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

• ClinicalTrials.gov Identifier: NCT02272946
• Recruitment Status: Completed
• First Posted: October 23, 2014
• Results First Posted: April 20, 2023
• Last Update Posted: April 20, 2023
• Sponsor: Priscilla Hsue, MD
• Collaborator: Massachusetts General Hospital
• Information provided by (Responsible Party): Priscilla Hsue, MD, University of California, San Francisco

Study Description

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.

Condition or disease	Intervention/treatment	Phase
HIV; Cardiovascular Disease	Drug: Canakinumab; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Effect of IL--1β Inhibition on Inflammation and Cardiovascular Risk
• Study Start Date: September 2015
• Actual Primary Completion Date: February 2021
• Actual Study Completion Date: December 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.

Secondary Outcome Measures :

1. Flow-Mediated Dilation (FMD) [ Time Frame: 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
2. Arterial Inflammation Measured at Baseline and Follow-up at Week 12 [ Time Frame: 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
3. D-Dimer [ Time Frame: Baseline, 4 weeks, 8 weeks, 12 weeks, and week 18 ]
   D-Dimer will be assessed from baseline to weeks 4, 8, 12, and 18.
4. Human Serum Amyloid A (SAA) [ Time Frame: Baseline, 4 weeks, 12 weeks, and week 18 ]
   SAA will be assessed from baseline to weeks 4, 12, and 18.
5. Tumor Necrosis Factor Alpha (TNFa) [ Time Frame: Baseline, 4 weeks, 12 weeks, and week 18 ]
   TNFa will be assessed from baseline to weeks 4, 12, and 18.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, California

San Francisco General Hospital

San Francisco, California, United States, 94110

Sponsors and Collaborators

Priscilla Hsue, MD

Massachusetts General Hospital

Investigators

• Principal Investigator: Priscilla Hsue, MD; University of California, San Francisco

  Study Documents (Full-Text)

Documents provided by Priscilla Hsue, MD, University of California, San Francisco:

Study Protocol and Statistical Analysis Plan  [PDF] January 11, 2019

More Information

Study Data/Documents: Clinical Study Report 

The link above shows the current enrollment table of the Canakinumab study as of March 2, 2020.

IL-1B inhibition [by way of Canakinumab] Reduces Atherosclerotic Inflammation in HIV Infection - Journal of the American College of Cardiology 

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Priscilla Hsue, MD, Professor of Medicine, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02272946
• Other Study ID Numbers: Canakinumab
• First Posted: October 23, 2014
• Results First Posted: April 20, 2023
• Last Update Posted: April 20, 2023
• Last Verified: March 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Cardiovascular Diseases; Inflammation; Pathologic Processes