Effect of IL--1β Inhibition on Inflammation and Cardiovascular Risk
Overview
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Priscilla Hsue, MD
- Enrollment
- 43
- Locations
- 1
- Primary Endpoint
- Change in Platelet Count From Baseline to Follow-up
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 40 Years to 59 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Safety Arm
In Stage 1: all 10 subjects will receive 150 mg Canakinumab subcutaneous injection. This will be a preliminary safety study (before Stage II).
Intervention: Canakinumab (Drug)
Canakinumab
In Stage II: About 67 subjects will receive 150mg Canakinumab subcutaneous injection.
Intervention: Canakinumab (Drug)
Placebo
In Stage II: About 33 subjects will receive 150mg placebo subcutaneous injection
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Change in Platelet Count From Baseline to Follow-up
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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 Outcomes
- D-Dimer(Baseline, 4 weeks, 8 weeks, 12 weeks, and week 18)
- Tumor Necrosis Factor Alpha (TNFa)(Baseline, 4 weeks, 12 weeks, and week 18)
- Arterial Inflammation Measured at Baseline and Follow-up at Week 12(Baseline (entry) and Week 12)
- Human Serum Amyloid A (SAA)(Baseline, 4 weeks, 12 weeks, and week 18)
- Flow-Mediated Dilation (FMD)(Baseline and Week 12)
Investigators
Priscilla Hsue, MD
Professor of Medicine
University of California, San Francisco