Coagulation Disorder
Conditions
Brief summary
A single centre, double-blind, randomized, placebo-controlled single dose study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of VMX-C001, conducted in two parts: Part 1: Single dose of VMX-C001 or placebo in healthy volunteers. Part 2: Single dose of VMX-C001 or placebo in combination with a selected factor 10a (FXa) direct oral anticoagulant (DOAC) in healthy older subjects.
Interventions
DRUGVMX-C001
VMX-C001 is human factor X engineered to be insensitive to factor Xa DOACs
DRUGPlacebo
VMX-C001 matched placebo
Fxa DOAC
Fxa DOAC
DRUGEdoxaban 60 mg Oral Tablet
Fxa DOAC
Sponsors
VarmX B.V.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind
Intervention model description
Placebo controlled, single dose.
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
1. In Part 1, men and women of any ethnic origin between 18 and 49 years of age, in Part 2, men and women of any ethnic origin between 50 and 79 years of age, inclusive, at the time of Screening. 2. 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. 3. 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. 4. Postmenopausal women must have had ≥12 months of spontaneous amenorrhea (with documented follicle-stimulating hormone (FSH) \>33.4 IU/L). 5. 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. 6. Subject must weigh between 60 and 120 kg, inclusive, and must have a BMI between 18.0 and 30.0 kg/m2, inclusive, at Screening and on Day -1. 7. 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). 8. Subject is willing and able to give their written informed consent to participate in the study and to abide by the study restrictions. 9. Subject has good upper limb venous access.
Exclusion criteria
1. The subject has taken tenoxicam in the 35 days prior to the first administration of study drug or FXa DOAC or has taken piroxicam in the two weeks prior to the first administration of study drug or FXa DOAC. 2. The subject has taken any non-aspirin, non-piroxicam, non-steroidal anti-inflammatory drug (NSAID) in the week prior to the first administration of study drug or FXa DOAC. 3. The subject requires or has taken during the month prior to first administration of study drug or FXa 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 subject 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 FXa DOAC. 5. The subject has received any prescribed oral, systemic or topical medication, including any vaccinations, within 14 days prior to the first administration of study drug or FXa 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 subject has used any non-prescribed systemic or topical medication (including herbal remedies) within one week prior to the first administration of study drug or FXa DOAC (with the exception of oral vitamin/mineral supplements \[including those that contain vitamin K when not taken for therapeutic purposes\] 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 subject 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) within 1 month (for small molecules) or 3 months (for biologicals) prior to administration of the study drug. 8. The subject has donated ≥500 mL blood, plasma, or platelets in the 3 months prior to Screening or any other blood amount within 30 days prior to Screening. 9. Because of an increased risk of thrombosis subjects with known diabetes mellitus or a fasted glucose ≥7.0 mmol/L at Screening. 10. The subject 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 subject 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 provoked or unprovoked arterial or venous thrombosis, including thromboembolism. 12. The subject has a significant history of drug allergy, as determined by the Principal Investigator. 13. The subject 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. For Part 1, the subject 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 2, the subject consumes \>14 alcoholic drinks/week or has a significant history of alcoholism or drug/chemical abuse, as determined by the Principal Investigator. 15. The subject has a positive drug screen, alcohol test or cotinine test result at Screening or on Day -1, confirmed by repeat testing. 16. The female subject has a positive pregnancy test at Screening or on Day -1 or is lactating. 17. The subject currently smokes or uses nicotine-containing products. Former smokers will be eligible, provided they have not smoked for at least 1 month prior to administration of the study drug. 18. The subject 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 subject has a positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody, or human immunodeficiency virus (HIV) antibody test result at Screening. 20. The subject 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 subject has any other condition that, in the opinion of the Principal Investigator, would compromise the safety of the subject or the subject's ability to comply with the protocol and complete the study. 22. The subject has renal insufficiency (serum creatinine level \> 1.25 times upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR) of \<60 mL/min\*1.73m2). 23. The subject has active liver disease (alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \>1.5x ULN, or total bilirubin \> 1.5x ULN at Screening or on Day -1. One re-test is allowed). 24. The subject has previously participated in a clinical study with VMX-C001. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in real time activated clotting time (ACT) following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | — |
| Change in diluted prothrombin time (dPT) following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | — |
| Change in diluted Russell Viper Venom time (dRVVT) following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | — |
| Change in thrombin generation, measured by time to peak, following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | Mean and median values, subjects on active treatment per group versus placebo |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] (Part 1) | From dosing up to Day 28 | Number of Subjects with One of More Drug Related Adverse Events (AEs) or any Serious AEs |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] (Part 2) | From dosing up to Day 31 | Number of Subjects with One of More Drug Related Adverse Events (AEs) or any Serious AEs |
| PK of VMX-C001 in plasma - Cmax | Up to 7 days post VMX-C001 dose | Maximal concentration in plasma |
| PK of VMX-C001 in plasma - tmax | Up to 7 days post VMX-C001 dose | Time of maximal concentration in plasma |
| PK of VMX-C001 in plasma - t1/2 | Up to 7 days post VMX-C001dose | Terminal elimination half-life in plasma |
| PK of VMX-C001 in plasma - AUC0-last | Up to 7 days post VMX-C001 dose | Area under the concentration-time curve from time of dosing to last measurable concentration in plasma |
| PK of VMX-C001 in plasma - AUC0-inf | Up to 7 days post VMX-C001 dose | Area under the concentration-time curve from time of dosing extrapolated to infinity in plasma |
| PK of VMX-C001 in plasma - Lambda z | Up to 7 days post VMX-C001 dose | Terminal elimination rate constant |
| PK of VMX-C001 in plasma - CL | Up to 7 days post VMX-C001 dose | Total body clearance |
| PK of VMX-C001 in plasma - Vz | Up to 7 days post VMX-C001 dose | Apparent volume of distribution |
| DOAC plasma concentrations (Part 2) | Up to Day 10 | — |
| Change in Prothrombin time (PT) following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | — |
| Change in activated partial thromboplastin time (aPTT) following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | — |
| Change in D-dimer following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | — |
| Change in prothrombin fragments F1 and 2 following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | Mean and median values, subjects on active treatment per group versus placebo |
| Change in thrombin generation, measured by lag time, following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | Mean and median values, subjects on active treatment per group versus placebo |
| Change in thrombin generation, measured by endogenous thrombin potential, following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | Mean and median values, subjects on active treatment per group versus placebo |
| Change in thrombin generation, measured by peak height, following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | Mean and median values, subjects on active treatment per group versus placebo |
| Change in thrombin generation, measured by velocity index, following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | Mean and median values, subjects on active treatment per group versus placebo |
| Change in thrombin generation, measured by time to tail, following dosing with VMX-C001 | Up to 7 days post VMX-C001 dose | Mean and median values, subjects on active treatment per group versus placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antibodies against human coagulation FX in plasma | Up to 28 days post VMX-C001 dose | Percentage of patients positive (active vs placebo), and titer (percentage of patients tested positive for each titer measured) |
| Antibodies against VMX-C001 in plasma | Up to 28 days post VMX-C001 dose | Percentage of patients positive (active vs placebo), and titer (percentage of patients tested positive for each titer measured) |
Countries
Netherlands
Outcome results
None listed