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Safety and Pharmacokinetics of Quinidine Alone and in Combination With Dabigatran Etexilate

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ClinicalTrials.gov Identifier: NCT02171624
Recruitment Status : Completed
First Posted : June 24, 2014
Last Update Posted : June 24, 2014
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:
Open-label, two-way crossover design with a quinidine sulfate run-in period followed by a randomised sequence of dabigatran etexilate plus quinidine sulfate or dabigatran etexilate alone to evaluate the safety of co-administration of dabigatran etexilate and quinidine. and the pharmacokinetic interaction between quinidine and dabigatran etexilate.

Condition or disease Intervention/treatment Phase
Healthy Drug: dabigatran etexilate Drug: quinidine Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Two-way Crossover Study to Evaluate the Safety and Pharmacokinetics of Quinidine Sulfate Alone (200 mg Orally q2h to a Maximum of 1,000 mg), Dabigatran Etexilate Alone (150 mg BID for Three Days), and the Co-administration of Dabigatran Etexilate (150 mg BID) With Quinidine Sulfate (200 mg q2h)
Study Start Date : March 2009
Actual Primary Completion Date : April 2009


Arm Intervention/treatment
Experimental: dabigatran etexilate
quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order
Drug: dabigatran etexilate
Drug: quinidine
Experimental: quinidine
quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order
Drug: dabigatran etexilate
Drug: quinidine



Primary Outcome Measures :
  1. Differences between treatments in systolic blood pressure profiles (using area under the BP-time curve) [ Time Frame: -0:15 before, and every 15 minutes for 2 hours post-dose, 3, 4 and 12 hours post dose ]
  2. Incidence of symptomatic hypotension [ Time Frame: -0:15 before, and every 15 minutes for 2 hours post-dose, 3, 4 and 12 hours post dose ]

Secondary Outcome Measures :
  1. Area under the effect curve (AUEC) for activated partial thromboplastin time (aPTT), thrombin time (TT) and ecarin clotting time (ECT) [ Time Frame: up to 48 hours after last dose ]
  2. Maximum effect ratio (ERmax) for activated partial thromboplastin time (aPTT), thrombin time (TT) and ecarin clotting time (ECT) [ Time Frame: up to 48 hours after last dose ]
  3. Occurrence of Adverse Events [ Time Frame: up to day 26 ]
  4. Abnormal findings in physical examination [ Time Frame: up to day 26 ]
  5. Changes from baseline in Vital Signs (Blood Pressure (BP), Heart Rate (HR)) [ Time Frame: up to day 26 ]
  6. Changes from baseline in 12-lead ECG (electrocardiogram) [ Time Frame: up to day 26 ]
  7. Changes from baseline in QT prolongation [ Time Frame: up to day 26 ]
  8. Changes in clinical laboratory tests [ Time Frame: up to day 26 ]
  9. Number of patients with adverse events leading to treatment discontinuation [ Time Frame: up to day 26 ]
  10. AUC (area under the concentration-time curve of the analyte in plasma) [ Time Frame: up to 48 hours after the last dose ]
  11. Cmax (maximum measured concentration of the analyte in plasma) [ Time Frame: up to 48 hours after the last dose ]
  12. tmax (time from dosing to the maximum concentration of the analyte in plasma) [ Time Frame: up to 48 hours after the last dose ]
  13. λz (terminal rate constant in plasma) [ Time Frame: up to 48 hours after the last dose ]
  14. t½ (terminal half-life of the analyte in plasma) [ Time Frame: up to 48 hours after the last dose ]
  15. Cpre (pre-dose concentration of the analyte in plasma immediately before administration of the following dose) [ Time Frame: up to 48 hours after the last dose ]
  16. MRTpo,ss (mean residence time of the analyte in the body at steady state after po administration) [ Time Frame: up to 48 hours after last dose ]
  17. Vz/F,ss (apparent volume of distribution during the terminal phase λz at steady state following an extravascular dose) [ Time Frame: up to 48 hours after last dose ]
  18. CL/F,ss (apparent clearance of the analyte in the plasma at steady state after extravascular administration) [ Time Frame: up to 48 hours after last dose ]
  19. Cavg (average concentration of the analyte in plasma under steady-state conditions) [ Time Frame: up to 48 hours after last dose ]
  20. Cmin,ss (minimum measured concentration of the analyte in plasma at steady state) [ Time Frame: up to 48 hours after last dose ]
  21. PTF (peak trough fluctuation) [ Time Frame: up to 48 hours after last administration ]
  22. RAUCt1-t2, MET, 5 (ratio of AUCt1-t2 of 3-OH-quinidine/quinidine) [ Time Frame: up to 48 hours after last dose ]


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

Inclusion Criteria:

  • Healthy male and female subjects
  • Age ≥18 and Age ≤55 years
  • Body Mass Index (BMI) ≥18.5 and BMI <30 kg/m2
  • Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation.

Exclusion Criteria:

  • Any finding of the medical examination (including Blood Pressure (BP), Pulse Rate (PR) and Electrocardiogram (ECG)) deviating from normal and of clinical relevance
  • Any evidence of a clinically relevant concomitant disease
  • Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
  • Surgery of the gastrointestinal tract (except appendectomy)
  • Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
  • History of relevant orthostatic hypotension, fainting spells or blackouts
  • Chronic or relevant acute infections
  • History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
  • Intake of drugs with a long half-life (>24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial
  • Use of drugs which might reasonably influence the results of the trial or that prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial
  • Participation in another trial with an investigational drug within thirty days prior to administration or during the trial
  • Inability to refrain from smoking on trial days Smoker (>10 cigarettes or >3 cigars or >3 pipes/day)
  • Alcohol abuse (more than 60 g/day)
  • Drug abuse
  • Blood donation (more than 100 mL within four weeks prior to administration or during the trial)
  • Excessive physical activities (within one week prior to administration or during the trial)
  • Any laboratory value outside the reference range that is of clinical relevance
  • Inability to comply with dietary regimen of trial site
  • A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms)
  • A history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
  • Taking drugs which are known P-gp and/or CYP3A4 inhibitors or inducers (verapamil, phenothiazine antipsychotics, macrolide antibiotics (clarithromycin, erythromycin), antifungal drugs, antiviral drugs (protease inhibitors like nelfinavir) or St. John´s Wort) within the last 4 weeks before screening
  • Taking drugs which are known CYP2D6 substrates (antidepressants, antiarrhythmics, beta blockers) within the last 2 weeks before screening
  • For female subjects:

    • Pregnancy or planning to become pregnant within 2 months of study completion
    • Positive pregnancy test
    • No adequate contraception e.g., sterilisation, IUD (intrauterine device), have not been using a barrier method of contraception for at least 3 months prior to participation in the study
    • Are not willing or are unable to use a reliable method of barrier contraception (such as diaphragm with spermicidal cream/jelly or condoms with spermicidal foam), during and up to 2 months after completion/termination of the trial
    • Chronic use of oral contraception or hormone replacement containing ethinyl estradiol as the only method of contraception
    • Partner is unwilling to use condoms
    • Currently lactating

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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02171624     History of Changes
Other Study ID Numbers: 1160.90
First Posted: June 24, 2014    Key Record Dates
Last Update Posted: June 24, 2014
Last Verified: June 2014
Additional relevant MeSH terms:
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Dabigatran
Quinidine
Quinidine gluconate
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 Enzyme Inhibitors