4-T5 The subjects received REF alone, followed by T1, followed by T2, followed by T3, followed by T4 and followed by T5. Trial medication was administered as a single oral dose in the fasted state in each treatment period. The six single dose treatment periods were separated from each other by a wash-out period of at least 6 days between the drug administrations. | 3 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Consent withdrawn further participation | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment (T) 1-T3-Reference (REF)-T5-T2-T4 | T2-REF-T4-T1-T5-T3 | T3-T5-T1-T4-REF-T2 | T4-T2-T5-REF-T3-T1 | T5-T4-T3-T2-T1-REF | REF-T1-T2-T3-T4-T5 | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 28.0 years STANDARD_DEVIATION 2.6 | 33.0 years STANDARD_DEVIATION 8.7 | 39.3 years STANDARD_DEVIATION 10.3 | 32.0 years STANDARD_DEVIATION 14.1 | 22.0 years STANDARD_DEVIATION 2.6 | 37.3 years STANDARD_DEVIATION 12.9 | 31.9 years STANDARD_DEVIATION 10 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 18 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 | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 16 | 4 / 15 | 2 / 17 | 2 / 15 | 3 / 15 | 2 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 | 0 / 17 | 0 / 15 | 0 / 15 | 0 / 16 |
Outcome results
Primary
Area Under the Curve of Rosuvastatin From 0 to the Last Quantifiable Data Point (AUC0-tz)
This outcome measure presents the area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz).
Time frame: Blood sampling within 3 hours (h) prior to the study drug administration, at the time of administration (0:00) and 30 minutes, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11h, 12h, 24h, 34h, and 48h thereafter.
Population: The pharmacokinetic (PK) parameter set (PKS) includes all randomised subjects who took at least one dose of study medication and provided at least one primary or secondary PK parameter that was not excluded from analysis due to non-evaluability or protocol violation relevant for the evaluation of the pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| REF Alone | Area Under the Curve of Rosuvastatin From 0 to the Last Quantifiable Data Point (AUC0-tz) | 81.5 nanomol (nmol) * hour (h) / Litre (L) | Geometric Coefficient of Variation 50.9 |
| Treatment 1 | Area Under the Curve of Rosuvastatin From 0 to the Last Quantifiable Data Point (AUC0-tz) | 87.8 nanomol (nmol) * hour (h) / Litre (L) | Geometric Coefficient of Variation 54.5 |
| Treatment 2 | Area Under the Curve of Rosuvastatin From 0 to the Last Quantifiable Data Point (AUC0-tz) | 88.7 nanomol (nmol) * hour (h) / Litre (L) | Geometric Coefficient of Variation 62.4 |
| Treatment 3 | Area Under the Curve of Rosuvastatin From 0 to the Last Quantifiable Data Point (AUC0-tz) | 126 nanomol (nmol) * hour (h) / Litre (L) | Geometric Coefficient of Variation 66.7 |
| Treatment 4 | Area Under the Curve of Rosuvastatin From 0 to the Last Quantifiable Data Point (AUC0-tz) | 91.5 nanomol (nmol) * hour (h) / Litre (L) | Geometric Coefficient of Variation 55.4 |
| Treatment 5 | Area Under the Curve of Rosuvastatin From 0 to the Last Quantifiable Data Point (AUC0-tz) | 97.2 nanomol (nmol) * hour (h) / Litre (L) | Geometric Coefficient of Variation 52.7 |
Comparison: This statistical analysis assess the effect of coadministration of 10 mg metformin hydrochloride on the primary outcome measure of the REF treatment.90% CI: [89.49, 116.15]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 50 mg metformin hydrochloride on the primary outcome measure of the REF treatment.90% CI: [96.12, 117.11]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 500 mg metformin hydrochloride on the primary outcome measure of the REF treatment.90% CI: [135.12, 171.41]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 1 mg furosemide on the primary outcome measure of the REF treatment.90% CI: [94.34, 121.3]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 5 mg furosemide on the primary outcome measure of the REF treatment.90% CI: [101.93, 131.82]ANOVA
Primary
Maximum Concentration of Rosuvastatin (Cmax)
This outcome measure presents the maximum measured concentration of rosuvastatin in plasma (Cmax).
Time frame: Blood sampling within 3 hours (h) prior to the study drug administration, at the time of administration (0:00) and 30 minutes, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11h, 12h, 24h, 34h, and 48h thereafter.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| REF Alone | Maximum Concentration of Rosuvastatin (Cmax) | 9.04 nmol/L | Geometric Coefficient of Variation 52.4 |
| Treatment 1 | Maximum Concentration of Rosuvastatin (Cmax) | 9.59 nmol/L | Geometric Coefficient of Variation 60.5 |
| Treatment 2 | Maximum Concentration of Rosuvastatin (Cmax) | 9.94 nmol/L | Geometric Coefficient of Variation 69.4 |
| Treatment 3 | Maximum Concentration of Rosuvastatin (Cmax) | 14.0 nmol/L | Geometric Coefficient of Variation 71.2 |
| Treatment 4 | Maximum Concentration of Rosuvastatin (Cmax) | 9.90 nmol/L | Geometric Coefficient of Variation 62 |
| Treatment 5 | Maximum Concentration of Rosuvastatin (Cmax) | 10.8 nmol/L | Geometric Coefficient of Variation 62.7 |
Comparison: This statistical analysis assess the effect of coadministration of 10 mg metformin hydrochloride on the primary outcome measure of the REF treatment.90% CI: [87.19, 120.42]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 50 mg metformin hydrochloride on the primary outcome measure of the REF treatment.90% CI: [92.54, 123.69]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 500 mg metformin hydrochloride on the primary outcome measure of the REF treatment.90% CI: [131.7, 180.24]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 1 mg furosemide on the primary outcome measure of the REF treatment.90% CI: [91.78, 124.3]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 5 mg furosemide on the primary outcome measure of the REF treatment.90% CI: [98.27, 141.65]ANOVA
Secondary
Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC0-∞)
This outcome measure presents area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞).
Time frame: Blood sampling within 3 hours (h) prior to the study drug administration, at the time of administration (0:00) and 30 minutes, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11h, 12h, 24h, 34h, and 48h thereafter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| REF Alone | Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC0-∞) | 99.7 nmol*h/L | Geometric Coefficient of Variation 39 |
| Treatment 1 | Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC0-∞) | 105 nmol*h/L | Geometric Coefficient of Variation 48 |
| Treatment 2 | Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC0-∞) | 102 nmol*h/L | Geometric Coefficient of Variation 55 |
| Treatment 3 | Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC0-∞) | 149 nmol*h/L | Geometric Coefficient of Variation 49.8 |
| Treatment 4 | Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC0-∞) | 108 nmol*h/L | Geometric Coefficient of Variation 47.9 |
| Treatment 5 | Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC0-∞) | 115 nmol*h/L | Geometric Coefficient of Variation 42 |
Comparison: This statistical analysis assess the effect of coadministration of 10 mg metformin hydrochloride on the primary outcome measure of the REF treatment.90% CI: [89.23, 114.82]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 50 mg metformin hydrochloride on the primary outcome measure of the REF treatment.90% CI: [97.65, 117.81]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 500 mg metformin hydrochloride on the primary outcome measure of the REF treatment.90% CI: [135.21, 158.62]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 1 mg furosemide on the primary outcome measure of the REF treatment.90% CI: [92.2, 121]ANOVA
Comparison: This statistical analysis assess the effect of coadministration of 5 mg furosemide on the primary outcome measure of the REF treatment.90% CI: [106.75, 130.67]ANOVA