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

Phase 2

Completed

Brief Summary: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	In Stage II: About 33 subjects will receive 150mg placebo subcutaneous injection
Safety Arm	Canakinumab	In Stage 1: all 10 subjects will receive 150 mg Canakinumab subcutaneous injection. This will be a preliminary safety study (before Stage II).
Canakinumab	Canakinumab	In Stage II: About 67 subjects will receive 150mg Canakinumab subcutaneous injection.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
D-Dimer	Baseline, 4 weeks, 8 weeks, 12 weeks, and week 18	D-Dimer will be assessed from baseline to weeks 4, 8, 12, and 18.
Tumor Necrosis Factor Alpha (TNFa)	Baseline, 4 weeks, 12 weeks, and week 18	TNFa will be assessed from baseline to weeks 4, 12, and 18.
Arterial Inflammation Measured at Baseline and Follow-up at Week 12	Baseline (entry) and 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
Human Serum Amyloid A (SAA)	Baseline, 4 weeks, 12 weeks, and week 18	SAA will be assessed from baseline to weeks 4, 12, and 18.
Flow-Mediated Dilation (FMD)	Baseline and Week 12	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