Conditions: HIV Cardiovascular Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 43
Healthy volunteers: no

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.

Detailed description:

Arms:
arm 1: In Stage 1: all 10 subjects will receive 150 mg Canakinumab subcutaneous injection. This will be a preliminary safety study (before Stage II). arm 2: In Stage II: About 67 subjects will receive 150mg Canakinumab subcutaneous injection. arm 3: In Stage II: About 33 subjects will receive 150mg placebo subcutaneous injection

Interventions: intervention 1: Canakinumab intervention 2: Placebo
Intervention descriptions: intervention 1: 150mg Canakinumab received subcutaneously intervention 2: 150mg Placebo received subcutaneously

Protocol document:
Prot_SAP_000.pdf: 
Version Date: 11JAN19 
 
1 
 
 
ClinicalTrials.Gov Cover Page 
 
Effect of IL-1β Inhibition on Inflammation and Cardiovascular 
Risk 
 
NCT02272946 
 
Principal Investigator: 
Priscilla Hsue, MD 
Professor of Medicine 
University of California, San Francisco 
Room 5G1 Cardiology 
San Francisco General Hospital 
1001 Potrero Avenue 
San Francisco, CA 94110 
415-206-8257 phone 
415-206-5447 fax 
 
Version Date: 
January 11, 2019 
 
 
 
 


Version Date: 11JAN19 
 
2 
 
Effect of IL-1β Inhibition on Inflammation and Cardiovascular Risk 
 
Local Protocol Number: 14-13830 
 
Pharmaceutical Support Provided by: Novartis Pharmaceuticals 
 
Principal Investigator:  
Priscilla Hsue, MD 
Professor of Medicine 
University of California, San Francisco 
Room 5G1 Cardiology 
San Francisco General Hospital 
1001 Potrero Avenue 
San Francisco, CA 94110 
415-206-8257 phone 
415-206-5447 fax 
priscilla.hsue@ucsf.edu 
 
Co-investigators: Steven Deeks, Peter Ganz, Paul Ridker, Rebecca Scherzer 
 
Final Version 
 
January 11, 2019 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according 
to local legal and regulatory requirements and applicable U.S. Federal regulations and ICH 
guidelines.  
Principal Investigator: _______________Priscilla Hsue__________             Print/Type 
 
Signed: __________________________________ 
 
Date:________________ 
 
 
 
 
 
 
 
 
 
 


Version Date: 11JAN19 
 
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CONTENTS 
 
 
Page 
PROTOCOL TEAM ROSTER ..................................................................................................... 5 
PROTOCOL-SPECIFIC GLOSSARY OF TERMS ....................................................................... 6 
SCHEMA 
9 
1.0 
KEY ROLES .................................................................................................................. 11 
2.0 
INTRODUCTION ........................................................................................................... 11 
2.1 
Rationale and Background ................................................................................. 11 
2.2 
Summary ........................................................................................................... 15 
2.3  
Hypothesis ......................................................................................................... 16 
2.4 
Potential Risks and Benefits .............................................................................. 16 
3.0 
OBJECTIVES ................................................................................................................ 18 
3.1 
Primary Objectives ............................................................................................. 18 
4.0        STUDY DESIGN .......................................................................................................... 19 
4.1 
Inclusion Criteria ................................................................................................ 19 
4.2 
Exclusion Criteria ............................................................................................... 21 
4.3 
Study Enrollment Procedures............................................................................. 24 
5.0 
STUDY TREATMENT ................................................................................................... 25 
5.1 
Regimens, Administration, and Duration ............................................................ 25 
5.2 
Study Product Formulation and Preparation ....................................................... 26 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 26 
5.4 
Concomitant Medications ................................................................................... 27 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 27 
6.1 Schedule of Events .................................................................................................. 27 
6.2 
Timing of Evaluations ......................................................................................... 28 
6.3 
Instructions for Evaluations ................................................................................ 33 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 40 
7.1 
Toxicity .............................................................................................................. 40 
7.2 
Management of Specific Toxicities ..................................................................... 41 
7.3 
Pregnancy.......................................................................................................... 42 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 42 
8.1 
Permanent Treatment Discontinuation ............................................................... 42 
8.2 
Premature Study Discontinuation ....................................................................... 42 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 43 
9.1 
General Design Issues ....................................................................................... 43 
9.2 
Endpoints ........................................................................................................... 43 
9.3 
Randomization and Stratification ........................................................................ 45 
9.4 
Sample Size and Accrual ................................................................................... 45 
9.5 
Monitoring .......................................................................................................... 47 
9.6 
Analysis Plan ..................................................................................................... 48 
9.7 Pharmacovigilance Plan .......................................................................................... 49 
10.0 
DATA MANAGEMENT AND COLLECTION .................................................................. 49 
10.1 
Data Management ............................................................................................. 49 
10.2 
Data Collection Instruments ............................................................................... 50 


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11.0 
CLINICAL SITE MONITORING AND ADVERSE EVENT REPORTING ........................ 51 
11.1 
Clinical Site Monitoring....................................................................................... 51 
11.2 
Adverse Event Reporting ................................................................................... 51 
12.0  HUMAN SUBJECTS ........................................................................................................ 52 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 52 
12.2 
Subject Confidentiality ....................................................................................... 52 
12.3  
Subject Recruitment ........................................................................................... 53 
12.4 
Subject Compensation ....................................................................................... 53 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 53 
14.0 
BIOHAZARD CONTAINMENT ...................................................................................... 54 
15.0 
REFERENCES .............................................................................................................. 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL TEAM ROSTER
Principal Investigator 
Priscilla Hsue, MD 
San Francisco General Hospital 
Room 5G1 
Cardiology SFGH 
1001 Potrero Avenue 
San Francisco, CA 94110 
Phone: 415-206-8257 
FAX: 415-206-5100 
E-Mail: phsue@medsfgh.ucsf.edu 
 
Co-Investigators 
Steven G. Deeks, MD 
San Francisco General Hospital  
Building 80, Ward 84  
995 Potrero Avenue, Box 0874  
San Francisco, CA  94110-2859 
Phone: 415-476-4082 X404 
FAX:  415-476-6953 
E-Mail:  sdeeks@php.ucsf.edu  
 
Peter Ganz, MD 
Division of Cardiology 
San Francisco General Hospital 
1001 Potrero Avenue, 5G1 
San Francisco CA 94110 
Phone:  415-206-3024 
FAX:  415-206-3503 
E-Mail: ganzp@medsfgh.ucsf.edu 
 
Paul Ridker, MD 
Center for Cardiovascular Disease 
Prevention 
Brigham and Women’s Hospital 
900 Commonwealth Avenue East 
Boston MA 02215 
Phone:  617-732-8790 
FAX:    617-734-1508 
E-Mail: pridker@partners.org 
 
Rebecca Scherzer, PhD 
UCSF School of Medicine 
4150 Clement Street 
San Francisco Ca 94121 
Phone:     415-221-4810 
E-Mail:      Rebecca.scherzer@ucsf.edu 
 
 
 
Co-Investigators continued 
Ahmed Tawakol, MD 
Cardiac Unit Associates 
55 Fruit Street 
Boston, MA 02114-2696 
Phone:   617-726-0786 
FAX:       617-724-4152 
E-Mail:    atawakol@partners.org 
 
Miguel Hernandez Pampaloni, MD 
UCSF School of Medicine 
505 Parnassus Avenue, Moffitt 
San Francisco, CA 94143 
Phone:    415-514-5681 
E-Mail:    miguel.pampaloni@ucsf.edu 
 
Immunology Laboratory 
Jeffrey Milush, PhD 
San Francisco General Hospital  
1001 Potrero Ave 
San Francisco, CA  94110 
Phone: 415-206-3881 
E-Mail: Jeffrey.Milush@ucsf.edu 
 
Laboratories  
Adam Rupert  
National Cancer Institute 
9609 Medical Center Drive 
Bethesda, MD 20892-9760 
Phone: 301-846-7113 
E-Mail: Arupert@mail.nih.gov 
 
Jeffrey Milush, PhD 
San Francisco General Hospital  
1001 Potrero Ave 
San Francisco, CA  94110 
Phone: 415-206-3881 
E-Mail: Jeffrey.Milush@ucsf.edu 
 
Pharmacologist 
Francesca Aweeka, PharmD 
Department of Clinical Pharmacy 
San Francisco General Hospital 
1001 Potrero Avenue 
Building 100, Room 157 
San Francisco, CA 94110 
Phone: 415-476-0339 
FAX: 415-476-0307 
E-Mail: faweeka@sfghsom.ucsf.edu


 
 
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PROTOCOL-SPECIFIC GLOSSARY OF TERMS  
ACTG 
AIDS Clinical Trials Group 
AE 
adverse events 
ALT 
aspartate aminotransferase 
ANC 
absolute neutrophil count 
ART 
antiretroviral therapy 
AST 
alanine aminotransferase 
AUC 
area under the curve 
BART 
brachial artery reactivity testing (used to measure flow-mediated 
vasodilation) 
°C 
degrees Celsius 
CAD 
coronary artery disease 
CAPS 
cryopyrin-associated periodic syndrome 
CDC 
Centers for Disease Control and Prevention 
CHR 
Committee on Human Research 
CK 
creatinine kinase 
CMV 
cytomegalovirus 
CRF 
case report form 
CV 
cardiovascular 
CVD 
cardiovascular disease 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
EAE 
expedited adverse event 
EBV 
Epstein-Barr virus 
°F 
degrees Fahrenheit 
FDA 
Federal Drug and Food Administration 
FDG-PET/CT 
Fluorodeoxyglucose-positron emission tomography/computed 
tomography 
FMD 
flow-mediated vasodilation (a marker of endothelial function, 
measured by BART) 
GCP 
Good Clinical Practices 


 
 
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HBV 
hepatitis B virus  
HCV 
hepatitis C virus 
HDL 
high-density lipoproteins 
HHS 
Human Health Services 
HIPAA 
Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
hsCRP 
high-sensitivity C-reactive protein 
IATA 
International Air Transport Association 
ICH 
International Conference on Harmonisation 
IL 
interleukin 
IRB 
Institutional Review Board 
IRIS 
immune reconstitution inflammatory syndrome 
ITSG 
Inflammation Transformative Science Group 
LDL 
low-density lipoprotein 
LFT 
liver function test 
LS tandem MS  
liquid chromatography/tandem mass spectrometry 
MACE 
Major Adverse Cardiac Event 
MCV 
mean corpuscular volume 
MI 
myocardial infarction 
NHLBI 
National Heart, Lung, and Blood Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PBMC 
peripheral blood mononucleated cell 
PCR 
polymerase chain reaction 
PHI 
Personally-Identifiable Health Information 


 
 
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PHP 
Positive Health Program 
PI 
Principle Investigator 
PK 
pharmacokinetic 
PPD 
purified protein derivative 
RNA 
ribonucleic acid 
sCD 
soluble CD 
SCOPE 
Study of the Consequences of the Protease Inhibitor Era 
SD 
standard deviation 
SFGH 
San Francisco General Hospital 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedures 
TB 
tuberculosis 
TNF 
tumor necrosis factor 
UCSF 
University of California San Francisco 
ULN 
upper limits of normal 
WBC 
white blood cell  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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SCHEMA 
Effect of IL1β Inhibition on Inflammation and Cardiovascular Risk 
 
DESIGN 
This is a randomized, double-blind, placebo-controlled trial to 
evaluate the safety and efficacy of canakinumab for the treatment 
for HIV-associated inflammation. 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.  
 
DURATION 
52 weeks (24 weeks of drug treatment/placebo followed by 
observation for an additional 28 weeks)  
 
SAMPLE SIZE 
Stage I: 10 subjects, all who receive 150mg of canakinumab  
 
Stage II: 100 (randomized 2:1 to 150mg canakinumab arm or 
placebo arm) 
 
POPULATION 
HIV-infected men and women ≥40years old and ≤59 years old 
• 
who have been virologically suppressed on continuous 
antiretroviral therapy for at least 12 months with no change in 
regimen 4 weeks prior to entry;  
• 
who have a CD4+ T-cell count ≥400 cells/mm3;  
AND 
• 
who have documented CVD or who are at increased CVD risk or 
have 1 CVD risk factor. 
 
REGIMEN  
Stage I: 10 subjects will be injected with 150 mg canakinumab.  
 
 
If the Stage I patients are clinically stable after 12 weeks of 
observation, study will then proceed to Stage II where 100 
additional subjects will be enrolled and randomized 2:1 to 150mg 
of canakinumab vs. placebo 
 
All subjects in Stage II will receive a dose of canakinumab vs. 
placebo at study entry and second dose at Week 12 and followed 
until Week 52. 
 
