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.

Inclusion Criteria:

1. 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
2. Age ≥18 and Age ≤40 years
3. Body mass index (BMI) ≥18.5 and ≤29.9 kg/m2 (Body Mass Index)
4. Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation.

Exclusion Criteria:

1. Any gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders

2. 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)

3. Relevant surgery of gastrointestinal tract

4. Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders

5. History of relevant orthostatic hypotension, fainting spells or blackouts

6. Chronic or relevant acute infections

7. History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator

8. Intake of any medication within four weeks of first dosing

9. 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

10. 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

11. Participation in another trial with an investigational drug within one month prior to administration or during the trial

12. Alcohol abuse (more than 60 g/day on a regular basis)

13. Drug abuse

14. 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

15. Blood donation (more than 100 mL within four weeks prior to administration)

16. Excessive physical activities (within one week prior to administration or during the trial)

17. Any laboratory value outside the reference range that is of clinical relevance

18. Inability to comply with dietary regimen of study centre

19. 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)