Conditions: Rheumatoid Arthritis
Keywords: tocilizumab subcutaneous injection rheumatoid arthritis plaque inflammation atherosclerotic plaque joint inflammation FDG-PET PET-MR ACTEMRA
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the hypothesis that anti-IL-6 therapy is effective for reducing plaque inflammation as measured by fluorine-2-deoxy-D-glucose positron emission tomography (FDG-PET) in patients with rheumatoid arthritis (RA) who are synthetic disease-modifying antirheumatic drugs (dMARD) inadequate responders and are naive to biologic therapy.

Detailed description:
This multi-center study will recruit 21 subjects to undergo an open-label tocilizumab treatment for 13-18 weeks in order to examine the efficacy of tocilizumab on plaque inflammation in RA patients. This multi-center study will employ PET/MR imaging of the carotid and coronary arteries and aorta to assess the effect of anti-IL-6 therapy on arterial inflammation in patients with RA who are synthetic dMARD inadequate responders and are naive to biologic therapy.

Secondary, exploratory evaluation will also examine correlations between atherosclerotic plaque inflammation and the inflammatory activity of the rheumatoid joint measured by PET-MR imaging, as well as how the changes in inflammation correlate with lipid and inflammatory biomarkers, and how stress levels are associated with inflammatory activity.

Adults between 50 and 75 years old diagnosed with RA will come in for an initial screening visit to assess for clinical eligibility criteria (visit 1). During the screening period, patient acceptability for the study will be assessed on the basis of medical history, concomitant medications, physical examination, and clinical laboratory test results. The study doctor will review the screening test results and procedures to determine the subject eligibility prior to imaging. Women able to become pregnant will be excluded due to teratogenic side effects.

A FDG-PET/MR imaging study will be performed at a second screening visit (visit 2) to assess for the presence of arterial, plaque and joint inflammation. A serum pregnancy test will be drawn and confirmed to be negative prior to imaging for female subjects of childbearing potential. Acceptability for study participants will be confirmed on the basis of a tissue-to-background ratio (TBR) of greater than or equal to 1.7 in qualifying vessel (calculated using the mean of the maximum SUV) as measured from FDG-PET/MR imaging. Participants who meet clinical and imaging eligibility criteria will be enrolled into the study (visit 3). Subjects will receive first dose of tocilizumab subcutaneously, on subsequent weeks, subjects will be instructed to self-administer tocilizumab at a dose of 162mg every week for a 12 week period. 4 weeks post-initiation, participants will return for a clinical safety follow-up (visit 4). Final evaluation will include physical exams, clinical assessments and carotid IMT test. A second FDG-PET/MR imaging session will take place 12 weeks post-administration (visit 5).

Effect of tocilizumab on arterial plaque inflammation will be examined by measuring the change in FDG uptake in the carotid arteries, coronary arteries and aorta between the baseline and 12 week FDG-PET/MRI.

Arms:
arm 1: tocilizumab will be given to rheumatoid arthritis patients at a dose of 162 mg subcutaneously a week

Interventions: intervention 1: tocilizumab
Intervention descriptions: intervention 1: subjects will be treated with 162mg of weekly subcutaneous tocilizumab in an open-label manner, this will be done addition to MTX or monotherapy. On subsequent weeks after the first dose of tocilizumab, subjects will be instructed to inject the full amount of syringe according to the directions provided in the Instructions For Use (IFU).

Protocol document:
Prot_SAP_000.pdf: 
 
1 
Protocol Version 7.0
 
 
 
  
 
NCT NCT02659150 
 
Study ID: ML29520 
 
Title: “Effect of Subcutaneous ACTEMRA on Inflamed Atherosclerotic Plaques in 
Patients With Rheumatoid Arthritis” 
 
Contains Detailed Study protocol (with embedded SA 
 
Protocol Date: Jun 3, 2019 
 
 


 
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 Massachusetts General Hospital 
& 
Brigham and Women’s Hospital 
Harvard Medical School 
 
 
 
 
 
Study Title 
A MULTICENTER, OPEN-LABEL, PROOF-OF-ACTIVITY STUDY OF THE 
EFFECT OF SUBCUTANEOUS ACTEMRA ON INFLAMED 
ATHEROSCLEROTIC PLAQUES IN PATIENTS WITH RHEUMATOID 
ARTHRITIS 
 
 Study  Drug 
Tocilizumab (ACTEMRA®) 
 
Support Provided By 
Genentech 
 
Sponsor Investigator 
Ahmed Tawakol, MD 
 
Research Coordinator 
Nicki Naddaf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Number: 
 
 
ML29520 
 
Protocol Version Date: 
7.0  
 
 
 
 6/03/2019 
 
 
 


 
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TABLE OF CONTENTS 
 
 
1.0 
INTRODUCTION 
1.1 
Disease Background 
1.2 
Tocilizumab Background 
1.3 
Other Study Drug(s) Background 
1.4 
Study Rationale 
 
2.0 
OBJECTIVES 
2.1 
Primary 
2.2 
Secondary 
 
3.0 
STUDY DESIGN 
3.1 
Description of the Study 
3.1.1 Study Schema 
3.2 
Rationale for the Study Design 
3.3 
Outcome Measures 
3.3.1 
Primary Outcome Measures 
3.3.2 
Secondary Outcome Measures 
3.3.3 
Safety Outcome Measures 
 
4.0 
STUDY POPULATION 
 
4.0.1 Overview 
4.1  
Inclusion Criteria 
4.2 
Exclusion Criteria 
4.3 
Immunization during Tocilizumab therapy 
4.4  
Criteria for Premature Withdrawal 
 
 
5.0 
TREATMENT PLAN 
 
6.0 
STUDY MEDICATION  
6.1 
Tocilizumab 
6.1.1 
Tocilizumab Dosage and Administration 
6.1.2 
Tocilizumab Storage 
6.1.3 
Tocilizumab Overdosage 
 
6.2 
Other Study Drug(s) 
 
7.0 
DOSE MODIFICATION / TOXICITY MANAGEMENT 
7.1 
Tocilizumab 
7.2 
Other Drug(s) 
 
8.0 
CRITERIA FOR SUBJECT DISCONTINUATION 


 
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8.1 
Tocilizumab Specific Criteria 
8.2 
General Criteria 
 
9.0 
CRITERIA FOR STUDY DISCONTINUATION 
 
10.0 
CLINICAL AND LABORATORY EVALUATIONS 
10.1 
Pre-Treatment Evaluations 
10.2 
Evaluations During Treatment 
10.3 
Post-Treatment Evaluations 
 
11.0 
REPORTING OF ADVERSE EVENTS 
11.1 
Adverse Event and Reporting Definitions 
11.2 
Reporting of Serious Adverse Events Associated With Tocilizumab  
11.3 
Tocilizumab Adverse Events of Special Interest 
 
12.0 
EVALUATION OF RESPONSE 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Determination of Sample Size 
13.2 
Planned Efficacy Evaluations 
13.2.1 
Primary Efficacy Variables 
13.2.2 
Secondary Efficacy Variables 
13.3 
Methods of Analysis 
 
14.0 
RETENTION OF RECORDS 
 
REFERENCES/BIBLIOGRAPHY 
 
APPENDICES 
          
Appendix A: Study Flowchart/Schema 
Appendix B: Schedule of Events 
Appendix C:  Genentech Drug Safety Fax Form  
 
 
 


 
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1.0 
INTRODUCTION 
 
1.1 
Disease Background  
 
Patients with rheumatoid arthritis (RA) suffer significantly increased cardiovascular 
(CV) morbidity and mortality when compared to the general population 1-3.  Women 
with RA have a 2-3 fold higher risk of myocardial infarction, even in the absence of 
traditional coronary risk factors 4-6.  Several studies suggest that systemic inflammation 
accelerates atherogenesis in RA, perhaps by accentuation of both established as well as 
novel risk factor pathways 6-8.  
 
1.2 
Tocilizumab Background 
 
Refer to the Tocilizumab Investigator Brochure for descriptions of completed Phase I, II, 
and III trials.  
 
1.1.2 Tocilizumab 
Tocilizumab (TCZ), formerly known as myeloma receptor antibody (MRA) is a 
recombinant humanized antihuman monoclonal antibody of the immunoglobulin IgG1 
subclass directed against the IL-6R and produced by recombinant DNA technology. 
Clinical efficacy and safety studies of TCZ have been conducted or are ongoing in 
various disease areas, including adult-onset RA, systemic-onset juvenile idiopathic 
arthritis and polyarticular juvenile idiopathic arthritis. 
 
For the intravenous (IV) formulation, the half-life of TCZ is approximately 12.9 days. 
The TCZ exposures were stable over 2- years of treatment. The observed mean (± SD) 
Ctrough at 8 mg/kg IV was 15.9 ± 12.0 at week 24 and 19.9 ± 17.0 at week 104. The 
observed mean (± SD) Ctrough at 4 mg/kg was 1.02 ± 6.14 at week 24 and 1.09 ± 2.77 at 
week 104. 
 
The pharmacokinetics of subcutaneous (SC) TCZ was characterized using a population 
pharmacokinetic analysis using a database composed of 1759 rheumatoid arthritis 
patients treated with 162 mg SC every week, 162 mg SC every other week, and 8 mg/kg 
every 4 weeks for 24 weeks. 
The pharmacokinetic parameters of TCZ did not change with time. For the 162 mg every 
week dose, the estimated mean (±SD) steady-state AUC1week, Cmin and Cmax of TCZ 
were 8200 ± 3600 mcg•h/mL, 44.6 ± 20.6 mcg/mL, and 50.9 ± 21.8 mcg/mL, 
respectively. The accumulation ratios for AUC, Cmin, and Cmax were 6.83, 6.37, and 
5.47, respectively. Steady state was reached after 12 weeks for AUC, Cmin, and Cmax. 
For the 162 mg every other week dose, the estimated mean (±SD) steady-state 
AUC2week, Cmin, and Cmax of TCZ were 3200 ± 2700 mcg•h/mL, 5.6 ± 7.0 mcg/mL, 
and 12.3 ± 8.7 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax 
were 2.67, 5.6, and 2.12, respectively. Steady state was reached after 12 weeks for AUC 
and Cmin, and after 10 weeks for Cmax. 


