Conditions: Giant Cell Arteritis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This study will evaluate the pharmacokinetics, pharmacodynamics, and safety of two dose levels of tocilizumab (TCZ) administered by intravenous (IV) infusion every 4 weeks (Q4W) to participants with giant cell arteritis (GCA).

Detailed description:

Arms:
arm 1: Participants will receive up to 6 doses of Dose 1 of TCZ IV Q4W followed by up to 6 doses of Dose 2 of TCZ IV Q4W.

Interventions: intervention 1: Tocilizumab
Intervention descriptions: intervention 1: TCZ will be administered by IV infusion at two dose levels Q4W. The maximum dose of TCZ that will be administered is 800 mg. The dose of TCZ infusion will be calculated on the basis of body weight measured prior to each infusion.

Protocol document:
Prot_000.pdf: 
 
Official Title: A Phase Ib, Open-Label, Dose-Ranging Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of Tocilizumab 
Administered by Intravenous Infusion to Patients With Giant Cell 
Arteritis 
NCT Number: NCT03923738 
Document Date: Protocol Version 4: 06-September-2019 
 
 
 


FINAL PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Tocilizumab—F. Hoffmann-La Roche Ltd
Protocol WP41152, Version 4
PROTOCOL
TITLE:
A PHASE Ib, OPEN-LABEL, DOSE-RANGING
STUDY TO EVALUATE THE PHARMACOKINETICS, 
PHARMACODYNAMICS, AND SAFETY OF 
TOCILIZUMAB ADMINISTERED BY INTRAVENOUS 
INFUSION TO PATIENTS WITH GIANT CELL 
ARTERITIS
PROTOCOL NUMBER:
WP41152
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-004718-17
IND NUMBER:
113,654
TEST PRODUCT:
Tocilizumab (RO4877533)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
12 December 2018
DATES AMENDED:
Version 2: 19 February 2019
Version 3:  11 April 2019
Version 4: See electronic date stamp below.
 
06-Sep-2019 16:16:06
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Tocilizumab—F. Hoffmann-La Roche Ltd
2/Protocol WP41152, Version 4
PROTOCOL AMENDMENT, VERSION 4
RATIONALE
Protocol WP41152 has been amended to modify the exclusion criterion for absolute 
neutrophil count (ANC).  Changes to the protocol, along with a rationale for each change, 
are summarized below:

Section 4.1.2 (Exclusion Criteria) has been revised to change the exclusion criterion 
for ANC from 2.0109/L (2000/mm3) to 1.5109/L (1500/mm3).
Historically, tocilizumab (TCZ) protocols recruiting TCZ-naive patients have used an 
exclusion criterion for neutrophils of 2.0109/L, and this value was used in the 
WP41152 study.  However, since Study WP41152 is recruiting patients already 
receiving TCZ and TCZ treatment is associated with a higher incidence of 
neutropenia, many patients being screened for this study are failing to meet the 
eligibility criteria because they have an ANC count below 2.0109/L.
ANC values in the 1.52.0109/L range are not considered clinically significant in 
TCZ-treated patients, and per the TCZ Swiss Prescribing Information risk mitigation 
guidelines, it is recommended that TCZ therapy is maintained unless ANC falls 
below 1.0109/L.
The protocol is therefore being amended to allow patients with an ANC 
of 1.5109/L to participate in the study.

In order to address the feedback from the Ethics Committee in Switzerland (where 
this study will be conducted), Section 4.5.7 (Laboratory, Biomarker, and Other 
Biological Samples) has been updated to provide details of the external laboratories 
used in Study WP41152, which will analyze and store samples until they are 
destroyed upon completion of the clinical study report.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Tocilizumab—F. Hoffmann-La Roche Ltd
3/Protocol WP41152, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 9
PROTOCOL SYNOPSIS .................................................................................... 10
1.
BACKGROUND .......................................................................................... 17
1.1
Background on Giant Cell Arteritis......................................... 17
1.2
Background on Tocilizumab .................................................. 18
1.2.1
Completed Clinical Studies in Patients with Giant 
Cell Arteritis ........................................................................... 19
1.2.1.1
Study ML25676:  Intravenous Tocilizumab............................ 19
1.2.1.2
Study WA28119:  Subcutaneous Tocilizumab....................... 19
1.2.2
Pharmacokinetics of Tocilizumab .......................................... 20
1.3
Study Rationale and BenefitRisk Assessment..................... 20
2.
OBJECTIVES AND ENDPOINTS ............................................................... 21
2.1
Pharmacokinetic Objectives .................................................. 21
2.2
Pharmacodynamic Objective................................................. 21
2.3
Safety Objective .................................................................... 22
2.4
Exploratory Objective............................................................. 22
3.
STUDY DESIGN......................................................................................... 22
3.1
Description of the Study......................................................... 22
3.2
End of Study and Length of Study......................................... 24
3.3
Rationale for Study Design.................................................... 24
3.3.1
Rationale for Selection of Tocilizumab Dose and 
Schedule................................................................................ 24
3.3.2
Rationale for Patient Population ............................................ 27
4.
MATERIALS AND METHODS .................................................................... 27
4.1
Patients.................................................................................. 27
4.1.1
Inclusion Criteria.................................................................... 27
4.1.2
Exclusion Criteria................................................................... 28
4.2
Method of Treatment Assignment.......................................... 30
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 30


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4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 30
4.3.1.1
Tocilizumab ........................................................................... 30
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 31
4.3.2.1
Tocilizumab ........................................................................... 31
4.3.3
Investigational Medicinal Product Accountability ................... 31
4.3.4
Continued Access to Tocilizumab.......................................... 32
4.4
Concomitant Therapy, Prohibited Therapy and 
Additional Restrictions ........................................................... 32
4.4.1
Permitted Therapy................................................................. 32
4.4.2
Cautionary Therapy ............................................................... 32
4.4.2.1
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes................................. 32
4.4.2.2
Herbal Therapies................................................................... 33
4.4.3
Prohibited Therapy ................................................................ 33
4.5
Study Assessments ............................................................... 33
4.5.1
Informed Consent Forms and Screening Log........................ 33
4.5.2
Description of Study Assessments ........................................ 34
4.5.3
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 34
4.5.4
Physical Examinations........................................................... 34
4.5.5
Vital Signs.............................................................................. 35
4.5.6
Disease-Specific Assessment ............................................... 35
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 35
4.5.8
Electrocardiograms................................................................ 37
4.5.9
Chest X-rays.......................................................................... 38
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 38
4.6.1
Study Treatment Discontinuation........................................... 38
4.6.2
Patient Discontinuation from Study........................................ 38
4.6.3
Study Discontinuation............................................................ 39
4.6.4
Site Discontinuation............................................................... 39


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5.
ASSESSMENT OF SAFETY....................................................................... 39
5.1
Safety Plan ............................................................................ 39
5.1.1
Risks Associated with Tocilizumab........................................ 40
5.1.1.1
Hypersensitivity Reactions, Including 
Anaphylaxis ........................................................................... 40
5.1.1.2
Serious Infections and Opportunistic Infections..................... 40
5.1.1.3
Gastrointestinal Perforations ................................................. 41
5.1.1.4
Hematologic Abnormalities.................................................... 41
5.1.1.5
Demyelinating Disorders........................................................ 42
5.1.1.6
Elevated Liver Enzymes ........................................................ 42
5.1.1.7
Elevated Lipids ...................................................................... 43
5.1.1.8
Malignancies.......................................................................... 43
5.1.1.9
Immunogenicity ..................................................................... 44
5.1.1.10
CYP450 Enzyme Normalization ............................................ 44
5.2
Safety Parameters and Definitions ........................................ 44
5.2.1
Adverse Events ..................................................................... 45
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 45
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 46
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 47
5.3.1
Adverse Event Reporting Period ........................................... 47
5.3.2
Eliciting Adverse Event Information....................................... 47
5.3.3
Assessment of Severity of Adverse Events ........................... 47
5.3.4
Assessment of Causality of Adverse Events ......................... 48
5.3.5
Procedures for Recording Adverse Events............................ 49
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 49
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 49
5.3.5.3
Persistent or Recurrent Adverse Events................................ 50
5.3.5.4
Abnormal Laboratory Values ................................................. 50
5.3.5.5
Abnormal Vital Sign Values ................................................... 51
5.3.5.6
Abnormal Liver Function Tests.............................................. 52


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5.3.5.7
Deaths ................................................................................... 52
5.3.5.8
Preexisting Medical Conditions.............................................. 52
5.3.5.9
Lack of Efficacy or Worsening of Giant Cell 
Arteritis .................................................................................. 53
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 53
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 54
5.4.1
Emergency Medical Contacts................................................ 54
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 55
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 55
5.4.2.2
Events That Occur after Study Drug Initiation........................ 55
5.4.3
Reporting Requirements for Pregnancies.............................. 55
5.4.3.1
Pregnancies in Female Patients............................................ 55
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 56
5.4.3.3
Abortions ............................................................................... 56
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 56
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 56
5.5
Follow-Up of Patients after Adverse Events .......................... 58
5.5.1
Investigator Follow-Up........................................................... 58
5.5.2
Sponsor Follow-Up ................................................................ 58
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 58
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 58
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 59
6.1
Determination of Sample Size ............................................... 59
6.2
Summaries of Conduct of Study............................................ 60
6.3
Summaries oF Baseline Characteristics................................ 60
6.4
Pharmacokinetic Analyses..................................................... 60
6.5
Pharmacodynamic Analyses ................................................. 60
6.6
Safety Analyses..................................................................... 61
6.7
Exploratory Efficacy Analyses ............................................... 61


Tocilizumab—F. Hoffmann-La Roche Ltd
7/Protocol WP41152, Version 4
7.
DATA COLLECTION AND MANAGEMENT ............................................... 61
7.1
Data Quality Assurance......................................................... 61
7.2
Electronic Case Report Forms............................................... 62
7.3
Source Data Documentation.................................................. 62
7.4
Use of Computerized Systems .............................................. 62
7.5
Retention of Records............................................................. 63
8.
ETHICAL CONSIDERATIONS.................................................................... 63
8.1
Compliance with Laws and Regulations ................................ 63
8.2
Informed Consent.................................................................. 63
8.3
Institutional Review Board or Ethics Committee.................... 64
8.4
Confidentiality........................................................................ 65
8.5
Financial Disclosure .............................................................. 65
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 65
9.1
Study Documentation ............................................................ 65
9.2
Protocol Deviations................................................................ 66
9.3
Site Inspections ..................................................................... 66
9.4
Administrative Structure......................................................... 66
9.5
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 66
9.6
Protocol Amendments ........................................................... 67
10. REFERENCES ........................................................................................... 68
LIST OF TABLES
Table 1
Median (Range) Population PK ModelEstimated TCZ 
Exposures in GCA versus RA by SC and IV Regimens.............. 26
Table 2
Risk Mitigation for Neutropenia................................................... 41
Table 3 
Risk Mitigation for Thrombocytopenia......................................... 42
Table 4 
Risk Mitigation for Liver Enzyme Abnormalities .......................... 43
Table 5
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 48
Table 6
Causal Attribution Guidance ....................................................... 49


Tocilizumab—F. Hoffmann-La Roche Ltd
8/Protocol WP41152, Version 4
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 23
Figure 2
Observed Serum TCZ Concentration Profile of the 8 mg/kg 
IV Q4W (ML25676), 162 mg SC QW, and 162 mg SC Q2W 
Doses  (WA28119) in Patients with GCA.................................... 25
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 70
Appendix 2
Schedule of Pharmacokinetic, IL-6, and sIL-6R Samples........... 74
Appendix 3
Tuberculosis Screening and Treatment Assessments................ 75


Tocilizumab—F. Hoffmann-La Roche Ltd
9/Protocol WP41152, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE Ib, OPEN-LABEL, DOSE-RANGING
STUDY TO EVALUATE THE PHARMACOKINETICS, 
PHARMACODYNAMICS, AND SAFETY OF 
TOCILIZUMAB ADMINISTERED BY INTRAVENOUS 
INFUSION TO PATIENTS WITH GIANT CELL 
ARTERITIS
PROTOCOL NUMBER:
WP41152
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-004718-17
IND NUMBER:
113,654
TEST PRODUCT:
Tocilizumab (RO4877533)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.


