Antiarrhythmic and Symptomatic Effect of ISIS CRP Rx Targeting CRP in Paroxysmal Atrial Fibrillation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate whether treatment with ISIS CRP Rx can reduce AF (Atrial Fibrillation) burden (percentage of time spent in AF) in subjects with paroxysmal AF

Official Title
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A Phase 2 Study to Assess the Antiarrhythmic and Symptomatic Effect of the Second Generation Antisense Oligonucleotide ISIS 329993 Targeting CRP in Patients With Paroxysmal Atrial Fibrillation

Conditions
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Paroxysmal Atrial Fibrillation

Intervention / Treatment
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* Drug: ISIS CRP Rx
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male of female; age over 18 years Dual chamber permanent pacemaker implanted Confirmed diagnosis of paroxysmal atrial fibrillation with an AF burden of 1 to 50%, as derived from pacemaker diagnostic algorithms Able to have pacemaker antiarrhythmic algorithms turned off for the duration of the study Able to discontinue all Class I and III antiarrhythmic medication for the duration of the study Therapeutically anticoagulated with warfarin or dabigatran, and anticipated to be for duration of the study High sensitivity C-Reactive Protein (hsCRP) between 2 and 10 mg/L (inclusive) Exclusion Criteria: Clinically significant abnormalities in medical history, physical examination, or screening laboratory results that would render a subject unsuitable for inclusion NYHA class III/IV heart failure Impaired left ventricular function of less than 45% determined by echocardiography within 3 months of screening Moderate or greater mitral regurgitation assessed by echocardiography within 3 months of screening Permanent AF Continuous Amiodarone therapy within 90 days prior to Study Day 1 Treatment with another Study Drug, biological agent, or device within one-month of screening, or five half-lives of study agent, whichever is longer Use of systemic corticosteroids or other anti-inflammatory medications including non-steroidal anti-inflammatory drugs (NSAIDs) Use of statins, ACE inhibitors or AT-receptor antagonists unless on a stable regimen for at least 3 months prior to dosing and will remain on a stable regimen for the duration of the study Uncontrolled hypertension (BP >160/100) Current or expected use of any anticoagulant apart from warfarin or dabigatran

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>ISIS CRP Rx followed by Placebo | Drug: ISIS CRP Rx<br> <br> Drug: Placebo<br> <br> |
| Experimental: Group B<br>Placebo followed by ISIS CRP Rx | Drug: ISIS CRP Rx<br> <br> Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AF burden reduction | Burden measured as percentage of time spent in AF as derived from continuous pacemaker monitoring | 113 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the effect of ISIS CRP Rx on the: | total number of AF episodes average duration of AF per episode average sinus rhythm duration atrial and ventricular rate during AF episodes | 113 Days | 
| To assess the effect of ISIS CRP Rx on ventricular rate during sinus rhythm |  | 113 Days | 
| To assess the effect of ISIS CRP Rx on measures of Quality of Life |  | 113 Days | 
| To assess whether treatment with ISIS CRP Rx reduces hsCRP in subjects with paroxysmal AF | Change from Baseline will be compared for each treatment period | 113 Days | 
| To assess the safety of ISIS CRP Rx in subjects with paroxysmal AF | Incidence rates of all Adverse Events will be tabulated by MedRA system Organ Class and by MedRA Term for each treatment group. Lab Tests, Vital Signs, And ECG Parameters will be summarized by study visit for each treatment group. | 113 Days | 
| To assess the tolerability of ISIS CRP Rx in subjects with paroxysmal AF | Incidence rates of all Adverse Events will be tabulated by MedRA system Organ Class and by MedRA Term for each treatment group. Lab Tests, Vital Signs, And ECG Parameters will be summarized by study visit for each treatment group. | 113 Days | 
| To assess the pharmacokinetics of ISIS CRP Rx in subjects with paroxysmal AF | Trough levels of ISIS CRP Rx will be assessed at intervals throughout the study | 113 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial Fibrillation, Paroxysmal Atrial Fibrillation, AF