Clinical trial NCT03726749
Conditions: Giant Cell Arteritis
Keywords: GCA Tocilizumab Prednisone
Sponsor: Massachusetts General Hospital
Start date: 2018-11-28; Completion date: 2021-12-29
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label pilot study of tocilizumab (TCZ) 162 mg weekly administered subcutaneously for 52 weeks in combination with 8 weeks of oral prednisone.

Detailed description:
This is a single center, open label study that will assess the efficacy and safety of 52 weeks of tocilizumab (TCZ) in combination with 8-weeks of prednisone in 30 patients with active giant cell arteritis (GCA). Active disease is defined as signs and/or symptoms of GCA plus increased inflammatory markers (e.g., erythrosedimentation rate \[ESR\] and/or C-reactive protein \[CRP\]).

The study will enroll subjects with new onset and with relapsing/refractory GCA, and consist of a screening phase (up to 6 weeks), a treatment phase (52 weeks) and a safety follow up phase (4 weeks).

The primary endpoint of the study, sustained remission, will be assessed at week 52.

The definition of sustained remission contains 3 elements:

1. Absence of clinical signs and symptoms of active GCA along with the normalization of the ESR (\< 40 mm/hour) and CRP (\< 10 mg/L).
2. Completion of the pre-specified prednisone taper protocol
3. Absence of disease flare (relapse) since the induction of remission by week 8.

Disease flare is defined as the re-appearance of unequivocal signs or symptoms of active GCA (with or without elevation of ESR and/or CRP) or the elevation of the ESR and/or CRP that is thought to be due to active GCA and that requires escape therapy.

Arms: arm 1: 1. TCZ 162 mg administered by subcutaneous injection weekly for 52 weeks.
2. Prednisone taper over 8 weeks with a starting dose between 20 and 60 mg.
Interventions: intervention 1: Tocilizumab intervention 2: Prednisone
Intervention descriptions: intervention 1: Tocilizumab is an interleukin-6 (IL-6) receptor inhibitor intervention 2: Prednisone is an anti-inflammatory medication

Protocol documents:
Prot_SAP_002.pdf: 
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PARTNERS HUMAN RESEARCH COMMITTEE 
DETAILED PROTOCOL 
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 
Study title 
TOCILIZUMAB PLUS A SHORT PREDNISONE TAPER FOR GIANT CELL ARTERITIS 
Study Drug 
Tocilizumab (Roche / Genentech) 
Study Drug and Financial Support Provided By 
Roche / Genentech 
Sponsor Investigators 
Sebastian H. Unizony, MD 
John H. Stone, MD, MPH 
Co-investigators 
Zachary S. Wallace, MD 
Flavia V Castelino, MD 
Mark Matza, MD 
Imaging 
Ahmed Tawakol, MD 
Study Manager 
Ana Fernandes 
Protocol Number 
2018P001913 
ClinicalTrials.Gov Number 
NCT03726749 
 
 
Last IRB continuing review: 02/09/2022


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1. BACKGROUND AND SIGNIFICANCE 
Giant cell arteritis (GCA), the most common form of primary vasculitis [1], is associated with severe morbidity 
[2], reduced quality-of-life [3, 4], and major treatment-related toxicities [5]. The disease is three times more 
common in women than in men [2] and its prevalence ranges from 24 to 280 cases per 100,000 individuals. It is 
estimated that more than 3 million people will be diagnosed with GCA in Europe, North America, and Oceania 
by 2050 [1]. The clinical manifestation of GCA include constitutional symptoms, headaches, jaw pain, visual 
symptoms (e.g., amaurosis fugax), and myoarthralgias (i.e., polymyalgia rheumatica [PMR]). The most serious 
complication of the disease is blindness [2]. Other possible complications include aortic aneurysm, limb ischemia 
from large-artery stenosis, stroke, mesenteric ischemia, and myocardial infarction [2] and venous 
thromboembolism [6]. 
The etiology of GCA remains unknown and the understanding of its pathogenesis is incomplete. Therefore, no 
curative treatment for this condition currently exists. Until recently, prolonged glucocorticoid tapering courses 
(e.g., 12-18 months) were the only treatment option available for disease control, and many patients remained on 
glucocorticoids for years. Nevertheless, up to 85% of patients treated with one full year of prednisone experience 
disease relapse when this medication is tapered [3]. Relapsing GCA leads to further glucocorticoid treatment and 
heightened glucocorticoid toxicity. More than 85% of the patients develop glucocorticoid-related side-effects 
(e.g., osteoporotic fractures, diabetes, infection, cataracts, hypertension, psychosis, dyslipidemia, and 
gastrointestinal bleeding) [5]. Studies of several potential “steroid-sparing” agents have failed or demonstrated 
only modest efficacy at best [7-10]. In contrast, a recent Phase III randomized controlled trial led by our group 
known as the GiACTA trial [3], demonstrated that 12 months of tocilizumab (TCZ), a monoclonal antibody 
directed against the interleukin (IL)-6 receptor (IL-6R), combined with a 6-month prednisone taper, is superior to 
the decades-old standard of care of prolonged prednisone taper alone. 
In the GiACTA study [3], 251 patients were randomized in a 1:1:1:2 ratio to one of four groups: 
• Placebo plus 26-week prednisone taper (PBO+26, N = 50) 
• Placebo plus 52-week prednisone taper (PBO+52, N = 51) 
• TCZ 162 mg every other week plus 26-week prednisone taper (TCZ Q2W, N = 50) 
• TCZ 162 mg weekly plus 26-week prednisone taper (TCZ QW, N = 100). 
The results of the study demonstrated that the addition of IL-6 signaling blockade therapy to a shorter 
glucocorticoid taper is more effective at achieving and maintaining disease remission, sparing the use of 
glucocorticoids, and improving the health-related quality-of-life of patients than the prior standard of care of 
glucocorticoid monotherapy [3, 4]. Based on the results of GiACTA [3], the subcutaneous TCZ formulation (the 
drug planned for this study) has been approved in the United States and Europe for use in patients with GCA. 
Shorter prednisone tapers leading to reduced cumulative prednisone exposure are likely to result in fewer 
glucocorticoid-related adverse events. In this regard, prednisone tapers over 6 months (e.g., GiACTA trial [3]) 
represent an important step forward in the treatment of GCA. However, 6 months of prednisone are not exempted 
from causing significant toxicity. As an example, patients in the prednisone-only treatment groups in GiACTA 
were more likely to have serious adverse events compared to patients in the TCZ plus prednisone groups. Further, 
in the study of Hoffman et al [7], at least 1 serious adverse event occurred in 25% of patients 


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receiving prednisone only therapy for 6 months. In addition, 50% of the subjects in this group developed an 
infection requiring antibiotics [7]. In the study of Seror et al. [9], at least 1 serious adverse event was observed in 
up to 50% of patients allocated to ~ 6 months of prednisone plus placebo. Finally, in the study of Jover et al. [11], 
several adverse events developed in patients that received prednisone monotherapy for 29 weeks. Those included 
hypertension (60%), infection (40%), diabetes or glucose intolerance (25%), cataracts (20%), osteoporosis-related 
fragility fractures (20%), and neuropsychiatric symptoms (50%). 
In summary, the era of IL6R blockade ushered in by the GiACTA trial offers the opportunity to reduce even 
further the glucocorticoid exposure in GCA. We therefore propose an open-label pilot study of TCZ 162 mg 
weekly for 52 weeks in combination with only 8-week of prednisone. 
2. OBJECTIVES 
The primary objective of this study is to evaluate the efficacy and safety of TCZ in combination with an 8-week 
prednisone taper in patients with GCA. The primary outcome measure will be the proportion of patients in 
sustained remission at week 52 following induction of remission and adherence to the protocol-defined prednisone 
taper. 
Key trial definitions are shown below: 
Remission: Defined as the absence of signs and symptoms attributable to active GCA. 
Sustained remission: Absence of flare following induction of remission up to the 52-week time point. 
Flare: Determined by the investigator based on recurrent signs or symptoms of GCA and/or ESR ≥ 30 mm/hr or 
CRP (≥ 10 mg/L) attributable to GCA. I order to fulfill the definition of disease flare; the investigator must make 
the clinical decision to increase the patient’s prednisone dose or re-initiate prednisone treatment. 
3. SUBJECT SELECTION 
3.a. Inclusion Criteria 
3.a.1. Ability and willingness to provide written or electronic informed consent and to comply with the study protocol 
3.a.2. Diagnosis of GCA classified per the following criteria: 
• Age 50 years or older 
AND at least one of the following: 
• Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp tenderness, temporal artery 
tenderness or decreased pulsation, ischemia-related vision loss, or otherwise unexplained mouth or jaw 
pain upon mastication) 


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• Symptoms of polymyalgia rheumatica (PMR), defined as shoulder and / or hip girdle pain associated 
with inflammatory morning stiffness 
AND at least one of the following: 
• Cranial artery biopsy revealing features of GCA (e.g., mononuclear cell infiltration or granulomatous 
inflammation). 
• Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such as MRA, 
CTA, or PET-CT 
• Ultrasound demonstration of features of GCA in a cranial artery. 
3.a.3. New-onset or relapsing/refractory active disease defined as follows: 
• New onset: diagnosis of GCA within 6 weeks of baseline visit 
• Relapsing/refractory: diagnosis of GCA > 6 weeks before baseline visit 
AND 
• Active GCA within 6 weeks of baseline visit defined as the presence of clinical signs and symptoms 
[cranial or PMR] 
3.b. Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
3.b.1. General exclusion criteria 
• Major surgery within 8 weeks prior to screening or planned major surgery within 12 months after 
randomization 
• Transplanted organs (except corneal transplant performed more than 3 months prior to screening) 
• Major ischemic event, unrelated to GCA, within 12 weeks of screening 
3.b.2. Exclusions related to prior or concomitant therapy* 
• Treatment with any investigational agent within 12 weeks (or 5 half-lives of the investigational drug, 
whichever is longer) of screening 
• Previous treatment with cell-depleting therapies, including investigational agents, including but not 
limited to Campath (alemtuzumab), anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20 
• Previous treatment with alkylating agents, such as chlorambucil, or with total lymphoid irradiation 
• Immunization with a live/attenuated vaccine within ≤ 4 weeks prior to baseline 
• Treatment with cyclosporine A, azathioprine, cyclophosphamide or MMF within 4 weeks of baseline. 
Patients on methotrexate at screening will require discontinuation of this agent prior to baseline visit. 


