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

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 Overview

• Status: Completed
• Conditions: Cardiovascular Disease; HIV
• Intervention / Treatment: Drug: Canakinumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 59 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. HIV infection,
2. Age ≥ 40 years < 60 years
3. On continuous ART for at least 12 months with no change in regimen in 12 weeks prior to study entry
4. CD4+ T cell count ≥ 400 cells/mm3
5. HIV RNA level below the standard limit of quantification for 52 weeks prior to entry
6. 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.)
7. Individuals on stable doses of lipid lowering therapy and/or anti-hypertensive medication will be allowed in the study.
8. Appropriate documentation from medical records of prior receipt of pneumococcal vaccinations

Exclusion Criteria:

1. Women of childbearing potential or pregnant/nursing women
2. CABG surgery in the past 3 years
3. Class IV heart failure
4. Uncontrolled HTN
5. History of tuberculosis or latent TB that is not treated
6. Nephrotic syndrome or eGFR< 30 ml/min/1.73m2
7. Active hepatic disease or active/chronic hepatitis B or C
8. Any prior malignancy including KS
9. Serious illness requiring hospitalization or active infection requiring antibiotics within 90 days
10. Requirement for live active vaccination 3 months prior to, during, and 3 months after study
11. Concurrent immune modulating therapy
12. Diabetes Mellitus
13. History of multiple imaging studies associated with radiation exposure
14. Neutropenia defined as ANC<1500/mm
15. Triglycerides>400 mg/dL
16. History of hypersensitivity to study drug
17. History of EBV-related lymphoproliferative disorders
18. Active or untreated latent TB infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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).	Drug: Canakinumab; 150mg Canakinumab received subcutaneously; Other Names: IL--1β
Experimental: Canakinumab; In Stage II: About 67 subjects will receive 150mg Canakinumab subcutaneous injection.	Drug: Canakinumab; 150mg Canakinumab received subcutaneously; Other Names: IL--1β
Placebo Comparator: Placebo; In Stage II: About 33 subjects will receive 150mg placebo subcutaneous injection	Drug: Placebo; 150mg Placebo received subcutaneously

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Priscilla Hsue, MD
• Collaborators: Massachusetts General Hospital
• Investigators: Principal Investigator: Priscilla Hsue, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Kentoffio K, Temu TM, Shakil SS, Zanni MV, Longenecker CT. Cardiovascular disease risk in women living with HIV. Curr Opin HIV AIDS. 2022 Sep 1;17(5):270-278. doi: 10.1097/COH.0000000000000756. Epub 2022 Jul 5.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): February 1, 2021
• Study Completion (Actual): December 1, 2021

Study Registration Dates

• First Submitted: October 13, 2014
• First Submitted That Met QC Criteria: October 21, 2014
• First Posted (Estimate): October 23, 2014

Study Record Updates

• Last Update Posted (Actual): April 20, 2023
• Last Update Submitted That Met QC Criteria: March 29, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Inflammation
• Other Study ID Numbers: Canakinumab

Plan for Individual participant data (IPD)

Study Data/Documents

1. Clinical Study Report
   Information comments: The link above shows the current enrollment table of the Canakinumab study as of March 2, 2020.
2. IL-1B inhibition [by way of Canakinumab] Reduces Atherosclerotic Inflammation in HIV Infection - Journal of the American College of Cardiology
   Information comments: The link above is the research publication written by Dr. Hsue (Primary Investigator) about how IL-1B inhibition [by way of Canakinumab] reduces atherosclerotic inflammation in the setting of HIV.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No