Atrial Fibrillation (AF), Stroke
Conditions
Keywords
randomized, prospective, blinded endpoint evaluation, abelacimab, MAA868, rivaroxaban, atrial fibrillation, Factor XI, stroke, bleeding events, anti-coagulant, anticoagulation therapy
Brief summary
The purpose of the ANT-006 study is to evaluate the bleeding profile of abelacimab relative to rivaroxaban in patients with atrial fibrillation (AF) at moderate-to-high risk of stroke.
Interventions
BIOLOGICALAbelacimab
Abelacimab provided as liquid in vial (150 mg/mL)
DRUGRivaroxaban
Rivaroxaban 15 mg and 20 mg provided as commercially available film-coated tablets
Sponsors
Novartis Pharmaceuticals
Anthos Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
All care providers are blinded with the exception of the pharmacist and study team member assigned to administer the subcutaneous injection of abelacimab.
Intervention model description
This is an event-driven, randomized, active-controlled, blinded endpoint, parallel-group study to evaluate the effect of two blinded doses of abelacimab relative to open-label rivaroxaban on the rate of major or clinically relevant non-major (CRNM) bleeding events in patients with atrial fibrillation (AF) who are at moderate-to-high risk of stroke.
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female patients ≥ 55 years old * Patients with a history of atrial fibrillation (AF) or atrial flutter with planned indefinite anticoagulation * Patients with a CHA2DS2-VASc of ≥4 OR a CHA2DS2-VASc of ≥3 with at least 1 of the following: 1. Planned concomitant use of antiplatelet medication use (i.e., aspirin and/or P2Y12 inhibitor) for the duration of the trial 2. Creatinine Clearance (CrCl) ≤50 ml/min by the Cockcroft-Gault equation
Exclusion criteria
* 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 Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of the First Occurrence of Composite of International Society on Thrombosis and Haemostasis (ISTH)-Defined Major Bleeding or Clinically Relevant Non-Major (CRNM) Bleeding Events | Assessed at every visit from randomization through the end of the randomized phase of the study, up to 33 months. | The number of participants experiencing the first occurrence of the composite of ISTH-defined major bleeding or CRNM bleeding events divided by the number of 100 person-years through the first event or end of treatment across all participants, is presented. For participants not experiencing events, person-years is calculated through the end of treatment during the randomized phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of the First Occurrence of ISTH-defined Major Bleeding Events | Assessed at every visit from randomization through the end of the randomized phase of the study, up to 33 months. | The number of participants experiencing the first occurrence of ISTH-defined major bleeding events divided by the number of 100 person-years through the first event or end of treatment across all participants, is presented. For participants not experiencing events, person-years is calculated through the end of treatment during the randomized phase. |
| Incidence Rate of the First Occurrence of ISTH-defined Major or CRNM or Minor Bleeding Events | Assessed at every visit from randomization through the end of the randomized phase of the study, up to 33 months. | The number of participants experiencing the first occurrence of the composite of ISTH-defined major or CRNM or minor bleeding events divided by the number of 100 person-years through the first event or end of treatment across all participants, is presented. For participants not experiencing events, person-years is calculated through the end of treatment during the randomized phase. |
Countries
Canada, Czechia, Hungary, Poland, South Korea, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Abelacimab 90 mg (MAA868) Treatment group 1: Abelacimab low dose subcutaneous (s.c.) monthly Abelacimab: Abelacimab provided as liquid in vial (150 mg/mL) | 427 |
| Abelacimab 150 mg (MAA868) Treatment group 2: Abelacimab high dose subcutaneous (s.c.) monthly Abelacimab: Abelacimab provided as liquid in vial (150 mg/mL) | 430 |
| Rivaroxaban Treatment group 3: Rivaroxaban 20 mg by mouth; orally (p.o.) once per day with the evening meal Participants with a Creatinine Clearance (CrCl) ≤50 ml/min by the Cockcroft-Gault equation will have a dose adaptation to rivaroxaban 15 mg p.o. daily. Rivaroxaban: Rivaroxaban 15 mg and 20 mg provided as commercially available film-coated tablets | 430 |
| Total | 1,287 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 31 | 36 | 34 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 14 | 3 | 6 |
Baseline characteristics
| Characteristic | Abelacimab 150 mg (MAA868) | Abelacimab 90 mg (MAA868) | Rivaroxaban | Total |
