Clinical trial NCT02171624: Safety and Pharmacokinetics of Quinidine Alone and in Combination With Dabigatran Etexilate
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2014-06-24
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Differences between treatments in systolic blood pressure profiles (using area under the BP-time curve)
timeFrame: -0:15 before, and every 15 minutes for 2 hours post-dose, 3, 4 and 12 hours post dose
measure: Incidence of symptomatic hypotension
timeFrame: -0:15 before, and every 15 minutes for 2 hours post-dose, 3, 4 and 12 hours post dose
Secondary outcomes:
measure: Area under the effect curve (AUEC) for activated partial thromboplastin time (aPTT), thrombin time (TT) and ecarin clotting time (ECT)
timeFrame: up to 48 hours after last dose
measure: Maximum effect ratio (ERmax) for activated partial thromboplastin time (aPTT), thrombin time (TT) and ecarin clotting time (ECT)
timeFrame: up to 48 hours after last dose
measure: Occurrence of Adverse Events
timeFrame: up to day 26
measure: Abnormal findings in physical examination
timeFrame: up to day 26
measure: Changes from baseline in Vital Signs (Blood Pressure (BP), Heart Rate (HR))
timeFrame: up to day 26
measure: Changes from baseline in 12-lead ECG (electrocardiogram)
timeFrame: up to day 26
measure: Changes from baseline in QT prolongation
timeFrame: up to day 26
measure: Changes in clinical laboratory tests
timeFrame: up to day 26
measure: Number of patients with adverse events leading to treatment discontinuation
timeFrame: up to day 26
measure: AUC (area under the concentration-time curve of the analyte in plasma)
timeFrame: up to 48 hours after the last dose
measure: Cmax (maximum measured concentration of the analyte in plasma)
timeFrame: up to 48 hours after the last dose
measure: tmax (time from dosing to the maximum concentration of the analyte in plasma)
timeFrame: up to 48 hours after the last dose
measure: λz (terminal rate constant in plasma)
timeFrame: up to 48 hours after the last dose
measure: t½ (terminal half-life of the analyte in plasma)
timeFrame: up to 48 hours after the last dose
measure: Cpre (pre-dose concentration of the analyte in plasma immediately before administration of the following dose)
timeFrame: up to 48 hours after the last dose
measure: MRTpo,ss (mean residence time of the analyte in the body at steady state after po administration)
timeFrame: up to 48 hours after last dose
measure: Vz/F,ss (apparent volume of distribution during the terminal phase λz at steady state following an extravascular dose)
timeFrame: up to 48 hours after last dose
measure: CL/F,ss (apparent clearance of the analyte in the plasma at steady state after extravascular administration)
timeFrame: up to 48 hours after last dose
measure: Cavg (average concentration of the analyte in plasma under steady-state conditions)
timeFrame: up to 48 hours after last dose
measure: Cmin,ss (minimum measured concentration of the analyte in plasma at steady state)
timeFrame: up to 48 hours after last dose
measure: PTF (peak trough fluctuation)
timeFrame: up to 48 hours after last administration
measure: RAUCt1-t2, MET, 5 (ratio of AUCt1-t2 of 3-OH-quinidine/quinidine)
timeFrame: up to 48 hours after last dose
Other outcomes:
Locations:
Study officials:
References: