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Transporter Cocktail Mutual Interaction

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ClinicalTrials.gov Identifier: NCT02854527
Recruitment Status : Completed
First Posted : August 3, 2016
Results First Posted : August 6, 2018
Last Update Posted : August 6, 2018
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:
Main objective is to investigate mutual pharmacokinetic drug-drug interactions of digoxin, furosemide, metformin, and rosuvastatin when given all together as a cocktail

Condition or disease Intervention/treatment Phase
Healthy Drug: Digoxin Drug: Furosemide Drug: Metformin Drug: Rosuvastatin Drug: Metformin hydrochloride Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Investigation of Mutual Pharmacokinetic Interactions of Digoxin, Furosemide, Metformin, and Rosuvastatin Given All Together as a Probe Cocktail for Key Drug Transporters (an Open-label, Randomised, Single-dose, Five-way Crossover Study)
Actual Study Start Date : August 22, 2016
Actual Primary Completion Date : November 11, 2016
Actual Study Completion Date : November 19, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Drug Reactions

Arm Intervention/treatment
Experimental: R1 (Reference 1) Digoxin
1 tablet (0.25 mg) digoxin as single dose
Drug: Digoxin
single dose

Experimental: R2 Furosemide
0.1 mL (1 mg) furosemide oral solution as single dose
Drug: Furosemide
single dose

Experimental: R3 Metformin hydrochloride
0.1 mL (10 mg) metformin oral solution as single dose
Drug: Metformin
single dose

Experimental: R4 Rosuvastatin
1 tablet (10 mg) rosuvastatin as single dose
Drug: Rosuvastatin
single dose

Experimental: T (Test)
1 tablet (0.25 mg) digoxin, 0.1 mL (1 mg) furosemide oral solution, 0.1 mL (10 mg) metformin oral solution, and 1 tablet (10 mg) rosuvastatin, all together as a single dose ('cocktail')
Drug: Digoxin
0.25 mg digoxin as single dose (all 4 drugs given together as a cocktail at the same time point)

Drug: Furosemide
1 mg furosemide as single dose (all 4 drugs given together as a cocktail at the same time point)

Drug: Metformin hydrochloride
10 mg metformin hydrochloride as single dose (all 4 drugs given together as a cocktail at the same time point)

Drug: Rosuvastatin
10 mg rosuvastatin as single dose (all 4 drugs given together as a cocktail at the same time point)




Primary Outcome Measures :
  1. Area Under the Curve of Digoxin From 0 to Last Quantifiable Data Point (AUC 0-tz) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration ]
    Area under the concentration-time curve of digoxin in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error. CI - confidence interval, gMean - geometric mean.

  2. Maximum Concentration of Digoxin (Cmax) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration ]
    This outcome measure presents the maximum measured concentration of digoxin in plasma (Cmax). Standard error presented is actually geometric standard error.

  3. Area Under the Curve of Furosemide From 0 to Last Quantifiable Data Point (AUC 0-tz) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 and 24:00 after drug administration ]
    Area under the concentration-time curve of furosemide in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error.

  4. Maximum Concentration of Furosemide (Cmax) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 and 24:00 after drug administration ]
    This outcome measure presents the maximum measured concentration of furosemide in plasma (Cmax). Standard error presented is actually geometric standard error.

  5. Area Under the Curve of Metformin From 0 to Last Quantifiable Data Point (AUC 0-tz) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00 and 48:00 after drug administration ]
    Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error.

  6. Maximum Concentration of Metformin (Cmax) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00 and 48:00 after drug administration ]
    This outcome measure presents the maximum measured concentration of metformin in plasma (Cmax). Standard error presented is actually geometric standard error.

  7. Area Under the Curve of Rosuvastatin From 0 to Last Quantifiable Data Point (AUC 0-tz) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration ]
    Area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error.

  8. Maximum Concentration of Rosuvastatin (Cmax) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration ]
    This outcome measure presents the maximum measured concentration of rosuvastatin in plasma (Cmax). Standard error presented is actually geometric standard error.


Secondary Outcome Measures :
  1. Area Under the Curve of Digoxin From 0 Extrapolated to Infinity (AUC 0-∞) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration ]
    Area under the concentration-time curve of digoxin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.

  2. Area Under the Curve of Furosemide From 0 Extrapolated to Infinity (AUC 0-∞) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 and 24:00 after drug administration ]
    Area under the concentration-time curve of furosemide in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.

  3. Area Under the Curve of Metformin From 0 Extrapolated to Infinity (AUC 0-∞) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00 and 48:00 after drug administration ]
    Area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.

  4. Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC 0-∞) [ Time Frame: Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration ]
    Area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria:

  • Healthy male subjects according to the investigator's assessment, based on a complete medical history including a physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests
  • Age of 18 to 55 years (incl.)
  • Body Mass Index (BMI) of 18.5 to 29.9 kg/m2 (incl.)
  • Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and local legislation

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 50 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, sulphonamides, or cardiac glycosides)
  • Use of drugs within 30 days prior to administration of trial medication that might reasonably influence the results of the trial (incl. QT/QTc interval prolongation (corrected Q-T interval)
  • Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication, or current participation in another trial involving administration of investigational drug
  • 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:

  • Hypokalemia, hypomagnesemia, or hypercalcemia
  • PQ ( (time between the onset of the P wave (atrial activity) and the QRS complex (ventricular activity)) interval greater than 220 ms in the ECG at screening
  • Myopathy
  • Hereditary galactose or fructose intolerance, lactase deficiency, or glucose-galactose malabsorption

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02854527


Locations
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Germany
Boehringer Ingelheim Pharma GmbH & Co KG
Biberach, Germany, 88397
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
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Study Chair: Boehringer Ingelheim Boehringer Ingelheim

Additional Information:
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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02854527    
Other Study ID Numbers: 352.2096
2016-001893-14 ( EudraCT Number )
First Posted: August 3, 2016    Key Record Dates
Results First Posted: August 6, 2018
Last Update Posted: August 6, 2018
Last Verified: October 2017
Additional relevant MeSH terms:
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Metformin
Digoxin
Furosemide
Rosuvastatin Calcium
Hypoglycemic Agents
Physiological Effects of Drugs
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Diuretics
Natriuretic Agents
Sodium Potassium Chloride Symporter Inhibitors
Membrane Transport Modulators
Anti-Arrhythmia Agents
Cardiotonic Agents
Protective Agents