 
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The Roche clinical development program in adult RA, comprised five pivotal Phase 3 
trials and two open-label, long-term treatment extension studies for the IV formulation 
and two pivotal Phase 3 trials with open-label, long-term treatment extension arms for the 
SC formulation.  
 
Further information on TCZ can be found in the Investigator’s Brochure (IB). 
 
1.3 
Other Study Drug(s) Background 
 
No other study drugs. 
 
1.4 
Study Rationale 
 
 
In human studies of rheumatoid arthritis, anti-IL-6 therapy with tocilizumab is 
associated with reduction in disease activity 9 and a substantial reduction in CRP, an 
important biomarker of inflammation and a risk factor for atherothrombotic events. 
However, use of tocilizumab is associated with an elevation in LDL10 and total 
cholesterol of unclear clinical significance.  We hypothesize that, despite these 
observed effects on lipids, the use of tocilizumab therapy in RA patients may be 
associated with a reduction in atherosclerotic plaque inflammation. 
 Positron Emission tomography with18fluorine-2-deoxy-D-glucose (FDG), has become 
the gold-standard tool for evaluation of cancer 11-13. FDG uptake reflects the rate of tissue 
glycolysis, which is higher in areas containing metabolically active tumor cells and in 
inflamed tissues. A large body of basic cellular physiology data demonstrate that 
activated macrophages have an unusually high metabolic rate 14,15especially after 
classical/innate activation16 hence avidly accumulate FDG 17. Moreover, our group 
showed in an animal model18, and was first to demonstrate in humans19, that FDG uptake 
(in atherosclerotic plaques) correlates with the density of macrophages (determined 
histologically), findings that have been confirmed by several other groups20-24. Taken 
together, these data provide a solid foundation for investigating the use of FDG PET 
imaging for evaluation of inflammation. 
 
Here we propose an open-label multi-center study that employs PET imaging of the 
carotid and coronary arteries and aorta to assess the effect of anti-IL-6 therapy on 
plaque inflammation in patients with rheumatoid arthritis.  Secondary, exploratory 
evaluation will also examine correlations between atherosclerotic plaque inflammation 
and the inflammatory activity of the rheumatoid joint measured by PET-MR imaging, 
as well as how the changes in inflammation as measured by PET-MR correlate with 
lipid and inflammatory biomarkers. Certain centers of the brain responsible for fear 
perception are hypothesized to be sensitive to IL-6. Accordingly, we plan to evaluate 
fear center activities in the brain before and after reaction to IL-6 antagonist 
tocilizumab.   
 
The Specific Aim of this Project:  
Test the hypothesis that anti-IL-6 therapy is effective for reducing plaque inflammation 
(measured as PET-determined plaque metabolism) in patients with rheumatoid arthritis 
who are synthetic dMARD and anti-TNF inadequate responders. A secondary aim is to 


 
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test the hypothesis that the reduction in arterial activity relates to reductions in synovial 
activity.   
 
2.0 
OBJECTIVES 
Test the hypothesis that anti-IL-6 therapy is effective for reducing plaque inflammation 
(measured as PET-determined plaque metabolism) in patients with rheumatoid arthritis.  
Secondary aims will test the hypothesis that the reduction in arterial activity relates to 
reductions in synovial activity and that it is independent of changes in LDL.  
 
2.1 
Primary 
 
The primary objective of this study is to test the hypothesis that tocilizumab reduces 
arterial inflammation in individuals with RA. The primary efficacy endpoint will be 
change from baseline in carotid FDG uptake at 12 weeks post initiation of therapy with 
tocilizumab.  
 
2.2 
Secondary 
 
Several additional objectives will be pursued, with the goal of providing an 
understanding of how tocilizumab leads to reduced arterial inflammation. 
 
1) We will test the hypothesis that changes in inflammation occur within atherosclerotic 
plaques per se. MRI imaging, as part of the PET-MR procedure, will be used to focus this 
analysis of treatment effect within arterial locations that have demonstrable plaque.  
 
2) We will test the hypothesis that reductions in arterial inflammation correlate with 
reductions in rheumatoid joint inflammation. 
 
3) We furthermore hypothesize that reductions in arterial FDG uptake will be unrelated to 
changes in LDL.  
 
4) We will also test the hypothesis that fear center (amygdala, and anterior cingulate cortex) 
activities, which reflects stress levels, will be reduced after randomization.  
 
3.0 
STUDY DESIGN 
 
 
3.1 
Description of the Study 
Here we propose an open-label multi-center study that employs PET/MR imaging of 
the carotid and coronary arteries and aorta to assess the effect of anti-IL-6 therapy on 
arterial inflammation in patients with rheumatoid arthritis who are synthetic dMARD 
and anti-TNF inadequate responder. Secondary, exploratory evaluation will also 
examine correlations between atherosclerotic plaque inflammation and the 
inflammatory activity of the rheumatoid joint measured by PET-MR imaging, as well 
as how the changes in inflammation correlate with lipid and inflammatory biomarkers, 
and how stress levels are associated with inflammatory activity.  
 
3.1.1    Study Schema 
 


 
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See Appendix A 
 
3.2 
Rationale for the Study Design and Dose 
Despite the availability and broad use of several therapies for the modification of risk 
factors, cardiovascular disease remains the major cause of death worldwide.  Additional 
modifiable mechanisms for the development of high-risk atheromatous plaques are 
needed.  The role of inflammation has been highlighted in the pathogenesis of 
atherosclerosis in which immune mechanisms interact with metabolic risk factors to 
initiate, propagate, and activate plaque lesions in the vascular tree 36,37 .  Inflammatory 
processes have thus become a target for the development of new therapies.   
 
Patients with rheumatoid arthritis (RA) suffer significantly increased cardiovascular (CV) 
morbidity and mortality when compared to the general population 1-3.  Women with RA have a 
2-3 fold higher risk of myocardial infarction, even in the absence of traditional coronary risk 
factors 4-6.  Several studies suggest that systemic inflammation accelerates atherogenesis in RA, 
perhaps by accentuation of both established as well as novel risk factor pathways 6-8.  
 
Anti-inflammatory therapy in RA is associated with a reduction cardiovascular mortality.  In 
patients with RA or psoriasis, methotrexate reduces CRP, IL-6, and TNF-, and at least 6 
observational studies have shown that methotrexate is associated with reduced CVD risk and 
mortality in these populations38-42. Data from a large registry study suggests that anti-
inflammatory therapies with TNF inhibitors may also be associated with significant reductions in 
fatal and nonfatal CVD outcomes 43. 
 
In human studies of rheumatoid arthritis, anti-IL-6 therapy with tocilizumab is 
associated with reduction in disease activity 9 and a substantial reduction in CRP, an 
important biomarker of inflammation and a risk factor for atherothrombotic events. 
However, use of tocilizumab is associated with an elevation in LDL10 and total 
cholesterol of unclear clinical significance.  We hypothesize that, despite adverse effects 
on lipids, the use of tocilizumab therapy in RA patients may be associated with a 
reduction in atherosclerotic plaque inflammation. 
 Positron Emission tomography with18fluorine-2-deoxy-D-glucose (FDG), has become 
the gold-standard tool for evaluation of cancer 11-13. FDG uptake reflects the rate of tissue 
glycolysis, which is higher in areas containing metabolically active tumor cells and in 
inflamed tissues. A large body of basic cellular physiology data demonstrate that activated 
macrophages have an unusually high metabolic rate 14,15especially after classical/innate 
activation16 hence avidly accumulate FDG 17. Moreover, our group showed in an animal 
model18, and was first to demonstrate in humans19, that FDG uptake (in atherosclerotic 
plaques) correlates with the density of macrophages (determined histologically), findings 
that have been confirmed by several other groups20-24. Taken together, these data provide 
a solid foundation for investigating the use of FDG PET/CT imaging for evaluation of 
inflammation.  
Imaging Atherosclerosis with FDG PET 
 
 Atherosclerosis disease activity can be defined as progression of atherosclerotic plaque 
and or development of atherothrombotic events.  In a multi-center trial employing both 
PET/CT and MRI imaging, published in the Lancet, we previously demonstrated that 
changes in the PET/CT signal predict the rate of plaque expansion eighteen months later27. 
In a separate study in humans (N=144), we observed that the initial PET signal predicts the 


 
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subsequent rate of atherosclerotic plaque progression, based on CT imaging44. Several 
studies have shown an association between the FDG signal and clinical risk factors or risk 
scores45-48 and soon after stroke 49and MI50.  Furthermore, higher arterial FDG uptake is 
predictive of an increased risk for subsequent stroke and MI51,52. Thus, there is substantial 
evidence to support the utility of FDG-PET/CT imaging to predict atherosclerotic disease 
progression and subsequent events. 
  