Tocilizumab—F. Hoffmann-La Roche Ltd
10/Protocol WP41152, Version 4
PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib, OPEN-LABEL, DOSE-RANGING STUDY TO 
EVALUATE THE PHARMACOKINETICS, PHARMACODYNAMICS, 
AND SAFETY OF TOCILIZUMAB ADMINISTERED BY 
INTRAVENOUS INFUSION TO PATIENTS WITH GIANT CELL 
ARTERITIS
PROTOCOL NUMBER:
WP41152
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-004718-17
IND NUMBER:
113,654
TEST PRODUCT:
Tocilizumab (RO4877533)
PHASE:
Phase Ib
INDICATION:
Giant cell arteritis
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the pharmacokinetics, pharmacodynamics, and safety of 6 and 7 mg/kg 
of tocilizumab (TCZ) administered by IV infusion every 4 weeks (Q4W) to patients with giant 
cell arteritis (GCA).  Specific objectives and corresponding endpoints for the study are 
outlined below.
Pharmacokinetic Objectives
The primary pharmacokinetic (PK) objective for this study is to characterize the 
pharmacokinetics of two dose levels of TCZ administered by IV infusion to patients with GCA, 
on the basis of the following endpoints:

Steady-state maximum serum concentration (Cmax) at specified timepoints

Trough concentration (Ctrough) at specified timepoints

Area under the concentrationtime curve (AUC) over the dosing interval of 4 weeks 
(AUC4weeks) at specified timepoints
Pharmacodynamic Objectives
The pharmacodynamic (PD) objective for this study is to assess the pharmacodynamics of 
two dose levels of TCZ administered by IV infusion to patients with on the basis of the 
following endpoints:

Serum concentration of interleukin-6 (IL-6) at specified timepoints

Serum concentration of soluble interleukin-6 receptor (sIL-6R) at specified timepoints

Serum concentration of C-reactive protein (CRP) at specified timepoints

Erythrocyte sedimentation rate (ESR) at specified timepoints
Safety Objectives
The safety objective for this study is to evaluate the safety and tolerability of two dose levels of 
TCZ administered by IV infusion to patients with GCA on the basis of the following endpoints:

Nature, frequency, severity, and causality of adverse events, with severity determined 
according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0


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11/Protocol WP41152, Version 4

Clinical safety laboratory results
Exploratory Objective
The exploratory objective for this study is to monitor the efficacy of two dose levels of TCZ 
administered by IV infusion to patients with GCA on the basis of the following endpoints:

Proportion of patients who experience a flare, defined as the recurrence of signs or 
symptoms of GCA and/or ESR 30 mm/h attributable to GCA as determined by the 
investigator, during each period

Proportion of patients in remission, defined as the absence of flare (defined above) and 
normalization of CRP (1 mg/dL), at each visit
Study Design
Description of Study
This is a Phase Ib, open-label, dose-ranging study designed to characterize the 
pharmacokinetics, pharmacodynamics, and safety of two dose levels of TCZ (6 and 7 mg/kg) 
administered by IV infusion Q4W to patients with GCA.  This study will enroll patients with GCA 
from at least two sites in Switzerland who have received at least five consecutive doses of 
8 mg/kg TCZ IV Q4W prior to baseline in clinical practice and who have reached remission, 
defined as the absence of flare and normalization of CRP (1 mg/dL). 
The study is divided into two periods:  In Period 1, approximately 25 patients who have been 
receiving 8 mg/kg TCZ IV Q4W for a minimum of five consecutive doses and who are in 
remission will receive five consecutive doses of 7 mg/kg TCZ IV Q4W.  Subsequently, if a 
patient is still in remission at the end of Period 1, the patient will enter Period 2 and receive five 
consecutive doses of 6 mg/kg TCZ IV Q4W.  Although five doses at each dose level are 
sufficient to achieve the primary study objectives, if absolutely necessary to accommodate 
patient availability for the intensive PK sampling during the last dosing cycle, the dosing 
periods may be extended by one dose for a total of six doses.  This will not be considered a 
protocol violation. 
The plan is to enroll approximately 25 patients into Period 1 in order to obtain data to robustly 
characterize the pharmacokinetics at each of the two dose levels.  Guidance from a statistical 
evaluation of the variability in PK parameters from IV dosing established a minimum of 
12 patients would be adequate.  Given the open-label nature of the study design, an evaluation 
of the data at the end of Period 1 will be undertaken.  If the dropout rate and/or variability are 
higher than planned, additional patients on 8 mg/kg TCZ IV Q4W (who have received at least 
five consecutive doses and are in remission) may be directly enrolled into Period 2.  Because 
the study design allows sufficient time to achieve steady state at the 6 mg/kg dose level, there is 
minimal influence from the small difference expected in PK and PD outcomes from prior dosing 
with 8 mg/kg versus 7 mg/kg; hence the protocol allows for direct enrollment of patients who 
had received either 8 mg/kg or 7 mg/kg TCZ IV Q4W into Period 2.  Data from all patients 
receiving 6 mg/kg TCZ IV Q4W in Period 2 will be combined.
PK samples will be obtained before and after each infusion of TCZ to characterize the Cmax and 
Ctrough of TCZ, and more intensive sampling during the last dosing cycle will be used to estimate 
the steady-state AUC4weeks at each dose level.  
The usage of glucocorticoids during the study is at the discretion of the investigator.  Only 
patients in remission at the end of Period 1 will be eligible for Period 2.
Number of Patients
The study will enroll approximately 25 adult patients with a diagnosis of GCA who are being 
treated with 8 mg/kg TCZ IV Q4W in clinical practice and have reached remission at the time of 
enrollment.
Target Population
Inclusion Criteria
Patients entering Period 1 or Period 2 directly (without prior participation in Period 1) must meet 
the following criteria for study entry:

Signed Informed Consent Form

Age 50 years at time of signing Informed Consent Form


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
Ability to comply with the study protocol, in the investigator’s judgment

Diagnosis of GCA classified according to the following criteria:
-
Age 50 years
-
History of ESR 50 mm/hour *
* If historic ESR is unavailable, a history of CRP 2.45 mg/dL is required. The CRP value 
was derived from published data both from GCA and rheumatoid arthritis (RA) patients 
(Hayreh et al. 1997; Wolfe 1997; Paulus et al. 1999).
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)
◦
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:
◦
Temporal artery biopsy revealing features of GCA
◦
Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study 
such as magnetic resonance angiography (MRA), computed tomography 
angiography (CTA), or positron emission tomography-computed tomography 
(PET-CT)

For patients entering Period 1: patients must be receiving treatment with TCZ 8 mg/kg IV 
Q4W and have received at least five consecutive doses prior to baseline and be in 
remission at baseline.

For patients entering Period 2 after completing Period 1: prior to the first dose of 
6 mg/kg TCZ IV, patients must be in remission at the end of Period 1.

For patients entering Period 2 directly (without prior participation in Period 1): patients must
be receiving treatment with TCZ 8 mg/kg IV Q4W and have received at least five 
consecutive doses prior to the first study visit in Period 2 and be in remission at the first 
study visit in Period 2.

For women:  not of childbearing potential.  A woman is considered to be not of childbearing 
potential if she has reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause) or has undergone surgical 
sterilization (removal of ovaries and/or uterus).  The definition of non-childbearing potential 
may be adapted for alignment with local guidelines or requirements.

For men:  not of reproductive potential (i.e., infertile or sterilized) or agreement to use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
use a condom during the treatment period and for at least 28 days after the final dose 
of TCZ.  Men must refrain from donating sperm during this same period.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Lack of peripheral venous access

Major surgery within 8 weeks prior to screening, or planned major surgery during the study 

Organ transplant (except corneal transplant performed more than 3 months prior to 
screening)

Major ischemic event, related or unrelated to GCA, within 12 weeks prior to screening

Treatment with any other investigational agent besides TCZ within 12 weeks (or 5 half-lives 
of the investigational drug, whichever is longer) prior to screening


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
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

Treatment with IV gamma globulin or plasmapheresis within 6 months prior to baseline 
(Day 1)

Previous treatment with alkylating agents, such as chlorambucil, or with total lymphoid 
irradiation

Immunization with a live or attenuated vaccine within 4 weeks prior to baseline

Treatment with hydroxychloroquine, cyclosporine A, azathioprine, or mycophenolate mofetil 
within 4 weeks prior to baseline (Day 1)

Treatment with other biologics (e.g., etanercept, infliximab, certolizumab, golimumab, 
abatacept, adalimumab, anakinra) or targeted synthetic disease-modifying anti-rheumatic 
drug (e.g., tofacitinib, baricitinib) within 12 weeks prior to baseline (Day 1)

Treatment with cyclophosphamide within 6 months of baseline (Day 1)

History of severe allergic or anaphylactic reactions to human, humanized, or murine 
monoclonal antibodies (including history of discontinuation of TCZ due to any 
infusion-related reaction or hypersensitivity) 

Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary 
(including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled 
diabetes mellitus), psychiatric, osteoporosis or osteomalacia, glaucoma, corneal ulcers or 
injuries, or gastrointestinal (GI) disease

Current liver disease, as determined by the investigator

History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative 
lower GI disease such as Crohn 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 should be screened for latent TB and, if positive, treated according to local 
practice guidelines prior to baseline.
Patients treated for TB with no recurrence within the last 3 years and patients treated 
for latent TB within last 3 years are eligible.

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)

History of alcohol, drug, or chemical abuse within 1 year prior to screening

Body weight 150 kg
At screening:

Serum creatinine 1.4 mg/dL (124 mol/L) in female patients and 1.6 mg/dL (141 mol/L) 
in male patients

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)

WBCs 3.0109/L (3000/mm3)


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
ANC1.5 109/L (1500/mm3)

Absolute lymphocyte count 0.5109/L (500/mm3)

Positive hepatitis B surface antigen test or positive hepatitis C antibody test
End of Study
The end of this study is defined as the date when the last patient, last visit occurs, which 
corresponds to approximately 28 days after the last dose.  The end of the study is expected to 
be approximately 10 months after enrollment of the last patient into Period 1. 
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 12 months.
In addition, the Sponsor may decide to terminate the study at any time.
Investigational Medicinal Products
The investigational medicinal product for this study is TCZ.
Test Product (Investigational Drug)
TCZ will be administered by IV infusion at doses of 7 or 6 mg/kg Q4W.  The maximum dose of 
TCZ that will be administered is 800 mg. The dose of TCZ infusion will be calculated on the 
basis of body weight measured prior to each infusion.
Statistical Methods
Primary Analysis
Given the small sample size, the short duration of the study, and open-label design without a 
control arm, a dose-related effect on flares is not expected to be observed.  Sample size 
estimates are entirely based on PK data.  PK, PD, safety, and efficacy data will be summarized 
descriptively. No formal statistical hypothesis testing is planned. A database lock will occur 
when the last patient has completed the final visit 28 days after the final dose.
The primary PK variables in this study are estimates of steady-state Ctrough, Cmax, and AUC4weeks
at the two dose levels of TCZ IV therapy (7 mg/kg Q4W and 6 mg/kg Q4W). For each dose 
level, Ctrough and Cmax will be summarized at each timepoint for each dose administered and
AUC4weeks estimated for the last dosing cycle will be summarized as geometric means, medians, 
ranges, and standard deviations.
Determination of Sample Size  
In order to provide a precise characterization of PK parameters (Ctrough, Cmax, and AUC4weeks), in 
this study, a hybrid of two approaches will be followed. The first of these approaches is the 
guidance for estimation of sample size in pediatric studies, which requires a study to be 
prospectively powered to target 95% CI within 60%140% of the geometric mean estimates of 
clearance and volume of distribution for the drug in each pediatric sub-group with at least 80% 
power. The second is the sample size guidance from the Food and Drug Administration for 
bioequivalence studies, which specifies the 90% CI for the geometric mean ratio (GMR) should
fall within 80%–125% of the GMR estimate.
Given the need to characterize the PK parameters to a higher precision than in a pediatric 
population, the sample size for this study was estimated based on achieving a target of 95% CI 
for estimates of Cmax and Ctrough at each dose level that would fall within 80%125% of the 
geometric mean estimate.
In Study ML25676, observed steady-state Ctrough data were available for 18 patients receiving 
8 mg/kg TCZ IV Q4W.  The geometric mean was 44.4 g/mL (95% CI: 37.0, 53.4), with the 
95% CI corresponding to 83% and 120% of the geometric mean estimate.
Using the variability in observed steady-state Ctrough in Study ML25676, a sample size of n 17 
will provide 80% power to characterize the geometric mean estimate of the observed Ctrough
and Cmax so that the 95% CI falls within 80%125% of the geometric mean estimate of the 
corresponding PK parameter. A minimal sample size of n 12 would provide 80% power for 
the 90% CI to fall within 80%–125% of the geometric mean estimate of the corresponding PK 
parameter.  To account for potential study dropouts, approximately 25 patients already receiving 
8 mg/kg IV TCZ and in remission will be enrolled in the Period 1 of this study with the goal of 
obtaining robust PK characterization at both dose levels. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AUC
area under the concentrationtime curve
AUC4weeks
area under the concentrationtime curve over 4 weeks 
(the dosing interval)
Caverage
average concentration
CL
clearance
Cmax
maximum serum concentration
Ctrough
trough concentration
CRO
contract research organization
CRP
C-reactive protein
CRS
cytokine-release syndrome
CS
corticosteroid
CSR
Clinical Study Report
CTA
computed tomography angiography
CTCAE
Common Terminology Criteria for Adverse Events
CYP450
cytochrome P450
DIBD
Development International Birth Date
DMC
Data Monitoring Committee
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ESR
erythrocyte sedimentation rate
FDA
Food and Drug Administration
GC
glucocorticoid
GCA
giant cell arteritis
GI
gastrointestinal
GMR
geometric mean ratio
HBsAg
hepatitis B surface antigen
ICH
International Council for Harmonisation
IL-6
interleukin-6
IL-6R
interleukin-6 receptor
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
MRA
magnetic resonance angiography
NCEP
National Cholesterol Education Program


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Abbreviation
Definition
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
PD
pharmacodynamic
pJIA
polyarticular juvenile idiopathic arthritis
Pop PK
population pharmacokinetics
PET-CT
positron emission tomography- computed tomography
PK
pharmacokinetic
PMR
polymyalgia rheumatica
PY
Patient years
Q2W
every 2 weeks
Q4W
every 4 weeks
QW
once a week
RA
rheumatoid arthritis
sIL-6R
soluble interleukin-6 receptor
sJIA
systemic juvenile idiopathic arthritis
TAK
Takayasu arteritis
TB
tuberculosis
TCZ
tocilizumab
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ON GIANT CELL ARTERITIS 
Giant cell arteritis (GCA; or temporal arteritis) is the most common primary systemic 
vasculitis.  GCA affects large- and medium-sized arteries and occurs almost exclusively 
in adults older than 50 years. The incidence increases with age and peaks during the 
eighth decade; the mean age at diagnosis is approximately 75 years. GCA is 2 to 
3 times more common in women than in men. The reported prevalence of documented
GCA in populations aged over 50 years varies significantly geographically and ranges 
between 24 and 200278 per 100,000 people in the European Union and United States, 
respectively (Salvarani et al. 2004; Lawrence et al. 2008; Lee et al. 2008). GCA can 
manifest with ischemic events due to vessel occlusion, most typically central retinal 
artery occlusion or anterior ischemic optic neuropathy, both of which lead to irreversible 
vision loss. In the past 25 years, awareness of the prevalence of aortitis that frequently 
leads to aneurysm and large-vessel vasculitis affecting the primary aortic branches has 
grown (Kermani et al. 2013). 
Until recently, corticosteroids (CS’s) were the mainstay of treatment for GCA. Typically, 
oral prednisone or prednisolone is used, although some physicians use pulsed IV CS’s
in patients presenting with visual loss. Although CS’s are highly effective at inducing 
remission of systemic inflammation and preventing acute damage (e.g., blindness), their 
use comes with a high toxicity burden, with 86% of patients experiencing CS-related 
adverse clinical events at 10-year follow-up (Proven et al. 2003). Among the most 
deleterious of these effects are osteoporosis, hypertension, hyperglycemia, and 
increased body mass (and redistribution of body fat). In addition, CS’s are not as 
effective at maintaining remission, with many patients (up to 50%) experiencing relapse 
or flare-up of symptoms during reduction or discontinuation of CS’s (Proven et al. 2003).
Various agents, including azathioprine, cyclophosphamide, methotrexate, infliximab, 
and etanercept, have shown conflicting or no evidence of benefit in the treatment of 
GCA. In spite of the paucity of evidence, methotrexate is used inconsistently as 
standard-of-care treatment for CS sparing in patients with refractory disease. Supportive 
therapies that have a place in standard-of-care treatment include antiplatelet agents 
(typically 5-aminosalicylic acid or aspirin) and preventative therapies for osteoporosis 
according to local practice.
In 2017, the SC formulation of the antiinterleukin-6 receptor (IL-6R) antibody 
tocilizumab (TCZ) was approved for the treatment of GCA in the United States, 
European Union, Switzerland, and other countries based on the results from the
Phase III WA28119 (GiACTA) study (see Section 1.2 for background on TCZ and 
Section 1.2.1.2 for additional information on Study WA28119).


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1.2
BACKGROUND ON TOCILIZUMAB
TCZ is a recombinant humanized, anti-human monoclonal antibody of the IgG1 subclass 
directed against soluble and membrane-bound IL-6R.  TCZ binds specifically to both 
soluble IL-6R (sIL-6R) and membrane-bound IL-6R and has been shown to inhibit both 
soluble and membrane-bound IL-6Rmediated signaling.  IL-6 is a pleiotropic 
pro-inflammatory multifunctional cytokine produced by a variety of cell types.  It has 
been shown to be involved in diverse physiological processes such as T-cell activation;
induction of acute-phase proteins; stimulation of hemopoietic precursor cell growth and 
differentiation; proliferation of hepatic, dermal, and neural cells; as well as bone 
metabolism, lipid metabolism, hepatoprotection, and fibrosis.  Elevated tissue and serum 
levels of IL-6 have been implicated in the disease pathology of several inflammatory and 
autoimmune disorders including rheumatoid arthritis (RA), Castleman disease, systemic 
juvenile idiopathic arthritis (sJIA), polyarticular juvenile idiopathic arthritis (pJIA), GCA, 
Takayasu arteritis (TAK), systemic sclerosis (SSc), and cytokine-release syndrome 
(CRS).
Inhibition of the biological activity of IL-6 or IL-6R has been effective in the treatment of 
RA, Castleman disease, sJIA, pJIA, GCA, TAK, and CRS, for which TCZ has been 
approved in many countries.
TCZ has IV and SC formulations.  Both formulations of TCZ have been approved for 
many of the indications listed above (RA, sJIA, and pJIA), whereas the IV formulation is 
approved exclusively for Castleman disease and CRS, and the SC formulation is 
approved exclusively for GCA and TAK. SC TCZ (162 mg once a week [QW] or every 
2 weeks [Q2W]) is approved in the European Union, United States, and Japan for the 
treatment of RA, sJIA, and GCA.  SC TCZ is also approved for the treatment of RA in 
more than 60 additional countries and for the treatment of GCA in 17 additional countries.  
SC TCZ is also approved in the United States, European Union, Japan, Nicaragua, 
Bangladesh, and Guatemala for the treatment of pJIA (162 mg Q2W or every 3 weeks).  
In Japan, SC TCZ has an additional indication for the treatment of TAK (162 mg QW 
or Q2W).
As of the Development International Birth Date (DIBD) (28 April 1997), an estimated 
22,968 patients had received TCZ (IV and SC combined, including blinded TCZ) during
clinical trial participation.  Cumulatively from the DIBD, 514 patients in clinical trials of 
special populations have received either IV or SC TCZ (446 pediatric patients and 
68 patients of different racial and/or ethnic origins).  The combined cumulative 
postmarketing exposure of patients to IV TCZ is estimated to be 781,084 patients 
(629,799 patient years [PY]), whereas the combined cumulative postmarketing exposure 
of patients to SC TCZ is 276,596 patients (226,918 PY).
Refer to the Tocilizumab Investigator's Brochure for details on nonclinical and 
clinical studies.


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1.2.1
Completed Clinical Studies in Patients with Giant Cell Arteritis
TCZ has been evaluated in two completed randomized controlled trials in patients with 
GCA.  In Study ML25676, 20 patients with GCA received IV TCZ (Villiger et al. 2016).  
In the Phase III WA28119 (GiACTA) study, 149 patients with GCA received SC TCZ
(Stone et al. 2017).
1.2.1.1
Study ML25676:  Intravenous Tocilizumab
Study ML25676 was a Phase II, investigator-initiated, single-center, randomized, 
double-blind study supported by F. Hoffmann-La Roche Ltd (hereafter referred to as 
Roche) that was conducted at the Inselspital (University Hospital) in Bern, Switzerland. 
This study evaluated the safety and efficacy of IV TCZ (8 mg/kg) (n20) compared with
placebo (n10) in the induction and maintenance of disease remission in patients with 
newly diagnosed or relapsing GCA (Villiger et al. 2016). Patients in both groups 
received oral prednisolone, starting at 1 mg/kg/day and tapered down to 0 mg during the 
study.  A significantly higher proportion of patients in the TCZ group reached complete 
remission at a prednisolone dose of 0.1 mg/kg/day at Week 12 compared with the 
placebo group (85% vs. 40%, respectively; risk difference45%; 95% CI: 11, 79; 
p0.0301).  The proportion of patients who achieved relapse-free survival by Week 52 
was also significantly higher in the TCZ group than the placebo group (85% vs. 20%; risk
difference65%; 95% CI: 36, 94; p0.0010). Importantly, the cumulative dose of 
prednisolone was significantly lower in patients treated with TCZ (43 mg/kg in the TCZ
group vs. 110 mg/kg in the placebo group after 52 weeks; p0.0005).
The safety profile of TCZ was comparable with the established TCZ safety profile with no 
new safety signal observed.  Serious adverse events were observed in 7 patients (35%) 
in the TCZ group and 5 patients (50%) in the placebo group.
1.2.1.2
Study WA28119:  Subcutaneous Tocilizumab
Study WA28119 was a Phase III, randomized, double-blind, placebo-controlled trial of 
SC TCZ in patients with GCA.  The study was composed of a 52-week blinded period
followed by a 104-week open-label period.  Patients (n251) were randomized in a 
2:1:1:1 ratio to receive 162 mg TCZ SC QW or Q2W combined with a 26-week 
prednisone taper, or placebo combined with a prednisone taper over a period of either 
26 weeks or 52 weeks. Sustained remission at Week 52 was achieved in significantly 
more patients in the TCZ groups than the placebo groups (56% of patients in the 
TCZ QW group and 53% of patients in the TCZ Q2W group vs. 14% in the placebo 
group that underwent the 26-week prednisone taper and 18% in the placebo group that 
underwent the 52-week prednisone taper; p0.001 for either TCZ group vs. placebo).  
The cumulative mean prednisone dose over the 52-week period was significantly lower 
in the TCZ groups compared with placebo groups (1862 mg in each TCZ group vs. 
3296 mg in the placebo group that underwent the 26-week taper [p0.001 for both 
comparisons] and vs. 3813 mg in the placebo group that underwent the 52-week taper 
[p0.001 for both comparisons]).


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Up to Week 52, serious adverse events were observed in 15% of patients in the 
TCZ QW group, 14% of patients in the TCZ Q2W group, and 22% and 25% of patients in 
the placebo groups who underwent the 26-week and 52-week prednisone tapers, 
respectively. The open-label part of the study has been completed and the results will 
be available in 2019. 
1.2.2
Pharmacokinetics of Tocilizumab
The pharmacokinetics of TCZ were characterized using non-linear elimination, which is a 
combination of linear clearance and Michaelis-Menten elimination. The non-linear part 
of TCZ elimination leads to an increase in exposure that is more than dose-proportional.  
The total clearance of TCZ is concentration dependent and equals the sum of linear 
clearance and non-linear clearance.  The concentration-dependent non-linear clearance 
plays a major role at low TCZ concentrations. Once the non-linear clearance pathway is 
saturated, at higher TCZ concentrations, clearance is mainly determined by the linear 
clearance. Owing to the effects of non-linear clearance, the half-life of TCZ varies with 
concentration.
The pharmacokinetics of TCZ after SC administration have been characterized in adult 
patients with GCA.   Peak serum concentrations are achieved by approximately 3 days 
after QW dosing in the patient populations with GCA. Following administration of 
162 mg TCZ QW at steady state, the apparent terminal half-life is up to 18.9 days, 
whereas after 162 mg TCZ Q2W the apparent terminal half-life is up to 7.9 days.
Following the 162 mg QW and Q2W regimens, approximately 90% of steady-state 
exposure was achieved by 17 and 14 weeks, respectively.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
On the basis of the data from the Phase III WA28119 trial, the SC formulation of TCZ
was approved for the treatment of GCA in multiple countries worldwide.  Although the 
approval of SC TCZ is a significant step to improve the treatment paradigm for patients 
with GCA and reduce the burden of glucocorticoid (GC)-associated toxicity, important 
challenges remain. The availability of the IV formulation will provide another 
administration option for those patients who prefer IV infusion because of needle phobia. 
There is also a significant unmet medical need owing to a patient access issue to 
TCZ SC under U.S. medical insurance, which would not apply to TCZ IV. Furthermore, 
the patient population with GCA is older than the patient population with RA, and an 
unmet medical need exists for a subset of this elderly population for whom the IV 
infusion will be preferable, as some patients may either have difficulty administering the
SC injections and/or may have suboptimal adherence to SC treatment.
Based on the extensive safety data in the RA program and GCA studies, the adverse 
effects of TCZ have been shown to be manageable, reversible, and usually not 
treatment limiting. Furthermore, the results of Study ML25676 described previously


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(see Section 1.2.1.1) indicate a positive benefitrisk profile for the IV route of 
administration of TCZ in GCA similar to that observed for the approved SC route.
Although Study ML25676 was conducted evaluating the 8 mg/kg IV dose every 4 weeks 
(Q4W) regimen and observed trough exposures were within the therapeutic range 
established in Study WA28119, model based predictions show that average exposures 
(area under the concentrationtime curve [AUC]), but not peak concentrations), over a 
dosing interval at steady state are higher than those observed in the RA population at 
the same dose.  Average steady-state concentration at the end of a dosing interval
(Ctrough) exposure in patients with GCA from the SC QW regimen (n100), SC Q2W 
regimen (n49), or 8 mg/kg IV (Q4W) regimen (n9) were higher than Ctrough from 
corresponding doses in patients with RA (67.93 vs. 44.17 g/mL, 12.2 vs. 8.23 g/mL,
and 36.9 vs. 21.1 g/mL, respectively; (Clinical Study Reports [CSRs] WA28119 and 
ML25676). Thus, at the same dose, patients with GCA have higher exposure by 
approximately 50% than patients with RA.
Although a post-hoc analysis of the pharmacokinetics of TCZ was undertaken using 
samples collected during Study ML25676, the data are sparse.  Therefore, in order to 
supplement the pharmacokinetic (PK) data collected in this study and to identify the 
optimal dose of IV TCZ that will best match the exposure leading to efficacy after SC 
TCZ administration as observed in Study WA28119, this study will examine exposures 
achieved at steady state from multiple doses of 6 and 7 mg/kg IV TCZ Q4W
(see Section 3.3.1 for the rationale for selection of TCZ dose and schedule). 
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the pharmacokinetics, pharmacodynamics, and safety of 6 and 
7 mg/kg of TCZ administered by IV infusion Q4W to patients with GCA. Specific 
objectives and corresponding endpoints for the study are outlined below.
2.1
PHARMACOKINETIC OBJECTIVES
The primary PK objective for this study is to characterize the pharmacokinetics of two 
dose levels of TCZ administered by IV infusion to patients with GCA, on the basis of the 
following endpoints:

Steady-state maximum serum concentration (Cmax) at specified timepoints

Ctrough at specified timepoints

AUC over the dosing interval of 4 weeks (AUC4weeks) at specified timepoints
2.2
PHARMACODYNAMIC OBJECTIVE
The pharmacodynamic (PD) objective for this study is to assess the pharmacodynamics 
of two dose levels of TCZ administered by IV infusion to patients with on the basis of the 
following endpoints:

Serum concentration of IL-6 at specified timepoints


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
Serum concentration of sIL-6R at specified timepoints

Serum concentration of C-reactive protein (CRP) at specified timepoints

Erythrocyte sedimentation rate (ESR) at specified timepoints
2.3
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety and tolerability of two dose 
levels of TCZ administered by IV infusion to patients with GCA on the basis of the 
following endpoints:

Nature, frequency, severity, and causality of adverse events, with severity 
determined according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

Clinical safety laboratory results
2.4
EXPLORATORY OBJECTIVE
The exploratory objective for this study is to monitor the efficacy of two dose levels of 
TCZ administered by IV infusion to patients with GCA on the basis of the following 
endpoints:

Proportion of patients who experience a flare, defined as the recurrence of signs or 
symptoms of GCA and/or ESR 30 mm/h attributable to GCA as determined by the 
investigator, during each period

Proportion of patients in remission, defined as the absence of flare (defined above) 
and normalization of CRP (1 mg/dL), at each visit
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase Ib, open-label, dose-ranging study designed to characterize the 
pharmacokinetics, pharmacodynamics, and safety of two dose levels of TCZ (6 and 
7 mg/kg) administered by IV infusion Q4W to patients with GCA.  This study will enroll 
patients with GCA from at least two sites in Switzerland who have received at least five 
consecutive doses of 8 mg/kg TCZ IV Q4W prior to baseline in clinical practice and who 
have reached remission (defined in Section 2.4).  An overview of the study design is 
shown in Figure 1.  A schedule of activities is provided in Appendix 1, and the schedule 
for PK and IL-6/sIL-6R sample collection is presented in Appendix 2.




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The usage of GC during the study is at the discretion of the investigator. Only patients in 
remission at the end of Period 1 will be eligible for Period 2. 
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs, which 
corresponds to approximately 28 days after the last dose.  The end of the study is 
expected to be approximately 10 months after enrollment of the last patient into Period 1.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 12 months.
In addition, the Sponsor may decide to terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Selection of Tocilizumab Dose and Schedule
The study is designed to robustly characterize the steady-state pharmacokinetics of TCZ 
in patients with GCA at two IV administration dose levels and compare with the 
previously characterized pharmacokinetics of TCZ in the GCA population after 
SC administration and in the RA population after IV administration.  The first dose of 
7 mg/kg TCZ IV Q4W was selected on the basis of 1) the cumulative knowledge of the 
concentration of TCZ required to saturate the target IL-6R; 2) the therapeutic levels 
established in Study WA28119, in which TCZ was administered to patients with GCA at 
doses of 162 mg SC QW or Q2W; 3) the Ctrough measured in Study ML25676, in which 
TCZ was administered to patients with GCA at a dose of 8 mg/kg IV Q4W; and 4) the 
exposure (AUC and Cmax) of TCZ in patients with RA based on a large global database 
of multiple Phase III trials (Frey et al. 2010; Abdallah et al. 2017).  
The safety of the 8-mg/kg TCZ IV Q4W dosing regimen has been well established in the 
RA population for which TCZ has been approved for 9 years in the European Union and 
8 years in the United States.  Ctrough after IV administration in Study ML25676 was
estimated to be within the range of the Ctrough in Study WA28119 (see Figure 2).  Results 
from Study ML25676 indicated that the 8 mg/kg TCZ IV Q4W dosing regimen was 
efficacious and no new safety signals were identified.  A combined population (pop)-PK 
model was developed based on data from both SC and IV doses of TCZ in patients with 
GCA.  The model revealed that clearance at steady state in patients with GCA is lower 
than in patients with RA. The exact cause for this is unknown.  This difference leads to a 
predicted 50% higher AUC, with no resultant effect on Cmax.  Because of this difference,
the AUC or average trough concentration (Caverage) in patients with GCA is anticipated to 
be higher than in patients with RA.


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Figure 2
Observed Serum TCZ Concentration Profile of the 8 mg/kg IV 
Q4W (ML25676), 162 mg SC QW, and 162 mg SC Q2W Doses 
(WA28119) in Patients with GCA 
GCA giant cell arteritis; Q2W every 2 weeks; Q4W every 4 weeks; QW once a week; 
TCZtocilizumab.
Simulations were conducted to estimate doses lower than 8 mg/kg that could be 
expected to deliver sufficient TCZ exposures to ensure efficacy in GCA patients 
(i.e., a Ctrough in between that achieved with 162 mg TCZ SC QW and Q2W in WA28119) 
with an overall exposure (Cmax, AUC) more comparable to that achieved in adult patients 
with RA.
A large database exists from the Phase III studies in patients with RA, which provides 
evidence of a positive benefitrisk assessment at these exposures.  Thus, it is 
anticipated that a TCZ regimen of 6 or 7 mg/kg Q4W will result in drug exposures that 
are efficacious and well tolerated in the GCA population. A further decrease in dose 
level to 4 mg/kg TCZ IV Q4W was not considered adequate given it is predicted to result 
in a Ctrough below that of 162 mg SC Q2W in patients with GCA (Table 1).




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Because Ctrough is expected to be within the therapeutic range from both doses, efficacy 
is anticipated to be maintained.  PK data from this study will be used to robustly 
characterize the trough, peak, and average concentrations of TCZ by IV administration 
in patients with GCA.  This, along with efficacy, safety, and PK results collected in 
Studies ML25676 and WA28119, will inform the selection of an optimal IV TCZ dose for 
the treatment of GCA.
3.3.2
Rationale for Patient Population
This study will enroll patients with GCA who are already receiving IV TCZ therapy in 
clinical practice at two sites in Switzerland. Patients who are already receiving stable IV 
TCZ therapy in clinical practice may have a preference for IV treatment and thus are 
likely to continue their participation in the trial while maintaining disease control.  Eligible 
patients with GCA must have been receiving TCZ 8 mg/kg IV Q4W for at least five 
consecutive doses and be in remission (defined in Section 2.4). Patients entering 
Period 2 of the study (see Section 3.1) must be in remission prior to the first dose of TCZ 
6 mg/kg IV.
4.
MATERIALS AND METHODS
4.1
PATIENTS
The study will enroll approximately 25 adult patients with a diagnosis of GCA who are
being treated with 8 mg/kg TCZ IV Q4W in clinical practice and have reached remission
at the time of enrollment.
4.1.1
Inclusion Criteria
Patients entering Period 1 or Period 2 directly (without prior participation in Period 1) 
must meet the following criteria for study entry:

Signed Informed Consent Form

Age 50 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Diagnosis of GCA classified according to the following criteria:
–
Age 50 years
–
History of ESR 50 mm/hour *
* If historic ESR is unavailable, a history of CRP 2.45 mg/dL is required. The CRP 
value was derived from published data both from GCA and RA patients (Hayreh et 
al. 1997; Wolfe 1997; Paulus et al. 1999).
AND at least one of the following:
o
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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o
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:
o
Temporal artery biopsy revealing features of GCA
o
Evidence of large-vessel vasculitis by angiography or cross-sectional imaging 
study such as magnetic resonance angiography (MRA), computed 
tomography angiography (CTA), or positron emission tomography-computed 
tomography (PET-CT)

For patients entering Period 1: patients must be receiving treatment with TCZ 
8 mg/kg IV Q4W and have received at least five consecutive doses prior to baseline 
and be in remission (as defined in Section 2.4) at baseline.

For patients entering Period 2 after completing Period 1: prior to the first dose of 
6 mg/kg TCZ IV, patients must be in remission (as defined in Section 2.4) at the end 
of Period 1.

For patients entering Period 2 directly (without prior participation in Period 1): 
patients must be receiving treatment with TCZ 8 mg/kg IV Q4W and have received 
at least five consecutive doses prior to the first study visit in Period 2 and be in 
remission (as defined in Section 2.4) at the first study visit in Period 2.

For women: not of childbearing potential.  A woman is considered to be not of 
childbearing potential if she has reached a postmenopausal state (12 continuous 
months of amenorrhea with no identified cause other than menopause) or has 
undergone surgical sterilization (removal of ovaries and/or uterus).  The definition of 
non-childbearing potential may be adapted for alignment with local guidelines or 
requirements.

