Interleukin-1 Blockade With Canakinumab to Improve Exercise Capacity in Patients With Chronic Systolic Heart Failure and Elevated High Sensitivity C-reactive Protein (Hs-CRP)

Study Overview
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Brief Summary
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The proposed study is a sub-study of the CANTOS trial (A randomized, double-blind, placebo-controlled, event driven trial of quarterly subcutaneous canakinumab in the prevention of recurrent cardiovascular events among stable post-myocardial infarction patients with elevated high sensitivity C-reaction protein (hsCRP) [CACZ885M2301]). The study proposes to perform serial Cardiopulmonary Exercise Tests (CPX) to prospectively measure changes in aerobic exercise capacity in patients with prior myocardial infarction (MI), elevated C reactive protein plasma levels, and symptomatic heart failure with reduced systolic function, who are enrolled in the main CANTOS trial and are randomly assigned to Canakinumab (3 different doses) or Placebo. The subjects enrolled in this substudy will undergo repeated CPX and echocardiograms over the first 12 months of the CANTOS trial. The subjects will received the experimental treatment as randomized in the main CANTOS trial and they will not receive any additional experimental treatment as part of the sub-study. This study is a an Investigator-initiated (Dr. Abbate) single-center (Virginia Commonwealth University) sub-study of the CANTOS trial, supported by Novartis pharmaceuticals.

Detailed Description
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Patients enrolled in the CANTOS trial (with prior acute myocardial infarction [>30 days] and elevated C reactive protein levels [CRP>2mg/l]) who also have reduced left ventricular ejection fraction (LVEF<50%) and are symptomatic for heart failure (New York Heart Association symptoms class II-III) will be offered to take part in this sub-study at the Virginia Commonwealth University site. As part of the sub-study, patients will undergo a cardiopulmonary exercise test (CPX) at baseline prior to initiation of treatment, then repeated at 3 and 12 months, and a transthoracic echocardiogram at baseline and at 12 months.

Official Title
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Substudy of the the CANTOS Trial (Interleukin-1 Blockade With Canakinumab to Improve Exercise Capacity in Patients With Chronic Systolic Heart Failure and Elevated Hs-CRP; CACZ885M2301)

Conditions
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Prior Acute Myocardial Infarction, Evidence of Systemic Inflammation (C Reactive Protein Plasma >2 mg/l), Reduced Left Ventricle Ejection Fraction (<50%), Symptoms of Heart Failure (NYHA Class II-III)

Intervention / Treatment
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* Other: Cardiopulmonary exercise test
* Other: Echocardiogram


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: all criteria listed in the CANTOS trial (CACZ885M2301) left ventricular ejection fraction <50% symptoms of heart failure (NYHA class II-III) Exclusion Criteria: all criteria listed in the CANTOS trial (CACZ885M2301) inability to complete a treadmill exercise test conditions preventing interpretation of the cardiopulmonary test (arrhythmias, ischemia, hypertension, pulmonary disease)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Other: Cardiopulmonary exercise test<br>* All patients will undergo a first CPX prior to initiation of treatment, a second one after 3 months, and a third one after 12 months of treatment.<br>* Other names: Cardiopulmonary exercise test (CPX);Other: Echocardiogram<br>* An echocardiogram (ultrasound of the heart) will be performed prior to initiation of treatment and then again 12 months later.<br>* Other names: Echocardiogram or Echo;|
| Active Comparator: Canakinumab 50 mg quarterly<br>Canakinumab 50 mg quarterly | Other: Cardiopulmonary exercise test<br>* All patients will undergo a first CPX prior to initiation of treatment, a second one after 3 months, and a third one after 12 months of treatment.<br>* Other names: Cardiopulmonary exercise test (CPX);Other: Echocardiogram<br>* An echocardiogram (ultrasound of the heart) will be performed prior to initiation of treatment and then again 12 months later.<br>* Other names: Echocardiogram or Echo;|
| Active Comparator: Canakinumab 150 mg quarterly<br>Canakinumab 150 mg quarterly | Other: Cardiopulmonary exercise test<br>* All patients will undergo a first CPX prior to initiation of treatment, a second one after 3 months, and a third one after 12 months of treatment.<br>* Other names: Cardiopulmonary exercise test (CPX);Other: Echocardiogram<br>* An echocardiogram (ultrasound of the heart) will be performed prior to initiation of treatment and then again 12 months later.<br>* Other names: Echocardiogram or Echo;|
| Active Comparator: Canakinumab 300 mg quarterly<br>Canakinumab 300 mg quarterly | Other: Cardiopulmonary exercise test<br>* All patients will undergo a first CPX prior to initiation of treatment, a second one after 3 months, and a third one after 12 months of treatment.<br>* Other names: Cardiopulmonary exercise test (CPX);Other: Echocardiogram<br>* An echocardiogram (ultrasound of the heart) will be performed prior to initiation of treatment and then again 12 months later.<br>* Other names: Echocardiogram or Echo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak oxygen consumption (VO2) | Difference in the interval change from baseline in peak VO2 at 3 months following a single dose of CANAKINUMAB 50 mg subcutaneous, 150 mg subcutaneous, or CANAKINUMAB 300 mg subcutaneous [all three groups combined] when compared with the interval change in placebo (placebo-corrected interval change). | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak VO2 change | Difference in the interval changes from baseline and 12 months in peak VO2 comparing CANAKINUMAB (all doses) with placebo | 12 months | 
| Ventilatory efficiency (VE/VCO2 slope) change | Difference in the interval changes from baseline and 3 months in the VE/VCO2 slope comparing CANAKINUMAB (all doses) with placebo | 12 months | 
| OUES | Difference in the interval changes from baseline and 12 months in oxygen utilization efficiency slope (OUES) comparing CANAKINUMAB (all doses) with placebo | 12 months | 
| LVEF change | Difference in the interval changes from baseline and 12 months in left ventricular ejection fraction (LVEF) comparing CANAKINUMAB (all doses) with placebo | 12 months | 
| Diastolic function change | Difference in the interval changes from baseline and 12 months in E/E' (diastolic function) comparing CANAKINUMAB (all doses) with placebo | 12 months |