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| ID | Type | Description | Link |
|---|---|---|---|
| 2015-003052-46 | EudraCT Number |
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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)).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| R (Reference) Rosuvastatin | Experimental | 1film-coated tablet as single dose, fasted |
|
| T1 (Test 1) Rosuvastatin + Metformin HCl | Experimental | Rosuvastatin: 1 film-coated tablet as single dose (10 mg), fasted / Metformin HCl (10 mg) as single dose, fasted |
|
| T2 (Test 2) Rosuvastatin + Metformin HCl | Experimental | Rosuvastatin: 1 film-coated tablet as single dose (10 mg), fasted / Metformin HCl (50 mg) as single dose, fasted |
|
| T3 (Test 3) Rosuvastatin + Metformin HCl | Experimental | Rosuvastatin: 1 film-coated tablet as single dose (10 mg), fasted / Metformin HCl (500 mg) as single dose, fasted |
|
| T4 (Test 4) Rosuvastatin + Furosemide | Experimental | Rosuvastatin: 1 film-coated tablet as single dose (10 mg), fasted / Furosemide: (1 mg) as single dose, fasted |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rosuvastatin | Drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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). | 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. |
| Maximum Concentration of Rosuvastatin (Cmax) | This outcome measure presents the maximum measured concentration of rosuvastatin in plasma (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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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-∞). | 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. |
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Inclusion criteria:
Exclusion criteria:
Any finding in the medical examination (including BP, PR or ECG) is deviating from normal and judged 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 bpm
Any laboratory value outside the reference range that the investigator considers to be of clinical relevance
Any evidence of a concomitant disease judged as clinically relevant by the investigator
Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and 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
Chronic or relevant acute infections
History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients)
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
Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial
Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication
Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
Inability to refrain from smoking on specified trial days
Alcohol abuse (consumption of more than 30 g per day)
Drug abuse or positive drug screening
Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial
Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial
Inability to comply with dietary regimen of trial site
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 exclusion criteria apply:
Myopathy
Hereditary galactose or fructose intolerance, lactase deficiency, or glucose-galactose malabsorption
Allergy or hypersensitivity against sulfonamides
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| Name | Affiliation | Role |
|---|---|---|
| Boehringer Ingelheim | Boehringer Ingelheim | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Humanpharmakologisches Zentrum Biberach | Biberach | 88397 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28685495 | Derived | Stopfer P, Giessmann T, Hohl K, Sharma A, Ishiguro N, Taub ME, Jungnik A, Gansser D, Ebner T, Muller F. Effects of Metformin and Furosemide on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Implications for Their Use as Probe Drugs in a Transporter Cocktail. Eur J Drug Metab Pharmacokinet. 2018 Feb;43(1):69-80. doi: 10.1007/s13318-017-0427-9. |
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Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents. Exceptions might apply, e.g. studies in products where Boehringer Ingelheim is not the license holder; studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; studies conducted in a single center or targeting rare diseases (in case of low number of patients and therefore limitations with anonymization).
For more details refer to: https://www.mystudywindow.com/msw/datatransparency
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| FG003 | 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. |
| FG004 | 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. |
| FG005 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The randomised set (RS) includes all randomised subjects, whether treated or not.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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). | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanomol (nmol) * hour (h) / Litre (L) | 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. |
|
From the first administration of study medication to the end of the 4 day residual effect period (96 hours after each administration of study medication) up to 24 days in total.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | REF Alone | The subjects received the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Photophobia | Eye disorders | MedDRA 18.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boehringer Ingelheim, Call Center | Boehringer Ingelheim | 1-800-243-0127 | clintriage.rdg@boehringer-ingelheim.com |
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| ID | Term |
|---|---|
| D000068718 | Rosuvastatin Calcium |
| D008687 | Metformin |
| D005665 | Furosemide |
| ID | Term |
|---|---|
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D005464 | Fluorobenzenes |
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| T5 (Test 5) Rosuvastatin + Furosemide | Experimental | Rosuvastatin: 1 film-coated tablet as single dose (10 mg), fasted / Furosemide: (5 mg) as single dose, fasted |
|
| Metformin HCl | Drug |
|
| Furosemide | Drug |
|
| Adverse Event |
|
| BG001 | 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. |
| BG002 | 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. |
| BG003 | 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. |
| BG004 | 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. |
| BG005 | 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. |
| BG006 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
The subjects received the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state.
