A Study to Investigate Andexanet Dosing and the Interaction Between Andexanet and Subsequent Enoxaparin in Healthy Participants

AstraZeneca

Status and phase: Enrolling; Phase 1

Conditions: Healthy Participants

Treatments: Drug: Apixaban; Other: Placebo; Drug: Enoxaparin; Drug: Rivaroxaban; Drug: Andexanet alfa

Study type: Interventional

Funder types: Industry

Identifiers

NCT07312851

D9609C00001

2025-522513-30-00 (Other Identifier)

Details and patient eligibility

About

The purpose of this study is to characterize andexanet posology and interaction between andexanet and enoxaparin post infusion in healthy participants.

Full description

This is a single-blind, placebo-controlled study. The study has 4 modules, which is then divided into 2 parts. Part A of the study will focus on further characterization of andexanet posology and Part B of the study will evaluate a re-institution of anticoagulation with enoxaparin.

Module 1, 2 and 4 - rivaroxaban, apixaban and enoxaparin: These modules are designed to determine the pharmacodynamic (PD) effect of andexanet by assessing its reversal effects on rivaroxaban and apixaban anticoagulation, or assessing its effects in the absence of anticoagulants, and to identify the time interval after andexanet administration at which andexanet shows no impact on enoxaparin.

Module 3 - rivaroxaban and apixaban: This Module is designed to determine the PD effect of bolus only andexanet by assessing its reversal effect on rivaroxaban and apixaban anticoagulation.

All the Modules will comprise:

• A Screening/Enrollment Period of maximum 28 days.
• An in-house stay comprising of a safety baseline lab period (Day -3 to Day -1)
• Treatment period (Day 1 to Day 2)
• Safety follow-up period (Day 3 to Day 5)
• A final Follow-up Visit within 30 days (+7 days) after the last andexanet/placebo administration.

Enrollment: 186 estimated patients

Sex: All

Ages: 18 to 55 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Main Inclusion Criteria:

• All females must have a negative pregnancy test at the Screening Visit.
• Females of childbearing potential must not be lactating and if heterosexually active must agree to use an approved method of highly effective contraception.
• Sexually active fertile male participants with partners of childbearing potential must adhere to the study specific contraception methods.
• Have a Body Mass Index (BMI) between 18.5 and 30.0 kg/m2 (both inclusive) and weigh at least 60 kg.
• Agree to abstain from alcohol consumption or smoking for the duration of the residential period, and from the use of drugs of abuse for the duration of the study.
• Be in good health and agree to have any dietary or nutritional supplements, if needed.

Main Exclusion Criteria:

• History of any clinically significant disease or disorder which may either put the participant at risk because of participation in the study or influence the results or the participant's ability to participate in the study.
• History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• History of abnormal bleeding or bleeding disorders (eg, hemophilia, von Willebrand disease), signs or symptoms of active bleeding, or risk factors for bleeding.
• History of adult asthma or chronic obstructive pulmonary disease or current regular or as needed use of inhaled medications.
• Family history of or known risk factors for a hypercoagulable or thrombotic condition or thrombotic event, such as anti-phospholipid syndrome; Factor V Leiden carrier or homozygote; Protein C, S, or AT3 activity below the normal range.
• Past or current medical history of thrombosis, any sign or symptom that suggests an increased risk of a systemic thrombotic condition, or recent events that may increase risk of thrombosis.
• Any medical or surgical conditions which may impair drug (anticoagulant or andexanet) uptake, metabolism, or excretion.
• An absolute or relative contraindication to anticoagulation or treatment with apixaban, rivaroxaban or enoxaparin.
• Any clinically significant illness or medical procedure within 4 weeks of the first administration of study intervention.
• Any clinically significant abnormalities in clinical chemistry, hematology, coagulation or urinalysis results
• Any positive result on Screening for serum hepatitis B surface antigen (HBsAg) OR anti-hepatitis B core (HBc) antibody, indicative of active hepatitis B (ie, participants with positive anti-HBc antibody result are acceptable if anti-HBc IgM antibodies are negative), anti- hepatitis C virus (HCV) or human immunodeficiency virus (HIV).
• History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, including heparin-induced thrombocytopenia, or history of hypersensitivity to drugs with a similar chemical structure or class to andexanet, apixaban, rivaroxaban, or enoxaparin or any of the vehicle ingredients.
• Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, intake of > 3 × daily recommended levels of vitamins and minerals during the 2 weeks prior to the first administration of study intervention or longer (> 5 half-lives) if the medication has a long half-life. The participant has taken (by any route) one or more doses of aspirin (including baby aspirin), salicylate or subsalicylate, other antiplatelet drugs (eg, ticagrelor, clopidogrel, ticlopidine), non-steroidal anti-inflammatory drugs, fibrinolytic, or any anticoagulant within 7 days prior to Admission or is anticipated to require such drugs during the study. The participant has been receiving (by any route) hormonal contraception, postmenopausal HRT (including over-the-counter products), or testosterone during the 4 weeks prior to Admission or is anticipated to require such drugs during the study.
• Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days or 5 half-lives (whichever is longest) of Admission.
• Participants who have previously received andexanet.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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186 participants in 14 patient groups

