- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02171598
Investigation of the Impact of Concomitant Use of Multiple Doses of Clopidogrel With Multiple Doses of Dabigatran Etexilate on the Pharmacokinetic and Pharmacodynamic Parameters in Healthy Male Subjects
Randomised, Open Label, 3-way Cross Over Phase I Study to Investigate the Impact of Concomitant Use of Multiple Doses of Clopidogrel (75 mg qd After a Loading Dose of 300 mg) With Multiple Doses of Dabigatran Etexilate (150 mg Bid) on the Pharmacokinetic and Pharmacodynamic Parameters, and Additionally the Impact of Single Oral Doses of 300 mg and 600 mg of Clopidogrel Administered Under Steady State Conditions of Dabigatran of 75 mg and 150 mg in Healthy Male Subjects
The primary objective of the study (Main Part 2) was to investigate whether and to which extent a combination of multiple oral doses (steady state conditions) of 75 mg of clopidogrel q.d. (after a loading dose of 300 mg) and multiple doses of 150 mg of dabigatran etexilate b.i.d. at steady state affects pharmacokinetic and pharmacodynamic parameters of dabigatran etexilate and clopidogrel.
The objective of the preceding Pilot Part 1 of the study was to explore the effect of a single dose of 300 mg clopidogrel administered after multiple doses of 75 mg and 150 mg dabigatran had reached steady state, regarding safety as well as pharmacokinetic and pharmacodynamic parameters.
The Main Part 3 of the study moreover was to compare intra-individually the effects of a single dose of 600 mg clopidogrel with the same dose, 600 mg clopidogrel, given additionally to multiple doses of 150 mg dabigatran in steady state condition with respect to safety and pharmacokinetic and pharmacodynamic parameters.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 1
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Healthy male subjects according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (blood pressure, pulse rate), body temperature, 12-lead electrocardiogram, clinical laboratory tests
- Age ≥18 and Age ≤40 years
- Body mass index (BMI) ≥18.5 and ≤29.9 kg/m2 (Body Mass Index)
- Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation.
Exclusion Criteria:
- Any gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
Subjects who in the investigator's judgement are perceived as having an increased risk of bleeding, for example because of:
- Hemorrhagic disorders or bleeding diathesis
- Occult blood in faeces or haematuria
- Trauma or surgery within the last month or as long as an excessive risk of bleeding persists after these events, or planned surgery during trial participation
- History of arteriovenous malformation or aneurysm
- History of gastroduodenal ulcer disease, gastrointestinal haemorrhage and haemorrhoids
- History of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intraarticular bleeding
- Use of drugs that may interfere with haemostasis during trial conduct (e.g.acetyl salicylic acid or other non-steroidal anti-inflammatory drugs)
- Relevant surgery of gastrointestinal tract
- 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 allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator
- Intake of any medication within four weeks of first dosing
- Use of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation within four weeks prior to administration or during the trial, especially inhibitors or inducers of P-gp, CYP3A4 CYP2C9 or CYP2C19
- Intake of medication, which influences the blood clotting, i.e., acetylsalicylic acid, nonsteroidal anti-rheumatic drugs, cumarin etc. within 10 days prior to administration or during the trial
- Participation in another trial with an investigational drug within one month prior to administration or during the trial
- Alcohol abuse (more than 60 g/day on a regular basis)
- Drug abuse
- Within 5 days of study medication no intake of grapefruit, grapefruit juice, or products containing grapefruit juice, Seville oranges, garlic supplements, or St. John's Worth
- Blood donation (more than 100 mL within four weeks prior to administration)
- 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 study centre
- Male subjects do not agree to minimise the risk of female partners becoming pregnant from the first dosing day until 3 months after the completion of the study. Acceptable methods of contraception comprises barrier contraception and a medically accepted contraceptive method for the female partner (intra-uterine device with spermicide, hormonal contraceptive since at least two months)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Fixed sequence 1
multiple-dose, fixed-sequence with 2 periods of 4 days separated by a washout period of at least 14 days.