The use of FDG-PET/CT imaging for evaluating changes in inflammation after 
interventions in human studies is well established. The PI’s group has pioneered the use of 
PET/CT imaging for evaluating changes in atherosclerotic inflammation in response to 
treatment; the PI is/has been Study Chairman on over a half-dozen multi-center multi-
modality imaging trials evaluating response to therapy. We, and others have shown that 
statin therapy (a well-described anti-inflammatory treatment in atherosclerosis) results in 
a significant reduction in arterial FDG uptake after 3 months 53-55. Moreover, we have 
shown that while statins provide a dose-dependent reduction in arterial inflammation 
(measured with PET), this change is independent of changes in LDL concentrations 
55. Further, the PI has recently reported the results of multi-center PET/CT imaging trials 
that demonstrated anti-inflammatory efficacy of: p38 MAP kinase antagonism56, high vs. 
low dose atorvastatin30, and a novel innate-immune modulator lecinoxoid57. Others have 
observed modulation of the FDG-PET/CT signal after treatment with additional drug 
classes, including tumor necrosis factor antagonists and pioglitazone 60. Additionally, 
PET/CT imaging has also been shown to predict lack of efficacy. We reported lack of 
efficacy of dalcetrapib, a CETP antagonist, on reducing atherosclerotic plaque 
inflammation27. The dalOUTCOMES Trial, of approximately 16,000 individuals, recently 
reported lack of efficacy of dalcetrapib on cardiovascular mortality61, findings that were 
presaged by the FDG-PET/CT findings. Similarly, we reported lack of efficacy for GSK’s 
LPPLA2 antagonist 62. Subsequently, a trial of over 16000 subjects recently demonstrated 
lack of clinical efficacy of GSKs LPPLA2 antagonist in a similar population 63. Thus, for 
all four drug classes studied with FDG-PET for which CV outcomes trial data are 
also available27,60,64,66, the directional changes on FDG PET imaging were consistent 
with the changes in clinical events noted in the CV endpoint trials59,63,66,67. 
Accordingly, available data suggest that FDG PET imaging of arterial inflammatory 
activity may provide clinically relevant insights. 
 
FDG PET Imaging in RA 
Moreover, several groups have shown that arterial inflammation, measured using PET, is 
increased in RA58,68, We recently observed in patients with RA that arterial inflammation 
correlates with joint activity by FDG-PET, (R=0.65, P=0.004)68 . Others have shown that 
treatment of RA with anti-TNF therapy results in a reduction in arterial inflammation by 
PET 58.  
 
Here we propose an open-label multi-center study that employs PET imaging of the 
carotid and coronary arteries and aorta to assess the effect of anti-IL-6 therapy on plaque 
inflammation in patients with rheumatoid arthritis.  Secondary, exploratory evaluation 
will also examine correlations between atherosclerotic plaque inflammation and the 
inflammatory activity of the rheumatoid joint measured by PET-MR imaging, as well as 


 
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how the changes in inflammation as measured by PET-MR correlate with lipid and 
inflammatory biomarkers.   
 
Fear center activation & Inflammation 
We propose to have an optional fMRI imaging session, as part of the PET-MR session to 
measure activation of the brain’s fear centers before and after looking at a series of faces 
(called the overt faces test). It is well-established by epidemiological studies that stress 
begets atherosclerosis. More recently, elegant animal studies show that emotional stress 
causes monocyte release from the bone marrow, and that IL6 intensifies the perception of 
stress59. One such study (attached) shows that IL6 antagonism reduces stress behavior. 
This is in line with several studies showing that inflammation intensifies stress behavior. 
By using techniques that effectively induces fear during PET-MR imaging (overt face 
test), we seek to measure BOLD signal changes in the fear center as a physiological 
measurement of psychological stress, and we seek to test the hypothesis that tocilizumab 
reduces the mental stress response (a reduction in the fMRI signal in fear centers of the 
brain). 
 
 
 
 
 


 
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Fig 1 Arterial FDG uptake in an individual with RA 
 
 
Fig 2  Synovial FDG uptake in an individual with RA  
 
 
 


 
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Fig 3  Arterial Inflammation (FDG uptake) in RA  vs. Matched Controls 
 
Fig 4  Close Relationship between Arterial vs. Synovial FDG uptake 


 
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The Specific Aim of this Project:  
Test the hypothesis that anti-IL-6 therapy is effective for reducing plaque inflammation 
(measured as PET-determined plaque metabolism) in patients with rheumatoid arthritis 
who are synthetic dMARD and anti-TNF inadequate responders.  A secondary aim is to 
test the hypothesis that the reduction in arterial activity relates to reductions in synovial 
activity 
 
Protocol Overview: 
o 
21 subjects with rheumatoid arthritis who are synthetic dMARD inadequate 
and anti-TNF responders who desire initiation of therapy with tocilizumab 
(weekly SC administration) will be recruited. 
o 
Subjects will undergo preliminary clinical screening involving medical and 
medication history interview, physical examinations, vital sign and symptoms 
measurements, TB test, IMT test, and blood draws. 
o 
Subjects will undergo a secondary screening, using PET-MR imaging to 
identify the presence of atherosclerotic plaque inflammation, defined as a 
TBR > 1.7 (target-to-background ratio of the SUV). 
o 
Approximately 18-20 patients who pass a primary clinical screening will be 
treated in an open-label manner with tocilizumab. This will be done either in 
addition to MTX or as monotherapy. 
o 
Plaque inflammation will be assessed using PET plaque imaging of the 
carotids and thoracic aorta at week 12. 
o 
Baseline and 12 week PET-MR imaging of the patient’s dominant hand/wrist 
will also be completed in order to evaluate the response to treatment in the 
diseased joints as well as correlations between changes in joint and plaque 
inflammation as assessed by FDG PET.  
o 
Baseline MRI imaging of the arterial wall, as part of the PET-MR procedure, 
will be performed in order to identify structurally evident atherosclerotic 
plaques. The localization of atherosclerotic plaques allows for a plaque-
specific analysis of treatment effect. 
o 
Patients will have the option to participate in fMRI imaging during the PET 
MR imaging session to assess the blood oxygenated level dependent signal 
changes of psychological stress induced by overt faces test. 
 
In summary: 
Arterial PET imaging has been studied extensively in trials by the cardiology community, 
and is now being used in several studies by the rheumatology community. It is accepted 
that the arterial signal:1) reflects atherosclerotic inflammation, 2) predicts CV disease 
risk, and 3) changes in response to treatment predict therapeutic efficacy on the target.  
We hypothesize that Actemra will greatly reduce arterial inflammation in plaques, and 
will do so in proportion to the reduction in synovial activity (and in a manner that is 
unrelated to changes in LDL). 
 
Implications to the medical community: 
• That Actemra may be effective at reducing atherosclerotic pathology 
• This may translate in a reduction in CV risk 


 
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• Beneficial changes in the joints may be mirrored by beneficial changes in the 
arterial milieu. 
• That as patients experience a reduction in joint symptoms, they may also 
experience concordant improvements in atherosclerotic disease. 
• These beneficial changes may be seen despite the small changes in LDL (since 
the atherosclerotic disease in RA is driven by systemic inflammation…not the 
LDL) 
 
Possible next steps in this line of research: 
 
Develop a "Treat to New Targets” imaging study in RA to test the hypothesis that more 
aggressive treatment of RA (beyond current approaches) provides a greater benefit in 
terms of improvements in atherosclerotic plaque inflammation.   
 
3.3 
Outcome Measures 
PET/MR Imaging will be performed at entry (prior to randomization) and again at week 
12 (while still on study drug) using methods that have been previously reported by our 
group21,25-28, and following detailed image acquisition guidelines. In brief, FDG is 
administered intravenously (10mCi) after an over-night fast. Imaging is performed 2 
hours later using a PET-MR scanner with the patient in the supine position.  Imaging is 
performed across approximately 4-8 bed positions, covering the neck, chest, and upper 
abdomen and selected joints. MR attenuation correction is performed. Each of the 2 
imaging visits will be associated with 7mSv, with 14 mSv in total of radiation exposure, 
which is substantially less than the 50mSv annual limit accepted by IRBs. Women of 
childbearing potential will undergo a serum pregnancy test on day of imaging prior to 
image acquisition. 
Arterial PET Image Analysis: will be performed by an experienced observer, as 
previously reported. A dedicated multi-modality workstation is used for analysis by an 
experienced observer. Image analysis is performed after careful assessment of image 
quality. Using the attenuation MR image that was generated during PET-MR imaging, we 
will identify the vessels of interest (right and left carotid arteries as well as the ascending 
aorta). Thereafter, regions of interest (ROIs) are drawn around the vessel (in axial 
orientation) to provide a maximum standardized uptake values (SUV) for each region of 
interest. The SUV is the decay-corrected tissue concentration of FDG (in kBq/ml) 
divided by the injected dose per body weight (kBq/g).This is repeated along the length of 
the vessel (every ~3.5 mm along the long axis of the vessel) to provide a stack of ROIs 
that compose the whole vessel (Fig). Then, the background corrected maximum SUVs 
are averaged to provide a whole vessel target-to-background ratio (TBR).  
Arterial PET Endpoints: The primary PET/MR parameter used to evaluate vascular 
inflammation is the arterial TBR. Plaque-Based Analysis: MRI Imaging of the artery 
wall will be performed, and will allow the identification of atherosclerotic plaques within 
the wall of the aorta and carotid arteries. This method has been used previously by our 
group in the context of multi-center trials31.  


 
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Synovial PET/MR Imaging: will be performed as previously reported by our group32, 
and as adopted from prior studies 33-35. We will measure FDG uptake in the wrists in all 
subjects and will additionally measure activity in the glenohumeral, acromioclavicular, 
and acetabulofemoral joints. Prior studies have suggested that the FDG-PET signal 
derived from the shoulder joints of RA patients provides a sensitive tool to assess 
synovial inflammation.(31) After manual co-registration using anatomical landmarks 
(from the MR datasets), target joints will be identified and a ROI will be placed in axial 
section. Care will be taken to avoid spill-over activity from surrounding tissues. The 
maximum SUV for each joint will be recorded and the average of all SUVs was 
calculated as a measure of synovial activity in each individual. Synovial TBR will be 
calculated in a similar fashion to arterial TBR (as ratio to mean venous blood SUV). 
Psychological Stress Assessment: The Perceived Stress Scale survey, a 10-question 
survey will be administered during the imaging visits to measure overall perceived 
Psychological Stress level. During the PET-MR imaging session, subjects will have the 
option to perform the tasks as previously reported from prior studies using overt faces, 
which will induce elevated stress levels. A series of overt fearful faces will be shown to 
the subject. The BOLD signal changes in the brain tissues during these tasks in the MR 
scan will be calculated as a measure of stress activity.   
 
