DDI (Effect of Metformin and Furosemide on Rosuvastatin PK)

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02574845
• Collaborator: (none)
• Enrollment: 18
• Location: 1
• Arms: 6
• Duration (Months): 2
• Patients Per Site Per Month: 9

Study Details

Study Description

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)).

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Rosuvastatin; Drug: Metformin HCl; Drug: Furosemide	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Effect of Different Doses of Metformin or Furosemide on Rosuvastatin Pharmacokinetics Following Oral Administration in Healthy Male Subjects (an Open-label, Randomised, Single-dose, Six-way Crossover Study)
• Study Start Date: Oct 1, 2015
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: R (Reference) Rosuvastatin 1film-coated tablet as single dose, fasted	Drug: Rosuvastatin
Experimental: T1 (Test 1) Rosuvastatin + Metformin HCl Rosuvastatin: 1 film-coated tablet as single dose (10 mg), fasted / Metformin HCl (10 mg) as single dose, fasted	Drug: Rosuvastatin; Drug: Metformin HCl
Experimental: T2 (Test 2) Rosuvastatin + Metformin HCl Rosuvastatin: 1 film-coated tablet as single dose (10 mg), fasted / Metformin HCl (50 mg) as single dose, fasted	Drug: Rosuvastatin; Drug: Metformin HCl
Experimental: T3 (Test 3) Rosuvastatin + Metformin HCl Rosuvastatin: 1 film-coated tablet as single dose (10 mg), fasted / Metformin HCl (500 mg) as single dose, fasted	Drug: Rosuvastatin; Drug: Metformin HCl
Experimental: T4 (Test 4) Rosuvastatin + Furosemide Rosuvastatin: 1 film-coated tablet as single dose (10 mg), fasted / Furosemide: (1 mg) as single dose, fasted	Drug: Rosuvastatin; Drug: Furosemide
Experimental: T5 (Test 5) Rosuvastatin + Furosemide Rosuvastatin: 1 film-coated tablet as single dose (10 mg), fasted / Furosemide: (5 mg) as single dose, fasted	Drug: Rosuvastatin; Drug: Furosemide

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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 Outcome Measures

1. 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-∞).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts 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 exclusion criteria apply:

1. Myopathy

2. Hereditary galactose or fructose intolerance, lactase deficiency, or glucose-galactose malabsorption

3. Allergy or hypersensitivity against sulfonamides

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Boehringer Ingelheim Investigational Site	Biberach		Germany

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02574845
• Other Study ID Numbers: 352.2094; 2015-003052-46
• First Posted: Oct 14, 2015
• Last Update Posted: Feb 13, 2017
• Last Verified: Dec 1, 2016

• Additional relevant MeSH terms: Metformin; Furosemide; Rosuvastatin Calcium

Study Results

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 Detail	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.

Arm/Group Title	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
Arm/Group Description	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.	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.	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.	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.	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.	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.
Period Title: Overall Study
STARTED	3	3	3	3	3	3
Received T1	3	2	3	3	2	2
Received T2	3	3	3	3	2	3
Received T3	2	2	3	3	2	3
Received T4	3	2	3	3	2	2
Received T5	3	2	3	3	3	2
Received R	3	2	3	3	2	3
COMPLETED	3	2	3	3	2	2
NOT COMPLETED	0	1	0	0	1	1