|---|---|---|---|---|
| Age, Customized ≥ 80 years | 81 Participants | 87 Participants | 90 Participants | 258 Participants |
| Anticoagulation ≥60 days Anticoagulation ≥60 days | 389 Participants | 389 Participants | 404 Participants | 1182 Participants |
| Anticoagulation ≥60 days Direct oral anticoagulant | 271 Participants | 283 Participants | 291 Participants | 845 Participants |
| Anticoagulation ≥60 days Parenteral agent | 9 Participants | 3 Participants | 6 Participants | 18 Participants |
| Anticoagulation ≥60 days Previous use of >1 anticoagulant | 21 Participants | 22 Participants | 23 Participants | 66 Participants |
| Anticoagulation ≥60 days Vitamin K antagonist | 130 Participants | 125 Participants | 130 Participants | 385 Participants |
| CHA₂DS₂-VASc score ≤4 | 213 Participants | 191 Participants | 186 Participants | 590 Participants |
| CHA₂DS₂-VASc score 5 | 131 Participants | 135 Participants | 130 Participants | 396 Participants |
| CHA₂DS₂-VASc score ≥6 | 86 Participants | 101 Participants | 114 Participants | 301 Participants |
| Coronary artery disease | 199 Participants | 218 Participants | 205 Participants | 622 Participants |
| Creatinine clearance ≤50 ml/min | 90 Participants | 86 Participants | 88 Participants | 264 Participants |
| Diabetes | 231 Participants | 223 Participants | 245 Participants | 699 Participants |
| HAS-BLED score ≥3 | 213 Participants | 210 Participants | 225 Participants | 648 Participants |
| Heart failure | 182 Participants | 192 Participants | 206 Participants | 580 Participants |
| History of bleeding Any bleeding | 34 Participants | 29 Participants | 36 Participants | 99 Participants |
| History of bleeding Gastrointestinal bleeding | 22 Participants | 16 Participants | 23 Participants | 61 Participants |
| Hypertension | 417 Participants | 410 Participants | 418 Participants | 1245 Participants |
| Median Age | 74 years | 75 years | 74 years | 74 years |
| Median body-mass index (IQR) | 30.0 kg/m² | 29.5 kg/m² | 30.3 kg/m² | 29.9 kg/m² |
| Median CHA₂DS₂-VASc score | 5.0 score | 5.0 score | 5.0 score | 5.0 score |
| Median HAS-BLED score | 2.0 score | 2.0 score | 3.0 score | 3.0 score |
| Pattern of atrial fibrillation First detected or paroxysmal | 220 Participants | 224 Participants | 225 Participants | 669 Participants |
| Pattern of atrial fibrillation Permanent | 120 Participants | 115 Participants | 106 Participants | 341 Participants |
| Pattern of atrial fibrillation Persistent or long-standing persistent | 84 Participants | 87 Participants | 97 Participants | 268 Participants |
| Planned concomitant antiplatelet medication Aspirin | 70 Participants | 72 Participants | 58 Participants | 200 Participants |
| Planned concomitant antiplatelet medication Dual antiplatelet therapy | 6 Participants | 9 Participants | 6 Participants | 21 Participants |
| Planned concomitant antiplatelet medication P2Y12 inhibitor | 29 Participants | 26 Participants | 42 Participants | 97 Participants |
| Previous ischemic stroke | 59 Participants | 57 Participants | 75 Participants | 191 Participants |
| Previous transient ischemic attack | 25 Participants | 38 Participants | 32 Participants | 95 Participants |
| Race/Ethnicity, Customized Asian | 15 Participants | 20 Participants | 24 Participants | 59 Participants |
| Race/Ethnicity, Customized Black | 5 Participants | 3 Participants | 2 Participants | 10 Participants |
| Race/Ethnicity, Customized White | 410 Participants | 404 Participants | 404 Participants | 1218 Participants |
| Region of Enrollment Asia | 15 Participants | 19 Participants | 22 Participants | 56 Participants |
| Region of Enrollment Europe | 309 Participants | 282 Participants | 305 Participants | 896 Participants |
| Region of Enrollment North America | 106 Participants | 126 Participants | 103 Participants | 335 Participants |
| Sex/Gender, Customized Female sex | 193 Participants | 195 Participants | 184 Participants | 572 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 31 / 427 | 36 / 430 | 34 / 430 |
| other Total, other adverse events | 215 / 425 | 257 / 427 | 227 / 428 |
| serious Total, serious adverse events | 158 / 425 | 157 / 427 | 167 / 428 |
Outcome results
Primary
Incidence Rate of the First Occurrence of Composite of International Society on Thrombosis and Haemostasis (ISTH)-Defined Major Bleeding or Clinically Relevant Non-Major (CRNM) Bleeding Events
The number of participants experiencing the first occurrence of the composite of ISTH-defined major bleeding or CRNM bleeding events divided by the number of 100 person-years through the first event or end of treatment across all participants, is presented. For participants not experiencing events, person-years is calculated through the end of treatment during the randomized phase.