 
 
 


 
 
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10 
 
 
 
Figure 1: Study Schema 
 
 
 
 
Study entry Stage I 
 
 
 
 
 
Study entry Stage II 
 
 
 
 
 
 
 Arm 1   
 
 
 
 
    Arm 2 
      
Study entry 
 
 
 
           
 
 
 
 
 
     
     Week 12 visit 
 
 
 
       Week 13,14, 
          15,16,18, 24, 30,  
        36, 40, 48 visit 
 
 
 
HIV-infected individuals ≥40 and ≤59 years old who have been 
virologically suppressed and on continuous ART for at least 12 months 
with no change in regimen ≥12 weeks with CD4+ ≥400 cells/mm3 and 
Stage I: 10 subjects receive 150mg of canakinumab at study entry; if 
safety endpoints are not met, the study will not continue to Stage II 
Placebo (150 mg) 
subcutaneous 
150 mg subcutaneous 
canakinumab injection 
Week 52 (final visit)  
Follow-up visit 
Follow-up visit 
150 mg subcutaneous 
canakinumab injection 
Randomize 2:1 (N=100) 
Placebo (150 mg) injection 
 


 
 
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1.0 
KEY ROLES 
Our group is uniquely qualified to perform this study of canakinumab in HIV. Over the past 
10 years, our group has established a highly effective cross-disciplinary team of 
investigators, each of whom has the requisite expertise to perform the type of research 
outlined in this proposal. Dr. Hsue, is among the few cardiologists devoting her efforts full 
time to understanding the epidemiology, pathogenesis and management of HIV-
associated cardiovascular disease and the role of HIV-related inflammation in non-AIDS 
conditions. Dr. Deeks, is an expert on HIV pathogenesis and directs the SCOPE cohort, 
which will be used to support the canakinumab clinical trial. SCOPE is an outpatient, clinic 
based cohort of over 2000 HIV-infected individuals with detailed HIV characteristics and 
outstanding patient follow-up. He has overseen numerous clinical trials in the past, and in 
the past two years has enrolled over 300 patients into studies such as the one outlined in 
this proposal. Dr. Ridker is the PI of both the CANTOS study (testing canakinumab) and 
CIRT (testing methotrexate) and is an international expert on inflammation and 
atherosclerosis. Dr. Ganz is an international authority in endothelial function, 
inflammation, and biomarkers. He heads the Center of Excellence in Vascular Research 
at SFGH and will help oversee the endothelial function and cardiovascular biomarker 
studies. Dr. Tawakol (Massachusetts General Hospital, MGH) is a pioneer in vascular 
FDG-PET/CT and will oversee the quality control, performance, and interpretation for the 
FDG-PET/CT procedures. Dr. Milush, Director of Core Immunology Laboratory, will 
perform the microbial translocation assays and will oversee all of the immunologic studies 
proposed in Aim 2. Dr. Rupert, Functional Advisor at AIDS monitoring labs; Leidos 
Biomedical Research, will perform the assays for inflammation and coagulation and will 
help interpret the T cell activation and reservoir data.   Dr. Aweeka, (director of the Drug 
Research Unit at SFGH and PI of the UCSF Pharmacology Laboratory for the ACTG) will 
perform the pharmacokinetic assays for the study. Dr. Milush will perform the assays for 
viral persistence. Dr. Scherzer (co-investigator) is an accomplished biostatistician with 
expertise in HIV studies. Drs. Deeks, Ganz, and Ridker are all co-investigators on the 
NHLBI study of HIV and methotrexate that was recently awarded to Dr. Hsue (PI). 
2.0 
INTRODUCTION 
2.1 
Rationale and Background 
Need for novel strategies to reduce inflammation in the setting of HIV infection   
By 2015, over half of HIV-infected individuals will be ≥ 50 years and CVD is becoming 
increasingly important in this unique patient population. Despite these unquestioned 
successes of therapy, antiretroviral treated-HIV infected adults have excess risk of 
morbidity and mortality1, 2. Compared to controls, HIV-infected individuals have an 
adjusted 50% increased risk of acute MI and this increased risk is present even among 
individuals with well-treated HIV3. Deaths due to CVD range from 6-15% in different HIV 
cohorts4 and HIV-infected individuals have a higher mortality from MI compared to 


 
 
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controls5 as well as higher rates of sudden cardiac death6.  Although the contribution of 
HIV to atherosclerosis and CVD risk is becoming increasingly clear, the 
pathophysiological mechanism(s) underlying these observations are less well 
understood.  The SMART study found that untreated HIV infection was associated with 
high levels of both interleukin-6 (IL-6) and D-dimers and that these biomarkers were 
strongly associated with all-cause mortality7 and CVD events8. High sensitivity C-
reactive protein (hsCRP), IL-6 and D-dimer levels remain high even among effectively 
treated HIV-infected individuals9. Treated and suppressed HIV-infected individuals are 
at risk for CVD and chronic inflammation in HIV is associated with increased carotid 
artery wall thickness as well as higher levels of arterial inflammation10-12.   Chronic 
inflammation in the setting of ART is thought to underlie not only the higher rates of CVD 
in HIV,  but also other non-AIDS conditions that are emerging in HIV-infected individuals 
such as kidney disease, bone disease, and neurologic complications13. Thus, 
therapeutic strategies to target inflammation in the setting of HIV infection may be 
beneficial in reducing not only CVD risk, but also other non-AIDS events resulting in 
improved mortality. The development of novel therapeutics which can decrease 
persistent inflammation and reduce cardiovascular risk depends on a precise 
understanding of the mechanism whereby HIV infection causes inflammation.  Our 
group feels strongly that the most definitive way to define a host factor in the 
pathogenesis of human disease is to manipulate that factor experimentally with the aim 
of enhancing a potentially beneficial response or preventing a potentially harmful 
outcome.  It is expected that a better understanding of these mechanisms may help 
identify other novel interventions to decrease the morbidity and mortality associated with 
HIV as well as non-AIDS conditions. These findings may also inform underlying 
mechanisms of atherosclerosis and treatment in the larger population as well.   
 
Inflammation may cause CVD in uninfected adults 
In the HIV-uninfected population, a strong body of evidence from over 20 cohort studies 
involving a wide range of patient populations demonstrates that markers of 
inflammation, particularly hsCRP, are strongly predictive of cardiovascular disease 
(CVD) events and mortality14-18. Targeting inflammation as a means of reducing CVD 
risk was partly addressed in the JUPITER trial, which showed that treatment with 
rosuvastatin among healthy individuals with normal LDL cholesterol and elevated 
hsCRP levels reduced myocardial infarction, stroke, and all-cause mortality by 44%19. 
This clinical benefit was proportional to the magnitude of hsCRP reduction, suggesting 
that rosuvastatin was acting partly through an anti-inflammatory mechanism20. However, 
in order to implicate inflammation in atherogenesis directly, an agent that targets 
inflammation without lipid-lowering and with an acceptable safety profile would be 
required. Such an agent would be particularly useful for patients at increased CVD risk 
on the basis of chronic inflammation rather than dyslipidemia; this may be the case for 
HIV-infected patients.  
The interleukin-1 family, inflammation, and atherothrombosis 
The interleukin-1 (IL-1) family which includes IL-1α, IL-1β and the IL-1 receptor 
antagonist plays a key role in mediating systemic inflammatory responses; namely 
imbalances in the IL-1β proteins which are proinflammatory and the IL-1Rα proteins 
which are anti-inflammatory are associated with clinical diseases.  For example, 


 
 
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mutations in the NLRP3 inflammasome which increase the secretion of IL-1β and 
subsequently cause severe imbalances in IL-1β and IL-Rα result in autoinflammatory 
diseases such as Muckle-Wells syndrome, cryopyrin-associated periodic syndrome 
(CAPS), and neonatal-onset multisystem inflammatory disease21 and treatment with 
canakinumab, a monoclonal antibody against IL-1β has successfully treated these 
conditions22. Moderate imbalances of the IL-1β system are associated with chronic 
inflammatory conditions including gout23, type 2 diabetes24,  psoriasis25 and 
inflammatory bowel disease26.  Increased levels of IL-1β are present in atherosclerotic 
coronary arteries27 and patients with acute coronary syndromes have higher  levels of 
IL-1 receptor antagonist as compared to asymptomatic patients28, interestingly among 
individuals with acute ST-segment elevation MI, increases in IL-1 receptor antagonist 
(which competitively blocks binding of IL-1β to the IL-1 receptor) precede elevations in 
troponin and CK, suggesting involvement in the pathogenesis of MI rather than being a 
consequence of myocardial necrosis29.  Among individuals with rheumatoid arthritis who 
have a high prevalence of CVD attributable to chronic inflammation similar to HIV-
infected individuals, treatment with anakinra, a IL-1 receptor antagonist reduced IL-6, 
hsCRP, and endothelin levels along with improving endothelial function as assessed by 
flow-mediated vasodilation of the brachial artery30.   
Canakinumab trial among individuals without HIV infection (CANTOS) 
Published results and safety data from the CANTOS trial has showed that in over 
10,000 individuals with prior MI and hsCRP level ≥2mg/L, canakinumab at a dose of 150 
mg every 3 months led to a significantly lower rate of cardiovascular events as 
compared to placebo (HR 0.85, 95%CI 0.74 to 0.98, p=0.021)31. Notably, most of the 
benefit was observed in those with high levels of inflammation (hsCRP ≥ 2). The 150 mg 
dose met the pre-specified threshold for significance for the primary and secondary 
endpoints (HR vs placebo 0.83, 95% CI 0.73 to 0.95, P=0.005), although there was no 
significant difference in all-cause mortality (HR 0.94, 95%CI 0.83 to 1.06, p=0.31).  
Additionally, in the CANTOS study, IL-1β inhibition was not associated  with increased 
risk of opportunistic infections, activation of TB or increased risk of cancers in the 
general population which suggests that canakinumab functions as an anti-inflammatory 
intervention as opposed to being immunosuppressive32.  
Those at greatest risk for infectious disease complications include older age and the 
presence of diabetes mellitus. Participants receiving canakinumab who achieved on-
treatment IL-6 levels below the study median of 1.65ng/L had a 32% reduction in MACE, 
a 52% reduction in CV mortality,  and a 48% reduction in all-cause mortality (p<0.0001 
for all of these endpoints). 
As HIV patients are excluded from CANTOS, the only way to determine safety in HIV is 
to perform a carefully done pilot study to confirm that the drug is safe in this patient 
population.  We will work to ensure safety in our trial by only enrolling HIV-infected 
adults on long-term effective antiretroviral therapy with a CD4+ T-cell count ≥ 400 
cells/mm3 and by performing a two-stage milestone drive study as outlined below.   
Safety 


 
 
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We constructed a two-stage, milestone driven study. In Stage I, we will treat a small 
cohort (n=10) of carefully monitored individuals. Pilot safety data will be reviewed by a 
Safety Monitoring Committee and NIH before moving on to randomized study (Stage II). 
This staged study design has been discussed extensively with NHLBI leadership, who 
support this approach. We have established protocols that were developed with experts 
in HIV, infectious disease, and oncology for carefully assessing the safety of 
canakinumab in the HIV-infected population.  All subjects will be followed for possible 
adverse events (AEs) throughout their involvement in the study. Routine blood work will 
be performed on a regular basis. AEs will be graded according to the NIH/NIAID Division 
of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. The 
Principal Investigator will review these data daily, assess their degree of severity, and 
make a relationship assessment to study agent/intervention. Primary safety endpoints 
are detailed in the appendix and will be similar to endpoints used for our low-dose 
methotrexate study in HIV which have been carefully developed with the ACTG which 
include 1)For subjects with entry CD4+ T cell count <700 cells/mm3, confirmed CD4+ 
decline >33% of baseline AND to <350 cells/mm3. 2)For subjects with entry CD4+ T cell 
count ≥700 cells/mm3, a confirmed CD4+ decline >50% of baseline, 3)Confirmed HIV-1 
RNA level >200 copies/mL in the absence of an interruption in ART, 4)New or recurrent 
CDC category C AIDS-indicator condition, or 5)Evidence of HIV-associated infection 
including CMV end-organ disease, varicella zoster, EBV related clinical disease.   
We will develop an independent Safety Monitoring Committee (SMC) prior to the 
initiation of the study. The final structure of this committee will be determined with input 
from NIH. We have recruited Dr. Judith Currier, Vice-Chair of the AIDS Clinical Trials 
Group (ACTG) from UCLA, Dr. Amir Lerman, a cardiologist with expertise in clinical 
trials and vascular function at the Mayo Graduate School of Medicine, Dr. Netanya 
Sandler Utay, a physician scientist with expertise in infectious diseases at University of 
Texas, Dr. Michael Lederman, a physician with expertise in infectious diseases at Case 
Western Reserve University, Dr. Vincent Marconi, director of infectious disease research 
at Atlanta VA Medical Center and Dr. Jason Baker, an infectious disease physician with 
research expertise in HIV and cardiovascular disease from the University of Minnesota 
(see letters of support). These individuals were selected based on their expertise in 
either the clinical management of HIV infection and/or their expertise with clinical trials. 
The committee will be chaired by Dr. Currier who has experience in the regulatory 
aspects of clinical trials.   
The SMC will meet quarterly during the study and at approximately 2 to 4 weeks after 
the last person in Stage I has been dosed. The decision to move to Stage II will be 
made by the SMC. A study data coordinator will produce administrative reports after 
completion of each cohort describing study progress including the following: (1) accrual, 
(2) demographics, (3) study subject status, and (4) number and type of serious AEs. The 
SMC will review study progress, efficacy data, all interim and total AEs, and 
unanticipated problems involving risk to participants. Reviews will be communicated to 
the UCSF Committee on Human Research (CHR), study sponsor, and/or federal 
agencies, as appropriate. The SMC will have access to treatment assignment. The 
study will be discontinued if the SMC determines that it is in the best interest of the 
subjects.  