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• Treatment with etanercept within 2 weeks; infliximab, certolizumab, golimumab, abatacept, or 
adalimumab within 8 weeks; or anakinra within 1 week of baseline 
• Patients requiring systemic glucocorticoid therapy for conditions other than GCA, which, in the opinion 
of the investigator, would interfere with adherence to the fixed glucocorticoid taper regimen and/or to 
assessment of efficacy in response to TCZ 
• Inability, in the opinion of the investigator, to withdraw GC treatment through protocol-defined taper 
regimen due to suspected or established adrenal insufficiency 
* Patients treated with TCZ before will be permitted to participate in the trial if they demonstrated treatment 
efficacy and they did not discontinue TCZ because of an adverse effect. 
3.b.3. Exclusions related to general safety 
• History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal 
antibodies or to prednisone 
• Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including 
obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), 
psychiatric, osteoporosis/osteomalacia, glaucoma, corneal ulcers/injuries, or gastrointestinal (GI) disease 
• Current liver disease, as determined by the investigator 
• History of diverticulitis or active chronic ulcerative lower GI disease such as Crohn's disease, ulcerative 
colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations 
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections 
(including but not limited to tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, and 
herpes zoster, but excluding fungal infections of the nail beds) 
• Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks 
of screening or oral antibiotics within 2 weeks of screening 
• Active TB requiring treatment within the previous 3 years. Patients treated for TB with no recurrence 
within 3 years are eligible 
• Untreated latent TB infection (LTBI). Patients should be screened for latent TB and, if positive, treated 
according to local practice guidelines prior to initiating TCZ treatment. Patients treated for LTBI within 3 
years are eligible. Patients with current LTBI are eligible for enrollment one month after initiating 
treatment for LTBI. 
• Primary or secondary immunodeficiency (history of or currently active) 
• Evidence of malignant disease or malignancies diagnosed within the previous 5 years (except basal and 
squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that have been excised and 
cured) 
• Females of childbearing potential and females who are breastfeeding 


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• Males of reproductive potential who are not willing to use an effective method of contraception, such as 
condom, sterilization, or true abstinence throughout study and for a minimum of 6 months after study drug 
therapy 
• History of alcohol, drug, or chemical abuse within 1 year prior to screening 
3.b.4. Laboratory exclusions (at screening) 
• ALT or AST > 1.5 × upper limit of normal (ULN) 
• Total bilirubin > ULN 
• Platelet count < 100× 109/L (100,000/mm3) 
• Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L) 
• White blood cells < 3.0 × 109/L (3000/mm3) 
• Absolute neutrophil count < 1.0 × 109/L (1000/mm3) 
• Absolute lymphocyte count < 0.5 × 109/L (500/mm3) 
3. b4. Imaging Exclusions (please see imaging protocol for more details) 
3.c. Source of Subjects and Recruitment Methods 
The source of patients will be the Massachusetts General Hospital Rheumatology clinic and the Massachusetts 
General Hospital Vasculitis and Glomerulonephritis Center, where staff physicians will be aware of this study 
protocol. Potential candidates will be initially approached at these two locations by their primary provider 
(subjects’ physician), who will review available treatment options, including this protocol. After this step, and if 
the subject is interested in participating in this study, either Drs. Unizony, Stone, Wallace, or Perugino will go 
over the informed consent process. 
4. SUBJECT ENROLLMENT 
Procedures for Obtaining Informed Consent 
• Drs. Unizony, Stone, Wallace, or Perugino will review the inform consent with the potential candidates. 
• Informed consent may be obtained in written form or through Electronic-Consent (e-Consent) in REDCap. REDCap 
implements consent forms through an online survey which can be accessed on a computer, mobile phone, or tablet. 
The e-Consent framework substitutes for a wet signature on a paper document. The e-Consent will include the 
consenting participants name (and date of birth in some cases) on the final consent form as extra documentation of 
their identity. The current e-Consent version and e-Consent type will be captured. The values for the fields below 
will be automatically inserted into the footer of the PDF consent form that the participant will review at the end of 
the survey, after which that PDF ‘hard-copy’ will be archived in the File Repository. Upon survey completion, a 
compact PDF copy of the survey response will be automatically stored in the project’s File Repository, from which 
the archived PDFs can be downloaded at any time.  


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• The diagnosis of GCA will be confirmed through appropriate evaluations that will include comprehensive 
history, complete physical examination, and review of the medical records for information pertaining to prior 
temporal artery biopsy, inflammatory markers, and the results of ultrasound and cross-sectional imaging 
studies (See Section 3. Inclusion Criteria). 
• Potential treatment options, including continued glucocorticoid monotherapy, conventional DMARDs (e.g., 
methotrexate), and TCZ in addition to prednisone tapers longer than 8 weeks, will be discussed. 


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• Adequate time will be permitted for patients to consider their potential treatment options and ask questions to 
Drs. Unizony, Stone, Wallace, or Perugino, and to discuss treatment options further with family members, 
primary care providers, or referring physicians. 
5. STUDY PROCEDURES 
5.a. Study Overview 
This is a single center, open label study that will assess the efficacy and safety of 52 weeks of TCZ plus an 8- 
week prednisone taper in 30 patients with active GCA. The study will enroll subjects with new onset GCA and 
subjects with relapsing/refractory GCA because the unmet need for lower prednisone exposure exists in both 
patient subpopulations. The study will consist of a screening phase (up to 6 weeks), a treatment phase (52 weeks) 
and a safety follow up phase (4 weeks). The primary efficacy assessment will take place at week 52.  The 
maximum duration of subject participation (including screening) is 62 weeks (See Table 1. Schedule of Events). 
5.b. Study Drugs 
5.b.1. Treatment Protocol 
All subjects will receive TCZ and prednisone 
• Tocilizumab: Prefilled syringes (PFS) containing 162 mg of TCZ (0.9 mL of a 180 mg/mL solution) will 
be administered by subcutaneous (SC) injection weekly by the patients or caregivers. Patients and 
caregivers will be trained on how to administer the medication by the study investigators or a designated 
study staff member during baseline and week 1 visits. TCZ interruptions or withdrawals will be as per the 
current U.S. product insert (See Attached Investigator’s Brochure). 
• Prednisone taper: Starting at baseline, all patients will receive concomitant prednisone therapy for 8 weeks 
per predefined taper regimens (See Table 2. Prednisone Taper Regimens). The initial dose of prednisone 
will be between 20 mg and 60 mg and will be chosen by the investigators according their best clinical 
judgment about a dose likely to control the patient’s GCA initially, with due consideration given to the 
patient’s disease severity and comorbidities. 
• Escape prednisone therapy: Patients who do not achieve remission by week 8 or patients that after 
achieving remission at any time experience a GCA disease flare before week 52, will be deemed failures 
for the primary endpoint. These patients will receive a second predefined taper regimen over 8 weeks (See 
Table 3. Prednisone Escape Therapy). The initial dose of the prednisone escape therapy will be between 
20 mg and 60 mg and will be chosen by the investigators following their best clinical judgment. The initial 
dose of the prednisone escape therapy may or may not be the same initial dose chosen at baseline. Patients 
requiring escape therapy will continue to receive TCZ up to week 52. 
During the screening phase, prednisone will be used at the discretion of the investigators with the intention of 
ensuring GCA control. 


