Healthy
Conditions
Brief summary
Study to determine the effect of steady-state plasma concentration of Tipranavir/ritonavir (TPV/r) on platelet aggregation in healthy subjects and investigate the effect of TPV/r at steady state plasma concentrations on other platelet functions and biomarkers of coagulation and fibrinolysis.
Interventions
DRUGTipranavir
DRUGRitonavir
DRUGDarunavir
DRUGAspirin
single dose on day 2
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Ability and willingness to give written informed consent to participate in this study (i.e., prior to any study-specific procedures) 2. Age ≥18 years and ≤50 years 3. Female subjects of child-bearing potential were eligible if: * They had used a barrier contraceptive method for at least 12 weeks before administration of study medication and had a negative serum pregnancy test result during the screening period (Day - 35 to Day -3); or, * Were abstinent for more than 12 weeks before screening and had a negative serum pregnancy test result during the screening period (Day -35 to Day -3); or, * Had a documented tubal ligation and had a negative serum pregnancy test result during the screening period (Day -35 to Day -3) 4. Ability to swallow capsules without difficulty 5. Reasonable probability of completing the study 6. Findings from medical history, physical examination and 12-lead ECG indicating subject was healthy and suitable for the trial in the opinion of the investigator 7. Agreement to abstain from alcohol consumption or drugs of abuse during the study 8. Agreement to abstain from ingestion of grapefruit, grapefruit juice, Seville oranges, or orange marmalade from screening period to the end of the study 9. Negative urine drug screen for drugs of abuse 10. Non smoker 11. Agreement to abstain from use of tobacco products from screening period to the end of the study 12. Negative HIV-1 serology by ELISA testing 13. Negative Hepatitis B surface Antigen test (HBsAg) 14. Negative Hepatitis C Virus antibody (anti-HCV) test by Enzyme Immunoassay 15. Platelet count ≥125,000/mm3 16. Hemoglobin ≥11.0 g/dL 17. Prothrombin time ≤1.0 x upper limit of normal (ULN) 18. Activated Partial thromboplastin time ≤1.0 x ULN
Exclusion criteria
1. Female subjects who: * had a positive serum pregnancy test during the screening period (Day -35 to Day -3) or during the study * were breast feeding or planing to breast feed at any time from the screening period through 30 days after the last dose of the study drug * were not willing to use a barrier method of contraception at any time from screening period through 30 days after the last dose of the study drug * were taking any hormonal therapy for any reason such as birth control or replacement therapy 2. Had used any investigational agent within 30 days prior to Visit 2 3. Blood or plasma donations (\>100 mL total) for research or altruistic reasons within 30 days prior to Visit 2 4. Had used aspirin or any non-steroidal anti-inflammatory agent (NSAID), and including COX-2 inhibitors, dipyridamole, clopidogrel, ticlopidine or other antiplatelet drugs within 14 days prior to Visit 2 or during the study 5. Active peptic ulceration or history of peptic ulcer disease 6. Known history of or suspected hypersensitivity to aspirin, any NSAID or any other component of the test drugs (Tipranavir, Darunavir, Ritonavir) 7. Known hypersensitivity to antiretroviral drugs (marketed or experimental drug in clinical research studies) 8. Active bleeding disorder or history of active bleeding disorder 9. Active Intra cranial hemorrhage (ICH) or history of ICH 10. Active coronary artery disease or history of coronary artery disease 11. Alcohol abuse (more than 60 g/day) 12. Any indication for current use of aspirin or any NSAID or indication for such use from Visit 2 to Visit 18 13. Had used any over-the-counter medication within 7 days prior to Visit 2, or current use of any prescription drug 14. Subjects who had an abnormal laboratory result of Grade 1 or greater, as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS), (result must have been available at least 3 days prior to Visit 2-Day 1), except the following screening laboratory values: * serum potassium, serum sodium, serum phosphate and uric acid, where central laboratory reference ranges will be used to determine eligibility rather than DAIDS table; or, * amylase or creatinine results of Grade 1 on DAIDS table if these results are considered clinically not significant by investigator; or * other marginally abnormal laboratory values not considered clinically significant by investigator and approved by clinical monitor 15. History of any illness that in the opinion of the investigator might confound the results of the study or pose additional risks in administering aspirin, Tipranavir, Darunavir, or Ritonavir 16. Hypersensitivity to sulphonamide drugs 17. Had used proton pump inhibitors during 14 days prior to Visit 2 18. Vitamin E intake in excess of 60 mg/day within 30 days prior to Visit 2 19. Vitamin E supplementation in excess of 60 mg/day during the study (Vitamin E content of multivitamin tablets is allowed)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent change from baseline in the area under the curve (AUC) of platelet aggregation in response to arachidonic acid (AA) | pre-dose, up to 48 h after drug administration | calculated as the ratio of the AUC at steady state TPV plasma concentrations and the baseline AUC |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in closure Time (CT) | pre-dose, up to 48 h after drug administration | Platelet Function Analyzer (PFA)-100 test |
| Changes in urinary thromboxane B2 metabolites | pre-dose, up to 48 h after drug administration | — |
| Changes in bleeding time | Baseline, up to day 30 | — |
| Changes in activated partial thromboplastin time (aPTT) | Baseline, up to day 30 | — |
| Changes in prothrombin time (PT) | Baseline, up to day 30 | — |
| Changes in fibrinogen | Baseline, up to day 30 | — |
| Changes in von Willebrand antigen | Baseline, up to day 30 | — |
| Changes in von anti-thrombin III antigen | Baseline, up to day 30 | — |
| Changes in anti-thrombin III activity | Baseline, up to day 30 | — |
| Changes in platelet aggregation in response to collagen | pre-dose, up to 48 h after drug administration | — |
| Changes in platelet aggregation in response to AA | pre-dose, up to 48 h after drug administration | — |
| Changes in factor II | Baseline, up to day 30 | — |
| Changes in factor VII | Baseline, up to day 30 | — |
| Changes in factor IX | Baseline, up to day 30 | — |
| Changes in platelet aggregation in response adenosine diphosphate (ADP) | pre-dose, up to 48 h after drug administration | — |
| Changes in plasminogen activity | Baseline, up to day 30 | — |
| Changes in alpha 2-antiplasmin | Baseline, up to day 30 | — |
| Changes in D-dimer | Baseline, up to day 30 | — |
| Changes in Plasminogen Activator Inhibitor (PAI-1) | Baseline, up to day 30 | — |
| Maximum measured concentration of the analyte in plasma (Cmax) | pre-dose, up to 48 h after drug administration | — |
| Serum concentration at 12 hours (Cp12h) | 12 hours after drug administration | — |
| Area under the curve from 0-12 hours (AUC0-12h) | up to 12 hours after drug administration | — |
| Time from dosing to the maximum measured concentration of the analyte in plasma (Tmax) | up to 48 h after drug administration | — |
| Total clearance of the analyte in plasma (CL/F) | pre-dose, up to 48 h after drug administration | — |
| Apparent volume of distribution (V/F) | pre-dose, up to 48 h after drug administration | — |
| Terminal half-life (t1/2) | pre-dose, up to 48 h after drug administration | — |
| Number of subjects with abnormal findings in laboratory tests | up to day 61 | — |
| Number of subjects with treatment-emergent adverse events | up to 96 days | — |
| Changes in factor X | Baseline, up to day 30 | — |
Outcome results
None listed