A Dose-range Finding Study of MAA868 in Patients With Atrial Fibrillation

Study Overview
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Brief Summary
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This study is a multicenter, randomized, subject and Investigator-blinded, placebo-controlled, parallel-group, multiple ascending dose-ranging study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) effects of MAA868 in patients with atrial fibrillation (AF) or flutter at low risk of thromboembolic stroke or peripheral embolism.

Official Title
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A Randomized, Placebo-controlled, Dose-range Finding Study to Assess the Pharmacokinetic and Pharmacodynamic Parameters, Safety, Tolerability, and Immunogenicity of MAA868 in Patients With Atrial Fibrillation

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Biological: MAA868 Cohort 1
* Biological: MAA868 Cohort 2
* Biological: MAA868 Cohort 3
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients ≥ 18 and < 85 years old with paroxysmal atrial fibrillation (PAF) or atrial flutter on 12 lead electrocardiography at Screening Or Patients with a history of PAF or atrial flutter, as documented by (telemetry, 12 lead electrocardiography or ambulatory [e.g. Holter] monitor) and not due to a reversible condition (e.g. alcohol binge drinking) can be entered even if they do not have PAF at Screening. There is not time-limit for this. Patients with a Congestive heart failure, Hypertension, Age ( > 65 = 1 point, > 75 = 2 points), Diabetes, previous Stroke/transient ischemic attack (2 points) (CHA2DS2-VASc) risk score (tool as a predictor for estimating the risk of stroke in patients with atrial fibrillation (AF); Lip et al 2010) of 0-1 for men and 1-2 for women and in whom, in the investigator's judgment, the use of an anticoagulant for stroke prevention is not indicated Exclusion Criteria: History of stroke, transient ischemic attack or systemic embolism History of major bleeding during treatment with an anticoagulant or antiplatelet therapy. (Patients who have had major bleeding on anticoagulants or antiplatelet therapy more than a year ago can be enrolled only if the bleeding was due to a reversible cause, e.g. gastro-duodenal ulcer that was successfully treated.) History of traumatic or non-traumatic intracranial, intraspinal or intraocular bleeding Known bleeding diathesis or any known active bleeding site at screening or baseline Family history of bleeding disorder Known active GI lesions predisposing to bleeding events Myocardial infarction, unstable angina pectoris or coronary artery bypass graft (CABG) surgery within 12 months prior to the Screening period Known clinically significant valvular heart disease including moderate or severe mitral stenosis (valve area <1.5 cm2) Patients with a prosthetic heart valve Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MAA868<br>Subcutaneous injection on Day 1 with two subsequent monthly injections | Biological: MAA868 Cohort 1<br>* Subcutaneous injection: low dose<br>Biological: MAA868 Cohort 2<br>* Subcutaneous injection: high dose<br>Biological: MAA868 Cohort 3<br>* Subcutaneous injection: Dose to be determined.<br>|
| Placebo Comparator: Placebo<br>Subcutaneous injection: Placebo on Day 1 with two subsequent monthly injections | Other: Placebo<br>* Subcutaneous injection: Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Achieved More Than or Equal to 50%, 80%, and 90% Factor XI Inhibition at Trough After the Third Dose (Day 91) at Different Dose Levels of MAA868 | Number of participants achieving more than or equal to 50%, 80%, and 90% inhibition of factor XI (less than 50%, 20%, or 10% free factor XI) at trough after the third dose on Day 91 at different dose levels of MAA868 | Day 91 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving More Than or Equal to 50%, 80%, and 90% Factor XI Inhibition at Trough After First (Day 31) and Second Doses (Day 61) at Different Dose Levels of MAA868 | Number of participants achieving more than or equal to 50%, 80%, and 90% inhibition of factor XI (less than 50%, 20%, or 10% free factor XI) at trough on Day 31 (after first dose) and Day 61 (after second dose) at different dose levels of MAA868 | Day 31 and Day 61 | 
| Overall Number of Participants Who Experienced Adverse Events, Including Serious Adverse Events, During the Treatment Period and Through End of Study | Overall number of participants who experienced adverse events following multiple subcutaneous administration of MAA868 compared to placebo in participants with atrial fibrillation or atrial flutter | Day 1 through end of study, up to 170 days | 
| Incidence of Major Bleeding Events, Clinically Relevant Non-major Bleeding Events and Total Bleeding With MAA868 Relative to Placebo | Occurrence of confirmed major bleeding events, clinically relevant non-major bleeding events and total bleeding events during the treatment period | Day 1 through end of study, up to 170 days | 
| Immunogenicity of MAA868 | Number of participants with anti-drug (MAA868) antibodies for all participants who received MAA868 120 mg or MAA868 180 mg. Non-evaluable observation refers to participants who had no sample collected (due to no visit or remote visit) or for whom the sample was not frozen. | Days 1, 31, 61, 71, 91, 121 and 170 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atrial fibrillation, flutter, paroxysmal atrial fibrillation, stroke, cardiac arrhythmia