 
 
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We will work closely with the antiviral division of the NIH to assist in safety monitoring for 
the trial. Grade 1 or 2 AEs will not result in any change to our study plans. If there is 
evidence for a Grade 3 AE that is not caused by the study drug, the study will continue 
as planned. On the other hand, Grade 3 AEs thought to be possibly caused by the 
intervention and any Grade 4 AEs will result in a hold on any future enrollments until a 
decision to proceed or to stop the study is made by the SMC, the NIH, and Novartis. 
Pharmacokinetic (PK) assessments: 
There are no known drug-drug interactions with canakinumab. There are theoretical 
concerns that antibody-mediated reductions in inflammation may affect drug 
metabolizing enzymes such as CYP450. Elevated IL-6 has been associated with higher 
AUC of simvastatin and cyclosporine33 and  inhibition of IL-6 using tocilizumab has been 
associated with higher concentrations of simvastatin34. Given these theoretical 
concerns, with Dr. Aweeka’s guidance, we plan to assess PK and carry out ART 
concentration measurements as troughs in N=60 subjects at 6 timepoints as shown in 
Table 1 which includes measurements prior to initiating and during treatment with 
canakinumab/placebo. For each trough sample collection, subjects will have PK trough 
levels drawn in the study clinic and will be instructed to hold their morning ART dose on 
the day of visit. Precise information on timing of the prior 3 doses will be collected from a 
patient diary as well as the precise time of sample collection. Venous PK sampling will 
be carried out prior to ART dosing. All samples will be processed for plasma and stored 
at -70ºC to await analysis. ART levels will be quantified using LC tandem MS 
instrumentation. Dr. Aweeka’s laboratory has extensive experience in ART 
quantitation35-41. Methods are optimized and fully validated to permit quantification of all 
analytes at the sensitivity necessary for clinical PK evaluations. Inter- and intra-day 
coefficients of variation for all assays are consistently within 10%. PK trough estimates 
in 60 subjects will permit intrasubject comparison of exposure to the specific ART the 
subject is stabilized on prior to initiating study drug and following study drug 
administration.  Subjects will serve as their own controls. In addition, PK exposure for 
the most commonly prescribed ART (e.g. atazanavir and efavirenz) will be compared 
between subjects receiving canakinumab to those subjects receiving placebo.  
2.2 
Summary 
We will perform the first study 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.  In Stage I of 
our study, we will administer canakinumab as a single dose (150mg) by subcutaneous 
injection to 10 individuals on stable antiretroviral regimens with undetectable plasma 
HIV RNA levels using conventional assays.  Based on safety data from the CANTOS 
study, we anticipate that this dose will be well tolerated and safe.  In Stage II of our 
study, if the drug is well tolerated, we will continue enrolling patients for N=100 
individuals and individuals will get two doses of 150mg (at baseline and 12 weeks). The 
pathogenesis-oriented approach will improve our understanding of the underlying 
mechanisms of the accelerated atherosclerosis observed in individuals with HIV 
infection, including the potential roles of inflammation and immune activation. By relating 
changes in inflammation and immune activation to changes in vascular function with IL-
1β inhibition, we will establish specific mechanistic links between HIV infection and its 


 
 
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leading non-HIV cause of death, CVD.  The results of this proof-of-concept trial could be 
potentially paradigm-shifting in this field; while the majority of studies to reduce HIV-
related inflammation have focused solely on antiretroviral medication, the anti-
inflammatory features of canakinumab can be applied to a variety of different disease 
manifestations in HIV. Theoretically, any intervention that decreases inflammation and T 
cell proliferation will result in a smaller reservoir.  Thus IL-1β inhibition using 
canakinumab may have broad clinical implications for HIV-infected individuals favorably 
impacting HIV reservoirs and potentially leading to viral eradication and ultimately cure 
of HIV.  
2.3  
Hypothesis  
Although antiretroviral therapy (ART) prolongs life, it does not fully restore health. For 
reasons that remain poorly defined, HIV-infected adults on otherwise effective therapy 
have a higher than expected risk of a number of “non-AIDS” conditions, including 
cardiovascular disease. Chronic inflammation predicts and possibly contributes to this 
risk. Although markers of T cell activation were dominant predictors in the era of untreated 
HIV disease, the most powerful and consistent predictors of morbidity in the modern ART 
era are those which reflect chronic activation of monocyte/macrophage systems. IL-6, 
sCD14, sCD163 and frequency of circulating monocytes with an activated phenotype 
have been found in multiple studies to be elevated in treated HIV disease and associated 
with increased risk of morbidity/mortality. Many of these pathways have also been 
associated with vascular dysfunction. These data collectively support a model in which a 
number 
of 
factors 
(e.g., 
microbial 
translocation, 
dysbiosis) 
activate 
monocyte/macrophages, leading eventually to vascular disease and end-organ tissue 
damage. There is ample precedent for this cardiovascular disease model in the general 
population, where resident inflammatory macrophages in vessels are central to the 
pathogenesis of atherosclerotic lesions and vascular dysfunction.  We hypothesize that 
canakinumab administered at a dose of 150mg subcutaneously every 12 weeks will be 
safe and well tolerated in ART-treated HIV infected adults.  We also hypothesize that IL-
1β inhibition will reduce arterial inflammation, improve FMD, lower inflammatory markers, 
and 
reduce 
T-cell 
activation 
among 
treated 
and 
suppressed 
HIV-infected 
individuals.  Finally, we predict that canakinumab-mediated inhibition of IL-1B signaling 
will reduce levels of CD4+ T cell activation, cell-associated RNA and cell-associated DNA. 
2.4 
Potential Risks and Benefits 
Risks 
The main risk is from the canakinumab intervention.  The most common side effects of 
canakinumab used at doses for CAPS are rarely life-threatening but do warrant careful 
monitoring and management, especially in the setting of HIV infection. The risk of bacterial 
and viral infections may be higher during treatment with canakinumab, including fatal 
infections. All patients should contact their primary care doctor immediately if they develop 
symptoms of an infection. This risk is higher for the oldest old and those with 
comorbidities.  For this reason, we have excluded those patients 60 years old or older. In 
clinical trials involving adults and children (ages 2-17 years), the most frequently reported 
adverse drug reactions were infections predominantly of the upper respiratory 


 
 
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tract.  Commonly reported infections were nasopharyngitis, influenza, rhinitis, bronchitis, 
gastroenteritis, 
pneumonia, 
tonsillitis, 
sinusitis, 
urinary 
tract 
infection, 
and 
pharyngitis.  There was one report of intra-abdominal abscess following appendectomy.  
TNF inhibitors have been associated with an increased risk of new tuberculosis or 
reactivation of latent tuberculosis and it is possible that IL-1 inhibitors may increase the 
risk of reactivation of TB.   For this reason, we will screen and exclude any individuals 
with untreated latent or reactivated TB before study entry.  To minimize risks, we will 
exclude individuals with active hepatitis prior to enrollment.   
The impact of IL-1 therapy on development of malignancies is not known so we will 
exclude any individual with any history of malignancy from the study.   
All participants must have adequate CD4+ T-cell counts and suppressed HIV prior to 
enrollment. CD4+ T cell counts and HIV-1 RNA titers will be measured frequently, as in 
the schedule of events.   In clinical trials, injection site reactions were mild (10% of the 
clinical trial population) to moderate (less than 2% of the clinical trial population).  No 
severe injection site reactions have been reported.  Common toxicities associated with 
canakinumab also include, diarrhea, upper abdominal pain, headache, vertigo, and 
nausea. These will be queried by exam and interim medical history taking. 
No hypersensitivity reactions have been reported with canakinumab therapy but we will 
exclude individuals if they have a known clinical hypersensitivity to the medication.   
As canakinumab may affect the immune response to live vaccines and no data are 
available on the efficacy of live vaccines in individuals receiving canakinumab, adults 
would receive all recommended vaccines prior to initiation of therapy with canakinumab, 
and we will exclude any individual who has a requirement for live vaccines during the 
study.   
Canakinumab has also been associated with a reduction in neutrophil count22.  In a phase 
IIb study of 556 individuals, 10.7% of canakinumab treated patients and 4.6% of placebo 
patients had some neutropenia during the trial defined as an ANC < 1500/mm32. For this 
reason, we will exclude all individuals with ANC< 1500/mm and carefully monitor WBC 
and ANC during the study.     
There may be temporary mild discomfort when the blood pressure cuff is inflated from the 
endothelial function studies.  Some patients may feel weak or get a headache after taking 
the nitroglycerin medication which is also temporary.  There is a risk of death if subjects 
are taking Viagra-like drugs and also take nitroglycerin at the same time; therefore 
subjects who have taken Viagra-like drugs within 48 hours of the study will not be 
administered nitroglycerin. Subjects will be monitored throughout the entire study and the 
exam will be terminated if severe symptoms develop.  These have not been associated 
with any complications as patients are supervised and monitored during the 
studies.  Trained technicians perform the procedures and Dr. Ganz and Dr. Hsue are 
available if any clinical issues arise.  Incidental findings will be communicated to the study 
subject, and the study subject’s physician and arrangements will be made to perform 
additional imaging or evaluation if clinically indicated.   Phlebotomy may cause some 
discomfort, bleeding or bruising where the needle enters the skin, and rarely, fainting or 
infection may occur.  No more than 480 ml (2 cups) of blood will be drawn over any two-


 
 
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month period. This is within Red Cross Guidelines (less than 500 ml every two 
months).  Risks of blood collection include anemia (low blood counts).  Symptoms of 
anemia include tiredness, weakness and dizziness. Patients will be checked for anemia 
at each visit.  If the investigator feels that an individual is at significant risk for anemia, the 
amount of blood collected will be reduced.  If the study participant’s hemoglobin falls 
below 9 g/dl or hematocrit falls below 27%, we will draw a 5 ml (1 teaspoon) of blood 
drawn to check the hemoglobin and hematocrit.  Other than the blood required to check 
the hemoglobin and hematocrit, there will not have more blood drawn until the hemoglobin 
rises above 9 g/dl or the hematocrit rises above 27%.  
The effects of canakinumab on an unborn baby are unknown.  Female subjects of 
childbearing age and pregnant or nursing women will be excluded from the study. Male 
subjects will be counseled to use two forms of birth control during the study.    
Other side effects that are not known at this time could occur during study treatment.  All 
drugs have a potential risk of an allergic reaction, which if not treated promptly, could 
become life-threatening.  During the course of the study, subjects will be told about any 
new information that may affect their decision to continue to participate. 
Benefits 
Although ART for patients with HIV prolongs life, it does not fully restore health.  Several 
factors contribute to the excess CVD risk observed in patients with HIV, including chronic 
inflammation and immune activation.  Thus, therapeutic strategies to target inflammation 
and immune activation in the setting of HIV infection may reduce CVD risk, leading to 
improved survival.  We will perform the first study ever to evaluate the effects of an anti-
inflammatory treatment strategy via IL-1B inhibition that does not affect traditional CVD 
risk factors and is not an HIV antiretroviral medication on endothelial function, 
inflammation, and immune activation in individuals with HIV infection.  Treatment of 
inflammation, other than through use of ART or lipid-lowering medications is a novel 
approach to reducing CVD risk in patients with HIV, and could potentially change 
preventive cardiology treatment paradigms in these patients by adding an additional tool 
to the arsenal of CVD risk-reducing interventions used in patients with and without HIV 
infection. 
While receiving the study drug, there is no anticipated benefit for patients participating in 
this exploratory study. 
3.0 
OBJECTIVES 
3.1 
Primary Objectives 
1. To determine the safety, tolerability, and pharmacokinetics of IL1-β inhibition 
using canakinumab in effectively treated and suppressed HIV infected adults. 
2.  To demonstrate that IL-1β inhibition decreases systemic inflammatory 
markers, T cell activation, and improves vascular inflammation and endothelial 
dysfunction among treated and suppressed HIV-infected individuals.   


 
 
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3.  To determine whether IL-1β inhibition decreases the size of the HIV reservoir 
in blood.   
4.0        STUDY DESIGN 
We will perform a double blinded study that will be performed in two stages.  In 
Stage I, 10 individuals will receive a dose of 150mg canakinumab and then 
followed for 12 weeks as detailed in Table 1.  If the drug is safely tolerated and 
none of the safety milestones have been reached at the end of followup period, 
we will proceed with Stage II of the study which entails the enrollment of a 100 
additional study participants who will be treated with two doses of canakinumab 
(150mg subcutaneous baseline and 12 weeks) or placebo. 
 
4.1 
Inclusion Criteria 
4.1.1 Currently on continuous ART for at least 12 months with no change in 
regimen in 4 weeks prior to study entry. This is defined as continuous 
active therapy for the 4-week period prior to study entry with no treatment 
interruption longer than 7 consecutive days and a total duration off 
treatment of no more than 14 days in the 90 days prior to study entry. 
4.1.2 CD4+ T-cell count ≥400 cells/mm3 obtained within 30 days prior to study 
entry by any US laboratory that has a Clinical Laboratory Improvement 
Amendments (CLIA) certification or its equivalent. 
 
4.1.3 HIV-1 RNA level below the limit of quantification using an FDA-approved 
assay for at least 52 weeks prior to study entry and confirmed within 60 
days prior to study entry. The assay used for eligibility can be performed 
by any US laboratory that has a CLIA certification or its equivalent. 
NOTE:  Single determinations that are between the assay quantification 
limit and 200 copies/mL are allowed as long as the preceding and 
subsequent determinations are below the level of quantification. 
 
4.1.4 The following laboratory values obtained within 60 days prior to study 
entry by any US laboratory that has a CLIA certification or its equivalent; 
• 
ALT [serum glutamic pyruvic transaminase (SGPT)] <2 times 
upper limit of normal (ULN) 
• 
Total bilirubin < 4 times ULN 
• 
AST [serum glutamic oxaloacetic transaminase (SGOT)] <2 x ULN 
• 
White blood cell (WBC) >3000/mm3 
• 
Hemoglobin >12.0 g/dL 
• 
Platelets >150,000/mm3  
• 
ANC ≥ 1500/mm 
 
4.1.5  Female subjects who are postmenopausal (i.e., of non-childbearing 
potential), defined as having either: 
 


 
 
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A) Appropriate medical documentation of prior hysterectomy and/or 
complete bilateral oophorectomy (i.e., surgical removal of the ovaries, 
resulting in “surgical menopause” and occurring at the age at which the 
procedure was performed),  
OR 
B) Permanent cessation of previously occurring menses as a result of 
ovarian failure with documentation of hormonal deficiency by a certified 
healthcare provider (i.e., “spontaneous menopause”). Hormonal 
deficiency should be properly documented in the case of suspected 
spontaneous menopause as follows: 
 
1. If age >54 years and with the absence of normal menses for at 
least 24 consecutive months: serum follicle stimulating hormone 
(FSH) level elevated to within the post-menopausal range based 
on the laboratory reference range where the hormonal assay is 
performed; 
2. If age ≤ 54 years and with the absence of normal menses for at 
least 24 consecutive months: Negative serum or urine (HCG) 
performed within 48 hours prior to study entry with concurrently 
elevated serum FSH level in the post-menopausal range, 
depressed estradiol (E2) level in the post-menopausal range, and 
absent serum progesterone level, based on the laboratory 
reference ranges where the hormonal assays are performed.   
 
