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

Study Description

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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. 20 individuals will receive a single dose of 150mg canakinumab with follow-up for 18 weeks.

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

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	110 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
Estimated Primary Completion Date :	April 2017
Estimated Study Completion Date :	June 2018

Arms and Interventions

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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

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Primary Outcome Measures :

1. Number of Adverse Events at week 1 as a measure of safety [ Time Frame: Week 1 ]
   Toxicities will be assessed and adverse events will be recorded at the study visit, including abnormal lab values for the following list of labs: CBC, AST, ALT, bilirubin, creatinine, glucose
2. Number of Adverse Events at week 2 as a measure of safety [ Time Frame: Week 2 ]
   Toxicities will be assessed and adverse events will be recorded at the study visit, including abnormal lab values for the following list of labs: CBC, AST, ALT, bilirubin, creatinine, glucose
3. Number of Adverse Events at week 4 as a measure of safety [ Time Frame: Week 4 ]
   Toxicities will be assessed and adverse events will be recorded at the study visit, including abnormal lab values for the following list of labs: CBC, AST, ALT, bilirubin, creatinine, glucose, CD4 count, HIV-1 RNA
4. Number of Adverse Events at week 8 as a measure of safety [ Time Frame: Week 8 ]
   Toxicities will be assessed and adverse events will be recorded at the study visit, including abnormal lab values for the following list of labs: CBC, AST, ALT, bilirubin, creatinine, glucose, CD4 count, HIV-1 RNA
5. Number of Adverse Events at week 12 as a measure of safety [ Time Frame: Week 12 ]
   Toxicities will be assessed and adverse events will be recorded at the study visit, including abnormal lab values for the following list of labs: CBC, AST, ALT, bilirubin, creatinine, glucose, CD4 count, HIV-1 RNA
6. Number of Adverse Events at week 18 as a measure of safety [ Time Frame: Week 18 ]
   Toxicities will be assessed and adverse events will be recorded at the study visit, including abnormal lab values for the following list of labs: CBC, AST, ALT, bilirubin, creatinine, glucose
7. Number of Adverse Events at baseline as a measure of safety [ Time Frame: Baseline ]
   Toxicities will be assessed and adverse events will be recorded at the study visit, including abnormal lab values for the following list of labs: CBC, AST, ALT, bilirubin, creatinine, glucose

Secondary Outcome Measures :

1. Change in brachial artery flow-mediated vasodilation (FMD) [ Time Frame: Baseline, 12 weeks ]
   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. Change From Baseline in Arterial Fluorodeoxyglucose (FDG) Uptake Assessed by FDG-PET/CT as a measure of vascular inflammation [ Time Frame: Baseline, 12 weeks ]
   Assessed by FDG-PET/CT scanning
3. Rate of change in inflammatory markers of CVD risk [ Time Frame: Baseline, 4 weeks, 12 weeks, 18 weeks ]
   Linear mixed modelling will be used to estimate rates of change over the 18 weeks of treatment. Inflammatory markers: 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

Eligibility Criteria

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Ages Eligible for Study:	40 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. HIV infection,
2. Age ≥ 40 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, diabetes medication (not including insulin) 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 or diabetes
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. Requirement for insulin
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

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Danny Li		danny.li@ucsf.edu
Contact: Sophia Hur, MPH		sophia.hur@ucsf.edu

Locations

United States, California
San Francisco General Hospital	Recruiting
San Francisco, California, United States, 94110
Contact: Danny Li 415-206-5801 danny.li@ucsf.edu
Contact: Sophia Hur, MPH 415-206-5145 sophia.hur@ucsf.edu
Principal Investigator: Priscilla Hsue, MD
Quest Clinical Research	Recruiting
San Francisco, California, United States, 94115
Contact: Ula Kowalczyk 415-353-0212 ula@questclinical.com
Contact: Shilpa Dutta 415-353-0212 shilpa@questclinical.com
Principal Investigator: Jay Lalezari, MD

Sponsors and Collaborators

University of California, San Francisco

Investigators

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

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT02272946 History of Changes
Other Study ID Numbers:	Canakinumab
First Posted:	October 23, 2014
Last Update Posted:	August 2, 2016
Last Verified:	July 2016

Additional relevant MeSH terms:

Inflammation; Cardiovascular Diseases; Pathologic Processes	Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs