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

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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 ]

Eligibility Criteria

• 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

Contacts and Locations

No Contacts or Locations Provided

More Information

Additional Information:

Related Info 

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02171624
• Other Study ID Numbers: 1160.90
• First Posted: June 24, 2014
• Last Update Posted: June 24, 2014
• Last Verified: June 2014

Additional relevant MeSH terms:

Quinidine; Dabigatran; 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