4.1.6 Moderate or high CVD risk or presence of one CVD risk factor defined as: 
 
A) Documented CVD as assessed by meeting at least 1 of 3 criteria 
below: 
1. Coronary artery disease (CAD): prior MI due to atherosclerosis, 
coronary artery bypass graft surgery, percutaneous coronary 
intervention, or angiographic CAD with luminal diameter stenosis of at 
least one coronary artery at least 50%. 
2. Cerebrovascular disease: prior ischemic stroke of carotid origin, 
carotid endarterectomy or stenting, or angiographic carotid stenosis of 
at least 50%. 
3. Peripheral arterial disease: prior lower extremity arterial surgical or 
percutaneous revascularization procedure, or angiographic lower 
extremity arterial stenosis of at least 50%.  
OR 
B)  At increased risk for CVD by meeting the criteria below: 
 
1. First degree relative who had heart attack, stroke, or documented CVD 
as defined in section 4.1.6.A that occurred when they were age: 
a. 55 years or younger for male relatives (father, uncle, or 
brother) 
b. 60 years or younger for female relatives (mother, aunt, or     
sister) 
OR 


 
 
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21 
 
C) One of the following CVD risk factors below:  
1. Current smoking: subject report of smoking at least a half a pack of 
cigarettes a day, on average, in the past month. 
2. Hypertension (HTN): two consecutive BP readings with either systolic 
>140 mmHg or diastolic > 90 mmHg; or currently on antihypertensive 
medications. 
3. Dyslipidemia: defined as non-HDL-C >160mg/dL, or HDL-C ≤ 40mg/dL 
regardless of medication use; or currently on lipid lowering 
medications. 
4. hsCRP ≥ 2mg/L obtained at screening. 
 
4.1.7 Men and women age ≥40 years and ≤ 59 years 
 
4.1.8  May be on stable lipid-lowering medication, and/or anti-hypertensive 
medication. 
 
4.1.9 Ability and willingness of subject to provide informed consent 
 
4.1.10 Appropriate documentation from medical records of prior receipt of 
pneumococcal vaccination (with both the 13 valent conjugant vaccine 
[PCV13] and 23 valent pneumococcal polysaccharide vaccine [PPV23]).  
Pneumococcal vaccination requirements will be determined on a case-by-
case basis according to IDSA guidelines 
(http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/idsa-
vaccinesimmunosupp2013).  
• 
If necessary, the PCV13 vaccination can be provided and 
administered before study entry given that the subject meets all 
other inclusion/exclusion criteria and primary care providers are 
unable to provide immunization.  Each subject’s primary care 
provider will be notified. 
 
4.1.11 Influenza and pneumococcal vaccination must be completed more than 14 days prior 
to study entry. 
 
4.2 
Exclusion Criteria 
4.2.1 Men and Women age ≥60  
 
4.2.2 Acute or serious illness requiring systemic treatment and/or hospitalization 
within 90 days prior to study entry.  
 
NOTE:  Treatment must have ended at least 60 days prior to study entry 
for eligibility.  
4.2.3 Documentation of any CDC category C AIDS-indicator condition within 90 
days prior to study entry.  
 


 
 
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4.2.4 Receipt of antibiotic therapy within 30 days prior to study entry. 
 
4.2.5 Active or latent TB infection (defined as a positive PPD ≥5 mm positive 
interferon-gamma release assay, or positive T-spot test at any time in the 
past) 
• 
Evidence of latent TB on a prior chest x-ray that has not been 
treated will be excluded 
o Subjects who have received latent TB treatment at least 
6 months prior to study entry will be allowed 
• 
Active TB disease requiring treatment will be excluded 
o Subjects who have received active TB treatment at least 
48 weeks prior to study entry will be allowed 
 
4.2.6 Women of child bearing age, pregnant or nursing women because the 
effects of canakinumab on fetal development are not known. 
 
4.2.7 CABG surgery in the past 3 years. 
 
4.2.8 New York Heart Association Class IV congestive heart failure.  
 
4.2.9 Uncontrolled hypertension within the past 90 days prior to study entry. 
 
4.2.10 A history of or current, active hepatitis B infection defined as positive 
hepatitis B surface antigen test or positive HBV DNA in subjects with 
isolated HBcAb  positivity, defined as negative HBsAg, negative HBsAb, 
and positive HBcAb within 24 weeks prior to study entry.  
 
NOTE: Subjects who are positive for hepatitis B surface antigen but 
who are HBV DNA negative are permitted in the study. 
 
 
4.2.11 Chronic hepatitis C infection defined as a positive hepatitis C antibody and 
positive hepatitis C RNA at any time prior to study entry. 
 
NOTE: Subjects who are positive for hepatitis C antibody but who are 
HCV RNA negative are permitted in the study. Participants who 
have been treated for hepatitis C must be HCV RNA negative for 
at least 24 weeks after completion of therapy to be eligible for the 
study. 
 
4.2.12 Patients with diabetes mellitus. 
 
4.2.13 Nephrotic syndrome or eGFR< 30ml/min/1.73m2 or kidney transplant 
(regardless of renal function). 
 
4.2.14 Any prior malignancies including Kaposi’s Sarcoma (KS), Cervical 
Cancer, and Non Hodgkin Lymphoma (NHL) with the exception of basal 
and squamous cell carcinoma. 
 


 
 
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23 
 
4.2.15 Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), 
HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy 
within 30 days prior to study entry or during study. 
 
4.2.16 Change in the ART regimen in the 4 weeks prior to study entry or 
intended modification of ART during the study. 
NOTE: Some modifications of ART doses during the 4 weeks prior to 
study entry are permitted. In addition, the change in formulation 
(e.g., from standard formulation to fixed-dose combination) is 
allowed within 4 weeks prior to study entry. A within class single 
drug substitution (e.g., switch from nevirapine to efavirenz or from 
atazanavir to darunavir) is allowed within 4 weeks prior to study 
entry, with the exception of a switch from any other NRTI to 
abacavir. No other changes in ART in the 4 weeks prior to study 
entry are permitted. 
4.2.17 Known allergy/sensitivity or any hypersensitivity to components of study 
drug(s) or their formulation. 
 
4.2.18 Requirement for live active vaccination during the study and vaccination 
(e.g., influenza, pneumococcal polysaccharide) within 30 days prior to 
study entry and 30 days after study completion or requirement for inactive 
vaccination within 2 weeks prior to study entry. 
 
4.2.19 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.20 Changes in lipid-lowering or antihypertensive medication within 90 days 
prior to study entry or expected need to modify these medications during 
the study. 
 
NOTE:  Lipid-lowering medication includes: statins, fibrates, niacin (dose 
≥250 mg daily), and fish-oil/omega 3 fatty acids (dose >1000 mg 
of marine oils daily). 
 
4.2.21  Planned surgery in the next 52 weeks because canakinumab may lead to 
changes in white blood cells may affect wound healing. 
4.2.22 Patients who have taken PDE-5 inhibitors within 72 hours of the FMD test 
because nitroglycerin administered during the FMD can have fatal side 
effects with PDE-5 inhibitors. 
4.2.23 Subjects with a history of multiple imaging studies associated with 
radiation exposure in order to reduce the overall burden of radiation. 
 
4.2.24 Patients with neutropenia defined as an ANC <1500/mm. 


 
 
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24 
 
4.2.25 Triglycerides > 400mg/dL because small increases in triglycerides are 
associated with canakinumab therapy. 
4.2.26 Patients with a history of EBV-related lymphoproliferative disorders. 
4.2.27 Known active or recurrent hepatic disorder (including cirrhosis, hepatitis B 
and hepatitis C (positive or indeterminate central laboratory results), or 
alanine aminotransferase/ aspartate aminotransferase (ALT/AST) levels > 
2 times ULN or total bilirubin > 4 times ULN). 
 
4.2.28 Additional exclusion criteria for the FDG-PET/CT imaging: 
• 
Significant radiation exposure during the year prior to randomization. 
Significant exposure is defined as i) more than 2 PCI procedures, ii) 
more than 2 myocardial perfusion studies, or iii) more than 2 CT 
angiograms. 
• 
Any history of radiation therapy. 
4.3 
Study Enrollment Procedures 
4.3.1 Subject recruitment and enrollment process  
As we have done in our prior studies, all HIV-infected subjects will either be 
recruited from the SCOPE study or co-enrolled in the SCOPE study. SCOPE is 
an ongoing prospective cohort of over 2000 HIV-infected adults and over 600 
individuals meet the entry criteria for this study ensuring rapid recruitment. 
Advantages of using SCOPE to perform our proposed study include: (1) the 
ability to leverage existing funds to support the proposed research; (2) rapid 
recruitment of eligible subjects from a well-characterized cohort; and (3) reliance 
on an established infrastructure for patient retention, data collection, laboratory 
testing, and data management. 
 
Quest Clinical Research will recruit from their cohort as well as screen referrals 
from sub-investigators. 
Prior to conducting any study-related activities, written informed consent and the 
Health Insurance Portability and Accountability Act (HIPAA) authorization must 
be signed and dated by the subject. The date of enrollment is the date the 
participant signs the informed consent form.  
4.3.2 
Randomization 
Due to the objectives of the study, the identity of the test and control treatments 
will not be known to investigators, research staff, or patients. 100 patients will 
undergo double-blinded 2:1 randomization using a SAS-based computer-
generated randomization scheme developed by the data management provider. 
Subjects will be assigned to receive canakinumab 150 mg or matching placebo 
for 6 months, while continuing their other antiretroviral drugs (Stage II). Those 
who enroll in Stage I of the study will receive an initial dose of 150mg. The dose 


 
 
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chosen for this study of 150 mg subcutaneous injection every 2 months is the 
FDA approved dose for CAPS.  
The DAIDS-approved SFGH investigational pharmacy offers in house 
investigational drug services and dispensing of research drugs. The pharmacist 
and credentialed pharmacy technician charged with dispensing research-related 
drugs receive protocol-specific training and are compliant with State Board of 
Pharmacy requirements, FDA Guidelines, and Good Clinical Practices. 
Pharmacy documents, including study drug accountability logs, study drug 
ordering and shipping logs, and regulatory documents are maintained by the 
pharmacy technician. Medication will be dispensed at baseline for Stage I and at 
baseline and 12 weeks for Stage II. 
5.0 
STUDY TREATMENT  
In Stage I, 10 subjects will receive 150mg of canakinumab.  After 12 weeks, if no 
safety endpoints have been met and are clinically stable as defined in section 9.2 
the study will proceed to Stage II. In Stage II, 100 additional patients will be 
randomized in a 2:1 ratio using a SAS-based computer-generated randomization 
scheme developed by the study data management provider to either Arm 1 or 
Arm 2 as shown in Figure 1 to receive 150mg canakinumab or placebo. 
At the week 12 study visit, if subjects in Stage II remain clinically stable, patients 
will receive another subcutaneous injection of 150mg of canakinumab.  The 
patients will receive a dose at entry and at 12 weeks. 
5.1 
Regimens, Administration, and Duration 
5.1.1 
Dose 
Canakinumab is FDA approved for treatment of CAPS at 150mg SQ injection 
given every 2 months; for systemic juvenile idiopathic arthritis in patients as 
young as 2 years it can be given at a maximum dose of 300mg SQ every 4 
weeks.  No adjustments are needed for renal or liver impairment or in the 
elderly.   In the CANTOS pilot study, doses given 5-150mg per month were 
associated with significant reductions in biomarkers. In Stage I, 10 individuals will 
be treated with 150mg injection once.  This dose was chosen as it was well 
tolerated in the CANTOS pilot study and resulted in significant decreases in 
inflammatory markers.   
If Stage I is safely tolerated, we will then proceed with Stage II with a 150mg 
subcutaneous injection at baseline and 12 weeks. This dose was chosen as it is 
the intermediate dose being used in the CANTOS study and after intensive 
discussion with Dr. Ridker and experts at Novartis.   
5.1.2 
Administration  
Medication will be administered as a subcutaneous injection during the patient 
visit by a trained study nurse who will ensure complete compliance and 


 
 
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medication delivery once (at baseline) during Stage I of the study and twice (at 
baseline and 12 weeks) during Stage II of the study.     
5.1.3 
Duration  
For stage I, subjects will be receiving study treatment at entry and followed for 12 
weeks for observation. The total study duration for Stage 1 for each subject is 12 
weeks. For Stage II, subjects will be on study treatment for 24 weeks and 
followed for 28 weeks of observation. The total study duration for Stage II for 
each subject is 52 weeks. 
5.2 
Study Product Formulation and Preparation 
5.2.1 
Canakinumab 
Canakinumab is supplied as prefilled syringes (PFS) of canakinumab 150 mg in 
1 mL in bulk. You will have to individually label these syringes for each patient 
but otherwise they are ready to use.  The PFS has to be stored in refrigerator 
(2°.C - 8°C) and protected from light. Prior to use the PFS are taken out of 
refrigerator into room temperature 20 min prior to use so that the PFS reaches 
room temperature prior to administration.   
5.2.2  
Placebo 
Placebo is supplied as a white powder for solution for subcutaneous injection. 
Reconstitution with 1mL preservative-free sterile water for injection in required 
prior to injection. The placebo will be stored in the refrigerator at 2°C -8°C (68°-
77°F) and protected from light.  
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
5.3.1 
Product Supply 
Canakinumab and matching placebo for canakinumab will be supplied through 
the study by Novartis. ART will not be supplied through the study.  
5.3.2 
Study Product Acquisition/Distribution 
Novartis will ship the study drug and placebo to the SFGH investigational 
pharmacy after all required regulatory documentation has been received by the 
Sponsor and a contract has been executed.  
5.3.3 
Study Product Accountability 
The DAIDS-approved SFGH investigational pharmacy offers in house 
investigational drug services and dispensing of research drugs.  The pharmacist 
and credentialed pharmacy technician charged with dispensing research-related 
drugs receive protocol-specific training and are compliant with State Board of 
Pharmacy requirements, FDA Guidelines, and Good Clinical Practices. 


 
 
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Pharmacy documents, including study drug accountability logs, study drug 
ordering and shipping logs, and regulatory documents are maintained by the 
pharmacy technician. Medication will be dispensed on a 3 monthly basis. 
5.4 
Concomitant Medications 
Subjects in both groups will continue to take their current anti-HIV 
medicines.  There are no medications that are prohibited while the patients are 
on the study treatment. There may be a loss of therapeutic effects for 
medications that require individualized dose adjustments.  Therefore, these 
concomitant medications will be continued during the trial if only medically 
necessary and with appropriate monitoring.  All concomitant medication and 
concurrent therapies will be documented at screening, and at visits on weeks 1, 
4, 8, 12, 24, 36, 40, 48, 52 and for any premature discontinuation.  
 
 
6.0 
CLINICAL AND LABORATORY EVALUATIONS 
6.1 Schedule of Events 
6.1.1 
Schedule of Events for Stage I (Table 1)1 
Event 
Scree
n 
Pre 
-Entry 
Entry 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Medical History 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical Exam 
x 
 
x 
x 
 
 
x 
 
x 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Latent TB testing 
x 
 
 
 
 
 
 
 
 
Hepatitis B and C 
x 
 
 
 
 
 
 
 
 
Pregnancy testing 
x 
 
x 
 
 
 
 
 
 
Hemoglobin A1C 
x 
 
 
 
 
 
 
 
 
Canakinumab (150mg) Stage I 
 
 
x3 
 
 
 
 
 
 
Safety Labs2 
x 
 
x 
x 
x 
x 
x 
x 
x 
CD4 count; HIV-1 RNA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Lipid panel 
x 
 
x 
x 
x 
x 
x 
x 
x 
1visit windows ± 4 days except weeks 1 and 2 (±3 days); 2CBC, AST, ALT, bilirubin, creatinine, glucose; 3Stage 1: ten 
subjects get 150mg canakinumab at entry with study visits as shown above.


 
 
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6.1.2 
Schedule of Events for Stage II (Table 1)1 
Event 
Scre
en 
Pre 
-
Entry 
Entry 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
13 
    
Wk 
14 
 
Wk  
15 
Wk  
16 
Wk 
18 
Wk 
24 
 
Wk  
3010 
Wk 
364 
 
Wk  
4010 
 
Wk  
4810 
 
Wk 
5210 
Premature Discont. 
Medical 
History 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical 
Exam 
x 
 
x 
x 
 
 
x 
 
x 
 
 
 
 
x 
 
x 
 
x 
x 
x 
x 
Concomita
nt 
Medication
s 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Latent TB 
testing 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B 
and C 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
testing 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobi
n A1C 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Canakinum
ab/PBO 
Stage II5 
 
 
x5 
 
 
 
 
 
x5 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
Labs2 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CD4 count; 
HIV-1 RNA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Lipid panel 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
Phamacoki
netics6 
 
 
x 
 
 
 
x 
 
x 
 
 
 
 
x 
x 
 
x 
 
 
 
 
Brachial 
Artery FMD 
 
 
x7 
 
 
 
 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
x 
FDG-
PET/CT 
 
 
x8 
 
 
 
 
 
 
 
 
 
 
x9 
 
 
 
 
 
 
 


 
 
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29 
 
 
1visit windows ± 4 days except weeks 1 and 2 (±3 days); 2CBC, AST, ALT, bilirubin, creatinine, glucose; 3hsCRP, IL-6, fibrinogen, sCD163, D-dimers; 4post-treatment 
visit for safety and to assess inflammatory marker rebound; 5in Stage II, N=100 subjects will be randomized to receive 150mg canakinumab SQ baseline and 12 
weeks vs. placebo; 6PK studies will be done in Stage II of the study; CMV PCR will be done to assess for reactivation of latent CMV; 7paired FMD (1 hour apart) and 
must occur within 30 days of entry injection; 8FDG-PET/CT Scan and FMD visit and 30 days of entry injection; 9FDG-PET/CT Scan must occur within ±1 week of 
FMD visit; if reimaging is deemed necessary at baseline or follow-up, second FDG-PET/CT scan must occur within 1 week; 10Study visit added to the shchedule fo 
events 
Inflammator
y Markers3 
 
 
x 
 
 
 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
x 
Monocyte/T 
Cell/CMV 
 
 
x 
 
 
 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
x 
HIV 
Persistence 
 
 
x 
 
 
 
x 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
Stored 
plasma/PB
MCs 
 
x 
x 
 
 
 
x 
 
x 
 
 
 
 
x 
x 
 
x 
 
 
x 
x 


 
 
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6.2 
Timing of Evaluations 
6.2.1 Screening Evaluations  
Screening evaluations must occur prior to the subject’s starting any study 
medications, treatments, or interventions. 
Screening evaluations to determine eligibility must be completed within 
120 days prior to study entry unless otherwise specified. 
NOTE:  The screening evaluations should be done in a fasting state (see 
section 6.3 for a definition of fasting), as indicated in section 6.1. If 
the potential subjects are not fasting at the screening visit, then 
they should come back to the clinic within 3 days of the originally 
scheduled screening visit for a fasting blood draw.  
In addition to data being collected on subjects who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be 
captured in a Screening Failure Results form. 
6.2.2    Pre-Entry Visit 
Prior to entry visit, subjects will come in for a blood draw to collect pre-
intervention serum and PBMC. 
6.2.3   Entry Evaluations 
Subject must begin study treatment within 24 hours after randomization. 
Paired FMD will be performed within 30 days prior to delivery of drug and 
FDG-PET/CT will be scheduled for completion within 1 week of the paired 
FMD. 
NOTES:  
• 
A qualified FDG-PET interpreter will measure the image within a week 
of the scan and may find it necessary to repeat the scan within one 
week due to subpar image quality.  Study drug dispensing will be 
delayed until after the repeat scan is completed. 
• 
The second FMD assessment must be completed within 72 hours after 
the first FMD and must occur before the subject takes the first dose of 
study treatment.  
• 
Paired FMD can be same day, at least 30 minutes apart. 
 
Depression Questionnaire (Optional) for Stage II Only 
• 
3-5 minute survey that asks questions to gauge whether or not the 
participant is experiencing symptoms of depression in order to study 
the link between depression and heart disease in HIV positive and HIV 
negative patients. 
 


 
 
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Transcranial Doppler Imaging and Neurocognitive Sub study (Optional) for 
Stage II Only 
• 
The transcranial Doppler imaging is a non-invasive ultrasound test to 
evaluate the blood vessels in the brain.  The visit will require a 12 
hours fast and will also include a walking speed assessment. 
• 
The neurocognitive test consists of a series of paper and pencil tests 
to examine your thinking, memory, motor function, and coordination, 
as well as a questionnaire about your daily function 
 
6.2.4 
Post-Entry Evaluations 
 
All post-entry evaluations occur in reference to the date on which the 
subject started study treatment.  
 
Return Fasting and Brachial FMD Visit (as needed) for Stage II Only 
If subjects are in a non-fasting state or have not abstained from exercise 
or smoking for at least 12 hours prior to the weeks 12 and 18 post-entry 
study visits, then they should return to the clinic within 3 days of the 
originally scheduled study visit for a fasting blood draw and brachial FMD 
assessment. In addition, the subject must be afebrile (oral T <38 °C or 
<100.4 °F) for at least 48 hours prior to the FMD assessments at weeks 
12 and 18. 
Return FDG-PET/CT visit (as needed) for Stage II Only 
A qualified FDG-PET interpreter will measure the image within a week of 
the scan and may find it necessary to repeat the scan within one week 
due to subpar image quality.  If the participant was already required to 
repeat the FDG-PET/CT at entry, the participant will not be asked to 
repeat the FDG-PET/CT at post-entry and vice versa.   
Confirmation of Virologic Failure 
For subjects with suspected virologic failure, a confirmatory plasma HIV-1 
RNA test is to be performed within 30 days after the receipt of the results 
of the initial HIV-1 RNA sample indicating suspected virologic failure. In 
light of ART interruption (including identified periods of non-adherence), 
confirmatory HIV-1 RNA testing is not required; adherence counseling is 
recommended as needed.  If a participant has a second episode of 
virologic failure during the study after having achieved full suppression 
following the previous virologic failure, this should also be confirmed 
within 30 days. 
NOTE:  Virologic failure is defined as confirmed HIV-1 RNA levels >200 
copies/mL at any time during the study in the absence of an 
interruption of ART. 
Modifications to ART medications only must be documented.  


 
 
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The study will trigger a DSMB review if ≥ 5% of subjects in Stage II have 
two confirmed episodes of virologic failure during the study. 
Confirmation of CD4+ T Cell Count 
For subjects with a suspected CD4 safety endpoint, a confirmatory CD4+ 
T-cell count is to be performed within 30 days after the receipt of the 
results of the initial CD4 result indicating suspected CD4 endpoint. 
NOTE: The CD4 safety endpoint is defined as indicated below. 
• 
For subjects with an entry CD4+ T cell count <700 cells/mm3, a 
confirmed CD4 decline >33% of baseline and to an absolute value 
<350 cells/mm3 
• 
For subjects with an entry CD4+ T cell count ≥700 cells/mm3, a 
confirmed CD4 decline >50% of baseline 
 
Study Completion Evaluations  
The week 52 evaluations will be completed as the subject’s final study 
visit. 
In addition to all the study visits mentioned above, participants will be 
contacted every week to ask about infectious symptoms and any other 
side effects by phone call.  
6.2.5 
Discontinuation Evaluations 
Evaluations for Randomized Subjects Who Do Not Start Study Treatment 
Subjects who do not start study treatment will be taken off study with no 
further evaluations required.  
All case report forms (CRFs) must be completed and keyed for the period 
up to and including entry. 
Premature Treatment Discontinuation Evaluations  
Premature discontinuation of study treatment is defined as permanently 
discontinuing canakinumab prior to week 24.  
Subjects who prematurely discontinue canakinumab will have the 
premature treatment discontinuation evaluations performed within 1 week 
and no later than the next scheduled study visit. Subjects will be 
encouraged to continue on study/off study treatment and receive all study 
evaluations per section 6.1 through completion of the study. 
NOTE:  Subjects who are on study/off study treatment do not need to 
have PK assessments or study treatment adherence assessments 
(subjects should continue to be evaluated for adherence to ART 
medications). 


 
 
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Premature Study Discontinuation Evaluations  
Subjects who prematurely discontinue from the study prior to the final visit 
at week 52 will have the premature study discontinuation evaluations 
performed as per section 6.1 and be taken off study. 
6.3 
Instructions for Evaluations 
All stated evaluations are to be recorded on the CRF and keyed into the 
database unless otherwise specified. This includes events that meet the 
International Conference on Harmonization (ICH) definitions for a serious 
adverse event. 
• 
Results in death 
• 
Life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Congenital anomaly/birth defect 
• 
Other important medical event (may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the events listed above)  
 
Fasting Instructions 
Fasting is defined as nothing to eat or drink except prescription medications and 
water for at least 12 hours prior to the procedure. If subjects are in a non-fasting 
state, they must come back to the clinic within 3 days of the originally scheduled 
study visit for a fasting blood draw and FMD assessments, as indicated in section 
6.1.  Patients will be fasting at every visit for both Stage I and Stage II. 
6.3.1 Demographics 
Demographic information (date of birth, gender, race) will be recorded at 
screening. 
6.3.2 Medical History 
In addition to reporting all diagnoses within the past 30 days, the following 
diagnoses should be reported regardless of when the diagnosis was made.  
• 
AIDS-defining conditions  
• 
Coronary heart disease  
• 
Cancer (exclusive of basal/squamous cell skin cancer)  
• 
Diabetes  
• 
Tuberculosis  
• 
Chronic hepatitis C  
• 
Chronic hepatitis B  
Any allergies to any medications and their formulations must also be 
documented.  
6.3.3 Medication History and Study Treatment Modifications 


 
 
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Medication History 
A medication history must be present, including start and stop dates (unless 
otherwise specified). The table below lists the medications that must be included 
in the history to be recorded on the CRFs.  
Medication Category 
Timeframe 
Antiretroviral therapy 
Complete history 
(start and stop dates only required for ART 
taken within past 2 years) 
Immune-based therapy 
Complete history 
HIV-1-related vaccines 
Complete history 
Drugs for treatment or prevention of 
opportunistic infections 
Complete history 
Prescription and non-prescription drugs 
All cardiac and diabetes medications taken 
currently and within past year 
All other medications within 6 months prior to 
entry 
Dietary supplements 
Within 6 months prior to entry 
 
Study Treatment Modifications 
All of the following criteria must be met at the week 1 and week 12 visits 
before Stage II of the study can be initiated.   
• 
WBC count is >2500/uL and ANC ≥1500/mm 
• 
Platelet count is >75,000/uL 
• 
ALT/AST levels are <2 x ULN 
• 
Hemoglobin >11.0 g/dL 
• 
Platelets >75,000/mm3 
• 
No clinically important symptoms (defined as stomatitis, persistent fever, 
vomiting, clinical bleeding, or worsening shortness of breath). 
 
Study participants who develop neutropenia (ANC < 1500/mm) after the initial 
canakinumab dose will not be re-dossed as these subjects are anticipated to 
be at increased risk of infection. 
                                      
6.3.4 Clinical Assessments 
Complete Physical Exam 


 
 
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At the screening visit, a complete physical examination is to include at a 
minimum an examination of the skin, head, mouth, and neck; auscultation of the 
chest; cardiac exam; abdominal exam; examination of the lower extremities for 
edema. The complete physical exam will also include signs and symptoms, 
height and weight, diagnoses, and vital signs (temperature, pulse and blood 
pressure). 
Targeted Physical Exam 
At entry and all post-entry visits, a targeted physical exam is to be driven by any 
previously identified or new signs or symptoms that the subject has experienced 
since the last visit. This exam also includes vital signs (temperature and blood 
pressure), height and weight, and diagnoses at all visits.  
CV Risk Assessment 
For screening, this should include evaluation of smoking within the past 30 days, 
treatment for high blood pressure, and subject self-reported history of prior 
diagnosis or treatment for CVD, MI, coronary artery bypass graft surgery, 
percutaneous coronary intervention [angioplasty or stent], stroke, transient 
ischemic attack, peripheral arterial disease, or diabetes mellitus [excluding 
gestational diabetes].  
Smoking status will also be assessed at each post-entry FMD visit.  
NOTE: Peripheral arterial disease should only be recorded if the subject reports 
a medical diagnosis of peripheral artery disease, a history of a revascularization 
procedure, or use of medications for peripheral arterial disease (i.e., cilostazol or 
pentoxifylline).  
Signs and Symptoms 
At entry, all grades of signs and symptoms that occurred within 30 days prior to 
entry must be recorded; at post-entry, only signs and symptoms Grade ε2 must 
be recorded. Record all signs and symptoms that led to a change in treatment, 
regardless of grade. Further evaluation will be required for those events that 
meet EAE or ICH reporting requirements. 
Patients will be asked for  any signs or symptoms of infection such as fever, 
chills, fatigue or rash. If present, the study participant will be asked to seek 
medical care immediately. The study team will notify the primary care physician, 
and arrange for expedited evaluation for infection and if indicated, provide 
antibiotics for immediate treatment. 
Diagnoses 
Record all of the following targeted diagnoses (as defined in Appendix 100, 
Diagnoses Appendix Criteria for Clinical and Other Events from the ACTG):  
• 
CDC category C AIDS indicator condition 
• 
oropharyngeal candidiasis (thrush) 


 
 
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• 
oral ulcers 
• 
single episodes of bacterial pneumonia, herpes simplex ulcers, and 
cryptosporidiosis should be reported regardless of whether they meet the CDC 
category C AIDS indicator definitions.  
• 
any serious clinical events 
• 
any CVD, hematologic, infectious, and neoplastic diseases 
• 
all hepatobiliary (i.e., viral hepatitis) and renal disorders (renal insufficiency) 
• 
all mycobacterial infections, lymphoproliferative disorders, and pulmonary 
disorders, including all cases of immune reconstitution inflammatory syndrome 
(IRIS) and interstitial pneumonitis. 
 
ART Medications 
All modifications to ART medications including initial doses, subject-initiated 
and/or protocol-mandated interruptions (e.g., single dose interruption), 
modifications, permanent discontinuations, and last doses on study will be 
recorded.  
6.3.5 
Laboratory Evaluations 
At screening and entry, all protocol-required laboratory values must be recorded. 
For post-entry assessments, fasting lipid, fasting glucose, hematology, liver 
function tests, and creatinine values regardless of grade and all other Grade ≥3 
laboratory values will be recorded. All laboratory toxicities that led to a change in 
treatment, regardless of grade, must be recorded. Further evaluation will be 
required for those events that meet EAE or ICH reporting requirements. 
hsCRP (real-time) 
A real-time hsCRP is required only at screening for those subjects whose 
eligibility will be determined based on Category C of section 4.1.6. hsCRP results 
do not need to be recorded on a CRF.  
Hematology 
Blood will be obtained and analyzed for determination of hemoglobin, hematocrit, 
mean corpuscular volume (MCV), WBC, WBC differential (including neutrophils, 
lymphocytes, monocytes, basophils, eosinophils, other cell types present), and 
platelets.  
Chemistries 
Blood will be analyzed for determination of sodium, potassium, chloride, 
bicarbonate/CO2, BUN, and creatinine. 
Liver Function Tests 
Blood will be analyzed for determination of total bilirubin, AST (SGOT), ALT 
(SGPT), and alkaline phosphatase.  


 
 
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Lipid Panel (fasting, real-time) 
Blood will be analyzed for determination of total cholesterol, high density 
lipoprotein cholesterol (HDL), calculated low-density lipoprotein cholesterol 
(LDL), and triglycerides.  
NOTE: If the subject is not fasting, it is mandatory that the subject return to the 
clinic within 3 days of the originally scheduled study visit, after fasting for 12 
hours.  
Glucose (fasting) 
Blood will be analyzed for glucose measurements..  
NOTE: If the subject is not fasting, it is mandatory that the subject return to the 
clinic within 3 days of the originally scheduled study visit, after fasting for 12 
hours.  
TB Test 
A PPD skin test, or interferon-gamma release assay must be performed prior to 
study entry to rule out latent TB unless there is documentation that the subject 
completed treatment for latent TB at least 6 months prior to entry. 
 
NOTE: The TB test results do not need to be recorded on a CRF. 
 
Hepatitis Serologies  
Hepatitis Serologies will be performed at screening with results available prior to 
study entry. 
 
For subjects with known hepatitis B immunity, prior documentation of positive 
HBsAb is acceptable. If documentation is not available, HBsAb, HBsAg, and 
HBcAb will be obtained at screening. Results must be available prior to study 
entry. Subjects who have positive HBcAb but negative HBsAg and HBsAb 
(isolated HBcAb positive status) must have HBV DNA polymerase chain reaction 
(PCR) performed and confirmed as negative for subject to be eligible. 
Negative hepatitis B tests (i.e., negative HBsAb, HBsAg, and HBcAb) performed 
within 6 months prior to enrollment need not be repeated. If the last negative test 
result is more than 6 months prior to enrollment, then testing should be 
performed at screening. Results of the hepatitis B serology must be available 
prior to study entry so that subjects who have active hepatitis B can be excluded 
from participating in the study. Hepatitis B serology results will be recorded on 
the CRFs.  
For subjects with known chronic HCV, prior documentation of positive  
HCV antibody is acceptable. Negative HCV antibody obtained <6 months prior to 
enrollment is acceptable. If documentation of HCV status is not available or if the 
initial HCV test was negative but was obtained >6 months prior to enrollment, 


 
 
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then an HCV antibody test should be obtained at screening. Results must be 
available prior to study entry and recorded on the CRF. 
6.3.7 
Immunologic Studies for Stage II only 
CD4+/CD8+ 
Absolute CD4+/CD8+ T-cell count and percentages within 120 days prior to entry 
must be obtained from a laboratory that possesses a CLIA certification or 
equivalent.  
During the study, CD4+/CD8+ T-cell count and percentages must be performed 
by a laboratory that possesses a CLIA certification or equivalent and is certified 
for protocol testing by the DAIDS Immunology Quality Assurance (IQA) Program. 
Stored Plasma and Serum for Inflammatory and Coagulation Markers 
Plasma and serum for IL-6, hsCRP, D-dimer, sCD163, IP-10, sCD14, tissue 
factor, and microbial translocation such as lipopolysaccharide will be collected, 
processed, and stored for analyses.  
Stored PBMC for Immunology Assays 
PBMC for markers of HIV immune activation (CD38 and HLA-DR markers on 
peripheral CD4+ and CD8+ T-cells), immune senescence (CD28-/CD57+ T-
cells), monocyte subpopulations (including adhesion/activation indices), and 
expression of CX3CR1 will be collected, processed, and stored for analysis.  
6.3.8 
Virologic Studies for Stage II only 
Plasma HIV-1 RNA  
Screening HIV-1 RNA must be performed within 120 days prior to study entry by 
a laboratory that possesses a CLIA certification or equivalent using any FDA- 
approved assay. Eligibility will be determined based on the screening value.  
Stored Blood for Quantitative CMV Assay (Batched) 
CMV DNA by PCR will be performed on frozen whole blood collected and 
batched for testing at a central laboratory that possesses a CLIA certification or 
equivalent and is certified for protocol testing by the DAIDS VQA Program.  
6.3.9  
Viral Reservoir Studies for Stage II only samples for the viral reservoir 
studies will be collected and stored from all subjects. 
Stored PBMC for Cell-associated HIV-1 RNA and DNA 
The cell-associated HIV-1 RNA and DNA will be performed on cryopreserved 
PBMC.  
Stored Plasma for Single-copy HIV-1 RNA Testing  
6.3.10 
Other Studies for Stage II only 


 
 
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Stored Plasma for Future Unspecified Assays 
Plasma will be collected, processed, and stored for analyses.  
Stored PBMC for Future Unspecified Assays 
PBMC will be collected, processed, and stored for analyses.  
6.3.11 
Brachial FMD for Stage II only 
All FMD assessments should be performed at the same time of the day (i.e., in 
the morning within half an hour of a previous FMD). The subject must be afebrile 
(oral T <38 °C or <100.4 °F) for at least 48 hours, be fasting, and have abstained 
from exercise and smoking for at least 12 hours prior to the FMD assessments. 
Paired FMD (At entry) 
Two FMD assessments are requested on all subjects, but are not mandatory. 
During paired FMDs, first performance will be done without nitroglycerin and 
following performance will be done with nitroglycerin. 
It is preferable to separate the paired FMDs by at least 24 hours, but if this is not 
possible, it is acceptable to separate the paired FMDs by at least 30 minutes. 
The first FMD must occur within 30 days prior to study entry and must be 
confirmed as acceptable.   
The second FMD assessment must be completed within 72 hours after the first 
FMD and must occur before the subject takes the first dose of study treatment. 
Single FMD (At subsequent visits) 
FMD assessments will also be performed at weeks 12 and 18 and at the 
premature discontinuation visit (if applicable). If the FMD cannot be performed 
within the specified window of the originally scheduled week 12 or week 18 visit, 
the subject must return to the clinic as soon as possible to complete the FMD 
assessment. The subject will remain on study for continued follow-up. 
 
6.3.12 FDG PET/CT scan for Stage II only 
The subject must be fasting and have eaten a protein only meal the night for at 
least 12 hours prior to the FDG PET/CT scan. The patient will be asked to avoid 
consuming alcohol and strenuous exercise for at least 24 hours prior to the 
scan. The scan will also be performed at entry and week 18. If the scan cannot 
be performed within the specified window of the originally scheduled entry or 
week 18 visit, the subject must return to the clinic as soon as possible to 
complete the FDG-PET/CT scan. A qualified FDG-PET/CT interpreter will 
measure the image within a week of the scan and may find it necessary to repeat 
the scan within one week due to subpar image quality at either entry or follow-up.  
Study drug dispensing will be delayed until after the repeat scan (if needed at 
entry) is completed. 


 
 
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The subject will remain on study for continued follow-up. 
6.3.13 Adherence Assessments 
Adherence to ART medications will be by self-report. Adherence to ART 
medications will be evaluated at entry. Post entry, adherence to study treatment 
and ART medications will be evaluated at all visits.  Adherence to study 
treatment will be verified by nurses at the study site. 
6.3.14 
Medication Diary for Stage II only 
At the entry study visit, a medication diary will be given to subjects who will have 
PK assessments done at entry and week 4, 12, 18, 24, and 36 study visits. 
Subjects will be instructed to record the doses of their ART medications on the 4 
days preceding the PK study visit.  
6.3.15 
PK Assessments for Stage II only 
PK assessments will be carried out at entry and week 4, 12, 18, 24, and 36 study 
visits.   
6.3.16 
Depression Questionnaire for Stage II only 
Optional questionnaire administered at every study visit. 
6.3.17 
Transcranial Doppler Imaging and Neurocognitive Substudy for Stage 
II only 
Optional substudy to occur at entry and week 18. 
6.3.18 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout 
the study. Duration (start and stop dates), severity/grade, outcome, treatment 
and relation to study drug will be recorded on the case report form. 
7.0 
CLINICAL MANAGEMENT ISSUES 
Criteria for subject management, dose interruptions, modifications, and discontinuation of 
treatment will be mandated only for toxicities attributable to canakinumab. 
7.1 
Toxicity 
Clinical symptoms of any drug toxicities are required to be documented on the adverse 
event form and submitted within 10 days of the event, according to UCSF CHR protocol. 
The following guidelines come from the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events and should be used to grade severity. 
Severity Grade 
Description 


 
 
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Mild (1) 
Symptoms causing no or minimal interference with usual social & 
functional activities 
Moderate (2) 
Symptoms causing greater than minimal interference with usual 
social & functional activities 
Severe (3) 
Symptoms causing inability to perform usual social & functional 
activities 
Potentially Life-
threatening (4) 
Symptoms causing inability to perform basic self-care functions  
OR  
Medical or operative intervention indicated to prevent permanent 
impairment, persistent disability, or death 
 
7.1.1 Grade 1 or 2 Toxicity 
Subjects who develop a Grade 1 or 2 AE or toxicity, except as stated in 
section 7.2, may continue study treatment. If a subject chooses to discontinue 
study treatment, complete the premature treatment discontinuation 
evaluations, and encourage the subject to complete any remaining study 
visits until the toxicity resolves. 
7.1.2 Grade 3 Toxicity 
If the site investigator has compelling evidence that the AE has NOT been 
caused by the study treatment, dosing may continue. Otherwise, subjects 
who develop a Grade 3 AE or toxicity should have study treatment withheld, 
except as stated in section 7.2. The subject should be reevaluated closely 
until the AE returns to Grade ≤2, at which time study treatment may be 
reintroduced at the discretion of the site investigator or according to standard 
practice. Subjects experiencing Grade 3 AEs requiring permanent 
discontinuation of study treatment should be followed closely for resolution of 
the AE to Grade ≤2 and the protocol core team must be notified. 
7.1.3 Grade 4 Toxicity 
Subjects who develop a Grade 4 symptomatic AE or toxicity will have study 
treatment discontinued, except as stated in section 7.2. If the site investigator 
has compelling evidence that the AE has not been caused by the study 
treatment, dosing may resume when the AE has resolved to Grade ≤2. 
Subjects experiencing Grade 4 AEs requiring permanent discontinuation of 
study treatment should be followed closely until resolution of the AE to Grade 
≤2 and the protocol core team must be notified. 
7.2 
Management of Specific Toxicities 
7.2.1  Hepatotoxicity 
LFT monitoring will be performed.  In the event that there is an increase in ALT 
or AST ≥2 x ULN, the canakinumab dose will be reduced downward and LFT 


 
 
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blood testing will be repeated every 2 weeks to determine if the values have 
returned to normal range.   
7.2.2 Hypertriglyceridemia/Hyperlipidemia 
If elevated triglycerides or lipid levels are from a non-fasting blood draw, 
repeat the draw after a 12 hour fast. Only levels done in a fasting state should 
be used to determine toxicity management. Subjects with asymptomatic 
Grade ≥ 3 triglyceride, total cholesterol, or LDL cholesterol elevations may 
continue study drugs, at the discretion of the site investigator. 
7.3 
Pregnancy  
Pregnancy should be avoided if either partner is receiving canakinumab during the 
study and for a minimum of 3 months after therapy for male subjects. Male subjects 
will be required to agree to the use of two forms of contraceptive during the entire 
study duration. In this study, all individuals will be made fully aware of the risks while 
taking canakinumab.  However, after study entry, male subjects whose partners 
become pregnant must notify site personnel within 24 hours after learning about or 
suspecting pregnancy. Male subjects may continue on study/on study treatment 
Male subjects whose partners become pregnant will be considered on study until the 
outcome of the pregnancy and the 6 month infant assessment has been obtained 
and reported on the CRF.  
Male subjects whose partners become pregnant within 12 weeks after the final study 
visit or last dose of study drugs should inform site personnel within 24 hours after 
learning about or suspecting pregnancy. Sites will collect data on pregnancy-related 
complications and pregnancy-related outcomes. A telephone contact or clinic visit 
will be conducted at 6 months post partner’s delivery to collect data regarding the 
health of the infant. 
8.0 
CRITERIA FOR DISCONTINUATION 
8.1 
Permanent Treatment Discontinuation 
• 
Drug-related toxicity (see section 7.1 Toxicity). 
• 
Reaching a primary safety endpoint (defined in section 9.2.1.1). 
• 
Completion of treatment as defined in the protocol. 
• 
Request by subject to terminate treatment. 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the toxicity section of the protocol. 
• 
Not taking ART for 2 consecutive weeks.  
8.2 
Premature Study Discontinuation 
The following is a list of possible reasons for study treatment discontinuation: 
• 
Request by the subject to withdraw. 