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Any disease flare that occurs after a subject has received prednisone escape therapy will be treated per best clinical 
judgment. 
Short-term prednisone may be administered in addition to the protocol-defined prednisone taper regimen, if 
deemed necessary for the management of the patient when additional prednisone may be required to prevent or 
treat adrenal insufficiency or other problems unrelated to GCA (e.g., asthma exacerbation). This will be 
administered per the medical judgment of the investigator. 
Upon trial completion, patients will be treated per best clinical judgment. 
5.b.2. Concomitant Medications 
Anti-platelet therapy. Subjects will be treated with aspirin 81 mg daily at the discretion of the investigators. 
Glucocorticoid-induced osteopenia/osteoporosis prevention and treatment. All the subjects will receive oral 
calcium (1200-1500 mg daily), 25-hydroxy vitamin D supplementation (800-1000 IU daily) and bisphosphonate 
therapy (e.g., alendronate 70 mg weekly or zolendronate 5 mg annually) at the discretion of the investigators for 
the prevention and/or treatment of glucocorticoid-induced osteopenia/osteoporosis. 
5.c. Study Visits (See Table 1. Schedule of Events) 
• Screening visit (-42 to 0 days before baseline). Complete medical history, physical examination and 
selective laboratory investigations will be obtained for the purpose of confirming the diagnosis of active GCA, 
determining study eligibility, and assessing baseline values for the outcomes of interest. 
During this visit the following procedures will be completed: 
Written or electronic informed consent. 
Subject demography. 
Medical and surgical history. 
GCA history evaluation (date of disease diagnosis, date of temporal artery biopsy, date of vascular 
imaging, disease signs and symptoms, prior GCA treatments, etc). 
Inclusion/exclusion criteria. 
Concomitant medications. 
Assessment of signs and symptoms of GCA/PMR activity. 
Vital signs and physical exam. 
Screening laboratory tests including CBC, creatinine, BUN, AST, ALT, total bilirubin, alkaline 
phosphatase, ESR, CRP, urinalysis, HCV antibody, HBV surface antigen, and HBV anti core antibodies. 
o CBC, creatinine, BUN, AST, ALT, total bilirubin, alkaline phosphatase, ESR, CRP, urinalysis 
not required if completed within 10 days prior to screening. If abnormal, it will be repeated at 
screening visit) 
o HCV antibody, HBV surface antigen, and HBV anti core antibodies. Not required if completed 
within 30 days prior to screening 
Chest x-ray (Not required if completed within 30 days prior to screening. If abnormal, it will be repeated 
at screening visit) 


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12-lead electrocardiogram (ECG) 
- Not required if collected within 30 days prior to screening visit unless clinically indicated 
Urine or serum pregnancy testing will be completed for female patients who report their last menstrual 
period within 12 months of the screening visit. 
Evaluation for latent TB infection with quantiferon test, T spot test, or PPD test 
o (Not required if completed within 30 days prior to screening. If abnormal, it will be repeated at 
screening visit) 
Blood samples for mechanistic studies. 
Following the Screening period, eligible subjects will proceed with a 52-week treatment phase 
• Baseline through week 52 visits 
Subjects will start the treatment phase of the study only if all eligibility criteria are met. The treatment phase of 
the study will consist of a baseline visit, and subsequent visits at weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
48 and 52. 
TCZ will be administered in site by the investigators or designated trained personnel at baseline and week 1 visits. 
During baseline and week 1 visits, the patients and/or caregivers will be trained on how to administer the TCZ 
injections after week 1. In addition, patients will follow a pre-specified prednisone taper (See Table 2. Prednisone 
Taper Regimens). 
During Baseline through week 52 visit the following procedures/assessments will be completed: 
Vital signs and physical exam. 
Concomitant medications. 
Adverse events assessments. 
Assessment of signs and symptoms of GCA/PMR activity. 
Ability to adhere to the pre-specify prednisone taper. 
TCZ administration (baseline and week 1). 
Laboratories including CBC, creatinine, BUN, AST, ALT, total bilirubin, alkaline phosphatase, ESR, 
CRP, and lipid profile. 
Patient reported outcomes (PROs) (see below). 
Glucocorticoid toxicity index (GTI) [12]. 
Blood samples for mechanistic studies. 
Skull base to mid-thigh positron emission tomography/magnetic resonance (PET/MR) (±4-week time 
window is allowed at baseline visit and week 52). 
o pregnant or breastfeeding (a quantitative serum hCG pregnancy test is required before the subject 
can participate) 
◻ Bone density assessment by DXA (dual-energy x-ray absorptiometry) (±2-week time window is allowed at 
baseline visit and week 52). (Baseline and Week 52 only) 
o Bone density assessment is not required if already available within 30 days prior to 
screening visit. 


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The main efficacy and safety endpoints will be measured at 52 weeks (See Section 6.a. Study Endpoints) 
Phone Call Assessments 
Phone call assessments will be completed by the study investigator in case a subject cannot attend to a study 
visit due to unforeseen circumstances beyond the research team control (e.g., snow storm). During a phone call, 
the investigator will assess adverse events (AEs), concomitant medications, and symptoms of GCA disease 
activity (i.e., flare). In case of any concern (e.g., serious AE or GCA flare), recommendations on how to 
proceed will be given over the phone. In case there is suspicion for a serious AE or a GCA flare that require 
immediate attention, the patient will be instructed to seek that attention at the nearest hospital immediately. In 
case there is suspicion for an AE or a GCA flare that do not require immediate attention, the patient will be set 
up for an unscheduled study visit on a timely manner. 
Phone call assessments will be completed if all the following conditions are met: 
No more than 2 phone call assessments occur in each subject during the entire study period. 
No phone call assessments may replace two consecutive visits. 
No phone call assessment may replace baseline visit, week 1 visit, and week 52 visit. 
If a phone call assessment should replace a visit that require safety labs including CBC and blood chemistry 
(i.e., weeks 4, 8, 16, 24, 32, 40, and 48), those safety labs will be completed locally within the timeframe 
required in the protocol (see Table 1. Schedule of events) 
If a phone call assessment was to replace week 24, which requires patient reported outcome questionnaires, 
those questionnaires will be completed over the phone by the PI or the study coordinator within the timeframe 
required in the protocol (see Table 1. Schedule of events) 
• Safety follow-up visit 
The participants will undergo a safety follow up visit at week 56. 
During the safety follow up the following procedures will be completed: 
Vital signs and physical exam. 
Concomitant medications. 
Adverse events assessments. 
Assessment of signs and symptoms of GCA/PMR activity. 
Laboratories including CBC, creatinine, BUN, AST, ALT, total bilirubin, alkaline phosphatase, ESR, 
and CRP. 
 
 
5.d. Patient-Reported Outcomes 
PRO data will be elicited from the patients at several time points. The PRO instruments will be provided as paper-
based documents. They will be distributed by the investigator staff and completed by the patient. Patients will use 
visual analogue scale (VAS) to report the Patient Global Assessment of disease activity (PGA). Visually impaired 


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patients unable to complete the VAS will be asked to give the score verbally. Other PROs will include the 36-
Item Short Form Health Survey (SF-36), the Euro QOL-5D-5L (EQ-5D-5L) health 


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questionnaire, and the Function Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. The SF-36 is a 
multipurpose, short-form health survey with 36 questions. It yields 8-scale profile of functional health and well- 
being scores as well as psychometrically-based physical and mental health summary measures and a preference- 
based health utility index. The EQ-5D-5L health questionnaire is a generic, preference-based health utility 
measure with questions about mobility, self-care, usual activities, pain/discomfort, and anxiety/depression that 
are used to build a composite of the patient’s health status. The FACIT-Fatigue score is a 13-item fatigue 
questionnaire with patients requested to score each on a 5-point scale. 
5.e. Toxicity Grading Scale 
All adverse events will be recorded and classified according to the most recent version of the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Please also refer to Appendix 1. 
Mandatory Genentech Safety Language. 
Adverse events will be recorded and graded 1 to 5 according to the CTCAE grades provided below: 
Grade 1 = Mild adverse event 
Grade 2 = Moderate adverse event 
Grade 3 = Severe and undesirable adverse event 
Grade 4 = Life-threatening or disabling adverse event 
Grade 5 = Death 
Contingency Plan Related to the COVID-19 Pandemic. 
In view of the COVID-19 pandemic we have modified the schedule of assessments in order to minimize the 
exposure of patients and study personnel to COVID-19 (see Table 1. Schedule of events). The modifications 
proposed take in consideration the potential morbidity associated with GCA and the study treatment and will 
unlikely impact the safety of patients. 
 
Screening visit, baseline visit, week 24 visit and week 52 visit will require an in-person evaluation in the clinic 
for the subject to have a physical exam including vital signs. During baseline visit the patients and/or caregivers 
will be trained on how to administer the TCZ injections and will receive the first TCZ injection by the 
investigators or designated trained personnel. In order minimize the time of the subjects in the clinic, other 
procedures may be completed via telemedicine. These procedures may include inform consent, I/E criteria, 
demographics and medical history, GCA history evaluation, AE assessment, concomitant medications, and 
assessment of symptoms of GCA activity (i.e., flare). 
 
All other visits will be done primarily via telemedicine until the medical and non-medical personnel schedules 
in the MGH Rheumatology Division return to baseline. During the telemedicine visits the study investigator 
will assess AEs, concomitant medications, and symptoms of GCA disease activity (i.e., flare). In case of any 
concern (e.g., serious AE or GCA flare), recommendations on how to proceed will be given. In case there is 
suspicion for a serious AE or a GCA flare that require immediate attention, the patient will be instructed to seek 


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that attention at the nearest hospital immediately. In case there is suspicion for an AE or a GCA flare that do 
not require immediate attention, the patient will be set up for an unscheduled study visit in-person at MGH on a 
timely manner. 
 