3.3.1 Primary Outcome Measures 
The primary outcome measures will be the change in arterial inflammation based on FDG 
PET - from initial imaging (just before Actemra Rx) to repeat imaging (at week 12).  
 
3.3.2 Secondary Outcome Measures 
Several secondary outcome measures will be assessed.   
 


 
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1) To test the hypothesis that changes in inflammation occur within atherosclerotic 
plaques per se, we will perform a secondary analysis limited to arterial locations that 
manifest arterial wall thickening on MRI (a plaque-based analysis). In this analysis, we 
will measure the change in carotid or aortic plaque FDG uptake at 12 weeks post 
randomization. MRI imaging will be used to focus this analysis of treatment effect within 
arterial locations that have demonstrable plaque.  
2) To test the hypothesis that reductions in arterial inflammation correlate with reductions 
in rheumatoid joint inflammation, we will additionally measure rheumatoid joint FDG 
uptake during the imaging visits. 
3) We furthermore hypothesize that reductions in arterial FDG uptake will be unrelated to 
changes in LDL. Accordingly, changes in LDL will be compared to changes in arterial 
inflammation over time.  
4) We hypothesize that BOLD signals at fear centers of the brain including the amygdala 
and the rostral anterior cingulate cortex (ACC) will be reduced after RA subjects are treated 
with ACTEMRA.  
 
3.3.3 Safety Outcome Measures 
Standard safety laboratory and clinical assessments will be performed 
 
3.4      End of Study  
Approx.13 weeks after initiation of Actemra in the last patient enrolled. 
 
4.0 
STUDY POPULATION 
 
4.0.1   Overview  
Subjects with rheumatoid arthritis who are inadequate responder to anti-TNF and 
dMARDS that are not currently on statins and who desire initiation of therapy with 
subcutaneous Actemra will be recruited from two major medical centers (Massachusetts 
General Hospital and Brigham and Women’s Hospital). Subjects recruited from Brigham 
and Women’s Hospital will complete imaging procedures at Massachusetts General 
Hospital, Charlestown Navy Yard. 
 
4.1  
Inclusion Criteria 
Patients must have Rheumatoid Arthritis. Patients will be included in the trial based on 
the following criteria: 
• 
Adults aged 40-75 
 
•  
Diagnosis of RA according to the revised 1987 American College of 
Rheumatology (ACR; formerly American Rheumatism Association), criteria. 
 
• 
Patients who have had an inadequate response to non-biologic disease-modifying 
anti-rheumatic drug (DMARD) and/or anti-TNF. 
 
• 
Presence of plaque inflammation, identified during secondary screening, defined 
as a target to baseline (TBR ratio) ≥ 1.7 in the carotid artery or ascending aorta. 
 


 
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• 
Not wheelchair or bedbound. 
 
• 
 At screening, active RA, defined as  ≥4 swollen joints (28 joint count) and ≥ 4 
tender joints  (28 joint count) and CDAI score ≥ 10.  
 
• 
If using other non-biologic DMARDS, (ex: methotrexate, sulfasalazine, 
hydroxychloroquine, azathioprine, cyclosporine, leflunomide), patient must 
demonstrate inadequate response, be on stable dose(s) for at least 4 weeks prior 
to baseline visit. For methotrexate: patients must be on stable does for at least 2 
weeks. 
 
• 
If taking corticosteroids (prednisone or equivalent), the following guidelines must 
be followed in order to be enrolled and remain on trial: 
 
  
- Dose must be relatively stable for at least 3 weeks before imaging . 
Relatively stable allows for adjustments of the dose of up to 2.5 mg, as long as 
the dose is not further adjusted during the last 1 week prior to imaging).  
 
  
-Dose should not exceed 10 mg daily of prednisone (or equivalent) the 3 
weeks prior to imaging. 
 
  
-During the first 3 weeks after baseline imaging: The steroid dose may be 
transiently increased (up to 20mg daily) as needed to control symptoms. 
However, the steroid dose must be tapered back to the pre-scan dose level (+/- 
2.5mg) by 3 weeks after initial imaging. 
 
  
-Beyond the first 3 weeks after baseline imaging: Additional changes 
(increases or decreases of +/- 2.5mg) are allowed (to achieve comfort) 
 
• 
Any investigational treatment not mentioned elsewhere must be discontinued for 
4 weeks or 5 half lives, whichever is longer, prior to the baseline visit.  
Exposure to any investigational biologics should be discussed with the Sponsor. 
 
• 
Signed informed consent (and informed assent of minor, if applicable). 
 
• 
*Note: a positive arterial PET scan is still required, thus the subjects will all still 
need to have confirmation of arterial inflammation before they are treated with 
study drug 
 
General Medical Concerns: 
• 
Men and women of reproductive potential must agree to use an acceptable 
method of birth control during treatment and for twelve months after completion 
of treatment. 
• 
Subject has provided written informed consent. 
 
4.2  
Exclusion Criteria 
 
A patient will be excluded if the answer to any of the following statements is “yes”. 
 
General: 


 
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1. 
Major surgery (including joint surgery) within 8 weeks prior to screening or 
planned major surgery within 6 months following randomization. 
 
Excluded Previous or Concomitant Therapy: 
 
1. 
Treatment with any investigational agent within 4 weeks (or 5 half-lives of the 
investigational drug, whichever is longer) of screening. 
2. 
Previous treatment with any cell-depleting therapies, including investigational 
agents or approved therapies, some examples include: CAMPATH, anti-CD4, 
anti-CD5, anti-CD3, anti-CD19 and anti-CD20. 
3. 
Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column 
within 6 months of baseline. 
4. 
Immunization with a live/attenuated vaccine within 4 weeks prior to baseline. 
5. 
Previous treatment with TCZ, Rituximab (within 1 year of Visit 1), Abatacept 
(within 3 months of Visit 1) 
6. 
Any previous treatment with alkylating agents such as chlorambucil, or with total 
lymphoid irradiation. 
 
Exclusions for General Safety: 
 
7. 
History of severe allergic or anaphylactic reactions to human, humanized or murine 
monoclonal antibodies. 
8. 
Evidence of serious uncontrolled concomitant cardiovascular, nervous system, 
pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine 
(include uncontrolled diabetes mellitus) or gastrointestinal disease (including 
complicated diverticulitis, ulcerative colitis, Crohn’s disease, or other 
symptomatic lower GI conditions that might predispose to perforations.) 
9. 
Diagnosis of liver disease or elevated hepatic enzymes, as defined by ALT, AST, or 
both  > 1.5 x the upper limit of age-determined normal (ULN) or total bilirubin 
> ULN. 
10. Serum creatinine > 1.6 mg/dL (141 µmol/L) in female patients and > 1.9 mg/dL 
(168 µmol/L) in male patients. Patients with serum creatinine values exceeding 
limits may be eligible for the study if their estimated glomerular filtration rates 
(GFR) are >30 
11. 
Any history of recent serious bacterial, viral, fungal, mycobacterial or other 
opportunistic infections. 
12. 
Have serologic evidence of current or past HIV, Hepatitis B, or Hepatitis C. 
13. 
Positive QuantiFERON TB, T-spot TB test, or PPD skin test, history of 
tuberculosis, or active TB infection without at least 4 weeks of adequate therapy 
for TB. 


 
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14. Active infection with EBV as defined by EBV viral load ≥ 10,000 copies per mL of 
whole blood. 
15. Active infection with CMV as defined by CMV viral load ≥ 10,000 copies per mL 
of whole blood. 
16. Any of the following hematologic abnormalities, confirmed by repeat tests: 
a. 
White blood count <3,000/μL or >14,000/μL;  
b. 
Lymphocyte count <500/μL; 
c. 
Platelet count <100,000 /μL; 
d. 
Hemoglobin <8.0 g/dL; or 
e. 
Neutrophil count <2,000 cells/μL. 
 
17. Any major episode of infection requiring hospitalization or treatment with IV 
antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior 
to screening. 
18. Primary or secondary immunodeficiency (history of or currently active) unless 
related to primary disease under investigation. 
19. Any medical or psychological condition that in the opinion of the principal 
investigator would interfere with safe completion of the trial. 
20. History of other malignancy within 5 years prior to screening, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, or Stage I uterine cancer. 
21. Pregnant women or nursing (breast feeding) mothers.  
22. Patients with reproductive potential not willing to use an effective method of 
contraception. 
23. History of alcohol, drug or chemical abuse within 1 year prior to screening. 
24. Neuropathies or other conditions that might interfere with pain evaluation unless 
related to primary disease under investigation. 
25. Rheumatic autoimmune disease other than RA, including SLE, MCTD, 
scleroderma, polymyositis, or significant systemic involvement secondary to 
RA (e.g., vasculitis, pulmonary fibrosis or Felty’s Syndrome). Secondary 
Sjogrens syndrome with RA is allowable. 
26. Prior history of, or current inflammatory joint disease other than RA (e.g., gout, 
Lyme disease, seronegative spondyloarthropathy including reactive arthritis, 
psoriatic arthritis, arthropathy of inflammatory bowel disease). 
27. Relatively significant radiation exposure over the course of the year prior to 
randomization. Significant exposure is defined as: 
      i)    More than 2 PCI within 12 months of randomization 
      ii)   More than 2 myocardial perfusion studies within the past 12 months 
      iii)  More than 2 CT angiograms within the past 12 months 
      iv)  Any subjects with history of radiation therapy. 
 
