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About
This is a randomized, double-blind, study in healthy volunteers dosed to steady state with fXa inhibitors, designed to (1) demonstrate PK/PD comparability between andexanet manufactured by the Generation 1 and Generation 2 processes, (2) evaluate the degree to which the Generation 2 andexanet reverses fXa-inhibitor-induced anticoagulation in comparison to placebo, and (3) evaluate safety of Generation 2 andexanet.
Enrollment
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Volunteers
Inclusion criteria
Must be in reasonably good health as determined by the Investigator based on medical history, full physical examination (including blood pressure and pulse rate measurement), 12-lead ECG, and clinical laboratory tests. Subjects with well-controlled, chronic, stable conditions (e.g., controlled hypertension, non-insulin dependent diabetes, osteoarthritis, hypothyroidism) may be enrolled based on the clinical judgment of the Investigator and if approved by the Medical Monitor.
Must be between the ages of 18 and 75 years, inclusive, at the time of signing of the informed consent form (ICF).
Agrees to have any dietary or nutritional supplements reviewed by the Investigator and potentially be withheld during the study if advised by the Investigator. Standard multivitamin and mineral supplementation will be permitted.
Agrees to comply with the contraception and reproduction restrictions of the study:
Systolic blood pressure < 160 mmHg and diastolic blood pressure < 90 mmHg at Screening and Day 1.
The following laboratory values must be within the normal laboratory reference range within 28 days of Day 1: prothrombin time (PT), activated partial thromboplastin time (aPTT), and activated clotting time (ACT); hemoglobin, hematocrit, and platelet count.
The following laboratory values must be equal to or below 2 times the upper limit of normal (ULN) range within 28 days of Day 1: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and total bilirubin.
The Screening serum creatinine must be below 1.5 mg/dL within 28 days of Day 1.
Body mass index between 19-30 kg/m2, inclusive, and body weight at least 50 kg.
Agrees to abstain from alcohol consumption for the duration of the domicile period, and from the use of drugs of abuse for the duration of the study.
Able to read and give written informed consent and has signed a consent form approved by the Investigator's Institutional Review Board (IRB) or Independent Ethics Committee (IEC).
Exclusion criteria
Previous use of andexanet or previous participation in the current study.
History of abnormal bleeding, signs or symptoms of active bleeding, or risk factors for bleeding.
Has a stool specimen that was positive for occult blood within 6 months of study Screening or during the Screening Period.
Past or current medical history of thrombosis, any sign or symptom that suggests an increased risk of a systemic thrombotic condition or thrombotic event, or recent events that may increase risk of thrombosis.
a. For example, subjects with a known or suspected hypercoagulable state, history of VTE, DVT, stroke, myocardial infarction [MI], cancer [other than non-melanoma skin cancer], atrial fibrillation, heart failure, cardiomyopathy, phlebitis, lower extremity edema, major surgery or trauma within 2 months of Study Day 1, airplane travel ≥ 2 hours during the 4 weeks prior to Study Day 1, or general immobility are excluded.
Absolute or relative contraindication to anticoagulation or treatment with apixaban, rivaroxaban, enoxaparin, or edoxaban.
Prior consumption of (by any route) one or more doses of aspirin (including baby aspirin), salicylate or subsalicylate, other antiplatelet drugs (e.g., ticlopidine, clopidogrel), non-steroidal anti-inflammatory drugs, fibrinolytic, or any anticoagulant within 7 days prior to Day 1 or is anticipated to require such drugs during the study.
Receipt of (by any route) hormonal contraception, post-menopausal hormone replacement therapy (HRT) (including over-the-counter products), or testosterone during the 4 weeks prior to Study Day 1 or is anticipated to require such drugs during the study.
Family history of or risk factors for a hypercoagulable or thrombotic condition, including one of the following:
History of adult asthma or chronic obstructive pulmonary disease or current regular or as-needed use of inhaled medications.
Active HBV, HCV, or HIV-1/2 infection
Use of any drugs that are strong dual inhibitors or inducers of CYP3A4 and P-gp within 7 days prior to Study Day 1 or anticipated need for such drugs during the study.
Participation in an investigational drug study within 28 days of Day 1 or Day 1 is within 5 half-lives of the investigational compound.
Positive screen for drugs of abuse at Day 1 that is not explained by a prescription medication that the subject is known to be taking.
A medical or surgical condition that may impair drug (fXa inhibitor or andexanet) metabolism.
Allergy to any of the vehicle ingredients: tris, arginine, sucrose, hydrochloric acid, mannitol, and polysorbate 80.
Current breastfeeding or a positive pregnancy test at Screening or Day 1.
Any condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or interpretation of the study results, or that would in the opinion of the Investigator increase the risk of the subject's participation in the study. This would include but is not limited to alcoholism, drug dependency or abuse, psychiatric disease, epilepsy, or any unexplained blackouts.
The subject is not judged by the study staff to have adequate bilateral venous access.
Unwillingness to adhere to the activity requirements of the study.
Primary purpose
Allocation
Interventional model
Masking
153 participants in 11 patient groups
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Data sourced from clinicaltrials.gov
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