Laboratories, CXR and EKG will continue to be done as per the original protocol regardless of whether the 
subject has an in-person or a telemedicine visit. The baseline and week 52 DEXA scans and PET/MRs will be 
done according to the availability and internal policies of the MGH bone density center (DEXA scan) and the 
Martinos Center (PET/MR).  
 
All the assessments completed by the study coordinators (e.g., PROs, drug accountability) will be done 
remotely. 
 
The study medication (TCZ) will be shipped to the patients. 
The study procedures will be done completely in the clinic as the as the MGH Rheumatology Division returns 
to normal operations and full capacity. 
6. BIOSTATISTICAL ANALYSIS 
Signs and symptoms of GCA activity, compliance with the prednisone taper, cumulative prednisone dosing, 
specific laboratory parameters (e.g., ESR, CRP) and the occurrence of adverse events will be assessed over time 
for the analysis of the efficacy and safety endpoints. 
6.a. Study Endpoints 
• Primary efficacy endpoint: 
1) Proportion of patients in sustained remission at 52 weeks. 
The definition of sustained remission contains 3 elements: 
- Absence of clinical signs or symptoms of active GCA and PMR along with the normalization of the ESR (< 
40 mm/hour) and CRP (< 10 mg/L). 
- Completion of the pre-specified prednisone taper protocol (See Table 2. Prednisone Taper Regimens). 
- Absence of disease flare (relapse) since the induction of remission by week 8. 


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Definition of flare: Re-appearance of unequivocal signs or symptoms of active GCA or PMR (with or without 
elevation of ESR and/or CRP) or the elevation of the ESR and/or CRP that is thought to be due to active GCA 
and that requires increase in the prednisone dose or re-initiation of prednisone treatment. 
• Secondary efficacy endpoints 
1) Proportion of patients in remission at 24 weeks. 
2) Time to GCA disease flare after remission. 
3) Number of disease flares at 24 and 52 weeks. 
4) Annualized flare rate. 
5) Cumulative prednisone dose at 52 weeks. 
6) Cumulative glucocorticoid toxicity index (GTI). 
7) HRQoL based on PROs including SF-36, PGA, FACIT-Fatigue, and EQ-5D-5L scores. 
• Safety endpoints 
1) The number, nature and severity of adverse events (AE) at 24 and 52 weeks. 
2) The number, nature and severity of serious AE (SAE) at 24 and 52 weeks. 
• Exploratory endpoints 
1) To assess the effects of TCZ in combination with an 8-week prednisone taper in the aorta and main aortic 
branches measured by PET/MR imaging at baseline and week 52. 
2) To complete mechanistic studies to gain insight into the pathogenesis of GCA and discover biomarkers of 
disease activity and risk of disease relapse. 
6.b. Statistical Methods 
Descriptive statistics and two-sided 95% confidence intervals will be calculated to assist the interpretation of 
efficacy and safety outcomes. Continuous data will be summarized using means, medians, standard deviations, 
ranges and interquartile ranges, where appropriate. Categorical data will be summarized as numbers and 
corresponding percentages. We expect missing data to be minimal because patients will be closely followed. 
However, in case that missingness is non-ignorable, we will use appropriate statistical methods (e.g., multiple 
imputation). 
6.b.1. Analysis of the Primary, Secondary and Safety Endpoints 
For the analysis of the primary endpoint, key secondary endpoints (e.g., cumulative prednisone dose, time to flare, 
and HRQoL), and safety endpoints, we will utilize as historical controls, the group of patients assigned to 


February 9, 2022 
16 
TCZ in the GiACTA trial. Of note, GiACTA [3] used eligibility criteria and definitions of disease remission and 
relapse (flare) equivalent to the proposed study. In GiACTA [3], the remission rates in patients receiving TCZ 
weekly and every other week were 56% and 53%, respectively, and the cumulative prednisone dose by week 52 
associated with these two arms was 1862 mg. 
The analysis of the proportion of patients experiencing at least 1 flare by week 52 (primary endpoint) will be done 
using multivariable logistic regression adjusted for relevant covariates. The cumulative prednisone dose by week 
52 will be compared with multivariable linear regression. Time to flare will be compared using multivariable-
adjusted Cox proportional hazards models. To compare HRQoL data we will use multivariable mixed effects 
models. The number of total adverse events and adverse events of grade 3 or higher will be compared with 
multivariable-adjusted Poisson regression. 
We will determine the relationships between the moving average of the GTI score and different HRQoL PROs 
using mixed effects regression where the PRO measure score is the outcome and the GTI score is the exposure. 
We will also assess for an association between the cumulative glucocorticoid dose and the PRO scores using 
mixed effects regression. 
6.b.2. Analysis of the Exploratory Endpoints 
Positron emission tomography/magnetic resonance 
The arterial uptake of 18fluorine-2-deoxy-D-glucose (FDG) will be determined via a skull base to mid-thigh 
PET/MR at baseline and week 52. The ascending aorta, aortic arch, descending aorta, abdominal aorta, carotid 
artery and subclavian artery territories will be assessed by maximum standardized uptake values (mSUV) 
measurement. For each territory, we will calculate average, most diseased segment (MDS) and most diseased 
slice (hottest spot) mSUVs. In addition, for each territory we will calculate target background ratios (TBR) using 
as background the vena cava (aortic measures) and the jugular veins (supra-aortic measures) (Figure 1). Changes 
in FDG between baseline and week 52 will be assessed using univariable (e.g., Wilcoxon signed rank test or 
paired Student’s t-test) and multivariable (e.g., multilevel models) methods as appropriate 
Mass spectrometry 
We will quantitatively map the plasma proteins of patients at baseline and either (1) during the first disease flare 
or (2) at week 52 for the patients who do not develop a disease relapse. We will use tandem mass tag (TMT) 
technology for multiplexed proteomics of the PLASMA samples [13, 14]. The measurements will be done on an 
Orbitrap Lumos mass spectrometer using the SPS-MS3 method. Samples will be fractionated off-line using  high 
pH reversed-phase (HPRP) chromatography, and twelve fractions will be analyzed on the mass spectrometer. 
Commonly about 1000 proteins can be quantified from one sample using this approach. A global comparison of 
the proteome changes will be done using hierarchical clustering and principal component 


February 9, 2022 
17 
analysis. The Student's t-test followed by multiple-hypothesis testing using the Benjamini-Hochberg procedure 
will be applied to identify plasma proteins with significant concentration differences between the status of active 
disease and disease remission. Similar methodology will be used to identify proteins with significant 
concentration differences at baseline between the group of patients with and without disease relapse by week 
52. Univariable comparisons will be followed by multivariable analyses to include confounders of interest. 
7. RISKS AND DISCOMFORTS 
Except for a shorter prednisone taper, which is experimental, all the procedures performed in this study are 
consistent with the standard of care for patients with GCA. 
7.a. Complications of Subcutaneous Medication Administration 
The injection of SC medications is associated with a mild degree of discomfort at the injection site for a short 
period. Small degrees of bleeding or bruising may occur at the injection site. Skin irritation (erythema) and rarely 
cellulitis can result at the site of injection. 
7.b. Risks Associated with TCZ Use 
• Infection. Patients treated with TCZ are at increased risk for developing serious infections that may lead to 
hospitalization or death, including tuberculosis (TB), bacterial, invasive fungal, viral, or other opportunistic 
infections. The overall safety profile of TCZ in GCA patients (defined in the GiACTA trial) was  comparable 
to the one observed in rheumatoid arthritis (RA) patients, except that there was an overall  higher incidence 
of infections in GCA patients relative to RA patients. The rate of infections was 200.2 per 100 patient-years 
in the TCZ QW group and 160.2 per 100 patient-years in the TCZ Q2W group, as compared to 156.0 per 100 
patient-years in the PBO+26 and 210.2 per 100 patient-years in the PBO+52 groups. The rate of serious 
infections was 9.7 per 100 patient-years in the TCZ QW group and 4.4 per 100 patient-years in the TCZ Q2W 
group, as compared to 4.2 per 100 patient-years in the PBO+26 and 12.5 per 100 patient-years in the PBO+52 
groups. 
• Hypersensitivity reactions. Hypersensitivity reactions, including anaphylaxis, have been reported in 
association with TCZ and anaphylactic events with a fatal outcome have been reported with intravenous 
(IV) infusion of TCZ. Anaphylaxis and other hypersensitivity reactions that required treatment 
discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of IV TCZ, 
0.2% (8 out of 4009) of patients in the IV all-exposure RA population, 0.7% (8 out of 1068) in the SC 6- 
month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the SC all-exposure population. In the 
systemic juvenile inflammatory arthritis (JIA) controlled trial with IV TCZ, 1 out of 112 patients (0.9%) 
experienced hypersensitivity reactions that required treatment discontinuation. In the polyarticular JIA 
controlled trial with IV TCZ, 0 out of 188 patients (0%) in the TCZ all-exposure population experienced 
hypersensitivity reactions that required treatment discontinuation. 