| OG001 | Treatment 1 | The subjects received test treatment 1 which is 10 mg metformin hydrochloride (oral solution, brand name: MetfoLiquid GeriaSan) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. |
| OG002 | Treatment 2 | The subjects received test treatment 2 which is 50 mg metformin hydrochloride (oral solution, brand name: MetfoLiquid GeriaSan) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. |
| OG003 | Treatment 3 | The subjects received test treatment 3 which is 500 mg metformin hydrochloride (oral solution, brand name: MetfoLiquid GeriaSan) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. |
| OG004 | Treatment 4 | The subjects received test treatment 4 which is 1 mg furosemide (oral solution, brand name: Lasix liquidum) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. |
| OG005 | Treatment 5 | The subjects received test treatment 5 which is 5 mg furosemide (oral solution, brand name: Lasix liquidum) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. |
|
|
|
| Primary | Maximum Concentration of Rosuvastatin (Cmax) | This outcome measure presents the maximum measured concentration of rosuvastatin in plasma (Cmax). | PKS | Posted | Geometric Mean | Geometric Coefficient of Variation | nmol/L | 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. |
|
|
|
|
| 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-∞). | Posted | Geometric Mean | Geometric Coefficient of Variation | nmol*h/L | 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. |
|
|
|
|
| 0 |
| 16 |
| 4 |
| 16 |
| EG001 | Treatment 1 | The subjects received test treatment 1 which is 10 mg metformin hydrochloride (oral solution, brand name: MetfoLiquid GeriaSan) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. | 0 | 15 | 4 | 15 |
| EG002 | Treatment 2 | The subjects received test treatment 2 which is 50 mg metformin hydrochloride (oral solution, brand name: MetfoLiquid GeriaSan) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. | 0 | 17 | 2 | 17 |
| EG003 | Treatment 3 | The subjects received test treatment 3 which is 500 mg metformin hydrochloride (oral solution, brand name: MetfoLiquid GeriaSan) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. | 0 | 15 | 2 | 15 |
| EG004 | Treatment 4 | The subjects received test treatment 4 which is 1 mg furosemide (oral solution, brand name: Lasix liquidum) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. | 0 | 15 | 3 | 15 |
| EG005 | Treatment 5 | The subjects received test treatment 5 which is 5 mg furosemide (oral solution, brand name: Lasix liquidum) together with the reference treatment (REF) which is rosuvastatin (film-coated, brand name: Crestor). Trial medication was administered as a single oral dose in the fasted state. | 0 | 16 | 2 | 16 |
| Toothache | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Rhinitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA 18.1 | Systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA 18.1 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Haematoma | Vascular disorders | MedDRA 18.1 | Systematic Assessment |
|
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| D006845 |
| Hydrocarbons, Fluorinated |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D013424 | Sulfanilamides |
| D000814 | Aniline Compounds |
| D000588 | Amines |
|
This statistical analysis assess the effect of coadministration of 50 mg metformin hydrochloride on the primary outcome measure of the REF treatment. |
| ANOVA |
ANOVA model on the logarithmic scale including the effects: 'sequence', 'subjects within sequence', 'period' and 'treatment'. |
| Adjusted geometric mean ratio T2/REF (%) |
| 106.98 |
| 2-Sided |
| 90 |
| 92.54 |
| 123.69 |
| Superiority or Other (legacy) |
| This statistical analysis assess the effect of coadministration of 500 mg metformin hydrochloride on the primary outcome measure of the REF treatment. | ANOVA | ANOVA model on the logarithmic scale including the effects: 'sequence', 'subjects within sequence', 'period' and 'treatment'. | Adjusted geometric mean ratio T3/REF (%) | 154.07 | 2-Sided | 90 | 131.70 | 180.24 | Superiority or Other (legacy) |
| This statistical analysis assess the effect of coadministration of 1 mg furosemide on the primary outcome measure of the REF treatment. | ANOVA | ANOVA model on the logarithmic scale including the effects: 'sequence', 'subjects within sequence', 'period' and 'treatment'. | Adjusted geometric mean ratio T4/REF (%) | 106.81 | 2-Sided | 90 | 91.78 | 124.30 | Superiority or Other (legacy) |
| This statistical analysis assess the effect of coadministration of 5 mg furosemide on the primary outcome measure of the REF treatment. | ANOVA | ANOVA model on the logarithmic scale including the effects: 'sequence', 'subjects within sequence', 'period' and 'treatment'. | Adjusted geometric mean ratio T5/REF (%) | 117.98 | 2-Sided | 90 | 98.27 | 141.65 | Superiority or Other (legacy) |
|
This statistical analysis assess the effect of coadministration of 50 mg metformin hydrochloride on the primary outcome measure of the REF treatment. |
| ANOVA |
ANOVA model on the logarithmic scale including the effects: 'sequence', 'subjects within sequence', 'period' and 'treatment'. |
| Adjusted geometric mean ratio T2/REF (%) |
| 107.26 |
| 2-Sided |
| 90 |
| 97.65 |
| 117.81 |
| Superiority or Other (legacy) |
| This statistical analysis assess the effect of coadministration of 500 mg metformin hydrochloride on the primary outcome measure of the REF treatment. | ANOVA | ANOVA model on the logarithmic scale including the effects: 'sequence', 'subjects within sequence', 'period' and 'treatment'. | Adjusted geometric mean ratio T3/REF (%) | 146.45 | 2-Sided | 90 | 135.21 | 158.62 | Superiority or Other (legacy) |
| This statistical analysis assess the effect of coadministration of 1 mg furosemide on the primary outcome measure of the REF treatment. | ANOVA | ANOVA model on the logarithmic scale including the effects: 'sequence', 'subjects within sequence', 'period' and 'treatment'. | Adjusted geometric mean ratio T4/REF (%) | 105.63 | 2-Sided | 90 | 92.20 | 121.00 | Superiority or Other (legacy) |
| This statistical analysis assess the effect of coadministration of 5 mg furosemide on the primary outcome measure of the REF treatment. | ANOVA | ANOVA model on the logarithmic scale including the effects: 'sequence', 'subjects within sequence', 'period' and 'treatment'. | Adjusted geometric mean ratio T5/REF (%) | 118.10 | 2-Sided | 90 | 106.75 | 130.67 | Superiority or Other (legacy) |