30. Prior history of diverticulitis 


 
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31. Contra-indications to PET-MR Imaging: 
     30a) Cardiac pacemaker that is not PET-MR compatible 
     30b) Surgical aneurysm clips 
     30c) Neurostimulator 
     30d) Implanted pumps 
     30e) Metal fragments in body / eyes 
     30f) Nitroglycerin patch that cannot be removed 
     30g) Colored contact lenses should not be worn in scanner 
     30h) Certain cochlear implants 
 
4.3 
Immunization during TCZ therapy 
 
Live/attenuated vaccines should not be given within 4 weeks prior to baseline and during 
the study as clinical safety has not been established. No data are available on the 
secondary transmission of infection from persons receiving live vaccines to patients 
receiving TCZ. Results from the VISARA vaccination study suggest TCZ- and MTX-
treated RA pts have comparable recall response to TTV, but response to 23VPPV is 
slightly reduced with TCZ. If possible, pneumococcal polysaccharide vaccination should 
be given before initiating TCZ to maximize response. These data are for two TCZ 
infusions and may only reflect initial effects of TCZ on the humoral immune response. 
The effects of long-term dosing are not addressed. Because IL-6 inhibition may interfere 
with the normal immune response to new antigen, patients should be brought up to date 
on all recommended vaccinations, except for live vaccines, prior to initiation of therapy 
with TCZ. The impact of SC dosing of TCZ on vaccination responses has not been 
evaluated. 
 
4.4     Criteria for Premature Withdrawal 
 
Patients have the right to withdraw from the study at any time for any reason. There 
should be an attempt to have all patients complete the withdrawal visits or follow-up 
phone calls as detailed in the Schedule of Assessments. 
If the patient decides to prematurely discontinue study treatment (“refuses treatment”), 
he/she should be asked if he/she can still be contacted for further information. The 
outcome of that discussion should be documented in both the medical records and in the 
CRF. A complete final evaluation at the time of the patient’s withdrawal should be made 
with an explanation of why the patient is withdrawing from the study. Before 
categorizing a patient as lost to follow-up, the investigator must attempt to contact the 
patient or a responsible relative by telephone followed by registered mail to determine if 
any new AEs occurred, follow-up of any ongoing AE and to establish as completely as 
possible the reason for the withdrawal. 
 
When applicable, patients should be informed of circumstances under which their 
participation may be terminated by the investigator without the patient’s consent. The 
investigator may withdraw patients from the study in the event of intercurrent illness, 


 
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adverse events, treatment failure, lack of compliance with the study and/or study 
procedures (e.g., dosing instructions, study visits), or any reason where it is felt by the 
investigator that it is in the best interest of the patient to be terminated from the study. 
The reason(s) for withdrawal must be documented and explained to the patient. 
If the reason for removal of a patient from the study is an adverse event, the specific 
event will be recorded on the CRF. There should be an attempt to follow the patient until 
the event has resolved or stabilized. 
 
An excessive rate of withdrawals can render the study non-interpretable; therefore, 
unnecessary withdrawal of patients should be avoided. Should a patient decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
 
5.0 
TREATMENT PLAN 
 
 
Open-label, pilot study 
Actemra will be given to approx. 20 subjects at a dose of 162 mg subcutaneously q week. 
Estimated rate of accrual rate: 3 individuals per month recruited from 2 large RA centers: 
Massachusetts General Hospital and Brigham and Women’s Hospital in Boston.  
Estimated date of study completion, including time of follow-up: Mar. 2015 
 
This research study protocol allows the subject to receive weekly SC administrations of 
Actemra for up to 12 weeks.  Even if the treatment is shown to be of benefit, additional 
SC administrations of Actemra beyond that allowed in the protocol cannot be given to the 
subject while she/he is participating in this study. Continued treatment decisions and 
safety follow up beyond Week 13 will be at the discretion of the patient’s treating 
rheumatologist. 
 
6.0 
STUDY MEDICATION  
 
6.1 
Tocilizumab 
 
Tocilizumab (ACTEMRA®) is a recombinant humanized anti-human interleukin 6 (IL-6) 
receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass 
with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 
214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and 
inter-molecularly by disulfide bonds. Tocilizumab has a molecular weight of 
approximately 148 kDa. 
 
Tocilizumab is supplied for SC injection at a concentration of 162 mg (0.9 ml) in a pre-
filled syringe. Tocilizumab is a colorless to pale yellow liquid, with a pH of about 6.5.  
 
Tocilizumab will be provided free of charge by Genentech. The Sponsor or designee of 
the study will ensure maintenance of complete and accurate records of the receipt, 
dispensation, and disposal or return of all study drug in accordance with 21 Code of 
Federal Regulations (C.F.R.), Part 312.57 and 312.62 and Genentech requirements.] 


 
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6.1.1 Tocilizumab Dosage and Administration 
 
Actemra will be self-administered by subjects after instruction by the nurse or physician: 
162 mg will be administered subcutaneously every week X12 weeks. 
 
Administration Guidelines for Adult Patient Population 
 
• Subjects will be instructed to inject the full amount in the syringe (0.9 mL), which 
provides 162 mg of ACTEMRA, according to the directions provided in the 
Instructions For Use (IFU).  
• Injection sites will be rotated with each injection.  
• Subjects will be instructed not to inject the ACTEMRA into moles, scars, or areas 
where the skin is tender, bruised, red, hard, or not intact.  
 
6.1.2 Tocilizumab Storage 
 
Do not use beyond expiration date on the container, package or prefilled syringe. 
ACTEMRA must be refrigerated at 2oC to 8oC (36°F to 46°F). Do not freeze. Protect the 
vials and syringes from light by storage in the original package until time of use, and 
keep syringes dry. Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration, whenever solution and container permit. 
If visibly opaque particles, discoloration or other foreign particles are observed, the 
solution should not be used. 
6.1.3 Tocilizumab Overdosage 
 
There are limited data available on overdoses with TCZ. One case of accidental overdose 
was reported in which a patient with multiple myeloma received a dose of 40 mg/kg. No 
adverse drug reactions were observed. No serious adverse drug reactions were observed 
in healthy volunteers who received single doses of up to 28 mg/kg, although all 5 patients 
at the highest dose of 28 mg/kg developed dose-limiting neutropenia. 
In case of an overdose, it is recommended that the patient be monitored for signs and 
symptoms of adverse reactions. Patients who develop adverse reactions should receive 
appropriate symptomatic treatment. 
 
6.2 
Other Study Drugs     
N/A 
 
7.0 
 DOSE MODIFICATION/TOXICITY MANAGEMENT 
 
A number of measures will be taken to ensure the safety of patients participating in this 
study.  These measures will be addressed through exclusion criteria (see Section 4.2) and 
routine monitoring as follows.   
 


 
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Patients enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and during their participation in this study.  Safety evaluations will consist of 
medical interviews, recording of adverse events, physical examinations, blood pressure, 
and laboratory measurements.  Subjects will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug interruption or 
discontinuation at each study visit for the duration of their participation in the study.   
  
7.1 
Tocilizumab 
Opportunistic Infections and Serious Infections  
Physicians should exercise caution when considering the use of TCZ in patients with a 
history of recurring infection or with underlying conditions (e.g., diverticulitis, diabetes), 
which may predispose patients to infections. Tocilizumab should not be administered in 
patients with active infection. The effects of TCZ on CRP, neutrophils, and the signs and 
symptoms of infection should be considered when evaluating a patient for a potential 
infection.  
Vigilance for timely detection of serious infection is recommended for patients receiving 
biologic agents for treatment of moderate to severe RA as signs and symptoms of acute 
inflammation may be lessened due to suppression of the acute phase reaction. Patients must 
be instructed to contact their physician immediately when any symptoms suggesting 
infection appear, in order to assure rapid evaluation and appropriate treatment.  
 
If a patient develops a serious infection, administration of TCZ is to be interrupted until 
the infection is controlled. The clinician should consider the benefit-risk before resuming 
treatment with TCZ. 
 Gastrointestinal Perforations   
Timely diagnosis and appropriate treatment may reduce the potential for complications of 
diverticulitis and thus reduce the risk of GI perforations. Therefore, patients should be 
made aware of the symptomatology potentially indicative of diverticular disease, and they 
should be instructed to alert their healthcare provider as soon as possible if these symptoms 
arise. In patients with a history of symptomatic diverticulosis, diverticulitis or chronic 
ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis or other chronic 
lower GI conditions that might predispose to perforations, the clinician should consider the 
benefit-risk before using TCZ.  Discontinuation of TCZ is recommended for patients who 
develop GI perforations. 
Demyelinating Disorders  
The impact of treatment with TCZ on demyelinating disorders is not known; events were 
rarely reported.  Patients should be closely monitored for signs and symptoms potentially 
indicative of central demyelinating disorders.  Physicians should exercise caution in 
considering the use of TCZ in patients with pre-existing or recent onset demyelinating 
disorders. Treatment with TCZ should be interrupted during assessment of a potential 
demyelination event and only resumed if the benefit of continuing study drug is favorable.   


 
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Hematologic Abnormalities and Bleeding Events 
Decreases in neutrophil and platelet counts have been observed following treatment with 
TCZ in combination with MTX. In addition, there may be an increased risk of neutropenia 
in patients who have previously been treated with a TNF antagonist. 
The risk mitigation strategies for neutropenia and thrombocytopenia are summarized in 
Tables 1 and 2, respectively.  For patients with concomitant medications associated with 
hematologic toxicity, the reduction or interruption of the suspected medication is 
recommended prior to modifying TCZ. 