February 9, 2022 
18 
• Neutropenia. Decreases in neutrophil counts have been observed following treatment with TCZ. 
• Thrombocytopenia. Decreases in platelet counts have been observed following treatment with TCZ. 
• Elevated liver enzymes. Transaminase elevations have been observed following treatment with TCZ. These 
elevations did not result in apparent permanent or clinically evident hepatic injury in clinical trials. 
• Lipid abnormalities. Increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterols, 
and/or HDL cholesterol has been observed following treatment with TCZ. 
• Gastrointestinal (GI) perforations. Events of GI perforation have been reported in clinical trials, primarily 
as complications of diverticulitis in RA patients. No GI perforations were reported in GCA clinical trials. 
• Immunosuppression and potential risk of malignancy. Although no imbalance of malignancies was 
observed in controlled clinical trials of TCZ, malignancies have been identified as a concern for other 
immunosuppressive agents. 
• Demyelinating disorders. The impact of treatment with TCZ on demyelinating disorders is not known, but 
multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in clinical 
studies. 
• Live vaccines. Vaccination with live vaccines may lead to infection in patients under immunosuppressive 
therapy including TCZ. 
• Pregnancy. The limited available data with TCZ in pregnant women are not sufficient to determine whether 
there is a drug-associated risk for major birth defects and miscarriage. 
Additional information on TCZ safety can be found in the attached Investigator’s Brochure. 
7.c. Risks Associated with GCA Relapse 
Patients enrolled in this study may be at risk of disease relapse. Disease relapses are frequent in GCA patients. 
Patients treated with prednisone monotherapy relapse within 24-48 months in 60-85% of the cases depending  on 
the duration of prednisone use [3, 15]. Patients treated with TCZ and 6 months of prednisone relapse in 
approximately 20% of the cases within 1 year [3]. Of note, the incidence of permanent vision loss is 


February 9, 2022 
19 
significantly low in GCA patients that have received treatment [2] and no cases of permanent vision loss occurred 
in the GiACTA study [3]. 
7.d. Loss of Confidentiality 
Risks to subjects include loss of confidentiality resulting from access to electronic health record data. 
8. POTENTIAL BENEFITS 
8.a. Potential Benefits to Subjects 
The subjects may benefit from using less amounts of prednisone and therefore having less risk of prednisone 
related toxicity (e.g., hypertension, diabetes, osteoporosis, gastrointestinal bleeding, glaucoma, cataracts, other). 
8.b. Potential Benefits to Society 
TCZ plus a short course of prednisone may prove to be effective in controlling GCA activity. If this is the case, 
this protocol may increase the quality of life of the patients and reduce the costs of treating glucocorticoid- related 
morbidity. Positive results in this pilot study will support the conduction of a larger clinical study. 
9. MONITORING AND QUALITY ASSURANCE 
Drs. Unizony and Stone will monitor study data to ensure the safety of patients. 
9.a. Specific Elements Related to the Safety of Study Subjects that will be Examined Include: 
• Deaths. 
• Hospitalizations from any cause. 
• Infections. 
• Injection site reactions. 
• Other unexpected and serious adverse events. 
9.b. Criteria for Dropping a Subject from the Study 
• The occurrence of any malignancy. 
• The occurrence of major cardiovascular events (e.g., stroke, acute coronary syndrome). 
• The occurrence of a severe hypersensitivity reaction, (e.g., anaphylaxis, bronchospasm, angioedema). 
• The occurrence of a serious, systemic, opportunistic, chronic/recurrent or blood-borne infection. 
• Pregnancy. 
• The occurrence of any marked laboratory abnormality including hemoglobin < 8 gr/dL, platelets < 50/mm3, 
absolute neutrophil count < 0.5 X 109/L (500/mm3), absolute lymphocyte count < 0.5 X 109/L (500/mm3), 
serum creatinine > 2 mg/dL, ALT or AST elevation > 5 x ULN, and ALT or AST elevation > 3 x ULN and 
at least one of the following: total bilirubin > 2 x ULN, international normalized ratio (INR) > 1.5, liver 


February 9, 2022 
20 
alkaline phosphatase > 2 x ULN or presence of worsening fatigue, nausea, vomiting, fever, rash, or 
eosinophilia. 
9.c. Specific Elements of Efficacy that will be Examined Include: 
• Improvement of active GCA symptoms, as judged by medical history, physical examination, and laboratory 
tests (ESR, CRP). 
• Ability to follow the pre-specified prednisone taper. 
• Ability of maintain disease remission off prednisone. 
• Glucocorticoid-sparing effects by analyzing the cumulative prednisone dose and the incidence of 
glucocorticoid-related side effects. 
9.d. Adverse Event Reporting Guidelines: 
Adverse events and unanticipated problems involving risks to subjects or others will be reported to the Partners 
Human Research Committee (PHRC) in accordance with PHRC adverse event and unanticipated problems 
reporting guidelines. Adverse events and unanticipated problems involving risks to subjects or others will also be 
reported to Genentech following the guidelines described in Appendix 1. Mandatory Genentech Safety 
Language. Genentech as the Marketing Authorization Holder will be responsible for the reporting of  individual 
case safety reports from the study to the regulatory authority in compliance with applicable regulations. 
9.e. Management of Specific Adverse Events 
• Complications of subcutaneous medication administration. To minimize this risk, we have experienced 
nurses who are experts in the administration of subcutaneous medications commonly used in the rheumatology 
practice. 
• Opportunistic infections and serious infections. Investigators will exercise caution when considering the 
use of TCZ in patients with a history of recurring infections or with underlying conditions (e.g., diabetes 
mellitus), which may predispose patients to infections. Infection including LTBI will be ruled out during the 
screening process. During the study, TCZ will not be administered to patients with active infection. The effects 
of TCZ on CRP, neutrophils, and the signs and symptoms of infection will be considered when evaluating a 
patient for potential infection. Although rarely reported within the TCZ clinical trial programs in RA and 
GCA based on the exclusion criteria at study entry, reactivation of viral and other serious infections (e.g., TB) 
has been observed with biologic therapies for RA and GCA, including TCZ. Vigilance for timely detection of 
serious infection will be exercised for patients receiving TCZ as signs and symptoms of acute inflammation 
may be lessened due to suppression of the acute phase reaction. Patients will be instructed to contact the 
investigators immediately when any symptoms suggesting infection appear, to ensure rapid evaluation and 
appropriate treatment. If a patient develops a serious infection, TCZ will be interrupted until the infection is 
controlled. The investigator will consider the benefits and risks to the patient before resuming treatment. 


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21 
• Gastrointestinal perforations. Diverticulitis, or chronic ulcerative lower GI disease such as Crohn’s disease, 
ulcerative colitis, or other chronic lower GI conditions might predispose patients to perforations. Therefore, 
patients with these conditions will be excluded from this study. Timely diagnosis and appropriate treatment 
may reduce the potential for complications of diverticular disease and thus, reduce the risk of GI perforations. 
Thus, patients will be made aware of the symptomatology potentially indicative of diverticular disease and 
instructed to alert the investigators as soon as possible if these symptoms arise. If patients develop GI 
perforations, TCZ will be discontinued permanently. 
• Demyelinating disorders. Patients will be closely monitored for signs and symptoms potentially indicative 
of demyelinating disorders. Investigators will exercise caution when considering the use of TCZ in patients 
with preexisting or recent-onset demyelinating disorders. Treatment with TCZ will be interrupted during 
assessment of a potential demyelination event and be resumed only if the benefit/risk assessment of continuing 
study drug is favorable. 
• Hematologic abnormalities and bleeding events. Patients with absolute neutrophil counts (ANC) less than 
1,000 per mm3 will not be eligible. Patients with platelets less than 100,000 per mm3 will not be eligible. The 
risk mitigation strategies for neutropenia and thrombocytopenia are summarized in Table 4 and Table 5, 
respectively. 
• Elevated liver enzymes. TCZ will be discontinued if ALT or AST elevation > 5 x ULN, and ALT or AST 
elevation > 3 x ULN and at least one of the following: total bilirubin > 2 x ULN, international normalized 
ratio (INR) > 1.5, liver alkaline phosphatase > 2 x ULN or presence of worsening fatigue, nausea, vomiting, 
fever, rash, or eosinophilia. Patients active hepatic disease or hepatic impairment (including elevated 
transaminases ALT or AST >1.5x ULN) will not be enrolled in this trial. The risk mitigation strategies for 
patients with elevated hepatic enzymes are presented in Table 6. 
• Cardiovascular events and elevated lipids. Patients with GCA are at increased risk for cardiovascular 
disorders; therefore, risk factors for cardiovascular disease (e.g., hypertension, hyperlipidemia) will be 
managed as part of their standard of care. For patients with LDL cholesterol levels ≥ 160 mg/dL, it is strongly 
recommended that investigators advise therapeutic lifestyle changes that may include initiation of 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 (2002) or other national guidelines. 
• Malignancies. The impact of treatment with TCZ on the development of malignancies is not known, but 
malignancies were observed in clinical studies with TCZ. TCZ is an immunosuppressant, and treatment with 