For men:  not of reproductive potential (i.e., infertile or sterilized) or agreement to 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must use a condom during the treatment period and for at least 28 days after 
the final dose of TCZ. Men must refrain from donating sperm during this 
same period.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Lack of peripheral venous access

Major surgery within 8 weeks prior to screening, or planned major surgery during 
the study 

Organ transplant (except corneal transplant performed more than 3 months prior 
to screening)

Major ischemic event, related or unrelated to GCA, within 12 weeks prior 
to screening


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
Treatment with any other investigational agent besides TCZ within 12 weeks 
(or 5 half-lives of the investigational drug, whichever is longer) prior to 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

Treatment with IV gamma globulin or plasmapheresis within 6 months prior to
baseline (Day 1)

Previous treatment with alkylating agents, such as chlorambucil, or with total 
lymphoid irradiation

Immunization with a live or attenuated vaccine within 4 weeks prior to baseline

Treatment with hydroxychloroquine, cyclosporine A, azathioprine, or mycophenolate 
mofetil within 4 weeks prior to baseline (Day 1)

Treatment with other biologics (e.g., etanercept, infliximab, certolizumab, golimumab, 
abatacept, adalimumab, anakinra) or targeted synthetic disease-modifying 
anti-rheumatic drug (e.g., tofacitinib, baricitinib) within 12 weeks prior to baseline
(Day 1)

Treatment with cyclophosphamide within 6 months of baseline (Day 1)

History of severe allergic or anaphylactic reactions to human, humanized, or murine 
monoclonal antibodies (including history of discontinuation of TCZ due to any
infusion-related reaction or hypersensitivity) 

Evidence of serious uncontrolled concomitant cardiovascular, nervous system, 
pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine 
(including uncontrolled diabetes mellitus), psychiatric, osteoporosis or osteomalacia, 
glaucoma, corneal ulcers or injuries, or gastrointestinal (GI) disease

Current liver disease, as determined by the investigator

History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic 
ulcerative lower GI disease such as Crohn 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 should be screened for latent TB and, if positive, treated according to 
local practice guidelines prior to baseline (see Appendix 3).
Patients treated for TB with no recurrence within the last 3 years and patients 
treated for latent TB within the last 3 years are eligible.

Primary or secondary immunodeficiency (history of or currently active)


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
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)

History of alcohol, drug, or chemical abuse within 1 year prior to screening

Body weight 150 kg
At screening:

Serum creatinine 1.4 mg/dL (124 mol/L) in female patients and 1.6 mg/dL 
(141 mol/L) in male patients

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)

WBCs 3.0 109/L (3000/mm3)

ANC 1.5 109/L (1500/mm3)

Absolute lymphocyte count 0.5 109/L (500/mm3)

Positive hepatitis B surface antigen (HBsAg) test or positive hepatitis C antibody test
4.2
METHOD OF TREATMENT ASSIGNMENT
This is a single-arm and open-label study with no randomization. The primary 
PK objective of this study is to characterize the pharmacokinetics of TCZ by
IV administration in patients with GCA.  To fulfill this objective, the use of a blind or 
a comparator arm is not necessary.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is TCZ.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Tocilizumab
TCZ will be supplied by the Sponsor as a sterile IV injection for reconstitution in 
20-mL glass vials with a 10 mL fill in each (200 mg /10 mL of TCZ).  An appropriate
number of vials (depending on the patient’s bodyweight) of TCZ will be assigned to 
each patient for each infusion to be administered every 28 (3) days. The amount of 
solution that is withdrawn from each vial will depend on the patient’s allocated dose.  
For information on the formulation and handling of TCZ, see the TCZ pharmacy manual, 
Tocilizumab Investigator's Brochure, and Switzerland prescribing information for TCZ.


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4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 5.4.4.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.
4.3.2.1
Tocilizumab
TCZ will be administered by IV infusion at doses of 7 or 6 mg/kg Q4W. The maximum 
dose of TCZ that will be administered is 800 mg. The dose of TCZ infusion will be 
calculated on the basis of body weight measured prior to each infusion (see Appendix 1).  
TCZ must be administered under close supervision of the investigator in a setting where 
medications and resuscitation facilities are available. Patients should be monitored for 
at least 2 hours after the TCZ infusion is completed.
The TCZ vials will be stored at a temperature of 2C–8C. The infusion bag of TCZ may 
be stored at 2C–8C for 24 hours providing that the infusion is prepared aseptically and 
allowed to return to room temperature before administration. The TCZ will be 
administered at room temperature by controlled infusion into an arm vein over a 1-hour 
period. In exceptional cases this time may be extended to up to 6 hours. The infusion 
speed must be 10 mL/hr for 15 minutes and then increased to 130 mL/hr to complete the 
dosing in 1 hour. The entire 100 mL-content of the infusion bag must be administered. 
A total of 20 mL of normal saline will be administered following the infusion of study 
medication to flush the remaining study drug through the intravenous set.
Refer to the Tocilizumab Investigator’s Brochure for further instructions regarding 
recommended storage conditions and packaging configuration.
4.3.3
Investigational Medicinal Product Accountability
The IMP (TCZ) required for completion of this study will be provided by the Sponsor.  
The study site will acknowledge receipt of IMPs supplied by the Sponsor by returning 
the appropriate documentation form to confirm the shipment condition and content.  
Any damaged shipments will be replaced.
The IMP will either be disposed of at the study site according to the study site's
institutional standard operating procedure or be returned to the Sponsor (if supplied by 
the Sponsor) with the appropriate documentation.  The site's method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor.  The site must obtain written 
authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
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Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Tocilizumab
The Sponsor does not have any plans to provide the Roche IMP (TCZ) or any 
other study treatments or interventions to patients who have completed the study.  
The Sponsor may evaluate whether to continue providing TCZ in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, available 
at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY, PROHIBITED THERAPY AND 
ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 28 days prior to initiation of 
study drug to the study completion/discontinuation visit. All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

CS’s may be used at the discretion of the investigator for the management of 
patients with refractory GCA or for safety reasons during the study.

Patients may receive other concomitant medications for GCA or other medical 
conditions during the study at the discretion of the investigator.
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists).  
4.4.2
Cautionary Therapy
4.4.2.1
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines 
(e.g., IL-6) during chronic inflammation. Therefore, for molecules that antagonize 
cytokine activity, such as TCZ, it is expected that the formation of CYP450 enzymes 
could be normalized. When starting TCZ therapy, patients taking medications that are 


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individually dose adjusted and metabolized by means of CYP450, CYP3A4, CYP1A2, or 
CYP2C9 (e.g., atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, 
cyclosporin, or benzodiazepines) are recommended to be monitored as doses may need 
to be adjusted to maintain their therapeutic effect. However, because patients in this 
study will have been treated with TCZ for a minimum of 5 months, it is expected that any 
effects on the clearance of these drugs would be stabilized by the time of enrollment into 
this study.
The above list of medications is not necessarily comprehensive.  The investigator should 
consult the prescribing information when determining whether a concomitant medication 
can be safely administered with study treatment.  In addition, the investigator should 
contact the Medical Monitor if questions arise regarding medications not listed above.
4.4.2.2
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Treatment with any investigational agent, cell-depleting therapies, biologic agents 
(e.g., tumor necrosis factor antagonists), Janus kinase inhibitors (e.g., tofacitinib, 
baricitinib), alkylating agents (e.g., chlorambucil, cyclophosphamide), thalidomide, 
IV gamma globulin, antithymocyte globulin, and azathioprine during the study

Bone marrow transplantation with total lymphoid irradiation during the study

Plasmapheresis or extracorporeal photopheresis during the study

Immunization with a live or attenuated vaccine for the duration of the patient’s study 
participation.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
The schedule for PK and IL-6/sIL-6R biomarker sample collection is presented in
Appendix 2.  All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and last available laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.


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All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Description of Study Assessments 
The sequence of assessments at each visit will be standardized as follows (at visits 
required in the schedules of assessments).
1.
Laboratory samples:  All samples (including for predose PK, safety, and efficacy) 
must be taken prior to study drug treatment, except for postdose samples for 
PK analyses, which will be obtained after study drug treatment.  The laboratory 
samples should be drawn at least 30 minutes before clinical assessment.
2.
Efficacy assessments: signs and symptoms of GCA
3.
Safety assessments:  review of adverse events, vital signs, concomitant 
medications
4.
IV infusion of TCZ
5.
Postdose PK samples (only at scheduled visits)
Schedules of assessments are found in Appendix 1 and Appendix 2.
4.5.3
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases within the past 10 years, 
surgeries, cancer history (including prior cancer therapies and procedures), smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline.  In addition, 
all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 28 days prior 
to initiation of study treatment will be recorded.  At the time of each visit, an interval 
medical history should be obtained and any changes in medications and allergies should 
be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.4
Physical Examinations
A complete physical examination, performed at screening, should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations may be performed at unscheduled 
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be recorded in patient notes.  New or worsened clinically significant abnormalities should 
be recorded as adverse events on the Adverse Event eCRF.
In addition, patient body weight will be measured at the timepoints specified in the 
schedule of activities (see Appendix 1).
4.5.5
Vital Signs
Vital signs will include measurements of pulse rate, systolic and diastolic blood pressure
while the patient is in a seated position, and temperature. Blood pressure 
measurements should be obtained prior to the infusion and after the patient has been 
seated for at least 5 minutes.
4.5.6
Disease-Specific Assessment 
Evaluation of clinical signs and symptoms by the investigator at every study visit 
according to the schedule of assessment will include the following:

Fever (38C or 100.4F)

Symptoms of polymyalgia rheumatica (PMR; morning stiffness and/or pain, in the 
shoulder and/or hip girdles)

Localized headache, temporal artery or scalp tenderness

Visual signs or symptoms such as acute or subacute vision loss due to arteritic 
anterior ischemic optic neuropathy, transient blurry vision (generally monocular or at 
least affecting one eye at a time, but potentially affecting both eyes)

Jaw or mouth pain

New or worsened extremity claudication

Other features judged by both the clinician-investigator to be consistent with a GCA 
or PMR flare
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

ESR (using the Westergren method; to be assessed locally using a kit provided by 
the Sponsor)

TB screening test (see Appendix 3 for detailed description)
The following samples will be sent to the Sponsor’s designees (as outlined below)
for analysis:

Serum samples for PK analysis

Serum samples for immunogenicity analysis (anti-drug antibodies)

Serum samples for PD assessment of sIL-6R

Serum samples for PD assessment of IL-6


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
CRP (high-sensitivity CRP)

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes,
other cells)

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin
(direct and indirect bilirubin will be performed if total bilirubin is greater than the 
ULN), ALP, ALT, AST, uric acid, CPK, and lactate dehydrogenase

Viral serology:  HBsAg, total hepatitis B core antibody, and hepatitis C virus 
antibody

Lipid panel: total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides
Overnight fasting (8 hours) is required

Pregnancy test
Urine pregnancy tests will be performed at screening and at the end of the 
study.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood)
and microscopic examination only if indicated after local dipstick analysis (sediment, 
RBCs, WBCs, casts, crystals, epithelial cells, bacteria)
Covance Laboratories will transport and analyze the safety samples collected during the 
study. Following analysis, any residual from these samples will be destroyed within 
7 days. In addition, Covance Laboratories will transport, temporarily store, and then
ship PK/PD/anti-drug antibody samples to QPS Netherlands for analysis and storage 
until the final clinical study report has been written, after which the samples will be 
destroyed. In the case of positive tests for anti-TCZ antibody, the samples will be sent 
to SRL, Inc. for IgE testing.
The addresses of the above-mentioned laboratories are provided below:
Covance Laboratories
Covance Central Laboratory Services SA
Rue Moïse-Marcinhes 7
1217 Meyrin/Genève
Switzerland
QPS Netherlands
QPS Netherlands B.V., Sample Team
Professor Rankestraat 4244
9713 GG Groningen
The Netherlands


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SRL, Inc.
SRL, Inc.
Second Hachioji Laboratory
Immuno-chemistry Dept.
51 Komiyacho, Hachioji
Tokyo, 192-8535
Japan
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Biological samples will be destroyed when the final CSR has been completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.8
Electrocardiograms
Single ECG recordings will be obtained at screening, as outlined in the schedule of 
activities (see Appendix 1), and may be obtained at unscheduled timepoints as clinically 
indicated. At screening, if an ECG has been obtained within the past 6 months that 
shows no clinically significant abnormality and no signs or symptoms suggestive of 
cardiovascular disease that would exclude the patient, then an additional ECG is 
not required.
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all 
ECG tracings.  Paper copies of ECG tracings will be kept as part of the patient's 
permanent study file at the site.


