A Randomised, Double-Blind, Placebo-Controlled, Single Dose Trial Evaluating Different Doses of Intravenously Administered VMX-C001 and to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of VMX-C001 in Healthy Subjects (Part 1) and in Combination with a Selected FXa Direct Oral Anticoagulant (DOAC) in Healthy Older Subjects (Part 2)
Overview
- Phase
- Phase 1
- Intervention
- Placebo
- Conditions
- Coagulation Disorder
- Sponsor
- VarmX B.V.
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- PK of VMX-C001 in plasma - Vz
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
- •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.
- •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.
- •Postmenopausal women must have had ≥12 months of spontaneous amenorrhea (with documented follicle-stimulating hormone (FSH) \>33.4 IU/L).
- •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.
- •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 -
- •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).
- •Subject is willing and able to give their written informed consent to participate in the study and to abide by the study restrictions.
- •Subject has good upper limb venous access.
Exclusion Criteria
- •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.
- •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.
- •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.
- •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.
- •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.
- •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.
- •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.
- •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.
- •Because of an increased risk of thrombosis subjects with known diabetes mellitus or a fasted glucose ≥7.0 mmol/L at Screening.
- •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:
Arms & Interventions
Part 2, Cohort 2:1 - Placebo + Rivaroxaban
Single dose placebo in combination with DOAC.
Intervention: Placebo
Part 2, Cohort 2:4 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Rivaroxaban 20 mg Oral Tablet
Part 2, Cohort 2:4 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Apixaban 5 mg Oral Tablet
Part 1, Cohort 1:1 - VMX-C001
Single dose active.
Intervention: VMX-C001
Part 1, Cohort 1:1 - Placebo
Single dose placebo.
Intervention: Placebo
Part 2, Cohort 2:1 - VMX-C001 + Rivaroxaban
Single dose active in combination with DOAC.
Intervention: VMX-C001
Part 2, Cohort 2:1 - VMX-C001 + Rivaroxaban
Single dose active in combination with DOAC.
Intervention: Rivaroxaban 20 mg Oral Tablet
Part 2, Cohort 2:1 - Placebo + Rivaroxaban
Single dose placebo in combination with DOAC.
Intervention: Rivaroxaban 20 mg Oral Tablet
Part 2, Cohort 2:2 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: VMX-C001
Part 2, Cohort 2:2 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: Rivaroxaban 20 mg Oral Tablet
Part 2, Cohort 2:2 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: Apixaban 5 mg Oral Tablet
Part 2, Cohort 2:2 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: Edoxaban 60 mg Oral Tablet
Part 2, Cohort 2:2 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Placebo
Part 2, Cohort 2:2 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Rivaroxaban 20 mg Oral Tablet
Part 2, Cohort 2:2 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Apixaban 5 mg Oral Tablet
Part 2, Cohort 2:2 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Edoxaban 60 mg Oral Tablet
Part 2, Cohort 2:3 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: VMX-C001
Part 2, Cohort 2:3 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: Rivaroxaban 20 mg Oral Tablet
Part 2, Cohort 2:3 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: Apixaban 5 mg Oral Tablet
Part 2, Cohort 2:3 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: Edoxaban 60 mg Oral Tablet
Part 2, Cohort 2:3 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Placebo
Part 2, Cohort 2:3 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Rivaroxaban 20 mg Oral Tablet
Part 2, Cohort 2:3 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Apixaban 5 mg Oral Tablet
Part 2, Cohort 2:3 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Edoxaban 60 mg Oral Tablet
Part 2, Cohort 2:4 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: VMX-C001
Part 2, Cohort 2:4 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: Rivaroxaban 20 mg Oral Tablet
Part 2, Cohort 2:4 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: Apixaban 5 mg Oral Tablet
Part 2, Cohort 2:4 - VMX-C001 + DOAC
Optional cohort - Single dose active in combination with selected DOAC.
Intervention: Edoxaban 60 mg Oral Tablet
Part 2, Cohort 2:4 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Placebo
Part 2, Cohort 2:4 - Placebo + DOAC
Optional cohort - Single dose placebo in combination with selected DOAC.
Intervention: Edoxaban 60 mg Oral Tablet
Outcomes
Primary Outcomes
PK of VMX-C001 in plasma - Vz
Time Frame: Up to 7 days post VMX-C001 dose
Apparent volume of distribution
Change in activated partial thromboplastin time (aPTT) following dosing with VMX-C001
Time Frame: Up to 7 days post VMX-C001 dose
Change in prothrombin fragments F1 and 2 following dosing with VMX-C001
Time Frame: Up to 7 days post VMX-C001 dose
Mean and median values, subjects on active treatment per group versus placebo
PK of VMX-C001 in plasma - tmax
Time Frame: Up to 7 days post VMX-C001 dose
Time of maximal concentration in plasma
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] (Part 1)
Time Frame: 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)
Time Frame: From dosing up to Day 31
Number of Subjects with One of More Drug Related Adverse Events (AEs) or any Serious AEs
Change in D-dimer following dosing with VMX-C001
Time Frame: Up to 7 days post VMX-C001 dose
PK of VMX-C001 in plasma - Cmax
Time Frame: Up to 7 days post VMX-C001 dose
Maximal concentration in plasma
PK of VMX-C001 in plasma - CL
Time Frame: Up to 7 days post VMX-C001 dose
Total body clearance
Change in diluted prothrombin time (dPT) following dosing with VMX-C001
Time Frame: Up to 7 days post VMX-C001 dose
PK of VMX-C001 in plasma - AUC0-last
Time Frame: Up to 7 days post VMX-C001 dose
Area under the concentration-time curve from time of dosing to last measurable concentration in plasma
DOAC plasma concentrations (Part 2)
Time Frame: Up to Day 10
Change in Prothrombin time (PT) following dosing with VMX-C001
Time Frame: Up to 7 days post VMX-C001 dose
PK of VMX-C001 in plasma - t1/2
Time Frame: Up to 7 days post VMX-C001dose
Terminal elimination half-life in plasma
PK of VMX-C001 in plasma - AUC0-inf
Time Frame: 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
Time Frame: Up to 7 days post VMX-C001 dose
Terminal elimination rate constant
Change in diluted Russell Viper Venom time (dRVVT) following dosing with VMX-C001
Time Frame: Up to 7 days post VMX-C001 dose
Change in real time activated clotting time (ACT) following dosing with VMX-C001
Time Frame: Up to 7 days post VMX-C001 dose
Change in thrombin generation, measured by lag time, following dosing with VMX-C001
Time Frame: 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
Time Frame: 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
Time Frame: 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 peak, following dosing with VMX-C001
Time Frame: 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
Time Frame: 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
Time Frame: Up to 7 days post VMX-C001 dose
Mean and median values, subjects on active treatment per group versus placebo
Secondary Outcomes
- Antibodies against VMX-C001 in plasma(Up to 28 days post VMX-C001 dose)
- Antibodies against human coagulation FX in plasma(Up to 28 days post VMX-C001 dose)