February 9, 2022 
22 
immunosuppressants may result in an increased risk of malignancies. Patients with a history of malignancy 
(except for local basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that have 
been excised and cured) within 5 years of randomization will be excluded. TCZ administration will be 
discontinued for patients with malignancies. 
• Hypersensitivity and anaphylaxis after TCZ injection. A systemic injection reaction is defined as an 
adverse event occurring during and within 24 hours after the SC injection of TCZ. This may include 
hypersensitivity reactions or anaphylactic reactions. The patients enrolled in this trial will be advised to seek 
immediate medical attention if they experience any symptoms of a hypersensitivity reaction. Signs of a 
possible hypersensitivity reaction include, but are not limited to the following: Fever, chills, pruritus, urticaria, 
angioedema, and skin rash. If anaphylaxis or other hypersensitivity reaction occurs, TCZ administration will 
be stopped immediately and discontinued permanently. TCZ will not be administered to patients with known 
hypersensitivity to TCZ. Subjects with a history of hypersensitivity reactions to monoclonal antibodies will 
be excluded from the trial. 
• Vaccinations. The use of live vaccines will be prohibited during the study. 
• Risks in women of childbearing potential. TCZ is not recommended during pregnancy or in women of 
childbearing potential not using effective contraception. Women of childbearing potential will be advised to 
avoid becoming pregnant while receiving treatment with TCZ and will be required by the protocol to use two 
effective forms of contraception. 
• GCA relapses. Patients enrolled in this clinical trial will be followed closely and will have easy access to the 
investigators in case of disease relapse. In addition, patients will be instructed to start high doses of prednisone 
without delay and present emergently to the nearest hospital in case of worrisome visual symptoms including 
amaurosis, amaurosis fugax, episodic blurry vision or diplopia. 
• Risk of loss of confidentiality. Each subject will be assigned a unique study number that does not include 
identifiers. The study code will be kept under lock and key of the site Principal Investigator’s office. Strict 
confidentiality will be maintained when reviewing subjects’ medical records. In all cases, access to protected 
health information will be limited to the fewest number of research staff required to complete a given trial 
aim. The data for the study will be stored on an SQL server on a shared drive that is password- protected and 
accessible only to study collaborators. All collaborators are CITI-certified and HIPAA- compliant. All 
workstations at all three participating sites are password protected and have updated antivirus software. Data 
will be stored behind the Partners firewall on the Partners server, which will be backed up nightly by the 
Partners Information Systems department to guard against data loss or corruption 


February 9, 2022 
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Appendix 1. Mandatory Genentech Safety Language 
SAFETY LANGUAGE INCLUDED IN THIS DOCUMENT IS MANDATORY AND MUST BE 
INCLUDED IN PROTOCOL OR A SEPARATE SAFETY DATA EXCHANGE AGREEMENT (SDEA) 
SHOULD BE CREATED 
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) per protocol. This includes all events of death, and any study specific issue of concern. 
Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 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 giant cell arteritis (GCA) that were not present prior to the AE 
reporting period. 
• Complications that occur because 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. 
• 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. 


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• 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 AEs and SAEs as described in section j where the patient has been exposed to 
Genentech product must be reported Reporting period 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 (Modify statement depending up on section g). 
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 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). 


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Expected adverse events are those adverse events that are listed or characterized in the Package Insert (P.I) or 
current Investigator Brochure (I.B). 
Unexpected adverse events are those not listed in the P.I or current 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 acceptable 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 I), 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”. 
c. Preexisting Medical Conditions 


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26 
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. Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5 .0 Update current versions) will be used for 
assessing adverse event severity. Below Table should be used for assessing severity for adverse events that are 
not specifically listed in the NCI CTCAE. 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
Grade 
Severity 
1 
 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age appropriate 
instrumental activities of daily living a 
3 
 
Severe or medically significant, but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the most recent version of NCI CTCAE (v{X}.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a)  
Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b)  
Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden. 


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c)  
If an event is assessed as a "significant medical event," it must be reported as a serious adverse 
event 
d) 
Grade 4 and 5 events must be reported as serious adverse events 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
Note: Based on the most recent version of NCI CTCAE (v {5.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and 
undressing, feeding oneself, using the toilet, and taking medications, as 
performed by patients who are not bedridden. 
c. If an event is assessed as a "significant medical event," it must be reported as a 
serious adverse event 
d. Grade 4 and 5 events must be reported as serious adverse events 
f. Pregnancy 
If a female subject becomes pregnant while receiving the study drug or within 90 days after the last dose of 
study drug, or if the female partner of a male study subject becomes pregnant while the study subject is 
receiving the study drug or within 90 days after the last dose of study drug, a report should be completed and 
expeditiously submitted to 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. 
g. Post-Study Adverse Events 


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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 [add 
if applicable-including pregnancy occurring in the partner of a male study subject] who participated in the 
study, this should be reported as an SAE adequately to Genentech drug Safety during follow up period 
h. Case Transmission Verification of Single Case Reports 
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single case reports have 
been adequately received by Genentech via Dr Unizony’s staff emailing Genentech a Quarterly line-listing 
documenting single case reports sent by Dr Unizony’s staff to Genentech in the preceding time period. The 
periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed time period. 
Confirmation of receipt should be received within the time period mutually agreed upon. 
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. The Sponsor shall receive reconciliation guidance documents within the ‘Activation Package’. 
Following Case Transmission Verification, single case reports which have not been received by Genentech shall 
be forwarded by PI’s staff to Genentech within five (5) calendar days from request by Genentech. 
At the end of the study, a final cumulative Case Transmission Verification report will be sent to Genentech 
i. AEs of Special Interest (AESIs) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the product, for 
which ongoing monitoring and rapid communication by the Investigator to the Sponsor is required. Such an 
event might require further investigation to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial Sponsor to other parties (e.g., Regulatory Authorities) may also be 
warranted. 
• Cases of potential drug-induced liver injury that include an elevated ALT or AST in combination 
with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
• Treatment-emergent ALT or AST > 3 ´ ULN in combination with total bilirubin 
> 2 ´ ULN 
• 
 
Treatment-emergent ALT or AST > 3 ´ ULN in combination with clinical 
jaundice 
The Tocilizumab Events of Special Interest are: 
Adverse events of special interest for this study include the following: 


February 9, 2022 
29 
• Infection 
• Drug-induced liver injury 
• Neutropenia 
• Thrombocytopenia 
• Bowel perforation 
• Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. A transmission of an 
infectious agent may be suspected from clinical symptoms or laboratory findings that indicate an infection in a 
patient exposed to a medicinal product. This term applies only when a contamination of the study drug is 
suspected 
j. Exchange OF SINGLE CASE REPORTS 
The PI will track all protocol-defined AE and pregnancy reports originating from the Study for the Product 
Investigators must report all Adverse Events/ Serious Adverse events (SAEs), AEs of Special Interest (AESIs) 
pregnancy reports and special situation reports and product complaint (if applicable) adequately to Genentech 
within the timelines described below. The completed MedWatch or CIOMS I form or Genentech approved 
reporting forms should be faxed immediately upon completion to Genentech Drug Safety at: 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) and Product 
Complaints with an AE should be sent to: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
All Product Complaints without an AE should be sent to: 
Email: kaiseraugst.global_impcomplaint_management@roche.com 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it becomes available 
and/or upon request 
Serious adverse events (SAEs), pregnancy reports (including pregnancy occurring in the partner of a male study 
subject) AEs of special interest (AESIs) and Special Situation Reports, where the patient has been exposed to 
the Genentech Product, will be sent on a MedWatch form or CIOMS I form or on Genentech approved 
reporting forms to Genentech Drug Safety. Transmission of these reports (initial and follow-up) will be either 
electronically or by fax and within the timelines specified below: 
• SADRs 
Serious AE reports that are related to the Product shall be transmitted to Genentech within fifteen (15) calendar 
days of the awareness date. 
• Other SAEs 


February 9, 2022 
30 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within thirty (30) 
calendar days of the awareness date. 
• AESIs 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date. 
• Pregnancy reports 
While such reports are not serious AEs or Adverse drug Reactions (ADRs) per se, as defined herein, any reports 
of pregnancy (including pregnancy occurring in the partner of a male study subject), where the fetus may have 
been exposed to the Product, shall be transmitted to Genentech within thirty (30) calendar days of the awareness 
date. Pregnancies will be followed up until the outcome of the pregnancy is known, whenever possible, based 
upon due diligence taken to obtain the follow-up information. 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately inform the investigator if 
their partner becomes pregnant during the study or within 30 days after the last dose of study drug. A Clinical 
Trial Pregnancy Reporting Form should be completed and submitted to Genentech within thirty (30) calendar 
days of the awareness date. 
Special situation reports 
In addition to all SAEs, pregnancy reports and AESIs, the following Special Situations Reports should be 
collected even in the absence of an Adverse Event and transmitted to Genentech within thirty (30) calendar 
days: 
• Data related to the Product usage during pregnancy or breastfeeding 
• Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous administration, medication error 
(including potentially exposed in case of medication errors or intercepted medication errors) or occupational 
exposure, with or without association with an AE/SAE unless otherwise specified in the protocol 
• Lack of therapeutic efficacy 
• Drug interaction 
• Use of a Medicinal Product in a Pediatric and Elderly population (in addition, reasonable attempts should be 
made to obtain and submit the age or age group of the patient, in order to be able to identify potential safety 
signals specific to a particular population) 
Occasionally Genentech may contact the reporter for additional information, clarification, or status of the 
patient for whom an adverse event was reported 
Product Complaint Guidelines 
WHAT IS A PRODUCT COMPLAINT? 
A product complaint is any written or oral information received from a complainant that alleges deficiencies 
related to identity, quality, safety, strength, purity, reliability, durability, effectiveness or performance of a 
product after it has been released and distributed to the commercial market or clinical trial. 


