Effect of IL--1β Inhibition on Inflammation and Cardiovascular Risk

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects of IL-1β inhibition on safety, measures of systemic and vascular inflammation and endothelial function (all indicators of cardiovascular risk) in treated and suppressed HIV infected individuals This study will assess the safety and effects of canakinumab on endothelial function (assessed by flow-mediated vasodilation [FMD] of the brachial artery), vascular inflammation (assessed by FDG-PET/CT scanning), key inflammatory markers of cardiovascular disease (CVD) risk (high-sensitivity C-reactive protein [hsCRP]), interleukin-6 (IL-6), soluble CD163 (sCD163), D-dimer, T-cell and monocyte activation in the blood, and size of the HIV reservoir. 10 individuals will receive a single dose of 150mg canakinumab with follow-up for 12 weeks. In the second part of the study, 100 participants will be randomized (2:1 - canakinumab to placebo) and will be followed by for 36 weeks.

Official Title
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Effect of IL--1β Inhibition on Inflammation and Cardiovascular Risk

Conditions
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HIV, Cardiovascular Disease

Intervention / Treatment
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* Drug: Canakinumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV infection, Age ≥ 40 years < 60 years On continuous ART for at least 12 months with no change in regimen in 12 weeks prior to study entry CD4+ T cell count ≥ 400 cells/mm3 HIV RNA level below the standard limit of quantification for 52 weeks prior to entry High risk for CAD as defined by either documented CVD (including prior MI) or diabetes mellitus or 1 CVD risk factor (current smoking, hypertension, dyslipidemia, or hsCRP≥2mg/L.) Individuals on stable doses of lipid lowering therapy and/or anti-hypertensive medication will be allowed in the study. Appropriate documentation from medical records of prior receipt of pneumococcal vaccinations Exclusion Criteria: Women of childbearing potential or pregnant/nursing women CABG surgery in the past 3 years Class IV heart failure Uncontrolled HTN History of tuberculosis or latent TB that is not treated Nephrotic syndrome or eGFR< 30 ml/min/1.73m2 Active hepatic disease or active/chronic hepatitis B or C Any prior malignancy including KS Serious illness requiring hospitalization or active infection requiring antibiotics within 90 days Requirement for live active vaccination 3 months prior to, during, and 3 months after study Concurrent immune modulating therapy Diabetes Mellitus History of multiple imaging studies associated with radiation exposure Neutropenia defined as ANC<1500/mm Triglycerides>400 mg/dL History of hypersensitivity to study drug History of EBV-related lymphoproliferative disorders Active or untreated latent TB infection

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 59 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Safety Arm<br>In Stage 1: all 10 subjects will receive 150 mg Canakinumab subcutaneous injection. This will be a preliminary safety study (before Stage II). | Drug: Canakinumab<br>* 150mg Canakinumab received subcutaneously<br>* Other names: IL--1β;|
| Experimental: Canakinumab<br>In Stage II: About 67 subjects will receive 150mg Canakinumab subcutaneous injection. | Drug: Canakinumab<br>* 150mg Canakinumab received subcutaneously<br>* Other names: IL--1β;|
| Placebo Comparator: Placebo<br>In Stage II: About 33 subjects will receive 150mg placebo subcutaneous injection | Drug: Placebo<br>* 150mg Placebo received subcutaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CD4 Count From Baseline to Follow-up | Change in CD4 count from baseline (entry) to follow-up at weeks 4, 8, 12, 18, 24, and 36. | weeks 4, 8, 12, 18, 24, and 36. | 
| Change in CD8 Count From Baseline to Follow-up | Change in CD8 count from baseline (entry) to follow-up at weeks 4, 8, 12, 18, 24, and 36. | weeks 4, 8, 12, 18, 24, and 36. | 
| Change in Absolute Neutrophil Count From Baseline to Follow-up | Change in absolute neutrophil count from baseline (entry) to follow-up at weeks 4, 8, 12, 18, 24, and 36. | weeks 4, 8, 12, 18, 24, and 36. | 
| Change in Platelet Count From Baseline to Follow-up | Change in platelet count from baseline (entry) to follow-up at weeks 4, 8, 12, 18, 24, and 36. | weeks 4, 8, 12, 18, 24, and 36. | 
| Change in Creatinine Count From Baseline to Follow-up | Change in creatinine count from baseline (entry) to follow-up at weeks 4, 8, 12, 18, 24, and 36. | weeks 4, 8, 12, 18, 24, and 36. | 
| Change in AST From Baseline to Follow-up | Change in AST from baseline (entry) to follow-up at weeks 4, 8, 12, 18, 24, and 36. | weeks 4, 8, 12, 18, 24, and 36. | 
| Change in ALT From Baseline to Follow-up | Change in ALT from baseline (entry) to follow-up at weeks 4, 8, 12, 18, 24, and 36. | weeks 4, 8, 12, 18, 24, and 36. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flow-Mediated Dilation (FMD) | Brachial artery FMD is calculated as the percentage increase in brachial artery diameter with hyperemia (an increase in the quantity of blood flow to a body part) induced relative to the resting brachial artery diameter. Percentage of brachial artery diameter is measured as FMD diameter/basal diameter | Baseline and Week 12 | 
| Arterial Inflammation Measured at Baseline and Follow-up at Week 12 | Change From Baseline in Arterial Fluorodeoxyglucose (FDG) Uptake Assessed by FDG-PET/CT and reported as target-to-background (TBR) ratio to measure of vascular inflammation | Baseline (entry) and Week 12 | 
| D-Dimer | D-Dimer will be assessed from baseline to weeks 4, 8, 12, and 18. | Baseline, 4 weeks, 8 weeks, 12 weeks, and week 18 | 
| Human Serum Amyloid A (SAA) | SAA will be assessed from baseline to weeks 4, 12, and 18. | Baseline, 4 weeks, 12 weeks, and week 18 | 
| Tumor Necrosis Factor Alpha (TNFa) | TNFa will be assessed from baseline to weeks 4, 12, and 18. | Baseline, 4 weeks, 12 weeks, and week 18 |