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4.5.9
Chest X-rays
Posterior–anterior and lateral chest X-rays (or chest X-rays in accordance with local 
requirements) should be obtained at screening and reviewed by the investigator or his or 
her designee. At screening, if a chest X-ray has been obtained within the past 6 months 
that shows no clinically significant abnormality and no signs or symptoms suggestive of 
pulmonary disease that would exclude the patient, then an additional chest X-ray is 
not required.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of 
the following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Any event that meets stopping criteria defined in Section 5.1.1
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment must withdraw from the 
study and may be replaced.
Patients will return to the clinic for a treatment discontinuation visit 28 (3) days after the 
final dose of study drug (see Appendix 1 for additional details).
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study may be replaced.  


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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with TCZ in 
clinical studies and post-market experience.  The important safety risks for TCZ are 
outlined below.  Please refer to the Tocilizumab Investigator's Brochure for a complete 
summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events and laboratory abnormalities, including criteria for dosage modification 
and treatment interruption or discontinuation, are provided below.


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5.1.1
Risks Associated with Tocilizumab
5.1.1.1
Hypersensitivity Reactions, Including Anaphylaxis
An infusion reaction is defined as any adverse event that occurs during or within
24 hours after the infusion. This may include hypersensitivity or anaphylactic reactions.
Stevens-Johnson syndrome has been reported during treatment with TCZ in the 
post-marketing setting.  Signs of a possible hypersensitivity reaction include, but are not 
limited to, the following:

Fever, chills, pruritus, urticaria, angioedema, and skin rash

Cardiopulmonary reactions, including chest pain, dyspnea, hypotension, or 
hypertension
TCZ infusions will be administered to patients at the site under close supervision.  
Health care professionals administering TCZ infusions should be trained in the 
appropriate procedures for TCZ administration, should be able to recognize the 
symptoms associated with potential hypersensitivity reactions, including anaphylaxis, 
and should have the appropriate medication available for immediate use in case of 
hypersensitivity reaction such as anaphylaxis during or after administration of TCZ.  
The patient should be treated according to the standard of care for management of the 
hypersensitivity reaction. 
Study site personnel should educate patients about the signs and symptoms of
hypersensitivity and anaphylaxis and instruct them to seek medical attention if they 
experience symptoms of a hypersensitivity reaction outside of the clinic.  Patients 
enrolled in this study will be provided with a Patient Information Card that contains 
this information.
If a patient has symptoms of serious hypersensitivity reactions, such as anaphylaxis, or 
requires an interruption of the study drug because of symptoms of hypersensitivity
including anaphylaxis, administration of TCZ must be discontinued permanently and the 
patient should be withdrawn from the study.
For any patients withdrawing from the study because of a serious or non-serious
hypersensitivity reaction, including anaphylaxis, blood samples for the presence of 
anti-TCZ antibodies and PK/PD assessments should be obtained at the time of the event 
and approximately 8 weeks after the last dose.
5.1.1.2
Serious Infections and Opportunistic Infections
Physicians should exercise caution when considering the use of TCZ in patients with 
increased risk of infection, such as a history of recurring infections or with underlying 
conditions (e.g., diabetes mellitus) which may predispose patients to serious infections
and opportunistic infections such as TB and viral reactivations (e.g., hepatitis B virus).
Vigilance for timely detection of serious infection is recommended for patients receiving 
biologic agents, as signs and symptoms of acute inflammation may be lessened 


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because of suppression of the acute-phase reaction. The effects of TCZ on CRP and 
neutrophils, and the signs and symptoms of infection, should be considered when 
evaluating a patient for a potential infection.  
Patients enrolled in this study will be provided with a Patient Information Card informing 
them and health care providers of the importance of recognition of early signs of 
infections so that appropriate diagnostic and therapeutic measures can be introduced in 
a timely manner.  Patients must be instructed to contact their physician immediately 
when any symptoms suggesting infection appear to ensure rapid evaluation and 
appropriate treatment.
If a patient develops a serious infection, administration of TCZ should be interrupted 
until the infection is controlled; therefore, the patient will be discontinued from the study. 
The investigator should consider the benefits and risks to the patient before resuming 
treatment with TCZ.
5.1.1.3
Gastrointestinal Perforations
Symptomatic diverticulosis, diverticulitis, or chronic ulcerative lower GI disease, such as 
Crohn disease, ulcerative colitis, or other chronic lower GI conditions, might predispose 
patients to GI perforations.  Therefore, patients with these conditions are excluded from 
the study (see Section 4.1.2). 
Timely diagnosis and appropriate treatment may reduce the potential for complications 
of diverticular disease and thus reduce the risk of GI perforations.  Therefore, patients 
should be made aware of the symptomatology suggestive of diverticular disease and be 
instructed to alert their health care provider as soon as possible if these symptoms arise. 
Discontinuation of TCZ is required for patients who develop GI perforations.
5.1.1.4
Hematologic Abnormalities
Decreases in neutrophil and platelet counts, and fibrinogen levels, have been observed 
following treatment with TCZ. Because the primary objective of the study is to 
characterize the PK parameters following 7 or 6 mg/kg TCZ IV Q4W, any deviation from 
the predefined study dose regimen will lead to study withdrawal. 
Risk mitigation strategies for neutropenia and thrombocytopenia are summarized in 
Table 2 and Table 3, respectively.
Table 2
Risk Mitigation for Neutropenia
Laboratory Value 
Action
ANC 1 cell109/L
Withdraw the patient from the study


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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 WBC count with differential count performed weekly until the ANC is 
1 cell109/L. If the ANC does not return to 1 cell109/L within 2 months (or sooner if 
deemed necessary by the investigator), a hematology referral is recommended.
Table 3
Risk Mitigation for Thrombocytopenia
Laboratory Value 
Action
Platelet count 100 cells 
103/L
Withdraw the patient from the study
Patients withdrawn from the study because of a reduced platelet count must repeat 
platelet tests weekly until the count is 100,000/L. If platelets do not return to 
100,000/L within 2 months (or sooner if deemed necessary by the investigator), a 
hematology referral is recommended.
5.1.1.5
Demyelinating Disorders
The effect of treatment with TCZ on demyelinating disorders is not known; events have 
been reported rarely.  Physicians should exercise caution when considering the use of 
TCZ in patients with preexisting or recent-onset demyelinating disorders.  
Patients should be closely monitored for signs and symptoms potentially indicative of 
central demyelinating disorders.  During assessment of a potential demyelination event, 
treatment with TCZ should be interrupted and patients will be discontinued from 
the study.
5.1.1.6
Elevated Liver Enzymes
Risk mitigation strategies for patients with elevated ALT or AST are presented in 
Table 4. Because the primary objective of the study is to characterize the 
PK parameters following administration of 7 or 6 mg/kg TCZ IV Q4W, any deviation from 
the predefined study dose regimen will lead to patient withdrawal from the study.


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Table 4
Risk Mitigation for Liver Enzyme Abnormalities
ALT or AST Values
Action
Greater than 1 to 3ULN a
Modify the dose of concomitant MTX if appropriate.
For persistent increases (e.g., at least two consecutive 
measurements) in this range, withdraw the patient from 
the study.
Greater than 3ULN a
(confirmed by repeat 
testing)
Withdraw the patient from the study.
MTX methotrexate; ULN upper limit of normal.
a ULN or the patient’s baseline value, whichever is higher
The Medical Monitor should be contacted for further discussion of the case if ALT or 
AST elevation 3ULN is combined with at least one of the following:

Total bilirubin 2ULN

INR 1.5

ALP 2ULN

Presence of worsening fatigue, nausea, vomiting, fever, rash, or eosinophilia
Patients who are withdrawn from the study because of elevated liver function tests must 
have repeat tests performed as clinically indicated until levels return to baseline.  If the 
patient’s liver function tests have not returned to normal or the patient’s baseline level 
within 6 months (or sooner if deemed necessary by the investigator), the investigator 
should consider referral to a specialist.  If the specialist deems a liver biopsy necessary, 
the prepared histologic slides will be requested by the Sponsor for central review by a 
third party, and the biopsy report should be forwarded to the Sponsor.
5.1.1.7
Elevated Lipids
Patients with GCA are at increased risk for cardiovascular disorders; therefore, risk 
factors for cardiovascular disease should be managed as part of standard of care.
For patients with LDL cholesterol levels of 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 by the National Cholesterol Education Program (NCEP) Adult 
Treatment Panel III (NCEP 2002) or other national guidelines.
5.1.1.8
Malignancies
The effect of IL-6R signaling inhibition on the development of malignancies is not known.  
Although no imbalance of malignancies was observed in controlled clinical trials of TCZ 


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in patients with RA, malignancies have been identified as a concern for other biologic 
agents. It is recognized that, given the latency for such events, identification of 
malignancies in TCZ-treated patients may require a longer period of surveillance. 
TCZ administration should be discontinued for patients with malignancies (with the 
exception of local basal or squamous cell carcinoma of the skin or carcinoma in situ of 
the cervix uteri that has been excised and cured).
5.1.1.9
Immunogenicity
Serious hypersensitivity reactions (i.e., clinically significant infusion reactions or 
anaphylaxis), and lack of efficacy or decreased efficacy, are potential risks that could be 
associated with development of anti-TCZ antibodies.
Because the patients recruited in the study have been previously treated with TCZ, the 
immunogenicity assessment in this study will be "event-driven."  A sample will be taken 
prior to the first study dose at baseline or the first visit at Period 2 for those patients 
entering Period 2 directly.  For any patients withdrawing from the study because of
serious or non-serious hypersensitivity reaction, including anaphylaxis, blood samples 
for the presence of anti-TCZ antibodies and PK/PD assessments should be obtained at 
the time of occurrence of the event and approximately 8 weeks after the last dose, as 
outlined in Appendix 1.
5.1.1.10
CYP450 Enzyme Normalization
The expression of hepatic cytochrome P450 (CYP450) enzymes is suppressed by
cytokines, such as IL-6, that stimulate chronic inflammation. TCZ normalizes 
expression of these enzymes.  The effect of TCZ on CYP450 enzymes (except
CYP2C19 and CYP2D6) is clinically relevant for CYP450 substrates with a narrow
therapeutic index and/or when the dose is individually adjusted.
When starting or stopping therapy with TCZ, patients taking medicinal products which
are individually dose adjusted and are metabolized via CYP450 CYP3A4, CYP1A2, 
CYP2B6, or CYP2C9 (e.g., atorvastatin, calcium- channel blockers, theophylline,
warfarin, phenprocoumon, phenytoin, cyclosporine, or benzodiazepines) should be
monitored as doses of these products may need to be adjusted to maintain their
therapeutic effect.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8
and 5.3.5.9 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)


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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

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 (see Section 5.3.5.6)

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.

Serious and/or medically significant infections

Myocardial infarction or acute coronary syndrome

GI perforations

Malignancies

Anaphylaxis or hypersensitivity reactions 

Stroke

Serious and/or medically significant bleeding events

Serious and/or medically significant hepatic events

Demyelinating disorders


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will 
be recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 5
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 (v5.0), 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 (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 6):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event


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Table 6
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only the diagnosis of liver failure or hepatitis 
rather than symptoms like 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, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.


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
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).


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5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

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 most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
This includes death attributed to progression of GCA.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of giant cell arteritis, “giant cell arteritis
progression" should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 


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recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Giant Cell Arteritis
Events that are clearly consistent with the expected pattern of progression of the
underlying disease should not be recorded as adverse events. These data will be
captured as efficacy assessment data only. The determination of clinical progression
will be based on investigator’s assessment at every visit. If there is any uncertainty 
as to whether an event is due to disease progression, it should be reported as an 
adverse event.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization for an adverse event that would ordinarily have been treated in an
outpatient setting had an outpatient clinic been available


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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Accidental overdoses or medication errors (see Section 5.4.4 for details on reporting 
requirements)
The investigator must report new significant follow-up information for these events to 
the Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB) or Ethics 
Committee (EC).
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor:
, M.D.
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 


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5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur more than 28 days after the 
final dose of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the final
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 


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Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
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
28 days after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
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
Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For TCZ, 
adverse events associated with special situations should be recorded as described 
below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with TCZ, regardless of whether they result 
in an adverse event, should be recorded on the Adverse Event eCRF and reported to 
the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.


