Evaluation of the Safety and Tolerability of Abelacimab Versus Rivaroxaban in Patients with Atrial Fibrillation: A Randomized Controlled Trial
- Trial ID
- 2023-509066-38-00
- Protocol
- CMAA868A2204/ANT-006
- Sponsor
- Anthos Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **abelacimab** relative to **rivaroxaban** on the rate of major or clinically relevant non-major (CRNM) bleeding events in patients with **atrial fibrillation**. This is clinically significant as it aims to determine the safety profile of abelacimab, potentially offering an alternative anticoagulant therapy with a different bleeding risk profile compared to rivaroxaban, which is widely used in managing atrial fibrillation.
Secondary objectives include:
- Evaluating the effect of abelacimab relative to rivaroxaban on the rate of major bleeding events.
- Assessing the effect of abelacimab relative to rivaroxaban on the rate of major or minor bleeding events.
Participants
The clinical trial involves a total of **304 participants** diagnosed with **Atrial Fibrillation**. The study population includes both male and female subjects aged 55 years and older. Participants were selected based on their ability to provide written informed consent and a history of atrial fibrillation or atrial flutter with planned indefinite anticoagulation. The trial includes individuals with a CHA2DS2-VASc score of 4 or higher, or a score of 3 with additional criteria such as planned concomitant use of antiplatelet medication or a creatinine clearance of 50 ml/min or less. The trial population is characterized by a diverse age range and includes a vulnerable population. Lifestyle factors such as diet and physical activity were not specified by the sponsor. The selection criteria ensure that participants are representative of the broader population affected by atrial fibrillation, with a focus on those requiring long-term anticoagulation therapy.
Plans and Procedures
The clinical trial is designed as a **randomized**, active-controlled study to evaluate the safety and tolerability of two blinded doses of **abelacimab** compared with open-label **rivaroxaban** in patients with **atrial fibrillation**. The trial is structured to be double-blind for the abelacimab doses, ensuring that neither the participants nor the investigators know which dose is being administered, while the rivaroxaban arm remains open-label. The primary objective is to assess the effect of abelacimab relative to rivaroxaban on the rate of major or clinically relevant non-major (CRNM) bleeding events. The trial is expected to run from January 2021 to October 2025, with a maximum treatment period of 24 months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, history of atrial fibrillation, and specific clinical scores. Following randomization, participants will attend regular follow-up visits to monitor safety, efficacy, and adherence to the study protocol. These visits will include assessments of bleeding events, laboratory tests, and other relevant clinical evaluations. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to gather comprehensive data on the primary and secondary endpoints.
The expected length of participant involvement is up to 24 months, contingent upon adherence to the study protocol and absence of any conditions that may necessitate early termination. Conditions leading to early withdrawal include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to achieve its objectives while maintaining participant safety and scientific integrity.
Treatment
The clinical trial involves the administration of **Xarelto 20 mg film-coated tablets**, which contain the active substance **rivaroxaban**. This pharmaceutical form is a film-coated tablet intended for **oral use**. The maximum daily dose is 20 mg, with a total maximum dose of 14,600 mg over a treatment period of 24 months. The medication is produced by Bayer AG and is classified under the ATC code B01AF01. The trial monitors participant compliance through regular assessments to ensure adherence to the dosing schedule.
Another treatment used in the study is **Xarelto 15 mg film-coated tablets**, also containing **rivaroxaban** as the active ingredient. Similar to the 20 mg formulation, these tablets are administered orally. The maximum daily dose for this formulation is 15 mg, with a total maximum dose of 10,950 mg over the same 24-month period. This formulation is also manufactured by Bayer AG and shares the same ATC classification. Compliance is monitored to ensure participants adhere to the prescribed dosing regimen.
The experimental medication in the trial is **Abelacimab 150 mg/ml solution for infusion**, containing the active substance **abelacimab**. This medication is provided as a concentrate for solution for infusion and is administered via **subcutaneous use**. The maximum daily dose is 150 mg, with a total maximum dose of 3,600 mg over a 24-month treatment period. Abelacimab is produced by Anthos Therapeutics Inc. and is categorized as a protein-based therapeutic. Participant compliance is closely monitored to ensure proper administration and adherence to the dosing schedule.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the effect of **abelacimab** relative to **rivaroxaban** on the rate of major or clinically relevant non-major (CRNM) bleeding events in patients with atrial fibrillation. The primary endpoint for efficacy evaluation is the time to the first event of a composite of International Society on Thrombosis and Haemostasis (ISTH)-defined major bleeding or CRNM bleeding events. Secondary endpoints include the time to the first event of ISTH-defined major bleeding events and the time to the first event of ISTH-defined major or minor bleeding events.