February 9, 2022 
31 
HOW DO I FILE A COMPLAINT? 
For all Investigator Initiated Studies (interventional and non-interventional): Product Complaints with an AE 
(adverse event) should be reported via email/fax to: usds_aereporting-d@gene.com OR 650-238-6067 
Product Complaints without an AE (adverse event) should be reported via email to: 
For Interventional Investigator Initiated Studies: kaiseraugst.global_impcomplaint_management@roche.com 
For Non-Interventional Investigator Initiated Studies: us-acmo-d@gene.com 
All complaints must be filed within 1 business day for pre-approved products and 15 calendar days for 
approved products. Complaints can be reported using a Medwatch, CIOMS or any Genentech-approved 
reporting form (same as SAEs, AESI etc.). 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS ORIGINATING FROM PATIENT 
REPORTED OUTCOMES 
Although sites are not expected to review the PRO data, if physician/study personnel become aware of a 
potential adverse event during site review of the PRO questionnaire data, he/she will determine whether the 
criteria for an adverse event have been met and, if so, these must be reported using the Adverse Event and 
Special Situation Reporting Form or MedWatch form. 
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) 


February 9, 2022 
32 
• MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
Genentech as the Marketing Authorization Holder will be responsible for the reporting of individual case safety 
reports from the study to the regulatory authority in compliance with applicable regulations 
Genentech will be responsible for the expedited reporting of safety reports originating from the Study to the 
EMA through Eudravigilance Clinical Trial Module (EVCTM). 
Dr Unizony will be responsible for the distribution of safety information to its own investigators, where 
relevant. Dr Unizony will be responsible for the distribution of safety information to Site IRB: 
Partners Human Research Committee 
399 Revolution Drive 
Suite # 710 
Somerville MA, 02145 
857-282-1900 
For questions related to safety reporting, please contact Genentech/Roche Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
AGGREGATE REPORTS 
IND ANNUAL REPORT 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to Genentech 
Copies of such reports should be emailed to Genentech at: Genentech Drug Safety CTV mail box: 
ctvist_drugsafety@gene.com 
Other Reports 
Dr Unizony will forward a copy of the Final Study Report to Genentech/Roche upon completion of the Study. 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to Genentech/Roche. 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 sent to Genentech/Roche. Copies of such reports should be 
mailed to the assigned Clinical Operations contact for the study: 
actemra-gsur@gene.com 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
QUERIES 


February 9, 2022 
33 
Queries related to the Study will be answered by Dr Unizony However, responses to all safety queries from 
regulatory authorities or for publications will be discussed and coordinated between the Parties. The Parties 
agree that Genentech/Roche shall have the final say and control over safety queries relating to the Product. Dr 
Unizony agrees that it shall not answer such queries from regulatory authorities and other sources relating to the 
Product independently but shall redirect such queries to Genentech/Roche. 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests for 
information or review of data are met. The Parties will clearly indicate on the request the reason for urgency and 
the date by which a response is required. 
SAFETY CRISIS MANAGEMENT 
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), on the conduct of 
the Study, may lead to labeling changes or regulatory actions that limit or restrict the way in which the Product 
is used, or where there is media involvement, the Party where the crisis originates will contact the other Party as 
soon as possible. 
The Parties agree that Genentech/Roche shall have the final say and control over safety crisis management 
issues relating to the Product. Dr Unizony agrees that it shall not answer such queries from media and other 
sources relating to the Product but shall redirect such queries to Genentech/Roche. 


February 9, 2022 
34 
 
SAFETY REPORTING FAX COVER SHEET Genentech 
Supported Research 
AE / SAE FAX No: (650) 238-6067 
 
Genentech Study Number 
 
 
Principal Investigator 
 
 
Site Name 
 
 
Reporter name 
 
 
Reporter Telephone # 
 
 
Reporter Fax # 
 
 
Initial Report Date 
 
[DD] / [MON] / [YY] 
 
Follow-up Report Date 
 
[DD] / [MON] / [YY] 
Subject Initials 
Enter a dash if patient has no middle 
name) 
 
 
 
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 


February 9, 2022 
35 
10. REFERENCES 
1. 
De Smit E, Palmer AJ, Hewitt AW: Projected worldwide disease burden from giant cell arteritis by 2050. J Rheumatol 
2015, 42(1):119-125. 
2. 
Salvarani C, Cantini F, Hunder GG: Polymyalgia rheumatica and giant-cell arteritis. Lancet 2008, 
372(9634):234-245. 
3. 
Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech 
J et al: Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med 2017, 377(4):317-328. 
4. 
Strand V, Dimonaco S, Tuckwell K, Klearman M, Collinson N, Stone J: Health-Related Quality of Life in Patients 
with Giant Cell Arteritis Treated with Tocilizumab in a Randomized Controlled Phase 3 Trial [Abstract]. Arthritis 
Rheumatol 2017, 69 (suppl 10). 
5. 
Proven A, Gabriel SE, Orces C, O'Fallon WM, Hunder GG: Glucocorticoid therapy in giant cell arteritis: 
duration and adverse outcomes. Arthritis Rheum 2003, 49(5):703-708. 
6. 
Unizony S, Lu N, Tomasson G, Zhang Y, Merkel PA, Stone JH, Antonio Avina-Zubieta J, Choi HK: Temporal Trends 
of Venous Thromboembolism Risk Before and After Diagnosis of Giant Cell Arteritis. Arthritis Rheumatol 2017, 
69(1):176-184. 
7. 
Hoffman GS, Cid MC, Rendt-Zagar KE, Merkel PA, Weyand CM, Stone JH, Salvarani C, Xu W, Visvanathan S, 
Rahman MU et al: Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a 
randomized trial. Ann Intern Med 2007, 146(9):621-630. 
8. 
Mahr AD, Jover JA, Spiera RF, Hernandez-Garcia C, Fernandez-Gutierrez B, Lavalley MP, Merkel PA: Adjunctive 
methotrexate for treatment of giant cell arteritis: an individual patient data meta- analysis. Arthritis Rheum 2007, 
56(8):2789-2797. 
9. 
Seror R, Baron G, Hachulla E, Debandt M, Larroche C, Puechal X, Maurier F, de Wazieres B, Quemeneur T, Ravaud P et 
al: Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised 
controlled trial. Ann Rheum Dis 2014, 73(12):2074-2081. 
10. 
Langford CA, Cuthbertson D, Ytterberg SR, Khalidi N, Monach PA, Carette S, Seo P, Moreland LW, Weisman M, Koening 
CL et al: A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Giant Cell Arteritis. 
Arthritis Rheumatol 2017, 69(4):837-845. 
11. 
Jover JA, Hernandez-Garcia C, Morado IC, Vargas E, Banares A, Fernandez-Gutierrez B: Combined treatment of giant-
cell arteritis with methotrexate and prednisone. a randomized, double-blind, placebo-controlled trial. Ann Intern 
Med 2001, 134(2):106-114. 
12. 
Miloslavsky EM, Naden RP, Bijlsma JW, Brogan PA, Brown ES, Brunetta P, Buttgereit F, Choi HK, DiCaire JF, 
Gelfand JM et al: Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. Ann 
Rheum Dis 2017, 76(3):543-546. 
13. 
McAlister GC, Russell JD, Rumachik NG, Hebert AS, Syka JE, Geer LY, Westphall MS, Pagliarini DJ, Coon JJ: Analysis 
of the acidic proteome with negative electron-transfer dissociation mass spectrometry. Anal Chem 2012, 84(6):2875-
2882. 
14. 
Ting YS, Shaffer SA, Jones JW, Ng WV, Ernst RK, Goodlett DR: Automated lipid A structure assignment from 
hierarchical tandem mass spectrometry data. J Am Soc Mass Spectrom 2011, 22(5):856-866. 
15. 
Alba MA, Garcia-Martinez A, Prieto-Gonzalez S, Tavera-Bahillo I, Corbera-Bellalta M, Planas-Rigol E, Espigol-Frigole G, 
Butjosa M, Hernandez-Rodriguez J, Cid MC: Relapses in patients with giant cell 


February 9, 2022 
36 
arteritis: prevalence, characteristics, and associated clinical findings in a longitudinally followed cohort of 106 
patients. Medicine (Baltimore) 2014, 93(5):194-201. 