 
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Table 1 : Neutropenia Risk Mitigation  
[Modify as appropriate for values related to specific indication] 
ANC (cells/mm3) 
Action 
> 1000 
Maintain dose. 
500 – 1000 
Interrupt tocilizumab dosing. 
When ANC increases to > 1000, resume tocilizumab as 
clinically appropriate and as described below: 
For patients receiving subcutaneous ACTEMRA, resume 
ACTEMRA at every other week and increase frequency to 
every week as clinically appropriate  
 
< 500 
Discontinue tocilizumab. 
ANC = absolute neutrophil count 
Patients withdrawn from tocilizumab treatment due to a reduced neutrophil count should 
be monitored for signs of infection, with treatment as deemed appropriate by the sponsor 
or designee, and should have a repeat white blood cell count with differential performed 
weekly until the ANC is above 1000 cells/mm3 (1.0 x 109/L). If the ANC does not return to 
above 1000 cells/mm3 (1.0 x 109/L) within 2 months (or sooner if deemed necessary by 
the sponsor or designee), a hematology referral is recommended. 
Table 2: Thrombocytopenia Risk Mitigation 
 
Platelet count 
(cells/mm3) 
Action 
> 100,000 
Maintain dose. 
50,000 – 100,000 
Interrupt tocilizumab dosing.  
When platelet count increases to > 100,000, resume 
tocilizumab as clinically appropriate 
 For patients receiving subcutaneous ACTEMRA, resume 
ACTEMRA at every other week and increase frequency to 
every week as clinically appropriate  
 
< 50,000 
Discontinue tocilizumab. 
Patients withdrawn from tocilizumab treatment due to a reduced platelet count should 
have a repeat platelet count performed weekly until the count is above 100,000 cells/mm3 
(100 x 109/L). If the platelets do not return to above 100,000 cells/mm3 (100 x 109/L) 
within 2 months (or sooner if deemed necessary by the sponsor or designee), a 
hematology referral is recommended. 
 
 
 


 
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Elevated Liver Enzymes and Hepatic Events 
 
Elevations in ALT and AST have been observed during treatment with the study 
medications. 
 
Table 3: 
 
Lab Value 
Action 
> 1 to 3x ULN 
Dose modify concomitant hepatotoxic medications  
 
For patients receiving subcutaneous ACTEMRA, reduce 
injection frequency to every other week or hold dosing until 
ALT or AST have normalized. Resume ACTEMRA at 
every other week and increase frequency to every week as 
clinically appropriate. 
 
 
> 3 to 5x ULN 
(confirmed by repeat 
testing) 
Interrupt tocilizumab dosing until < 3x ULN and follow 
recommendations above for >1 to 3x ULN 
 
For persistent increases > 3x ULN, discontinue tocilizumab 
> 5x ULN 
Discontinue tocilizumab 
Patients withdrawn from tocilizumab treatment due to elevated liver function tests should 
have repeat tests performed, as clinically appropriate, until levels return to baseline.  If 
the patient’s liver function tests have not returned to baseline within 6 months (or sooner, 
if deemed necessary by the sponsor or designee), an ultrasound and/or liver biopsy 
should be considered. 
Cardiovascular Events and Elevated Lipids 
Patients with RA have an increased risk for cardiovascular disorders, therefore, risk factors 
for cardiovascular disease (e.g., hypertension, hyperlipidemia) should be managed as part 
of their standard of care.  See section on Drug Interactions.   
For patients with LDL cholesterol ≥160 mg/dL, it is strongly recommended that 
investigators advise therapeutic lifestyle changes that may include initiation lipid-lowering 
agents. Lipid-lowering agents should also be considered for patients with lower LDL 
cholesterol levels as part of their therapeutic lifestyle changes depending on their overall 
risk as defined in NCEP ATP III or other national guidelines. 


 
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Malignancies 
The impact of immunosuppression on the development of malignancies is not known, 
however an increased rate of some malignancies, notably lymphoma, has been observed in 
RA patients. Although no imbalance of malignancies was observed in controlled clinical 
trials of TCZ, malignancies have been identified as a concern for other biologics.  It is 
recognized that identification of such events in TCZ-treated patients may require a longer 
period of surveillance.  TCZ should be discontinued in patients with malignancies (with 
the exception of local basal or squamous cell carcinoma of the skin that is completely 
excised with free margins). 
Hypersensitivity or Anaphylaxis: 
 
An infusion/injection reaction is defined as an adverse event occurring during and within 
24 hours after the infusion or subcutaneous injection of TCZ. This may include 
hypersensitivity reactions or anaphylactic reactions. 
Signs of a possible hypersensitivity reaction include but are not limited to: 
•  fever, chills, pruritus, urticaria, angioedema, and skin rash. 
• cardiopulmonary reactions, including chest pain, dyspnea, hypotension or  
hypertension. 
Healthcare professionals administering TCZ subcutaneous injections should be trained in 
the appropriate administrative procedures, be able to recognize the symptoms associated 
with potential anaphylactic or hypersensitivity reactions, and have the appropriate 
medication available for immediate use in case of anaphylaxis or hypersensitivity 
reaction during or after administration of TCZ.  Healthcare professionals should also 
instruct patients to seek medical attention if they experience symptoms of a 
hypersensitivity reaction outside of the clinic. 
If a patient has symptoms of anaphylaxis or hypersensitivity, or requires an interruption 
of the study drug because of symptoms of anaphylaxis or hypersensitivity, administration 
of TCZ must be discontinued permanently and the patient should be withdrawn from the 
study.  The patient should be treated according to the standard of care for management of 
the hypersensitivity reaction.  A blood sample for the presence of anti-TCZ antibodies 
should be obtained at time of event and at least 6 weeks or 8 weeks after the last SC dose, 
respectively. 
 
Viral Reactivation 
Though rarely reported within the TCZ program due to exclusion criteria at study entry, 
reactivation of viral and other serious infections (e.g. EBV or TB) has been observed with 
biologic therapies for RA, including TCZ. 
 
Drug Interaction 
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines 
(e.g., IL-6) during chronic inflammation. Therefore, it is expected that for molecules that 


 
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antagonize cytokine activity, such as TCZ, the formation of CYP450 enzymes could be 
normalized. When starting or stopping therapy with TCZ, patients taking medications 
which are individually dose-adjusted and metabolized via CYP450, 3A4, 1A2, or 2C9 
(e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, 
cyclosporin, or benzodiazepines) should be monitored as doses may need to be adjusted 
to maintain their therapeutic effect. Given its long elimination half-life (t1/2), the effect 
of TCZ on CYP450 enzyme activity may persist for several weeks after stopping 
therapy. 
7.2 
Other Study Drug(s)    
None given 
 
8.0 
CRITERIA FOR SUBJECT DISCONTINUATION 
8.1 
Tocilizumab-Specific Criteria 
Subjects who meet the following criteria should be discontinued from the study: 
• Anaphylaxis or hypersensitivity reaction or requires an interruption of the study 
drug because of symptoms of anaphylaxis or hypersensitivity (TCZ should be 
permanently discontinued from these patients) 
• ALT or AST value > 5X ULN or persistent elevation > 3X ULN 
• Platelet count (cells/mm3) < 50,000 
• ANC (cells/mm3) < 500 
8.2       General Criteria Inability of subject to comply with study requirements 
• Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
Subjects who are carriers of hepatitis B at the time of discontinuation from study treatment 
will continue to be followed for clinical and laboratory signs of active HBV infection and 
for signs of hepatitis. 
 
9.0 
CRITERIA FOR STUDY DISCONTINUATION       
For a given subject, criteria for study discontinuation: 
A) Any significant adverse events or loss of consent. 
B) Lab values that will trigger discontinuation are shown in Section 7.1 
 
 
 


 
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10.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
 
10.1 
Pre-Treatment Evaluations 
 
The following evaluations must be performed within four weeks prior to the date of each 
patient's initial treatment with TCZ: 
 
• Pregnancy test (serum) for women of childbearing potential on the day of imaging. 
 
• Medical history and documentation of the rationale for treatment of the patient's 
disease with TCZ. 
 
• Physical examination, including vital signs, blood pressure, performance status and 
tumor assessment. 
 
• Hematology (within 2 weeks of treatment): complete blood count (CBC) with 
differential and platelet count. 
 
• Serum Chemistries: glucose, BUN, creatinine, uric acid, total bilirubin, alkaline 
phosphatase, LDH, total protein, albumin, SGOT(AST), SGPT (ALT), and calcium. 
 
10.2 
Evaluations During Treatment 
 
• Neutrophils will be monitored at baseline, week 4 following initiation of therapy, 
then at the post study visit. 
• Platelets will be monitored at baseline, week 4 following initiation of therapy, 
then at the post study visit. 
• ALT and AST levels will be monitored at baseline, week 4 following initiation of 
therapy, then at the post study visit. 
• Assessment of lipid parameters will be assessed at the post study visit. 
 
 
Baseline samples for immunogenicity testing will be drawn and stored for all patients but 
analyzed only for those patients meeting the criteria below. 
 
Post-baseline, for patients who meet any of below criteria, immunogenicity samples will 
be additionally collected at the time of the event, and then again at least 6 weeks post-
hypersensitivity for IV and 8 weeks post-hypersensitivity for SC. 
 
Event: 
anaphylaxis 


 
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serious hypersensitivity 
study treatment (Actemra) discontinuation due to hypersensitivity (serious or non-
serious)                  
  
Immunogenicity assays: screening, confirmation and IgE 
 
All patients experiencing events related to serious hypersensitivity or 
anaphylactic reactions that cause the patient to be withdrawn from TCZ treatment dose 
for anti-TCZ testing. 
Reports of the results of these analyses will be provided to the investigator for patients 
testing positive for anti-TCZ antibodies.  
10.3 
Post-Treatment Evaluations      
Subjects will return at week 10-12 for post-treatment evaluation. Evaluation will included 
physical exam and history as well as laboratory assessments as shown in the 
schedule of events. 
 
Subjects of both sexes must practice adequate birth control for a minimum of twelve 
months post-treatment. 
 
