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

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

Tracking Information

• First Submitted Date: June 20, 2014
• First Posted Date: June 24, 2014
• Last Update Posted Date: June 24, 2014
• Study Start Date: March 2009
• Actual Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 20, 2014)

• 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 ]
• 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 ]

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: June 20, 2014)

• 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 ]
• 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 ]
• Occurrence of Adverse Events [ Time Frame: up to day 26 ]
• Abnormal findings in physical examination [ Time Frame: up to day 26 ]
• Changes from baseline in Vital Signs (Blood Pressure (BP), Heart Rate (HR)) [ Time Frame: up to day 26 ]
• Changes from baseline in 12-lead ECG (electrocardiogram) [ Time Frame: up to day 26 ]
• Changes from baseline in QT prolongation [ Time Frame: up to day 26 ]
• Changes in clinical laboratory tests [ Time Frame: up to day 26 ]
• Number of patients with adverse events leading to treatment discontinuation [ Time Frame: up to day 26 ]
• AUC (area under the concentration-time curve of the analyte in plasma) [ Time Frame: up to 48 hours after the last dose ]
• Cmax (maximum measured concentration of the analyte in plasma) [ Time Frame: up to 48 hours after the last dose ]
• tmax (time from dosing to the maximum concentration of the analyte in plasma) [ Time Frame: up to 48 hours after the last dose ]
• λz (terminal rate constant in plasma) [ Time Frame: up to 48 hours after the last dose ]
• t½ (terminal half-life of the analyte in plasma) [ Time Frame: up to 48 hours after the last dose ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• Cavg (average concentration of the analyte in plasma under steady-state conditions) [ Time Frame: up to 48 hours after last dose ]
• Cmin,ss (minimum measured concentration of the analyte in plasma at steady state) [ Time Frame: up to 48 hours after last dose ]
• PTF (peak trough fluctuation) [ Time Frame: up to 48 hours after last administration ]
• RAUCt1-t2, MET, 5 (ratio of AUCt1-t2 of 3-OH-quinidine/quinidine) [ Time Frame: up to 48 hours after last dose ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Healthy

Intervention

• Drug: dabigatran etexilate
• Drug: quinidine

Study Arms

• Experimental: dabigatran etexilate
  quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order
  Interventions:

  • Drug: dabigatran etexilate
  • Drug: quinidine
• Experimental: quinidine
  quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order
  Interventions:

  • Drug: dabigatran etexilate
  • Drug: quinidine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 20, 2014): 42
• Original Actual Enrollment: Same as current
• Study Completion Date: Not Provided
• Actual Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT02171624
• Other Study ID Numbers: 1160.90
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Boehringer Ingelheim
• Original Responsible Party: Same as current
• Current Study Sponsor: Boehringer Ingelheim
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Boehringer Ingelheim
• Verification Date: June 2014