 
 
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• 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the subject. 
• 
Subject judged by the investigator to be at significant risk of failing to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results. 
• 
At the discretion of the IRB, Food and Drug Administration, Office for Human 
Research Protections (OHRP), NIAID, other government agencies as part of their 
duties, or investigator.  
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom 
has resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early 
discontinuation visit as soon as possible and then should be encouraged to complete 
all remaining scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified 
in the subject’s source documents 
9.0 
STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues 
This is a double-blind, 52 week study to evaluate if treating virologically suppressed 
HIV-infected individuals with canakinumab is safe and reduces CVD risk as 
measured by endothelial function and HIV-associated inflammation.  
Due to the lack of safety data on canakinumab in patients with HIV, we will perform 
our study in two stages.  In Stage I, 10 individuals will all receive 150mg 
canakinumab once and undergo followup for 12 weeks.   
9.2 
Endpoints 
9.2.1 Primary Endpoints  
9.2.1.1 Safety 
Subjects who experienced any one of the following safety milestones 
during study follow-up (from entry to week 52) will be considered to 
have reached the primary safety endpoint: 
• 
For subjects with an entry CD4+ T-cell count <700 cells/mm3, a confirmed CD4 
decline >33% of baseline and to an absolute value <350 cells/mm3 
• 
For subjects with an entry CD4+ T-cell count ≥700 cells/mm3, a confirmed CD4 
decline >50% of baseline 


 
 
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• 
Confirmed HIV-1 RNA >200 copies/ml in the absence of interruption in HIV 
medication  
• 
New or recurrent CDC category C AIDS indicator condition 
• 
Evidence of HIV-associated infection including CMV end-organ disease, thrush, HSV 
reactivation, varicella zoster, EBV-related clinical disease 
 
9.2.1.2 Endothelial function 
Change from baseline to week 18 in brachial artery FMD (%) defined 
as the maximum FMD (%) calculated from RH 45, 60, 75, and RH 90 
relative to resting artery diameter (baseline). 
9.2.2 Secondary Endpoints  
9.2.2.1 Secondary/supportive measures of endothelial function 
• 
Change from baseline to week 12 in brachial artery FMD (%) 
• 
Change from baseline to week 12 in brachial artery diameter (mm) 
• 
Change from baseline to week 18 in brachial artery diameter (mm) 
• 
Change from baseline to week 18 in brachial artery hyperemic flow velocity (time-
integrated, cm) 
 
9.2.2.2 Vascular inflammation as measured by FDG-PET/CT scan from 
baseline to week 18 
9.2.2.3 Markers related to CVD risk, inflammation, and coagulation 
Changes from baseline to week 24 in levels of hsCRP, IL-6, sCD163, 
and D-dimer. 
9.2.2.4 Markers of monocyte subpopulations, adhesion and activation indices, 
and CX3CR1 expression 
Change from baseline to week 24 in monocyte levels, adhesion and 
activation indices, and CX3CR1 expression.   
9.2.3 Exploratory Endpoints 
9.2.3.1 Exploratory soluble and cellular biomarkers 
Change from baseline to week 24. 
NOTE:  The final choice of soluble and cellular biomarkers to be 
evaluated will be determined closer to the time of analysis 
based on the current state of knowledge and interest at that 
time. Biomarkers currently of interest include: 
• 
Inflammation, coagulation, and microbial translocation: sCD14, IP-10, tissue factor, and 
lipopolysaccharide (LPS) 
• 
Monocyte activation: Expression of CD14 and CD16, their activation marker (CD69) 
and homing molecule (CX3CR1) expression 
• 
Immune activation: CD38+HLA-DR+ expression on peripheral CD4+ and CD8+ 


 
 
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• 
Immune senescence: CD57+CD28+ expression on peripheral CD4+ and CD8+ cells 
 
9.2.3.2 Reactivation of latent CMV and CMV replication 
Qualitative (detectable and undetectable) and quantitative CMV DNA 
levels at baseline and over time to week 24. 
NOTE:  For qualitative outcome, baseline CMV level will be considered 
detectable if either the screening or entry samples have 
detectable virus. 
9.2.3.3 HIV-1 persistence 
HIV-1 RNA level at baseline and over time as quantified by Abbott 
assay with limit of quantification of 40 copies/mL categorized as no 
signal detected; signal <40 copies/mL; signal ≥40 copies/mL.  
HIV-1 RNA level at baseline and over time as quantified by SCA. 
Quantitative and qualitative endpoint (detectable/undetectable) will be 
evaluated.  
NOTE:  For the qualitative outcome, week 18/24 HIV-1 RNA will be 
considered detectable if either the week 18 or week 24 
samples have detectable virus. 
9.2.3.4 Cellular HIV-1 expression 
Changes in HIV-1 DNA: RNA ratios in CD4+ T-cells from baseline 
over time to the average of weeks 18 and 24. 
9.3 
Randomization and Stratification 
Study participants will be randomized in a double-blinded fashion in a 2:1 ratio of 
canakinumab to placebo.  A blocked randomization scheme will be generated using 
SAS Proc PLAN. 
9.4 
Sample Size and Accrual 
Power calculations (Aim 1): All power calculations were performed using SAS, 
version 9.3 (SAS Institute, Inc., Cary, North Carolina, USA) for 80% power, with all 
calculations assuming a two-tailed α=0.05. 
Stage I: The primary focus of the initial pilot study is to verify the safety of 
canakinumab. Rates of AEs will be tabulated, with exact confidence intervals. With 
10 participants, the ability of this pilot study to detect the occurrence of rare events is 
limited; however, common toxicities are likely to be detected. If none of the 10 
subjects getting active treatment experience any AEs, then the upper confidence 
bound for the probability of having an AE would be 31% (using an exact binomial 
interval); hence, we would have strong evidence that the probability of having an AE 
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The sample size was determined based on the primary endpoint for endothelial 
function, while at the same time ensuring that the study will be well powered to 
demonstrate the safety of the intervention.  
9.4.1  Endothelial Function 
Based on a superiority trial design with two-sided α=0.05, assuming a 
standard deviation (SD) of 3% and a 10% drop out rate, a sample size of 100 
participants (67 active, 33 placebo) will ensure 80% power to detect a 
between-groups difference of 1.9%. An effect size of 1.5-2% change in FMD is 
considered clinically relevant and is detectable with brachial artery FMD 
studies of this size42. This magnitude of FMD improvement has been seen in 
studies of ART43 and statins44, 45 in patients with HIV-infection. In the 
Cardiovascular Health Study46 a 1% FMD difference was associated with an 
~14% adjusted CVD risk reduction. 
 
9.4.2 Vascular Inflammation 
We will also measure between-treatment arm differences in the change aortic 
TBR (the measure of arterial inflammation by PET/CT). The assumed SD for 
change in TBR is 0.18; this value is derived from Elkhwad et al47 and takes 
into account the multi-center nature of PET/CT measurements in this study. 
That SD is chosen conservatively, since it is for change in TBR from the aorta 
and carotid arteries combined (which is a secondary endpoint in this 
application, and which is associated with a larger SD for change compared to 
single-vessel endpoints). Based on previous work in a comparable cohort by 
Subramanian et al12, the anticipated average baseline value in our cohort will 
be approximately 2.23. Based on a superiority trial design with two-sided 
α=0.05, a total of 82 subjects entering and 66 subjects providing complete, 
evaluable data sets will ensure 93% power to detect a between-groups 
difference of 0.156 (which is 7% of a mean baseline TBR value of 2.23). The 
minimum meaningful expected change on therapy of 7% is based on the 
observation that low-dose and moderate dose statins are associated with 
~8%48 and ~19%49 reduction in TBR, respectfully. Of note, the SD for change 
in TBR for the aorta, the primary endpoint in this application, is smaller 
(0.14)50 and hence we expect to have larger residual power than calculated 
here. 
9.4.3  Safety – Stage II: 
Safety of active treatment will be demonstrated if it can be shown that active 
treatment provides no more than an 18% point absolute higher rate of safety 
events than the background rate. That is, a non-inferiority hypothesis on the 
difference in the proportions of subjects with safety events between the 
groups utilizing a non- inferiority bound of 18%.  
Assuming an underlying true probability of safety endpoints of 8% with 
placebo compared to 10% with treatment, accepting a one-sided 10% type 1 
error rate, and assuming 10% dropout rate, a sample size of 30 subjects in 
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demonstrate that the difference in the probability of a safety endpoint 
between the two treatment strategies is less than 18%.  
The power of the study to rule out a 18 percentage point (absolute) increase 
in the probability of a safety event over 24 weeks will be adversely impacted if 
the true event probability in the placebo group is higher than that assumed or 
if treatment results in more than an absolute 2 percentage point increase in 
the event probability (Figure 9.1). 
Figure 9.1: Power to exclude a difference in the 24 week probability of safety events 
(canakinumab – placebo) of 18 percentage points (absolute) or greater with a sample size 
of N=30 in placebo and N=60 in canakinumab group.  
 
9.4.4 Viral Reservoir Studies 
A sample size of 30 subjects in placebo and 60 in canakinumab group will 
provide sufficient precision to estimate the difference in the proportion of 
subjects with undetectable viremia between the two groups with a 95% 
confidence interval with maximal width of 0.30 (+/-0.15). 
9.5 
Monitoring 
Summaries of deaths and serious and targeted adverse events pooled across study 
regimens will be reviewed on a regular basis by the protocol core team. The core 
protocol team will also review study conduct in terms of pooled rates of accrual and 
study and treatment discontinuation as well as completeness of data and specimen 
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The study will undergo quarterly reviews for safety by the Study Monitoring 
Committee (SMC) that includes Dr. Currier, Dr. Lerman, Dr. Marconi, Dr. Sandler, 
Dr. Lederman and Dr. Baker.   
9.6 
Analysis Plan 
9.6.1 Safety 
 
Analytic plan: We will compare baseline characteristics by treatment group 
(canakinumab vs. placebo) using a t-test for normally distributed variables 
and using the Mann-Whitney U test for continuous variables that are non-
normally distributed, and Fisher’s exact test for categorical variables.  
Analyses for aim 1 will involve comparisons of continuous measures at 
multiple visits following treatment initiation (through week 52). We will use 
linear mixed models to evaluate the association of treatment group with CD4 
count and HIV RNA level, in separate models for each outcome. Because 
these measures are known to be right-skewed, each outcome will be log-
transformed for analysis; results will be back-transformed to produce 
estimated percentage differences by treatment group. To account for the 
possibility of missing data due to loss to follow-up or study discontinuation, 
which could bias the treatment effect, we will adjust estimates using an 
inverse probability weighting approach51. We will model each participant’s 
probability of having a non-missing outcome, with separate weights 
calculated at each visit. The inverse of this probability will then be used as a 
weight applied to persons with non-missing outcomes in the regression 
analyses.  
 