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5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the final dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Tocilizumab Investigator's Brochure


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The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Given the small sample size, the short duration of the study, and open-label design 
without a control arm, a dose-related effect on flares is not expected to be observed. 
Sample size estimates are entirely based on PK data. PK, PD, safety, and efficacy data 
will be summarized descriptively. No formal statistical hypothesis testing is planned. 
A database lock will occur when the last patient has completed the final visit 28 days 
after the final dose.
The primary PK variables in this study are estimates of steady-state Ctrough, Cmax, and 
AUC4weeks at the two dose levels of TCZ IV therapy (7 mg/kg Q4W and 6 mg/kg Q4W).
For each dose level, Ctrough and Cmax will be summarized at each timepoint for each dose 
administered and AUC4weeks estimated for the last dosing cycle will be summarized as 
geometric means, medians, ranges, and standard deviations.
6.1
DETERMINATION OF SAMPLE SIZE
In order to provide a precise characterization of PK parameters (Ctrough, Cmax, and 
AUC4weeks), in this study, a hybrid of two approaches will be followed. The first of these 
approaches is the guidance for estimation of sample size in pediatric studies, which 
requires a study to be prospectively powered to target 95% CI within 60%140% of the 
geometric mean estimates of clearance and volume of distribution for the drug in each 
pediatric sub-group with at least 80% power (Wang et al. 2012). The second is the 
sample size guidance from the Food and Drug Administration (FDA) for bioequivalence 
studies, which specifies the 90% CI for the geometric mean ratio (GMR) should fall 
within 80%125% of the GMR estimate (U.S. FDA 2001).
Given the need to characterize the PK parameters to a higher precision than in a 
pediatric population, the sample size for this study was estimated based on achieving a 
target of 95% CI for estimates of Cmax and Ctrough at each dose level that would fall within 
80%125% of the geometric mean estimate.
In Study ML25676, observed steady-state Ctrough data were available for 18 patients 
receiving 8 mg/kg TCZ IV Q4W.  The geometric mean was 44.4 g/mL (95% CI: 37.0, 
53.4), with the 95% CI corresponding to 83% and 120% of the geometric mean estimate.
Using the variability in observed steady-state Ctrough in Study ML25676, a sample size of 
n17 will provide 80% power to characterize the geometric mean estimate of the 


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observed Ctrough and Cmax so that the 95% CI falls within 80%125% of the geometric 
mean estimate of the corresponding PK parameter. A minimal sample size of n12 
would provide 80% power for the 90% CI to fall within 80%–125% of the geometric 
mean estimate of the corresponding PK parameter.  To account for potential study 
dropouts, approximately 25 patients already receiving 8 mg/kg IV TCZ and in remission 
will be enrolled in the Period 1 of this study with the goal of obtaining robust PK 
characterization at both dose levels. 
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete each study period and the
study overall will be summarized.  Reasons for premature study withdrawal will be listed 
and summarized.  Enrollment and major protocol deviations will be listed and evaluated 
for their potential effects on the interpretation of study results. The number of doses 
received will be summarized for each study period. A listing of patients in each period 
detailing dosing of TCZ will be prepared.
6.3
SUMMARIES OF BASELINE CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, body weight) will be 
summarized using means, standard deviations, medians, and ranges for continuous 
variables and proportions for categorical variables, as appropriate.  
Medical history data, including surgeries, procedures, and baseline conditions, will be
summarized descriptively using the safety population. Previous and concomitant 
treatment will be summarized descriptively. 
6.4
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of patients who have received one dose of TCZ 
and have one valid PK sample, with patients grouped according to treatment received. 
Individual and mean serum TCZ concentration versus time data will be tabulated and 
plotted by dose level.  The serum pharmacokinetics of TCZ will be summarized by 
estimating total exposure (AUC4weeks), Cmax, and Ctrough at steady state. Estimates for 
these parameters will be tabulated and summarized (mean, standard deviation, 
coefficient of variation, median, minimum, and maximum).  Inter-patient variability and 
drug accumulation will be evaluated. Additional PK analyses will be conducted as 
appropriate.
6.5
PHARMACODYNAMIC ANALYSES
The PD analysis population will be identical to the safety analysis population. 
Individual and mean serum concentration versus time data will be tabulated and plotted 
by dose level.  CRP and ESR data will be summarized as median and ranges.
Estimates for CRP levels and ESR at steady state (after the last dose at each dose 


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level) will be tabulated and summarized (mean, standard deviation, coefficient of 
variation, median, minimum, and maximum).
6.6
SAFETY ANALYSES
The safety analysis population will consist of all patients who received at least one dose 
of study drug and had at least one safety assessment.
Safety will be assessed in terms of adverse events (nature, frequency, severity, and 
causality).  Adverse events will be summarized by study period and listed.
Values, along with change from baseline, will be summarized using descriptive statistics 
for each laboratory test and vital sign parameter.  Marked abnormalities will be listed.
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to NCI CTCAE v5.0.
6.7
EXPLORATORY EFFICACY ANALYSES
The analysis population for the efficacy summaries and listings will consist of all patients
who received at least one dose of study drug and had at least one efficacy assessment.  
A summary by study period and supportive listing of the number of patients with flare(s), 
and the number of patients in remission by visit will be produced. 
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.


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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 


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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards 
for Expedited Reporting).  Studies conducted in the United States or under a 
U.S. Investigational New Drug (IND) Application will comply with U.S. FDA regulations 
and applicable local, state, and federal laws.  Studies conducted in the European Union
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 


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IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study. Patients will be told that they are free to refuse to 
participate and may withdraw their consent at any time for any reason.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient.  All signed and 
dated Consent Forms must remain in each patient's study file or in the site file and must 
be available for verification by study monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate
medical personnel responsible for the patient's welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted clinical study reports and other summary reports will be provided 
upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will 
receive the patient data, including an audit trail containing a complete record of all 
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9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Two sites in Switzerland will participate to enroll approximately 25 patients.
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests and PK analyses), as specified in Section 4.5.7.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
European Medicines Agency, and in peer-reviewed journals. The Sponsor will comply 
with all requirements for publication of study results.  Study data may be shared with 
others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 


Tocilizumab—F. Hoffmann-La Roche Ltd
67/Protocol WP41152, Version 4
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Tocilizumab—F. Hoffmann-La Roche Ltd
68/Protocol WP41152, Version 4
10.
REFERENCES
Abdallah H, Hsu JC, Lu P, et al. Pharmacokinetic and Pharmacodynamic Analysis of 
Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 
Randomized, Controlled Trials: SUMMACTA and BREVACTA. J Clin Pharmacol 
2017;57:459−68.
Frey N, Grange S, Woodsworth T. Population pharmacokinetic analysis of tocilizumab in 
patients with rheumatoid arthritis. J Clin Pharmacol 2010;50:754−66.
Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. 2001. 
Available from https://www.fda.gov/downloads/drugs/guidances/ucm070244.pdf.
Hayreh SS, Podhajsky PA, Raman R. Giant cell arteritis: validity and reliability of various 
diagnostic criteria. American Journal of Ophthalmology 1997;123:28596.
Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 
criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:11228.
Kermani TA, Warrington KJ, Crowson CS, et al. Large-vessel involvement in giant cell 
arteritis: a population-based cohort study of the incidence-trends and prognosis. 
Ann Rheum Dis 2013;72:198994.
Lawrence RC, Felson DT, Hemick CG, et al. Estimates of the prevalence of arthritis and 
other rheumatic conditions in the United States. Arthritis Rheum. 2008;58:2635.
Lee JL, Naguwa GS, Cheema GS, et al. The geo-epidemiology of temporal (giant cell) 
arteritis. Clinic Rev Allergy Immunol 2008;35:8895.
National Institutes of Health, National Heart, Lung, and Blood Institute, National 
Cholesterol Education Program. Third report of the National Cholesterol Education 
Program (NCEP) expert panel on detection, evaluation, and treatment of high 
blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 
2002;106:3143–421. Available from: 
http://circ.ahajournals.org/content/106/25/3143.long
Paulus HE, Ramos B. Equivalence of the acute phase reactants C-reactive protein,
plasma viscosity, and Westergren erythrocyte sedimentation rate when used to 
calculate American College of Rheumatology 20% improvement criteria or the 
disease activity score in patients with early rheumatoid arthritis. J Rheumatol 
1999;26:232431.
Proven A, Gabriel SE, Orces C, et al. Glucocorticoid therapy in giant cell arteritis: 
duration and adverse outcomes. Arthritis Rheum 2003 Oct 15;49(5):7038.
Salvarani C, Crowson C, O’Fallon M, et al. Reappraisal of the epidemiology of giant cell 
arteritis in Olmsted County, Minnesota, over a fifty-year period. Arthritis Rheum 
2004;51:2648.
Stone JH, Tuckwell K, Dimonaco S, et al. Trial of Tocilizumab in Giant-Cell Arteritis. 
N Engl J Med 2017;377 ;31728.


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Villiger PM, Adler S, Kuchen S, et al. Tocilizumab for induction and maintenance of 
remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-
controlled trial. Lancet 2016;387:19217.
Wang Y, Jadhav PR, Lala M, et al. Clarification on precision criteria to derive sample 
size when designing pediatric pharmacokinetic studies. J. Clin Pharmacol 
2012;52:1601–6.
Wolfe F. Comparative usefulness of C-reactive protein and erythrocyte sedimentation
rate in patients with rheumatoid arthritis. J Rheumatol 1997;24:1477−85


Tocilizumab—F. Hoffmann-La Roche Ltd
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Appendix 1
Schedule of Activities
Period
Scrn 
(D28 
to
1) a
Period 1
Period 2
Early 
WD b
Month
1
2
3
4
5
6
7
8
9
10
Week
1
4
8
12
16
17
18
19
20
24
28
32
36
37
38
39
40
(EOS)
Day
1
29
57
85
113
120
127
134
141
169
197
225
253
260
267
274
281
Visit window (days)
3
3
3
3
1
1
1
1
3
3
3
3
1
1
1
1
3
Informed consent c
x
Demographic data
x
Medical history and 
baseline conditions
x
Physical 
examination d
x
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
x
x
x
x
x
Chest X-ray f
x
ECG g
x
Tuberculosis 
screening h
x
Hematology i
x
x
x
x
x
x
x
Chemistry panel j
x
x
x k
x
x
x l
x
x
x
Viral serology m
x
Lipid panel n
x
x
x
x
Pregnancy test o
x
x
x


Appendix 1: Schedule of Activities
Tocilizumab—F. Hoffmann-La Roche Ltd
71/Protocol WP41152, Version 4
Period
Scrn 
(D28 
to
1) a
Period 1
Period 2
Early 
WD b
Month
1
2
3
4
5
6
7
8
9
10
Week
1
4
8
12
16
17
18
19
20
24
28
32
36
37
38
39
40
(EOS)
Day
1
29
57
85
113
120
127
134
141
169
197
225
253
260
267
274
281
Visit window (days)
3
3
3
3
1
1
1
1
3
3
3
3
1
1
1
1
3
Urinalysis p
x
x
x
x
ESR
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
CRP
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IL-6 and sIL-6R
See Appendix 2
x q
TCZ PK
See Appendix 2
x q
Anti-TCZ Ab 
x
x r
x q
Adverse events s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Clinical 
assessment of
GCA signs and 
symptoms
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
TCZ administration 
(7 mg/kg IV)
x
x
x
x
x
TCZ administration 
(6 mg/kg IV)
x
x
x
x
x