A single dose of 300 mg clopidogrel will be given on top of 75 mg or 150 mg dabigatran in steady state.
|
|
Experimental: Crossover
clopidogrel + dabigatran / clopidogrel / dabigatran in randomized order
|
|
Experimental: Fixed sequence 2
intra-individual comparison with the fixed sequence of a single dose of 600mg clopidogrel alone and the combination of dabigatran 150 mg in steady state plus single dose of 600 mg clopidogrel
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
AUCτ,ss (area under the concentration-time curve of the analyte in plasma over one dosing interval at steady state)
Time Frame: up to 19 days
|
for total dabigatran, clopidogrel and the inactive metabolite SR26334
|
up to 19 days
|
AUC0-24,1 (area under the concentration-time curve of the analyte in plasma over one dosing interval after the loading dose)
Time Frame: up to 19 days
|
for clopidogrel and the inactive metabolite SR26334
|
up to 19 days
|
Cmax,ss (maximum measured concentration of the analyte in plasma at steady state)
Time Frame: up to 19 days
|
for total dabigatran, clopidogrel and the inactive metabolite SR26334
|
up to 19 days
|
Cmax,1 (maximum measured concentration of the analyte in plasma after the loading dose)
Time Frame: up to 19 days
|
for total dabigatran, clopidogrel and the inactive metabolite SR26334
|
up to 19 days
|
AUECIPA,0-24 (area under the effect curve of inhibition of platelet aggregation after the first dose of clopidogrel)
Time Frame: up to 19 days
|
up to 19 days
|
|
Emax,IPA,0-24 (maximum percentage change - compared to baseline - in adenosine diphosphate-induced platelet aggregation after the loading dose of clopidogrel)
Time Frame: baseline, up to 19 days
|
baseline, up to 19 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
tmax (time from dosing to the maximum concentration of the analyte in plasma)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334 after the loading dose
|
up to 8 weeks
|
AUC0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334 after the loading dose
|
up to 8 weeks
|
AUC0-tz (area under the concentration-time curve of the analyte in plasma from the time point 0 to the last quantifiable analyte plasma concentration)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334 after the loading dose
|
up to 8 weeks
|
λz (terminal rate constant in plasma)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334 after the loading dose
|
up to 8 weeks
|
t1/2 (terminal half-life of the analyte in plasma)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334 after the loading dose
|
up to 8 weeks
|
MRTpo (mean residence time of the analyte in the body after oral administration)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334 after the loading dose
|
up to 8 weeks
|
CL/F (apparent clearance of the analyte in the plasma after extravascular administration)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334 after the loading dose
|
up to 8 weeks
|
Vz/F (apparent volume of distribution during the terminal phase λz following an extravascular dose)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334 after the loading dose
|
up to 8 weeks
|
Cmax, ss
Time Frame: up to 8 weeks
|
free dabigatran after multiple dosing
|
up to 8 weeks
|
AUCτ,ss
Time Frame: up to 8 weeks
|
free dabigatran after multiple dosing
|
up to 8 weeks
|
AUC0-tz,ss (area under the concentration-time curve of the analyte in plasma from the time point 0 after the last dose at steady state to the last quantifiable analyte plasma concentration within the uniform dosing interval τ)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
tz,ss (time of last measureable concentration of the analyte in plasma within the dosing interval τ at steady state)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
tmax,ss (time from last dosing to the maximum concentration of the analyte in plasma at steady state on day 4)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
CL/F,ss (apparent clearance of the analyte in the plasma at steady state after extravascular multiple dose administration)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
Cmin,ss (minimum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
tmin,ss (time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval τ)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
Cpre,ss (predose concentration of the analyte in plasma at steady state immediately before administration of the next dose)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
MRTpo,ss (mean residence time of the analyte in the body at steady state after oral administration)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
Vz/F,ss (apparent volume of distribution during the terminal phase λz at steady state following an extravascular administration)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
PTF (peak trough fluctuation)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
Cavg (average concentration of the analyte in plasma at steady state over a uniform dosing interval)
Time Frame: up to 8 weeks
|
Clopidogrel and SR 26334; dabigatran (free and total) after multiple dosing
|
up to 8 weeks
|
AUECt1-t2 (area under the effect curve (baseline corrected by ratio))
Time Frame: up to 8 weeks
|
for activated partial thromboplastin time, thrombin time and ecarin clotting time
|
up to 8 weeks
|
ERmax (maximum effect ratio)
Time Frame: up to 8 weeks
|
for activated partial thromboplastin time, thrombin time and ecarin clotting time
|
up to 8 weeks
|
tmax (time to maximum effect)
Time Frame: up to 8 weeks
|
for activated partial thromboplastin time, thrombin time and ecarin clotting time
|
up to 8 weeks
|
Occurence of Adverse Events
Time Frame: up to 13 weeks
|
up to 13 weeks
|
|
Assessment of Tolerability by investigator
Time Frame: up to 13 weeks
|
up to 13 weeks
|
Collaborators and Investigators
Sponsor
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Platelet Aggregation Inhibitors
- Purinergic P2Y Receptor Antagonists
- Purinergic P2 Receptor Antagonists
- Purinergic Antagonists
- Purinergic Agents
- Protease Inhibitors
- Antithrombins
- Serine Proteinase Inhibitors
- Anticoagulants
- Clopidogrel
- Dabigatran
Other Study ID Numbers
- 1160.83
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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