Module 1: Rivaroxaban + Andexanet (dose A)

Experimental group

Description:

Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose A) dosing, the participants will receive an additional dose of rivaroxaban. Participants will be further allocated to groups to receive doses of enoxaparin at different time points after the end of andexanet bolus.

Treatment:

Drug: Andexanet alfa

Drug: Rivaroxaban

Drug: Enoxaparin

Module 1: Rivaroxaban + Andexanet (dose B)

Experimental group

Description:

Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose B) dosing, the participants will receive an additional dose of rivaroxaban.

Treatment:

Drug: Andexanet alfa

Drug: Rivaroxaban

Module 1: Rivaroxaban + Andexanet (dose C)

Experimental group

Description:

Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose C) dosing, the participants will receive an additional dose of rivaroxaban.

Treatment:

Drug: Andexanet alfa

Drug: Rivaroxaban

Module 1: Rivaroxaban + Placebo

Experimental group

Description:

Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before placebo (equivalent to dose B of andexanet) dosing, the participants will receive an additional dose of rivaroxaban. Participants will be further allocated to groups to receive doses of enoxaparin at different time points after placebo administration.

Treatment:

Drug: Rivaroxaban

Drug: Enoxaparin

Other: Placebo

Module 2: Apixaban + Andexanet (dose B)

Experimental group

Description:

Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose B) dosing, the participants will receive an additional dose of apixaban. Participants will be further allocated to groups to receive doses of enoxaparin at different time points after the end of andexanet bolus.

Treatment:

Drug: Andexanet alfa

Drug: Enoxaparin

Drug: Apixaban

Module 2: Apixaban + Andexanet (dose C)

Experimental group

Description:

Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose C) dosing, the participants will receive an additional dose of apixaban.

Treatment:

Drug: Andexanet alfa

Drug: Apixaban

Module 2: Apixaban + Andexanet (dose D)

Experimental group

Description:

Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose D) dosing, the participants will receive an additional dose of apixaban.

Treatment:

Drug: Andexanet alfa

Drug: Apixaban

Module 2: Apixaban + Placebo

Experimental group

Description:

Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before placebo (equivalent to dose B of andexanet) dosing, the participants will receive an additional dose of apixaban. Participants will be further allocated to groups to receive doses of enoxaparin at different time points after placebo administration.

Treatment:

Drug: Enoxaparin

Other: Placebo

Drug: Apixaban

Module 3: Rivaroxaban + Andexanet (Dose A)

Experimental group

Description:

Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose A) dosing, the participants will receive an additional dose of rivaroxaban.

Treatment:

Drug: Andexanet alfa

Drug: Rivaroxaban

Module 3: Apixaban + Andexanet (Dose B)

Experimental group

Description:

Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose B) dosing, the participants will receive an additional dose of apixaban.

Treatment:

Drug: Andexanet alfa

Drug: Apixaban

Module 3: Rivaroxaban + Placebo

Experimental group

Description:

Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before placebo (equivalent to dose A of andexanet) dosing, the participants will receive an additional dose of rivaroxaban.

Treatment:

Drug: Rivaroxaban

Other: Placebo

Module 3: Apixaban + Placebo

Experimental group

Description:

Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before placebo (equivalent to dose B of andexanet) dosing, the participants will receive an additional dose of apixaban.

Treatment:

Other: Placebo

Drug: Apixaban

Module 4: Placebo + Andexanet (dose C)

Experimental group

Description:

Participants will receive daily dose of one placebo tablet from Day -3 to Day -1. On Day 1, approximately 3 hours before andexanet (dose C) dosing, the participants will receive an additional placebo tablet.

Treatment:

Drug: Andexanet alfa

Other: Placebo

Module 4: Placebo + Andexanet (dose B)

Experimental group

Description:

Participants will receive daily dose of one placebo tablet from Day -3 to Day -1. On Day 1, approximately 3 hours before andexanet (dose B) dosing, the participants will receive an additional placebo tablet. Participants will be further allocated to groups to receive doses of enoxaparin at different time points after the end of andexanet bolus.

Treatment:

Drug: Andexanet alfa

Drug: Enoxaparin

Other: Placebo