| Eligibility |
Inclusion Criteria:
1. In Part 1, men and women of any ethnic origin aged between 18 and 49 years of age,
inclusive, at the time of Screening.
2. In Part 2, men and women of any ethnic origin aged between 50 and 79 years of age,
inclusive, at the time of Screening.
3. Male subjects must be willing to use appropriate contraception, such as a condom, and
to refrain from sperm donation during the study and until 90 days after study drug
administration.
4. Women of child-bearing potential must agree not to attempt to become pregnant and to
use a highly effective form of birth control during the study and for 90 days after
study drug administration when their sexual partner has not been vasectomized. Highly
effective forms of birth control entail the use of combined (estrogen- and
progestogen-containing) or progestogen-only hormonal contraception associated with
inhibition of ovulation, an intrauterine device (IUD), an intrauterine
hormone-releasing system (IUS) or abstinence.
5. Postmenopausal women must have had =12 months of spontaneous amenorrhea (with
documented follicle-stimulating hormone (FSH) =30 milli-International units (mIU)/mL).
6. Surgically sterile women are defined as those who have had a surgical bilateral
oophorectomy with or without hysterectomy, total hysterectomy or tubal ligation at
least six weeks before taking study treatment. In case of oophorectomy alone, the
reproductive status of the woman has to be confirmed by follow-up hormone level
assessment. Women who are surgically sterile must provide documentation of the
procedure by an operative report or by ultrasound.
7. All women must have a negative pregnancy test result at Screening and on Day -1.
8. Subject must weigh between 60 and 120 kg, inclusive, and must have a BMI between 18.0
and 30.0 kg/m^2, inclusive, at Screening and on Day -1.
9. Subject must be in good health, as determined by a medical history, physical
examination, 12-lead ECG and clinical laboratory evaluations (congenital non hemolytic
hyperbilirubinemia is acceptable).
10. Participant is willing and able to give their written informed consent to participate
in the study and to abide by the study restrictions.
11. Participant has good upper limb venous access.
Exclusion Criteria:
1. The participant has taken piroxicam in the two weeks prior to the first administration
of study drug or DOAC.
2. The participant has taken any non-aspirin non-piroxicam NSAID in the week prior to the
first administration of study drug or DOAC.
3. The participant requires or has taken during the month prior to first administration
of study drug or DOAC, vitamin K for therapeutic reasons. Vitamin K not taken for
therapeutic purposes is acceptable, e.g. as part of a multivitamin supplement.
4. The participant is receiving or requires, for any cause, any anticoagulant or
antiplatelet therapy including warfarin, clopidogrel or aspirin or any other
anticoagulant or antiplatelet agent or has used these therapies in the month prior to
the first administration of study drug or DOAC.
5. The participant has received any prescribed oral, systemic or topical medication,
including coronavirus disease (COVID)-19 vaccination, within 14 days prior to the
first administration of study drug or DOAC (with the exception of contraceptives),
unless in the opinion of the Principal Investigator and the Medical Monitor the
medication will not interfere with the study procedures or compromise safety.
6. The participant has used any non-prescribed systemic or topical medication (including
herbal remedies) within one week prior to the first administration of study drug or
DOAC (with the exception of oral vitamin/mineral supplements (that do not contain
vitamin k) and paracetamol), unless in the opinion of the Principal Investigator and
the Medical Monitor the medication will not interfere with the study procedures or
compromise safety.
7. The participant is currently participating in a clinical study, e.g. attending
follow-up visits or has been administered an investigational drug (new chemical or
biological entity) in the 3 months prior to administration of the study drug.
8. The participant has donated >500 mL blood, plasma or platelets in the 3 months prior
to Screening.
9. Because of an increased risk of thrombosis participants with known diabetes mellitus
or a fasted glucose =7.0 mmol/l at Screening.
10. The participant has any bleeding diathesis, any increased risk of bleeding or, in the
opinion of the Principal Investigator, is at increased risk of the consequences of
bleeding including but not limited to the following:
1. gastro-intestinal ulceration within the last 3 months
2. known or suspected oesophageal varices.