Time frame: Assessed at every visit from randomization through the end of the randomized phase of the study, up to 33 months.
Population: The analysis population is the number of randomized participants who received at least one dose of study treatment. The difference between the overall number of participants analyzed and the overall number of participants assigned to the arm represents those who never received a dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Abelacimab 90 mg (MAA868) | Incidence Rate of the First Occurrence of Composite of International Society on Thrombosis and Haemostasis (ISTH)-Defined Major Bleeding or Clinically Relevant Non-Major (CRNM) Bleeding Events | 2.64 participants with event/100 person-years |
| Abelacimab 150 mg (MAA868) | Incidence Rate of the First Occurrence of Composite of International Society on Thrombosis and Haemostasis (ISTH)-Defined Major Bleeding or Clinically Relevant Non-Major (CRNM) Bleeding Events | 3.22 participants with event/100 person-years |
| Rivaroxaban | Incidence Rate of the First Occurrence of Composite of International Society on Thrombosis and Haemostasis (ISTH)-Defined Major Bleeding or Clinically Relevant Non-Major (CRNM) Bleeding Events | 8.39 participants with event/100 person-years |
p-value: <0.00195% CI: [0.192, 0.513]Stratified Log Rank Test
p-value: <0.00195% CI: [0.243, 0.602]Stratified Log Rank Test
Secondary
Incidence Rate of the First Occurrence of ISTH-defined Major Bleeding Events
The number of participants experiencing the first occurrence of ISTH-defined major bleeding events divided by the number of 100 person-years through the first event or end of treatment across all participants, is presented. For participants not experiencing events, person-years is calculated through the end of treatment during the randomized phase.
Time frame: Assessed at every visit from randomization through the end of the randomized phase of the study, up to 33 months.
Population: The analysis population is the number of randomized participants who received at least one dose of study treatment. The difference between the overall number of participants analyzed and the overall number of participants assigned to the arm represents those who never received a dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Abelacimab 90 mg (MAA868) | Incidence Rate of the First Occurrence of ISTH-defined Major Bleeding Events | 0.99 participants with event/100 person-years |
| Abelacimab 150 mg (MAA868) | Incidence Rate of the First Occurrence of ISTH-defined Major Bleeding Events | 1.22 participants with event/100 person-years |
| Rivaroxaban | Incidence Rate of the First Occurrence of ISTH-defined Major Bleeding Events | 3.73 participants with event/100 person-years |
p-value: <0.00195% CI: [0.121, 0.572]Stratified Log Rank Test
p-value: 0.00195% CI: [0.159, 0.663]Stratified Log Rank Test
Secondary
Incidence Rate of the First Occurrence of ISTH-defined Major or CRNM or Minor Bleeding Events
The number of participants experiencing the first occurrence of the composite of ISTH-defined major or CRNM or minor bleeding events divided by the number of 100 person-years through the first event or end of treatment across all participants, is presented. For participants not experiencing events, person-years is calculated through the end of treatment during the randomized phase.
Time frame: Assessed at every visit from randomization through the end of the randomized phase of the study, up to 33 months.
Population: The analysis population is the number of randomized participants who received at least one dose of study treatment. The difference between the overall number of participants analyzed and the overall number of participants assigned to the arm represents those who never received a dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Abelacimab 90 mg (MAA868) | Incidence Rate of the First Occurrence of ISTH-defined Major or CRNM or Minor Bleeding Events | 7.05 participants with event/100 person-years |
| Abelacimab 150 mg (MAA868) | Incidence Rate of the First Occurrence of ISTH-defined Major or CRNM or Minor Bleeding Events | 10.43 participants with event/100 person-years |
| Rivaroxaban | Incidence Rate of the First Occurrence of ISTH-defined Major or CRNM or Minor Bleeding Events | 15.30 participants with event/100 person-years |
p-value: <0.00195% CI: [0.332, 0.638]Stratified Log Rank Test
p-value: 0.0195% CI: [0.512, 0.912]Stratified Log Rank Test