The measurement and collection of these efficacy parameters will be conducted throughout the trial duration, with specific timepoints for assessment not explicitly detailed. The analysis will focus on the time to the first occurrence of the specified bleeding events, utilizing validated criteria established by the ISTH to ensure consistency and reliability in the evaluation of bleeding events. The trial is designed as a multicenter, randomized, active-controlled study, ensuring a robust comparison between the two treatment groups.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to provide written informed consent before the first study assessment is performed.
- Male and female patients ≥ 55 years old.
- History of AF or atrial flutter with planned indefinite anticoagulation. Patients with newly diagnosed AF are eligible.
- A CHA2DS2-VASc of ≥4 OR a CHA2DS2-VASc of ≥3 with at least 1 of the following: • Planned concomitant use of antiplatelet medication (e.g. aspirin and/or P2Y12 inhibitor) for the duration of the trial. • CrCl ≤50 ml/min by the Cockcroft-Gault equation.
- Extension period inclusion criteria: Ongoing study treatment for the randomized part of the trial at the EoT visit.
- Extension period inclusion criteria: Able to provide written informed consent to enter the extension period.
Exclusion Criteria
- Use of other investigational drugs within 5 half-lives prior to enrollment or until the expected pharmacodynamic effect has returned to baseline, whichever is longer.
- History of hypersensitivity to any of the study drugs (including rivaroxaban) or its excipients, to drugs of similar chemical classes, or any contraindication listed in the label for rivaroxaban.
- Patients with an intracranial or intraocular bleed within the 3 months prior to screening.
- Clinically significant mitral stenosis (valve area <1.5 cm2).
- Mechanical heart valve or other indication for anticoagulation therapy other than atrial fibrillation (e.g., venous thromboembolism).
- Known presence of an atrial myxoma or left ventricular thrombus.
- History of left atrial appendage closure or removal.
- Active endocarditis.
- Systolic BP >180 mm Hg or diastolic BP >100 mm Hg on repeated measurements at screening.
- Planned invasive procedure with potential for uncontrolled bleeding (e.g. major surgery).
- Any stroke within 14 days before randomization or TIA within 3 days before randomization.
- A CrCl <15 mL/min or on dialysis at the time of Screening.
- Platelet count ≤70,000/mm3 at the Screening Visit.
- Hemoglobin <8 g/dL at the Screening Visit.
- aPTT or PT >1.5x the upper limit of normal (ULN) at the Screening Visit, if the patient is anticoagulant-naïve.
- Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception during their participation in the trial and for at least 10 weeks after the last dose of abelacimab for women randomized to abelacimab. Highly effective contraception methods include: • Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment • Male sterilization of sexual partner (at least 6 months prior to screening). For female patients in the study, the vasectomized male partner should be the sole partner for that patient • Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. Hormonal contraceptive methods should not be used or encouraged if considered to be contraindicated. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of reported menopausal status or oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment with follicle stimulating hormone (FSH) is she considered not of child-bearing potential.
- Sexually active males with female partners who are WOCBP must agree to use a condomor use other reliable birth control methods during their time in the study and should notfather a child or donate sperm during the study period.
- History of drug addiction or alcohol abuse in the past 2 years, as judged by the Investigator.
- Significant illness which has not resolved within two (2) weeks prior to the start of the study drug.
- Any medical or psychiatric condition which in the judgment of the Investigator may preclude patients of complying with study requirements for the duration of the study.
- Extension period exclusion criteria: History of hypersensitivity to abelacimab.
- Extension period exclusion criteria: Patients with an intracranial or intraocular bleed within the 3 months prior to EoT.
- Extension period exclusion criteria: Clinically significant mitral stenosis (valve area <1.5 cm2) Mechanical heart valve or other indication for anticoagulation therapy other than atrial fibrillation (e.g., venous thromboembolism).
- Extension period exclusion criteria: Known presence of an atrial myxoma or left ventricular thrombus.
- Extension period exclusion criteria: History of left atrial appendage closure or removal.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 23 Jan 2021 | 247 |
 Hungary | Not Recruiting | 23 Jan 2021 | 362 |
 Poland | Not Recruiting | 23 Jan 2021 | 287 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Xarelto 15 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 15 | 24 | PRD3003417 |
Abelacimab 150 mg/ml solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | SUBCUTANEOUS USE | 150 | 24 | PRD8078109 |
Xarelto 20 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 20 | 24 | PRD3003532 |