11.0 
REPORTING OF ADVERSE EVENTS 
 
11.1 
Safety Reporting of Adverse Events 
 
Assessment of Safety 
 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) that are considered related to {study drug}, all events of 
death, and any study specific issue of concern. 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other protocol-
imposed intervention, regardless of attribution. 
 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
tocilizumab that were not present prior to the AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 


 
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Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
• It results in death (i.e., the AE actually causes or leads to death). 
• It is life threatening (i.e., the AE, in the view of the investigator, places the subject 
at immediate risk of death. It does not include an AE that, had it occurred in a 
more severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
• It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
 
Methods and Timing for Assessing AND Recording Safety variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study are collected and reported to the FDA, appropriate IRB(s), and 
Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports).  
 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is 
earlier. After this period, investigators should only report SAEs that are attributed to prior 
study treatment. 
 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the tocilizumab (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply 
the following general guideline: 
 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration 
of the tocilizumab and the AE cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 


 
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response to the tocilizumab; and/or the AE abates or resolves upon discontinuation of the 
tocilizumab or dose reduction and, if applicable, reappears upon re-challenge. 
 
No 
Evidence exists that the AE has an etiology other than the tocilizumab  (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to tocilizumab administration (e.g., 
cancer diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B. For 
example, under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. 
only referred to elevated hepatic enzymes or hepatitis. 
 
 
 
 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time-points should 
be adopted. Examples of non-directive questions include:  
• “How have you felt since your last clinical visit?” 
• “Have you had any new or changed health problems since you were last here?”  
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is ok to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
b. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 
11.2), regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal outcome 
should be reported as the single medical concept. If the cause of death is unknown and 
cannot be ascertained at the time of reporting, report “Unexplained Death”. 


 
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c. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only if 
the frequency, severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
d. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE. If a subject is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the procedure 
itself, should be reported as the SAE. For example, if a subject is hospitalized to undergo 
coronary bypass surgery, record the heart condition that necessitated the bypass as the 
SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
e. 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 90 
days after the last dose of study drug, a report should be completed and expeditiously 
submitted to the Genentech, Inc. Follow-up to obtain the outcome of the pregnancy 
should also occur. Abortion, whether accidental, therapeutic, or spontaneous, should 
always be classified as serious, and expeditiously reported as an SAE. Similarly, any 
congenital anomaly/birth defect in a child born to a female subject exposed to the {study 
drug} should be reported as an SAE. 
f. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior tocilizumab exposure. 
If the investigator should become aware of the development of cancer or a congenital 
anomaly in a subsequently conceived offspring of a female subject who participated in 
the study, this should be reported as an SAE.  
g. 
Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor 
will agree to the reconciliation periodicity and format, but agree at minimum to exchange 
monthly line listings of cases received by the other party. If discrepancies are identified, 
the Sponsor and Genentech will cooperate in resolving the discrepancies. The responsible 
individuals for each party shall handle the matter on a case-by-case basis until 
satisfactory resolution. 
h. AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a result of 
safety monitoring of the Product (see listing in section 11.3 below).  


 
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11.2 
Reporting of Serious Adverse Events Associated with Tocilizumab 
 
Immediate Reporting Requirements 
 
The Investigator must report the following events to Genentech Drug Safety within 24 
hours after learning of the event, regardless of relationship to study drug: 
• 
SAEs. 
• 
Non-serious and serious AEs of special interest. 
• 
Pregnancies. 
 
The Investigator must report new significant follow-up information for these events to 
Genentech Drug Safety within 24 hours after becoming aware of the information.  New 
significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis. 
• 
Significant new diagnostic test results. 
• 
Change in causality based on new information. 
• 
Change in the event’s outcome, including recovery. 
• 
Additional narrative information on the clinical course of the event. 
 
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/EC. 
SAE Reporting 
Investigators must report all SAEs to Genentech within the timelines described above. 
The completed MedWatch/case report should be faxed immediately upon completion to 
Genentech Drug Safety using the SAE fax cover sheet (Appendix C) at: 
 
(650) 225-4682 
OR 
(650) 225-5288 
 
• Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available. 
• Serious AE reports that are related to the tocilizumab and AEs of Special Interest 
(regardless of causality) will be transmitted to Genentech within 24 hours of the 
Awareness Date. 
• Serious AE reports that are unrelated to the tocilizumab will be transmitted to 
Genentech within 24 hours of the Awareness Date. 
• Additional Reporting Requirements to Genentech include the following: 
• Any reports of pregnancy following the start of administration with the 
tocilizumab will be transmitted to Genentech 24 hours of the Awareness Date.  


 
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• All Non-serious Adverse Events originating from the Study will be forwarded in 
quarterly reports to Genentech. 
 
Note: Investigators should also report events to their IRB as required. 
 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with 
the original MedWatch 3500A form  
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, 
if assigned, brief adverse event description, and notation that additional or follow-
up information is being submitted (The patient identifiers are important so that the 
new information is added to the correct initial report) 
Occasionally Genentech may contact the reporter for additional information, clarification, 
or current status of the patient for whom and adverse event was reported. For questions 
regarding SAE reporting, you may contact the Genentech Drug Safety representative 
noted above or the MSL assigned to the study. Relevant follow-up information should be 
submitted to Genentech Drug Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
 
Additional Reporting Requirements for IND Holders 
For Investigator-Sponsored IND Studies, some additional reporting requirements for the 
FDA apply in accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following 
guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the use 
of tocilizumab. An unexpected adverse event is one that is not already described in the 


 
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tocilizumab Investigator Brochure. Such reports are to be telephoned or faxed to the FDA 
and Genentech within 7 calendar days of first learning of the event. 
 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered reasonably 
or possibly related to the use of tocilizumab. An unexpected adverse event is one that is 
not already described in the tocilizumab investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32. All safety reports previously filed by the investigator 
with the IND concerning similar events should be analyzed and the significance of the 
new report in light of the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, Genentech, and all participating investigators within 15 calendar days of first 
learning of the event. The FDA prefers these reports on a MedWatch 3500 form, but 
alternative formats are acceptable (e.g., summary letter). 
Randomization Codes for blinded clinical trials 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also 
be faxed to Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-5288 
 
And to the Site IRB: 
Partners Human Research Committee 
Tel: 617-424-4100, Fax: 617-424-4199 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-5288 
 
IND Annual Reports 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. Copies of such reports should be faxed to Genentech Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-5288 
 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final 
study report). Additionally, any literature articles that are a result of the study should be 


 
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sent to Genentech. Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
 
E-mail: ACTEMRA IST Central Mailbox: actemra-gsur@gene.com 
 
11.3 
AEs of Special Interest (AESIs) 
Adverse events of special interest (non-serious and serious) are required to be reported by 
the Investigator to Genentech Drug Safety within 24 hours after learning of the event (see 
Section 11.2 for reporting instructions).  Non-serious and serious AEs of special interest 
for this study include the following: 
• 
Infections including all opportunistic infections and non-serious infections as 
defined by those treated with IV anti-infectives 
• 
Myocardial infarction/acute coronary syndrome. 
• 
GI perforation and related events. 
• 
Malignancies. 
• 
Hypersensitivity reactions. 
• 
Demyelinating disorders. 
• 
Stroke. 
• 
Bleeding events. 
• 
Hepatic events. 
 
12.0 
EVALUATION OF RESPONSE 
 
Arterial inflammation will be assessed at imaging visits  
 
13.0 STATISTICAL CONSIDERATIONS 
 
13.1   Determination of Sample Size     
Sample size calculation for primary endpoint: 
Assuming total of 21 enter and 18 patients complete study, the probability is 98 percent 
that the study will detect a treatment difference at a two-sided 0.05 significance level. 
This is based on the assumption that the within-patient standard deviation of the response 
variable is 0.244 and the minimal meaningful detectable difference is 0.25 (10%). To 
achieve a cohort of 18 completers, 21 individuals will need to be enrolled for imaging 
screening. 
Derivation of assumptions: 
1) A minimum meaningful expected change in TBR on therapy of 10% is based on the 
observation that high dose statins are associated with 18% reduction in TBR, (53,54), and 
anti-TNF therapy in RA is associated with a 17% reduction in arterial TBR, see Maki-
Petaja et al, Circulation 2012) (49).  The anticipated average baseline value of 2.5 is 


 
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based on the average of GLACIER (2.55) as well as Maki-Petaja et al (2.5). Hence a 10% 
reduction would be 0.25. 
3) The standard deviation of the difference between the two values for the same 
patient of 0.24 is based on two recently completed studies, on single center experience 
(Elkhawad et al, SD for change 0.188 in the placebo group) [66], and one multi-center 
trial (GLACIER Trial, SD for change in the placebo group 0.30). We have employed an 
average SD based on these two studies,. However, we believe that this is a conservative 
estimate of the SD for change since we think the SD for this study will closer to that 
observed in Elkhawad et al (a single-imaging center trial) than in GLACIER (a multi-
imaging center trial). 
4) A combined drop-out rate of 12% is anticipated. This drop-out rate is based on an 
anticipated 6% imaging screen failures plus 6% drop-out after randomization. The 
imaging screen failure rate is chosen conservatively, based on similar trials. Note, in this 
population with active joint disease, we anticipate a screen failure rate of less than 5%. 
The 6% drop-out rate after randomization is based on similar multi-center trial 
experiences such as GLACIER (5.4%.drop-out there) 
Sample size calculation for secondary endpoint analysis (correlation between changes in 
artery wall and changes in synovial activity).  The probability is 80 percent that the study 
will detect a relationship between the independent and the dependent variables at a two-
sided 0.05 significance level, if the true change in the dependent variables is 0.704 units 
per unit change in the independent variable. This is based on the assumption that the 
standard deviation of the two PET variables are similar (0.24).  
 