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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.	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.	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	3	3	3	3	3	3	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.0 (2.6)	33.0 (8.7)	39.3 (10.3)	32.0 (14.1)	22.0 (2.6)	37.3 (12.9)	31.9 (10.0)
Gender (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	3 100%	3 100%	3 100%	3 100%	3 100%	3 100%	18 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve of Rosuvastatin From 0 to the Last Quantifiable Data Point (AUC0-tz)
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	REF Alone	Treatment 1	Treatment 2	Treatment 3	Treatment 4	Treatment 5
Arm/Group Description	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.	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.	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.	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.	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.	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.
Measure Participants	16	15	16	15	15	16
Geometric Mean (Geometric Coefficient of Variation) [nanomol (nmol) * hour (h) / Litre (L)]	81.5 (50.9)	87.8 (54.5)	88.7 (62.4)	126 (66.7)	91.5 (55.4)	97.2 (52.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 1
	Comments	This statistical analysis assess the effect of coadministration of 10 mg metformin hydrochloride on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T1/REF (%)
	Estimated Value	101.95
	Confidence Interval	(2-Sided) 90%; 89.49 to 116.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 2
	Comments	This statistical analysis assess the effect of coadministration of 50 mg metformin hydrochloride on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T2/REF (%)
	Estimated Value	106.09
	Confidence Interval	(2-Sided) 90%; 96.12 to 117.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 3
	Comments	This statistical analysis assess the effect of coadministration of 500 mg metformin hydrochloride on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T3/REF (%)
	Estimated Value	152.18
	Confidence Interval	(2-Sided) 90%; 135.12 to 171.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 4
	Comments	This statistical analysis assess the effect of coadministration of 1 mg furosemide on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T4/REF (%)
	Estimated Value	106.97
	Confidence Interval	(2-Sided) 90%; 94.34 to 121.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 5
	Comments	This statistical analysis assess the effect of coadministration of 5 mg furosemide on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T5/REF (%)
	Estimated Value	115.92
	Confidence Interval	(2-Sided) 90%; 101.93 to 131.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Maximum Concentration of Rosuvastatin (Cmax)
Description	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.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	REF Alone	Treatment 1	Treatment 2	Treatment 3	Treatment 4	Treatment 5
Arm/Group Description	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.	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.	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.	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.	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.	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.
Measure Participants	16	15	16	15	15	16
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	9.04 (52.4)	9.59 (60.5)	9.94 (69.4)	14.0 (71.2)	9.90 (62.0)	10.8 (62.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 1
	Comments	This statistical analysis assess the effect of coadministration of 10 mg metformin hydrochloride on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T1/REF (%)
	Estimated Value	102.47
	Confidence Interval	(2-Sided) 90%; 87.19 to 120.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 2
	Comments	This statistical analysis assess the effect of coadministration of 50 mg metformin hydrochloride on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T2/REF (%)
	Estimated Value	106.98
	Confidence Interval	(2-Sided) 90%; 92.54 to 123.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 3
	Comments	This statistical analysis assess the effect of coadministration of 500 mg metformin hydrochloride on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T3/REF (%)
	Estimated Value	154.07
	Confidence Interval	(2-Sided) 90%; 131.70 to 180.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 4
	Comments	This statistical analysis assess the effect of coadministration of 1 mg furosemide on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T4/REF (%)
	Estimated Value	106.81
	Confidence Interval	(2-Sided) 90%; 91.78 to 124.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 5
	Comments	This statistical analysis assess the effect of coadministration of 5 mg furosemide on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T5/REF (%)
	Estimated Value	117.98
	Confidence Interval	(2-Sided) 90%; 98.27 to 141.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC0-∞)
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	REF Alone	Treatment 1	Treatment 2	Treatment 3	Treatment 4	Treatment 5
Arm/Group Description	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.	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.	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.	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.	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.	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.
Measure Participants	15	14	16	14	15	16
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	99.7 (39.0)	105 (48.0)	102 (55.0)	149 (49.8)	108 (47.9)	115 (42.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 1
	Comments	This statistical analysis assess the effect of coadministration of 10 mg metformin hydrochloride on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T1/REF (%)
	Estimated Value	101.22
	Confidence Interval	(2-Sided) 90%; 89.23 to 114.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 2
	Comments	This statistical analysis assess the effect of coadministration of 50 mg metformin hydrochloride on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T2/REF (%)
	Estimated Value	107.26
	Confidence Interval	(2-Sided) 90%; 97.65 to 117.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 3
	Comments	This statistical analysis assess the effect of coadministration of 500 mg metformin hydrochloride on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T3/REF (%)
	Estimated Value	146.45
	Confidence Interval	(2-Sided) 90%; 135.21 to 158.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 4
	Comments	This statistical analysis assess the effect of coadministration of 1 mg furosemide on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T4/REF (%)
	Estimated Value	105.63
	Confidence Interval	(2-Sided) 90%; 92.20 to 121.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	REF Alone, Treatment 5
	Comments	This statistical analysis assess the effect of coadministration of 5 mg furosemide on the primary outcome measure of the REF treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio T5/REF (%)
	Estimated Value	118.10
	Confidence Interval	(2-Sided) 90%; 106.75 to 130.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	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.
Arm/Group Title	REF Alone		Treatment 1		Treatment 2		Treatment 3		Treatment 4		Treatment 5
Arm/Group Description	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.		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.		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.		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.		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.		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.
All Cause Mortality
	REF Alone		Treatment 1		Treatment 2		Treatment 3		Treatment 4		Treatment 5
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	REF Alone		Treatment 1		Treatment 2		Treatment 3		Treatment 4		Treatment 5
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/15 (0%)		0/17 (0%)		0/15 (0%)		0/15 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	REF Alone		Treatment 1		Treatment 2		Treatment 3		Treatment 4		Treatment 5
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/16 (25%)		4/15 (26.7%)		2/17 (11.8%)		2/15 (13.3%)		3/15 (20%)		2/16 (12.5%)
Eye disorders
Photophobia	0/16 (0%)		0/15 (0%)		1/17 (5.9%)		0/15 (0%)		0/15 (0%)		0/16 (0%)
Gastrointestinal disorders
Toothache	1/16 (6.3%)		0/15 (0%)		0/17 (0%)		0/15 (0%)		1/15 (6.7%)		0/16 (0%)
Infections and infestations
Nasopharyngitis	0/16 (0%)		0/15 (0%)		0/17 (0%)		1/15 (6.7%)		0/15 (0%)		1/16 (6.3%)
Rhinitis	0/16 (0%)		1/15 (6.7%)		0/17 (0%)		0/15 (0%)		1/15 (6.7%)		1/16 (6.3%)
Injury, poisoning and procedural complications
Contusion	0/16 (0%)		1/15 (6.7%)		0/17 (0%)		0/15 (0%)		0/15 (0%)		0/16 (0%)
Procedural pain	0/16 (0%)		0/15 (0%)		0/17 (0%)		0/15 (0%)		1/15 (6.7%)		0/16 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/16 (0%)		1/15 (6.7%)		0/17 (0%)		0/15 (0%)		0/15 (0%)		0/16 (0%)
Myalgia	0/16 (0%)		1/15 (6.7%)		0/17 (0%)		0/15 (0%)		0/15 (0%)		0/16 (0%)
Nervous system disorders
Headache	1/16 (6.3%)		1/15 (6.7%)		1/17 (5.9%)		1/15 (6.7%)		1/15 (6.7%)		0/16 (0%)
Paraesthesia	1/16 (6.3%)		0/15 (0%)		0/17 (0%)		0/15 (0%)		0/15 (0%)		0/16 (0%)
Vascular disorders
Haematoma	1/16 (6.3%)		0/15 (0%)		0/17 (0%)		0/15 (0%)		0/15 (0%)		0/16 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.