3. vascular aneurysms or known arteriovenous malformations;
4. history of known major intraspinal or intracerebral vascular abnormalities.
5. history of brain, spinal or ophthalmic surgery within the last year.
6. any intracranial hemorrhage.
7. uncontrolled severe hypertension.
11. The participant has, in the opinion of the Principal Investigator, any increased risk
of thrombosis or thromboembolism including any known thrombophilia, such as
antiphospholipid syndrome, or any past history of thrombosis.
12. The participant has a significant history of drug allergy, as determined by the
Principal Investigator.
13. The participant has, at Screening or on Day -1, a supine blood pressure or supine
pulse rate = 150/95 mmHg and 100 beats per minute (bpm), respectively, or < 90/40 mmHg
and 40 bpm, respectively, confirmed by a repeat assessment.
14. The participant consumes >21 alcoholic drinks/week for men or >14 alcoholic
drinks/week for women (one unit of alcohol equals ½ pint [285 mL] of beer or lager,
one glass [125 mL] of wine, or 1 measure [25 mL] of spirits), or has a significant
history of alcoholism or drug/chemical abuse, as determined by the Principal
Investigator for Part 1. For Part 2, the participant consumes >7 alcoholic
drinks/week.
15. The participant has a positive urine drug screen, alcohol breath test or cotinine test
results at Screening or on Day -1, confirmed by repeat testing.
16. The female participant has a positive pregnancy test at Screening or on Day -1 or is
lactating.
17. The participant currently smokes or uses nicotine-containing products. Former smokers
will be eligible, provided participants have not smoked for at least 3 months prior to
administration of the study drug.
18. The participant has, or has a history of, any clinically significant neurological,
gastrointestinal, renal, hepatic, cardiovascular, psychiatric, respiratory, metabolic,
endocrine, hematological or other major disorders, as determined by the Principal
Investigator.
19. The participant has a positive Hepatitis B surface antigen (HBsAg), Hepatitis C
antibody, or human immunodeficiency virus (HIV) antibody test result at Screening.
20. The participant has an abnormality in the 12-lead ECG at Screening or on Day -1 that,
in the judgement of the Principal Investigator may, during the study, interfere with
the interpretation of 12-lead ECG results, including average QTcF interval >450 msec
for men or >470 msec for women, 2nd or 3rd degree atrioventricular block, complete
left bundle branch block, complete right bundle branch block or Wolff-Parkinson-White
Syndrome, defined as average PR<110 msec, confirmed by a triplicate repeat ECG.
21. The participant has any other condition that, in the opinion of the Principal
Investigator, would compromise the safety of the participant or the participant's
ability to comply with the protocol and complete the study.
22. The participant has renal insufficiency (serum creatinine level > 1.25 times upper
limit of normal (ULN) or estimated glomerular filtration rate (eGFR) of =60
mL/minute).
23. The participant has active liver disease (ALT/ aspartate aminotransferase (AST) >1.5x
ULN, total bilirubin > 1.5x ULN at Screening or on Day -1. One re-test is allowed).
Additional exclusion criteria for Part 2 only:
24. Because of an effect on DOACs,participants are to be excluded if he/she receives or
has received medication that is an inhibitor of P-glycoprotein or CYP3A4. (eg
clarithromycin, erythromycin and azole-antimycotics such as ketoconazole,
itraconazole, voriconazole and osaconazole or HIV protease inhibitors.) within 30 days
prior to first administration of DOAC.
25. Because of an effect on DOACs, participants are to be excluded if he/she receives or
has received treatment with CYP3A4 inducers (eg St. John's wort, rifampicin,
phenytoin, carbamazepine, phenobarbital within 30 days prior to first administration
of DOAC.
26. Because of an effect on DOACs, participants are to be excluded if he/she receives or
has received treatment with selective serotonin reuptake inhibitors (SSRIs) or
selective noradrenaline reuptake inhibitors (SNRIs) within 30 days prior to first
administration of DOAC.
27. The participant has any contra-indication to treatment with DOACs.
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