February 9, 2022 
37 
Table 1. Schedule of events 
 
 
 
 
 
 
 
EVALUATION 
STUDY VISIT (week +/- 7 days) 
 
S 
C 
 
B 
L 
 
1 
 
4 
 
8 
 
12 
 
16 
 
20 
 
24 
 
28 
 
32 
 
36 
 
40 
 
44 
 
48 
 
52 
56/ 
E 
W8, 
9 
flar 
e 
Informed 
Consent (remote) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria (remote) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and medical 
history 
(remote) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCA history 
evaluation1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Assessment 
(remote) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con. Meds (remote) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
Physical Exam2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Evaluation for 
LTBI3 
(remote) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TCZ 
Administration 
 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Signs/symptoms of 
GCA activity4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
*ESR (onsite) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*CRP (onsite) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Blood 
Chemistry5 
(onsite) 
X 
 
X 
X 
X  
X  
X  
X  
X  
X 
X 
X 
X 
*CBC 
(onsite) 
X 
 
X 
X 
X  
X  
X  
X  
X  
X 
X 
X 
X 


February 9, 2022 
38 
Fasting lipid 
profile6 
(onsite) 
 
X  
 
 
 
X  
X  
X  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EVALUATION 
STUDY VISIT (week +/- 7 days) 
 
S 
C 
 
B 
L 
 
1 
 
4 
 
8 
 
12 
 
16 
 
20 
 
24 
 
28 
 
32 
 
36 
 
40 
 
44 
 
48 
 
52 
56/ 
E 
W8, 
9 
flar 
e 
*HBsAg, anti- 
HBc Ab and anti-HCV 
Ab 
(onsite) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UA 
(onsite) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*CXR 
(onsite) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
(onsite) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Pregnancy test7 
(onsite) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum/plasma10 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
*EKG 
(onsite) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROs11 
(remote) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
GTI12 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Imaging13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


February 9, 2022 
39 
STAT 
quantitative serum hCG 
pregnancy 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 


February 9, 2022 
40 
1. Including date of diagnosis, date of temporal artery biopsy, date of prednisone initiation, and initial prednisone 
dose. 
2. Complete examination including assessments of the skin, head, eyes, throat, neck, lungs, heart, abdomen, lymph 
nodes, and musculoskeletal (MSK) system. 
3. Interferon gamma releasing assay (IGRA) such as quantiferon gold or T spot test. Alternatively, a PPD test can be 
performed. 
4. Temporal artery or scalp tenderness with palpation; unequivocal jaw claudication; visual changes such us transient 
diplopia, transient blurry vision, amaurosis fugax, or new/worsening decrease visual acuity; or unequivocal evidence 
of active PMR as manifested by shoulder and/or pelvic girdle pain and stiffness (e.g. morning stiffness). 
5. Creatinine, BUN, eGFR, AST, ALT, alkaline phosphatase, total bilirubin. 
6. Total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides. 
7. If last menstrual period within 12 months of screening visit. 
8. Week 56 visit will be a safety follow up visit. Treatment from this time point will be guided as per best clinical 
judgment. 
9. In case of early withdrawal, an early withdrawal visit will take place 4 weeks after the visit preceding the 
withdrawal. 


February 9, 2022 
41 
10. Plasma for mass spectrometry will be collected at screening and week 52 or during disease flare. DNA and serum 
will be obtained at several timepoints for mechanistic studies TBD. 
11. PROs including patient VAS, EQ-5D-5L, SF-36 and FACIT-fatigue score. 
12. Glucocorticoid toxicity index (GTI). 
13. Skull base to mid-thigh positron emission tomography/magnetic resonance (PET/MR) (±4-week time window is 
allowed at baseline visit and week 52). Bone density assessment by DXA (dual-energy x-ray absorptiometry) (±2- 
week time window is allowed at baseline visit and week 52). 
*Note: The following will not be required/collected at screening unless abnormal: 
• Clinical labs (if collected 10 days prior to screening: CBC, creatinine, BUN, AST, ALT, total bilirubin, 
alkaline phosphatase, ESR, CRP, urinalysis 
• Serology profile (30 days prior to screening): TB and hepatitis panel 
• CXR imaging: Not required if collected within 30 days prior to screening visit 
• EKG: Not required if collected within 30 days prior to screening visit unless cardiovascular risk is indicated. 
*Note: Phone call Assessments: If for unforeseen circumstances a subject cannot come to one or two non- 
consecutive study visit (excluding baseline, week 1 and week 52), the study investigator will contact the subject, to 
see if you are taking the study drug correctly and to collect information about his orher health and well-being. 
SC = screening; BL = baseline; EW = early withdrawal; I/E = inclusion/exclusion; AE = adverse events; Con. Meds 
= concomitant medications; LTBI = latent tuberculosis infection; ESR = erythrocyte sedimentation rate, CRP = C- 
reactive protein; CBC = complete blood count; HBsAg = hepatitis B surface antigen; anti-HBc Ab = anti hepatitis B 
core antibody; anti-HCV Ab = anti hepatitis C virus antibody; UA = urinalysis; CXR = chest x-ray; EKG = 
electrocardiogram; phys. = physician 


February 9, 2022 
42 
Table 2. Prednisone Taper Regimens 
Week 
Initial prednisone dose (mg)* 
1 
60 
50 
40 
30 
20 
2 
50 
40 
30 
20 
20 
3 
40 
30 
20 
15 
15 
4 
30 
20 
15 
15 
15 
5 
20 
15 
15 
10 
10 
6 
15 
10 
10 
10 
10 
7 
10 
5 
5 
5 
5 
8 
5 
2.5 
2.5 
2.5 
2.5 
cumulative dose (mg) 
1610 
1207.5 
962.5 
752.5 
682.5 
(*) Rational for allowing patients to enter the prednisone taper at different initial doses. New onset patients 
usually require doses of prednisone between 40 to 60 mg for induction of remission. In contrast, the prednisone 
dose required for induction of remission in patients with relapsed disease is variable. Relapses characterized by 
cranial symptoms (e.g., headaches, jaw claudication, visual manifestations) usually require higher prednisone 
doses (40 to 60 mg). In contrast, a relapse characterized by polymyalgia rheumatica (PMR) symptoms, typically 
responds to lower prednisone doses (e.g., 20 mg). In addition, other patient’s comorbidities (e.g., diabetes, 
hypertension, etc) may influence the prednisone dose selection as lower prednisone doses are associated with 
lower prednisone-induced toxicity. 
Table 3. Prednisone Escape Therapy 
Week 
Initial prednisone dose (mg)* 
1 
60 
50 
40 
30 
20 
2 
50 
40 
30 
20 
20 
3 
40 
30 
20 
15 
15 
4 
30 
20 
15 
15 
15 
5 
20 
15 
15 
10 
10 
6 
15 
10 
10 
10 
10 
7 
10 
5 
5 
5 
5 
8 
5 
2.5 
2.5 
2.5 
2.5 
cumulative dose (mg) 
1610 
1207.5 
962.5 
752.5 
682.5 


February 9, 2022 
43 
Table 4. Risk mitigation for neutropenia 
ANC= absolute neutrophil count; qw = every week; q2w = every 2 weeks; SC = subcutaneous; TCZ= 
tocilizumab; OL = open label 
Note: Patients withdrawn from the study because of a reduced ANC must be followed closely for signs of 
infection, with treatment as deemed appropriate by the investigator, and must have a repeat white blood cell count 
with differential count performed weekly until the ANC is > 1000 cells/mm³ (1.0 × 109/L). If the ANC does not 
return to > 1000 cells/mm³ within 2 months (or sooner if deemed necessary by the investigator), a hematology 
referral is recommended. 
Table 5. Risk Mitigation for Thrombocytopenia 
qw= every week; q2w= every 2 weeks; SC = subcutaneous; TCZ = tocilizumab; OL = open label 
Note: Patients withdrawn from the study because of a reduced platelet count must repeat platelet tests weekly 
until the count is above 100,000 /mm³ (100 ×109/L). If the platelets do not return to > 100,000 cells/mm³ (100 × 
109/L) within 2 months (or sooner if deemed necessary by the investigator), a hematology referral is 
recommended. 


February 9, 2022 
44 
Table 6. Hepatic Enzyme Elevation Risk Mitigation 
qw = every week; q2w= every 2 weeks; SC = subcutaneous; TCZ = tocilizumab; ULN = upper limit of normal, 
OL = open label. 
a The ULN or the patient’s baseline value, whichever is higher. 
Patients withdrawn from the study because of elevated liver function test results must have repeat tests performed 
as clinically indicated until levels return to baseline values. If the patient’s liver function test results have not 
returned to normal or to the patient’s baseline level within 6 months (or sooner if deemed necessary by the 
investigator), a specialist referral is recommended and an ultrasound and liver biopsy should be considered. 


February 9, 2022 
45 
Figure 1. Positron emission tomography/magnetic resonance (PET/MR) 18-FDG uptake determinations 
SVC 
 
 
Aorta 
 
Measured 
Arterial 
SUV 
 
Imaging Endpoints 
 
Whole 
Vessel 
MDS 
Hottest spot 
(most diseased slice) 
mSUV = 2.5 
MDS 
mSUV = 2.23 
SVC (background) mSUV = 0.70 
Whole Vessel 
mSUV = 1.77 
TBR = 2.53 
mSUV = maximum standardized uptake value, MDS = most diseased 
segment, TBR = target to background ratio, SVC = superior vena cava 
Coronal 
Axial 


February 9, 2022 
46 
SIGNATURE OF INVESTIGATOR 
I agree to conduct the study outlined above in accordance with the terms and conditions of the protocol, ICH 
guidelines on GCP and with applicable regulatory requirements. All information pertaining to the study shall be 
treated in a confidential manner. 
Dr. Sebastian Unizony, M.D 
Principal Investigator 
 
Date (day/month/year) 
Study title 
TOCILIZUMAB PLUS A SHORT PREDNISONE TAPER FOR GIANT CELL ARTERITIS 
Study Drug 
Tocilizumab (Roche / Genentech) 
Study Drug and Financial Support Provided By 
Roche / Genentech 
Version Date: January 21, 2020