 
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13.2    Planned Efficacy Evaluations 
 
13.2.1 Primary Efficacy Variables 
Change in arterial inflammation in the carotids, measured as a target to background ration 
(TBR) of the standardized uptake values (SUVs) in the artery divided by the SUV in the 
blood (blood background) 
 
13.2.2 Secondary Efficacy Variables 
1) Change in carotid plaque FDG uptake (TBR) at 12 weeks post randomization. MRI 
imaging will be used to focus this analysis of treatment effect within arterial locations that 
have demonstrable plaque.  
 
2) Change in rheumatoid joint (dominant wrist first, mean shoulders, second) FDG uptake 
(TBR) 0-12 weeks post randomization. 
 
4) Correlations between change in atherosclerotic plaque FDG uptake (TBR) and change 
in rheumatoid joint FDG uptake 0-12 weeks post randomization. 
 
5) Correlations between change in atherosclerotic plaque FDG uptake (TBR) and change 
in LDL 0-12 weeks post randomization. 
 
5) Correlation between change in atherosclerotic plaque FDG uptake (TBR) and CRP 0-12 
weeks post randomization. 
 
6) Correlation between change in BOLD signals in the amygdala and anterior cingulate 
cortex with atherosclerotic plaque FDG uptake 
 
13.3   Methods of Analysis 
 
A paired T-test will be used to compare baseline and post-treatment measures of 
arterial inflammation. Similar approach will be used to assess change in mean joint 
inflammation. Correlation coefficients and scatter plots will be used to assess the 
magnitude of the association between arterial inflammation (TBR) and joint 
inflammation.  These results will be supported by adjusted linear regression analyses.  A 
similar analysis strategy will be applied to assess the correlations of the changes in TBR 
and the changes in joint inflammation from baseline to week 12.  The linear regression 
analyses will also adjust for baseline values 
 
14.0 
RETENTION OF RECORDS 
 
All documentation of adverse events, records of trial drug receipt and dispensation, and all IRB 
correspondence will be retained for at least 2 years after the investigation is completed. 
 
 


 
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Cardiology 2006:j.jacc.2006.03.069. 
54. Ishii H, Nishio M, Takahashi H, et al. Comparison of Atorvastatin 5 and 20 mg/d for Reducing F-
18 Fluorodeoxyglucose Uptake in Atherosclerotic Plaques on Positron Emission 
Tomography/Computed Tomography: A Randomized, Investigator-Blinded, Open-Label, 6-
Month Study in Japanese Adults Scheduled for Percutaneous Coronary Intervention. Clinical 
Therapeutics 2010;32:2337-47. 
55. Tawakol A, Fayad ZA, Mogg R, et al. High Dose Statin Results in a Further Reduction in 
Atherosclerotic Inflammation Compared with Low Dose Statin: Results of a Multi-Center PET-
CT Study. Circulation 2011;124:A18242. 
56. Elkhawad M, Rudd JH, Sarov-Blat L, et al. Effects of p38 Mitogen-Activated Protein Kinase 
Inhibition on Vascular and Systemic Inflammation in Patients With Atherosclerosis. JACC 
Cardiovasc Imaging 2012;5:911-22. 
57. Kimball AB, Cohen YC, Fayad ZA, et al. Safety and Efficacy of VB-201, a Novel Immune-
modulator, on Inflammation of Atherosclerotic Disease in Patients with Moderate to Severe 
Plaque Psoriasis: A phase 2  Randomized Placebo Controlled Trial American Academy of 
Dermatology Annual Meeting. San Diego, CA, 2012. 
58. Maki-Petaja KM, Elkhawad M, Cheriyan J, et al. Anti-tumor necrosis factor-alpha therapy 
reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation 
2012;126:2473-80. 


 
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59. Hodes, Georgia E. et al. Individual differences in the peripheral immune system promote 
resilience versus susceptibility to social stress. PNAS 2014; 111(45): 16136-16141. 
60. Mizoguchi M, Tahara N, Tahara A, et al. Pioglitazone Attenuates Atherosclerotic Plaque 
Inflammation in Patients With Impaired Glucose Tolerance or Diabetes A Prospective, 
Randomized, Comparator-Controlled Study Using Serial FDG PET/CT Imaging Study of Carotid 
Artery and Ascending Aorta. JACC Cardiovasc Imaging 2011;4:1110-8. 
61. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute 
coronary syndrome. N Engl J Med 2012;367:2089-99. 
62. Tawakol A, Singh P, Rudd JHF, et al. Effect of Treatment for 12 weeks with Rilapladib, a 
Lipoprotein-associated Phospholipase A2 Inhibitor, on Arterial Inflammation as Assessed with 
18F-Fluorodeoxyglucose-PET Imaging. Journal of the American College of Cardiology 2013:in 
press. 
63. GSK announces top-line results from pivotal Phase III study of darapladib in chronic coronary 
heart disease. 2013. (Accessed Nov 12, 2013, at http://www.gsk.com/media/press-
releases/2013/gsk-announces-top-line-results-from-pivotal-phase-iii-study-of-d.html.) 
64. Tawakol A, Fayad ZA, Mogg R, et al. Intensification of statin therapy results in a rapid reduction 
in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission 
tomography/computed tomography feasibility study. J Am Coll Cardiol 2013;62:909-17. 
.65. Tawakol A, Singh P, Rudd JH, et al. Effect of Treatment for 12 weeks with Rilapladib, a 
Lipoprotein-associated Phospholipase A2 Inhibitor, on Arterial Inflammation as Assessed with 
18F-Fluorodeoxyglucose-PET Imaging. Journal of the American College of Cardiology 2013. 
66. LaRosa JC, Grundy SM, Waters DD, et al. Intensive Lipid Lowering with Atorvastatin in Patients 
with Stable Coronary Disease. New England Journal of Medicine 2005;352:1425-35. 
67. Wilcox R, Kupfer S, Erdmann E. Effects of pioglitazone on major adverse cardiovascular events 
in high-risk patients with type 2 diabetes: Results from PROspective pioglitAzone Clinical Trial 
In macro Vascular Events (PROactive 10). American heart journal 2008;155:712-7. 
68. Emami H, Vijayakumar J, E V, et al. Arterial Inflammation in Rheumatoid Arthritis Correlates 
with Synovial Activity: A Human FDG-PET/CT Study. JACC Cardiovascular Imaging 2014 in 
press. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
45 
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APPENDIX A:  STUDY FLOW CHART/SCHEMA 
 
 
 
 
 
 


 
46 
Protocol Version 7.0
 
 
 
  
 
APPENDIX B: SCHEDULE of EVENTS 
  
 
 
 
EVENT 
-2 to -28 
days 
-1 to -14 
days 
0 
4 weeks 
12 ± 1 
week 
within 10 
days 
of 
imaging 
  
Screening 
Baseline 
Imaging 
Rx 
Initiatio
n 
Clinical 
Follow-
Up 
Final 
Imaging 
Post 
Study 
 F/U Visit 
  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
  
Inclusion/Exclusion Criteria 
x 
Informed Consent 
x 
 
 
 
 
 
Medical and Surgical History 
x 
 
x 
x 
 
x 
Weight, BMI, Blood Pressure 
x 
 
x 
x 
 
x 
Concomitant Medications 
x 
 
x 
x 
 
x 
Adverse Event 
 
 
x 
x 
 
x 
DAS-28 
x 
 
 
 
 
x 
CDAI 
x 
 
x 
x 
 
 
Subject VAS 
x 
 
x 
x 
 
x 
Physician Global 
x 
x 
x 
x 
Swollen & Tender Joint Count 
x 
x 
x 
x 
 
 
  
 
 
 
 
 
 
Creatinine 
x 
 
 
x 
 
 
BUN 
x 
x 
CBC (diff) 
x 
 
 
x 
 
x 
Glucose 
x 
 
 
 
 
 
Fasting Lipid Profile 
x 
 
 
 
 
x 
LFT 
x 
 
 
x 
 
x 
HIV 
x 
 
 
 
 
 
HEP B 
x 
 
 
 
 
 
HEP C 
x 
 
 
 
 
 
Uric Acid 
x 
 
 
 
 
 
Calcium 
x 
 
 
 
 
 
CRP 
x 
 
 
 
 
x 
ESR 
x 
 
 
 
 
x 
Inflammatory Biomarkers  
x 
 
 
 
 
x 
Pregnancy Test  
 
x 
 
x 
x 
 
  
  
 
 
 
 
 
 
Arterial FDG PET 
 
x 
 
 
x 
 
Arterial MRI 
 
x 
 
 
x 
 
Synovial FDG PET 
 
x 
 
 
x 
 
Carotid IMT 
x 
x 
  
 
 
 
 
 
 
  
TB Test (PPD, T-spot, or 
QuantiFERON) 
 
x 
 
 
 
 
 
Stress Scale 
 
x 
 
 
x 
 
Blood Tests 
EXAMINATIONS 
Imaging 
Other 
Tests 


 
47 
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APPENDIX C: GENENTECH SAFETY REPORTING FAX COVER SHEET 
 
SAFETY REPORTING FAX COVER SHEET 
Investigator Sponsored Trials 
 
SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-5288 
 
Study Number 
(Genentech study number) 
 
Principal Investigator 
 
Site Name 
 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
(DD/MON/YYYY) 
 
____ / _____ /_____ 
Follow-up Report Date 
(DD/MON/YYYY) 
 
____ / _____ /_____ 
 
 
Subject Initials 
(Please enter a dash if the patient 
has no middle name) 
____ - ____ -____ 
 
 
PLEASE PLACE MEDWATCH REPORT or IND SAFETY REPORT BEHIND THIS 
COVER SHEET 
 
 
Please contact Genentech Safety for any questions regarding SAE or IND Safety 
reporting at (888) 835-2555 
 
 
 
 
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