9.6.2 Secondary/Exploratory Outcomes 
Primary inference for all remaining continuous study outcomes will be based 
on a comparison of the change in the endpoints from baseline to week 24 
between the two study groups using a stratified Wilcoxon rank sum test using 
an intent-to-treat approach including all randomized subjects. Subjects with 
missing week 24 outcome data will be imputed with worst rank. These results 
will be supported by baseline adjusted analyses using stratified analysis of 
covariance. For all analyses, missing outcome data assumed to be ignorable. 
All analyses will be presented with longitudinal scatter plots of observed 
changes by study group and with two-sided 95% confidence intervals of the 
within group changes and differences in changes between the two study 
groups. The proportions of subjects with detectable HIV-1 RNA levels, and 
detectable CMV will be plotted over time and compared by study arms at 
week 18/24 using Fisher’s exact test. Given sufficient numbers of individuals 
with detectable levels of HIV-1 RNA and CMV, the rate of change in virus 
levels over time will be estimated.  
Given adequate sample sizes within each stratum, exploratory subgroup 
analyses by current use of statins within the past 8 weeks versus none will be 
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9.7 Pharmacovigilance Plan 
Given the small number of patients and short exposure time in our study, we do not anticipate 
many unexpected malignances in our study.  An unblinded expert from the DSMB will monitor 
adverse events of malignancy throughout the entirety of the study.  In addition to looking at 
malignancy adverse event numbers, the unblinded expert will also review narratives to detect 
any unusual malignancies.  Our study will incorporate a cancer adjudication SOP that our group 
has used for prior NIH-sponsored studies.  After the study is completed, we will call patients 
once a year for 2 years to evaluate for malignances.   
10.0 DATA MANAGEMENT AND COLLECTION 
10.1 Data Management 
 
All data for our proposed study will be managed by the UCSF Data Coordinating 
Center, which is housed in the Department of Epidemiology and Biostatistics.  All 
issues related to data management, specimen storage and data analysis for this 
study will be directed by Dr. Jeffrey Martin, who co-directs the SCOPE cohort with 
Dr. Deeks. 
The UCSF Data Coordinating Center was created to develop and support data 
management systems for clinical researchers.  The web-based systems currently in 
use encompass all aspects of a clinical research study's life cycle. They are utilized 
by small, medium and large-sized studies both within and outside UCSF.  The 
standard research data system is a customized hybrid of off-the-shelf software that 
combines decentralized data submission, centralized and remote data editing, and a 
centralized database structure designed to collect, transfer, and store data for 
clinical research studies.  The system integrates scannable forms with Internet 
capabilities to provide rapid and timely access to highly accurate data.  In this 
system, data are collected and transmitted via the Internet to the Coordinating 
Center by remote clinical sites. After the data have been electronically received by 
the Coordinating Center, they are assessed for quality via a combination of 
automated and manual processes and then written to the study database, which has 
a powerful and flexible data dictionary for subsequent query generation. Every 24 
hours, queries (data discrepancies) are generated to identify potential errors in the 
study data. These queries are accessible via a secure study web site so that clinic 
staff can immediately resolve them in a timely manner. When appropriate, sites can 
audit data in real-time via the web site, which automatically generates a full audit 
trail. Data from outside sources such as participating laboratories are integrated into 
the study database. The ultimate result is elimination of delays in identifying missing 
data, improved data quality, and faster time to data analysis.  The standard system 
includes a password-protected study web site which can be accessed from 
anywhere in the world for administrative coordination and data operations. The 
typical study web site has several distinct components: administrative (meeting 
planner, document archives), data system support (user manuals, Q&A), forms 
tracking, querying and editing reports, and other types of reporting (recruitment, 
retention, editing).  Finally, the standard system is compliant with all Federal 


 
 
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Government confidentiality guidelines. The 13 staff members of the Coordinating 
Center, with experience in programming, web design, server set-up and 
maintenance, form development, and training users how to use the systems, are 
available to assist with all aspects of system set-up and maintenance.  
Work already performed in SCOPE in developing the forms, the relational database, 
the web-based reporting, and the creation of complex derived variables presents an 
enormous cost and time saving for the proposed study.     
10.2 Data Collection Instruments 
All study participants complete an interviewer-administered questionnaire that will 
include a validated form developed specifically for Dr. Hsue’s cardiovascular 
studies.  These forms collect data regarding antiretroviral medication usage and 
adherence, quality of life, recreational drug use, HIV transmission behaviors and 
traditional cardiac risk factors.  Study forms are created using Teleform Elite 
software (Cardiff Corp., Vista, CA) and are transmitted via an internet scanner to the 
Data Coordinating Center, where they are read by optical character recognition and 
stored in a Microsoft SQL-server database. After human verification of key text 
fields, an automated error and consistency-checking algorithm is performed, and all 
errors resolved on-line in real time by the original interviewers.  Data from outside 
sources such as participating laboratories are integrated into the study database. 
The ultimate result is elimination of delays in identifying missing data, improved data 
quality, and faster time to data analysis. The standard system is compliant with all 
Federal Government confidentiality guidelines. 
 
Questionnaire development. All study participants will complete interviewer- and self-
administered questionnaires developed for this study.  These forms will collect data 
regarding antiretroviral medication usage and adherence, as well as quality of life, 
recreational drug use, and HIV transmission behaviors.  Study forms will be created 
using Teleform Elite software (Cardiff Corp., Vista, CA) and eventually transmitted 
via an internet scanner form our clinical research sites to the UCSF Data 
Coordinating Center, which is located several miles away.   Using an established 
system, these forms will be read by optical character recognition and stored in a 
Microsoft SQL-server database. After human verification of key text fields, an 
automated error and consistency-checking algorithm will be performed, and all errors 
reported the next day on the study’s password-protected website where they are 
resolved on-line by the original interviewers.   
 
Instruments for this study will be developed based upon existing questionnaires used 
in the SCOPE cohort.  Data obtained from these forms will be will be housed using 
the same variable labels and coding in our existing SCOPE database, thus 
eliminating substantial start up time and expense on database 
development.  Detailed questionnaires similar to that in SCOPE will be administered 
at baseline and at the primary outcome visits.   We will also develop shorter forms to 
be given at the interim visits.   These forms will contain a standard set of questions 
addressing the following domains: 
 


 
 
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Demographic characteristics.  At baseline and annually thereafter, we will obtain 
information on race/ethnicity (baseline only), education, employment, income, and 
residence.   
General health.  Participants will be asked about the occurrence and degree of 
severity of a list of 20 symptoms developed by the ACTG.   This index is widely used 
in ongoing studies throughout the world.  It includes symptoms commonly related to 
antiretroviral therapy.  Information will also be obtained regarding emergency room 
use and hospitalizations. 
HIV-related history.  Participant’s self-reported last known negative HIV antibody test 
and first known positive test will be obtained.  Self-reported CD4+ T-cell nadir will 
also be recorded, but this will be supplemented by objective review of the each 
participant’s medical chart.  A focused chart review will also obtain all plasma HIV 
RNA and CD4+ T-cell counts performed since entry into clinic.   
AIDS-related diagnoses.  Participants will be asked about the occurrence of any 
AIDS-defining diagnosis listed in the 1993 Revised CDC AIDS case definition.  All 
affirmative responses will be confirmed by clinical chart review.   
Use of opportunistic infection prophylaxis.  Participants will be shown a list of drugs 
used for prophylaxis and will be asked about past 4 month and current use.   
Antiretroviral medication use and adherence. At each visit, participants will be asked 
about their use of antiretroviral medications in the prior 4 months and be prompted 
with a list of names as well pictures.  As is performed in SCOPE, participants taking 
antiretroviral medications will be asked about the number of missed dosages in the 
past 4 days (asking about each day separately) and the total number of dosages 
missed in the prior 30 days.  In addition, the time of the last dose of each drug will be 
recorded for future pharmacokinetic work using stored samples.  
11.0 CLINICAL SITE MONITORING AND ADVERSE EVENT 
REPORTING 
11.1 Clinical Site Monitoring 
 
Site monitors under contract to the NIH will visit our clinical research site to review the 
individual subject records, including consent forms, CRFs, supporting data, laboratory 
specimen records, and medical records (physician progress notes, nurses’ notes, 
individuals’ hospital charts), to ensure protection of study subjects, compliance with the 
protocol, and accuracy and completeness of records.  The monitors also will inspect 
sites’ regulatory files to ensure that regulatory requirements are being followed and 
sites’ pharmacies to review product storage and management. 
11.2 Adverse Event Reporting 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of 
a patient administered a pharmaceutical product and that does not necessarily have a 
causal relationship with the treatment.  An AE is therefore any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the administration of an investigational product, whether or 
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A Serious Adverse Event (SAE) is defined as any AE that results in any of the following 
outcomes: death, a life-threatening adverse experience, inpatient hospitalization, a 
persistent or significant disability/incapacity, a congenital anomaly/birth defect. Study 
sites will document all SAEs that occur (whether or not related to study drug) per UCSF 
CHR Guidelines.  The collection period for all SAEs will begin after informed consent is 
obtained and end after procedures for the final study visit have been completed. 
All subjects will be followed for possible adverse events throughout their involvement in 
the study.  At each interaction study personnel will elicit subject input as to discomforts 
or adverse experiences while taking the medications.  Subjects will be seen and 
interviewed by a study nurse at screening, day 0, and weeks 1, 2, 4, 8, 12, 13, 14, 15, 
16, 18, 24, 30, 36, 40, 48 and 52. At each visit, they will be assessed for any new 
symptoms and vital signs will be obtained.  A complete blood count, complete metabolic 
panel, CD4+ T cell count, and plasma HIV-1 RNA level will be performed on most 
visits.  Subjects will also be seen after study drug administration is completed on week 
24 (12 weeks after the last dose).    
Adverse events will be reported within 10 working days of the Investigator’s awareness 
of the event, according to UCSF CHR Guidelines. Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. The collection period for all SAEs will begin after 
informed consent is obtained and end after procedures for the final study visit have 
been completed. If a subject is withdrawn from treatment due to an adverse event, the 
subject will be followed by the Investigator until the abnormal parameter or symptom 
has resolved or stabilized. 
12.0  HUMAN SUBJECTS 
12.1 Institutional Review Board (IRB) Review and Informed Consent 
All protocols receive approval from the Committee on Human Research, UCSF’s 
institutional review board.  The consent process is conducted in accordance with the 
division’s SOP, which is based on GCP and HHS guidelines.  All staff at PHP have 
completed the NIH computer based-training on the Protection of Human Research 
Subjects.  Certificates for this training are on file.  In addition, all staff have 
completed the Human Subject Protections online course developed by UCSF.  In 
accordance with HIPAA regulations, subjects will be identified by a four-digit code 
(as is currently done in SCOPE).   
 
Research staff will ensure that candidates understand all elements of the consent 
form by addressing questions posed during the consent procedure and by asking for 
verbal confirmation that the candidate has no additional questions and verbally 
understands the purpose of the study, study intervention, basic procedures, risks, 
and that participation is voluntary.  Subjects will be given as much time as they need 
to read, understand and sign the approved informed consent document.  The subject 
will receive a signed/dated copy of the consent form to keep along with the UCSF 
Subject Bill of Rights and the HIPPA form to keep.  
12.2 Subject Confidentiality 


 
 
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All biologic specimens and clinical data obtained from this study will be linked to this 
code and not to personal identifying information (e.g., name, social security number, 
medical record number).  A key which will link the four-digit code to the personal 
information will be maintained in a secure pass-word protected file maintained by Dr. 
Hsue.   
 
HIPAA Compliance:  All sites are committed to ensuring that appropriate measures 
are taken to protect the privacy and confidentiality of all Personally-Identifiable 
Health Information (PHI) for which it is responsible.  This includes compliance with 
all regulations set forth by the HIPAA Privacy Rule, as well as with existing State and 
Federal laws pertaining to PHI.  All entering study volunteers will be given a copy of 
the Notice of Privacy Practices.  Good faith efforts will be made to obtain each 
individual’s written acknowledgement of receipt of the Notice(s).  The rights 
mandated by the HIPAA Privacy Rule concerning an individual’s ability to access, 
amend, and disclose certain sections of his or her own PHI are fully respected, and 
every effort will be made to assist patients who choose to exercise these rights. 
12.3  Subject Recruitment 
Recruitment of eligible subjects will be greatly aided by an established prospective, 
clinic-based cohort study of HIV-infected adults (the “Study of the Consequences of 
the Protease Inhibitor Era,” or SCOPE (S. Deeks, PI, H8211-17887)).  To date, 
SCOPE has enrolled over 2000 subjects: over 600 are expected to meet criteria 
outlined in this proposed study.  During the enrollment period all SCOPE patients 
who come in for regular cohort check-ups will be asked if they would like to learn 
more about the canakinumab trial.  Subjects in the SCOPE study have already given 
consent allowing the SCOPE team to approach them for other studies. 
 
Dr. Felicia Sterman, a HIV physician in the community will refer individuals to the 
study.  
  
When a protocol opens to accrual, our group initiates a large-scale education effort 
to inform both providers and patients about study aims, requirements, and 
procedures. Drs. Hsue and Deeks maintain a large primary care clinic and are in the 
clinic nearly every day.   
12.4 Subject Compensation 
Subjects will receive reimbursements to cover costs related to the study. They will 
receive the following amounts for each procedure: $25 at the completion of each 
study visit that does not include imaging, $25 for each FMD and $100 for each FDG-
PET/CT scan.  
13.0 PUBLICATION OF RESEARCH FINDINGS 
Research findings from this study will be published in a timely manner.  The principal 
investigator will have full control over the content of such publications. 


 
 
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14.0 BIOHAZARD CONTAINMENT 
As the transmission of HIV and other blood-borne pathogens can occur through 
contact with contaminated needles, blood, and blood products, appropriate blood 
and secretion precautions will be employed by all personnel in the drawing of blood 
and shipping and handling of all specimens for this study, as currently recommended 
by the Centers for Disease Control and Prevention and the National Institutes of 
Health. 
All dangerous goods materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. 
Please refer to instructions detailed in the International Air Transport Association 
(IATA) Dangerous Goods Regulations.  
 
15.0 REFERENCES 
1. 
Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a 
collaborative analysis of 14 cohort studies. Lancet (London, England). 2008;372:293-9. 
2. 
Bhaskaran K, Hamouda O, Sannes M, Boufassa F, Johnson AM, Lambert PC and Porter K. 
Changes in the risk of death after HIV seroconversion compared with mortality in the general 
population. Jama. 2008;300:51-9. 
3. 
Freiberg MS, Chang CC, Kuller LH, Skanderson M, Lowy E, Kraemer KL, Butt AA, Bidwell Goetz M, 
Leaf D, Oursler KA, Rimland D, Rodriguez Barradas M, Brown S, Gibert C, McGinnis K, Crothers K, Sico J, 
Crane H, Warner A, Gottlieb S, Gottdiener J, Tracy RP, Budoff M, Watson C, Armah KA, Doebler D, Bryant 
K and Justice AC. HIV infection and the risk of acute myocardial infarction. JAMA internal medicine. 
2013;173:614-22. 
4. 
Boccara F, Lang S, Meuleman C, Ederhy S, Mary-Krause M, Costagliola D, Capeau J and Cohen A. 
HIV and coronary heart disease: time for a better understanding. Journal of the American College of 
Cardiology. 2013;61:511-23. 
5. 
Pearce D, Ani C, Espinosa-Silva Y, Clark R, Fatima K, Rahman M, Diebolt E and Ovbiagele B. 
Comparison of in-hospital mortality from acute myocardial infarction in HIV sero-positive versus sero-
negative individuals. The American journal of cardiology. 2012;110:1078-84. 
6. 
Tseng ZH, Secemsky EA, Dowdy D, Vittinghoff E, Moyers B, Wong JK, Havlir DV and Hsue PY. 
Sudden cardiac death in patients with human immunodeficiency virus infection. Journal of the American 
College of Cardiology. 2012;59:1891-6. 
7. 
Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, 
Neuhaus J, Nixon D, Paton NI and Neaton JD. Inflammatory and coagulation biomarkers and mortality in 
patients with HIV infection. PLoS medicine. 2008;5:e203. 
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