Appendix 1: Schedule of Activities
Tocilizumab—F. Hoffmann-La Roche Ltd
72/Protocol WP41152, Version 4
Abantibody; BLbaseline; CRP C-reactive protein; EOS end of study; ESR erythrocyte sedimentation rate; GCAgiant cell arteritis; 
HBcAbtotal hepatitis B core antibody; HBsAghepatitis B surface antigen; HCVhepatitis C virus; IL-6 interleukin 6; LDH lactate 
dehydrogenase; NA not applicable; sIL-6Rsoluble IL-6 receptor; PDpharmacodynamic; PK pharmacokinetic; Q4W every 4 weeks; 
Scrnscreening; TCZ tocilizumab; ULNupper limit of normal; WDwithdrawal.
Notes: Laboratory samples should be drawn at least 30 minutes before clinical assessment. If any patients enter Period 2 directly, the Period 1 
assessments should be followed with the exception that patients should receive 6 mg/kg TCZ IV instead of 7 mg/kg.
a Screening applies to all patients enrolling in Period 1 or directly into Period 2.  Results of standard-of-care tests or examinations performed prior 
to obtaining informed consent and within 28 days prior to Day 1 may be used; such tests do not need to be repeated for screening.
b Patients will return to the clinic for a study discontinuation visit at 28 (3) days after the final dose of study drug.
c Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 28 days before 
initiation of study treatment.
d Physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurologic systems.  Limited, symptom-directed physical examinations may be performed at 
unscheduled post-baseline visits as clinically indicated per the investigator’s discretion.  
e Vital signs include pulse rate, systolic and diastolic blood pressure (after patient has been seated for at least 5 minutes), and temperature.  
f
Not required if a normal chest X-ray has been obtained within 6 months prior to screening.
g ECG recordings will be obtained at screening and subsequently as clinically indicated. An ECG is not required if a normal ECG has been 
obtained within 6 months prior to screening.
h Tuberculosis screening will be performed according to local guidance.
i
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
j
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin (direct and indirect bilirubin will 
be performed if total bilirubin is greater than the ULN), ALP, ALT, AST, uric acid, CPK, and LDH.
k Chemistry panel at Week 4 only required for patients who had received only five consecutive doses of 8 mg/kg TCZ IV Q4W prior to baseline.
l
Chemistry panel at Week 24 only required for patients entering Period 2 directly (without prior participation in Period 1) who had received only 
five consecutive doses of 8 mg/kg TCZ IV Q4W prior to the first study visit in Period 2. 
m Patients will be screened for HBsAg, total HBcAb, and HCV antibody.
n Lipid panel includes total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. Patients are required to fast overnight (8 hours). 
o All women will have a urine pregnancy test at screening and the end of study.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test.  Pregnancy test on freshly voided urine may be performed at any visit at the investigator’s discretion.


Appendix 1: Schedule of Activities
Tocilizumab—F. Hoffmann-La Roche Ltd
73/Protocol WP41152, Version 4
p Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination only if indicated after local 
dipstick analysis (sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria). 
q For any patients withdrawing from the study because of a serious or non-serious hypersensitivity reaction, including anaphylaxis, blood samples 
for the presence of anti-TCZ antibodies and PK/PD assessments should be obtained at the time of occurrence of the event and approximately
8 weeks after the last dose.
r
Only applies to patients who enter Period 2 directly, without first participating in Period 1.
s After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until the end of study/early withdrawal visit.  
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to 
prior study drug treatment (See Section 5.6). 
t
Medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient in 
addition to protocol-mandated treatment from 28 days prior to initiation of study drug until the end of study visit. 


Tocilizumab—F. Hoffmann-La Roche Ltd
74/Protocol WP41152, Version 4
Appendix 2
Schedule of Pharmacokinetic, IL-6, and sIL-6R Samples 
Study visit 
(Weeks)
Study Visit (Days)
Timepoint a
PK
IL-6 and 
sIL-6R 
Week 1
Day 1
Predose
x
x
EOI
x
Week 4
Day 29 (3 d)
Predose
EOI
Week 8
Day 57 (3 d)
Predose
x
EOI
x
Week 12
Day 85 (3 d)
Predose
x
x
EOI
x
Week 16
Day 113 (3 d)
Predose
x
x
EOI
x
Week 17
Day 120 (1 d)
At visit
x
Week 18
Day 127 (1 d)
At visit
x
Week 19
Day 134 (1 d)
At visit
x
Week 20
Day 141 (1 d)
Predose
x
x
EOI
x
Week 24
Day 169 (3 d)
Predose
EOI
Week 28
Day 197 (3 d)
Predose
x
EOI
x
Week 32
Day 225 (3 d)
Predose
x
x
EOI
x
Week 36
Day 253 (3 d)
Predose
x
x
EOI
x
Week 37
Day 260 (1 d)
At visit
x
Week 38
Day 267 (1 d)
At visit
x
Week 39
Day 274 (1 d)
At visit
x
Week 40
(EOS)
Day 281 (1 d)
At visit
x
x
Dday; EOI = end of infusion; IL-6interleukin-6; PKpharmacokinetic;
sIL-6Rsoluble interleukin-6 receptor.
a Predose PK, IL-6, and sIL-6R assessments will be obtained from a single 
specimen and should be taken 03 hours before the start of infusion.  EOI 
samples should be taken 015 minutes after the saline flush marking the end of 
infusion and should be obtained from the patient’s opposite arm relative to the 
dosing arm.


Tocilizumab—F. Hoffmann-La Roche Ltd
75/Protocol WP41152, Version 4
Appendix 3 Tuberculosis Screening and Treatment 
Assessments
Tuberculosis Screening
Before initiation of therapy with study drug, all patients must be evaluated for both active
and inactive (latent) tuberculosis (TB; Mycobacterium TB infection).  This evaluation may 
include the following (additional local recommendations may apply):

Medical history

Physical examination

Test for TB infection (TB skin test or special blood test)

Chest radiograph (X-ray)

Appropriate bacteriologic or histologic examinations (tests to see whether 
TB bacteria are in the sputum)
A test for latent TB (per local practice guidelines or as described below) must be 
performed within 3 weeks prior to the initiation of study drug treatment. 

The Mantoux tuberculin skin test (purified protein derivative [PPD]) and interferon 
(IFN)-–based test (e.g., the QuantiFERON®-TB Gold [QFT-G]) are examples of 
acceptable screening assays for latent TB in this study. 

An IFN-–based test should be considered when the results of the tuberculin skin 
test are not considered reliable (e.g., positive PPD test in a patient with previous 
bacille Calmette Guérin vaccination or a negative PPD test in a patient who may 
be anergic).
All TB testing will be performed locally.  Investigators are reminded of the risk of 
false-negative tuberculin skin test results, especially for patients who are severely ill or 
immunocompromised.
TB Treatment
If active TB is diagnosed, study drug treatment must not be initiated.
If inactive (latent) TB is diagnosed, appropriate treatment for latent TB must be started 
with anti-TB prophylaxis therapy 4 weeks before the treatment with study drug is initiated.  
If a full course of anti-TB treatment for latent TB has been completed previously, there is 
no need to initiate the treatment again; however, the potential risk of re-infection should 
be evaluated.
If inactive (latent) TB is suspected, a physician with expertise in the treatment of TB 
should be consulted.  In all situations described below, the benefit–risk balance of 
therapy should be carefully considered.
Use of anti-TB therapy should also be considered before the initiation of study drug in 
patients with a history of inactive (latent) or active TB in whom an adequate course of 


Tocilizumab—F. Hoffmann-La Roche Ltd
76/Protocol WP41152, Version 4
Appendix 3 Tuberculosis Screening and Treatment 
Assessments (cont.)
treatment cannot be confirmed.  Some patients who have previously received treatment 
for inactive (latent) or active TB have developed active TB while being treated with study 
drug.  If an individual is determined to have a positive TB test result based on
country-specific guidelines (or U.S. guidelines if none exist), the local country guidelines 
should be consulted for acceptable anti-TB treatment regimens.  If no local guidelines 
exist for treatment of immunocompromised individuals, then the U.S. guidelines must 
be followed.
Patients should be instructed to seek medical advice if signs or symptoms 
(e.g., persistent cough, wasting/weight loss, low-grade fever) suggestive of TB occur 
during or after therapy with study drug.
The U.S. guideline can be found at the following link:  http://www.cdc.gov/tb/.

SAP_001.pdf: 
 
Official Title: A Phase Ib, Open-Label, Dose-Ranging Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of Tocilizumab 
Administered by Intravenous Infusion to Patients With Giant Cell 
Arteritis 
NCT Number: NCT03923738 
Document Date: SAP Version 2: 11-January-2021 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd}.
Tocilizumab —F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WP41152
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE Ib, OPEN-LABEL, DOSE-RANGING STUDY TO 
EVALUATE THE PHARMACOKINETICS, 
PHARMACODYNAMICS, AND SAFETY OF TOCILIZUMAB 
ADMINISTERED BY INTRAVENOUS INFUSION TO 
PATIENTS WITH GIANT CELL ARTERITIS
PROTOCOL NUMBER:
WP41152
STUDY DRUG:
Tocilizumab (RO4877533)
VERSION NUMBER:
2
IND NUMBER:
113,654
EUDRACT NUMBER:
2018-004718-17
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
DATE FINAL:
See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
11-Jan-2021 08:46:02
Company Signatory




Tocilizumab —F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan WP41152
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 7
2.
STUDY DESIGN........................................................................................... 7
2.1
Protocol Synopsis.................................................................... 8
2.2
Endpoints................................................................................. 8
2.2.1
Pharmacokinetic Endpoints ..................................................... 8
2.2.2
Pharmacodynamic Endpoints.................................................. 8
2.2.3
Safety Endpoints ..................................................................... 8
2.2.4
Exploratory Efficacy Endpoints................................................ 9
2.3
Determination of Sample Size ................................................. 9
2.4
Analysis Timing ..................................................................... 10
3.
STUDY CONDUCT..................................................................................... 10
3.1
Randomization....................................................................... 10
4.
STATISTICAL METHODS .......................................................................... 10
4.1
Analysis Populations ............................................................. 10
4.1.1
All Patients Population........................................................... 10
4.1.2
Efficacy Population................................................................ 11
4.1.3
Pharmacokinetic-Evaluable Population ................................. 11
4.1.4
Pharmacodynamic Population............................................... 11
4.1.5
Safety Population .................................................................. 11
4.2
Analysis of Study Conduct..................................................... 11
4.3
Summaries of Baseline Data ................................................. 11
4.3.1
Demographics and Disease Characteristics.......................... 11
4.3.2
Medical History...................................................................... 13
4.4
Surgeries and Procedures..................................................... 13
4.5
Previous and Concomitant Medications................................. 13
4.6
Visit Windows ........................................................................ 13
4.7
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 15
4.7.1
Pharmacokinetic Analyses..................................................... 15
4.7.2
Pharmacodynamic Analyses ................................................. 15


Tocilizumab —F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan WP41152
4.8
Exploratory Efficacy Analysis................................................. 15
4.8.1
Sensitivity Analyses............................................................... 16
4.8.2
Subgroup Analyses ............................................................... 16
4.9
Safety Analyses..................................................................... 16
4.9.1
Exposure of Study Medication............................................... 16
4.9.2
Adverse Events ..................................................................... 16
4.9.3
Laboratory Data..................................................................... 18
4.9.4
Vital Signs.............................................................................. 20
4.9.5
Immunogenicity Assessment................................................. 20
4.10
Missing Data.......................................................................... 21
4.11
Interim Analyses .................................................................... 21
5.
REFERENCES ........................................................................................... 21
LIST OF TABLES
Table 1
Time Windows for Assigning Assessment Study Days to 
Study Visits (Weeks) for Efficacy Exploratory Endpoints, 
CRP, ESR................................................................................... 14
Table 2
National Cholesterol Education Program (ATPIII) Thresholds .... 20
Table 3
Blood Pressure JNC 7 Category Criteria .................................... 20
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 23
Appendix 2
Study Schema............................................................................. 28
Appendix 3
Schedule of Activities.................................................................. 29
Appendix 4
Schedule of Pharmacokinetic, IL-6, and sIL-6R Samples........... 33


Tocilizumab —F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan WP41152
GLOSSARY OF ABBREVIATIONS
Abbreviation
Definition
AESI
Adverse events of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentrationtime curve
AUC4weeks
area under the concentrationtime curve over 4 weeks 
(the dosing interval)
BUN
blood urea nitrogen
Cmax
maximum serum concentration
Ctrough
trough concentration
CRP
C-reactive protein
CPK
creatine phosphokinase
CSR
Clinical Study Report
CTA
computed tomography angiography
CTCAE
Common Terminology Criteria for Adverse Events
EC
Ethics Committee
eCRF
electronic Case Report Form
ESR
erythrocyte sedimentation rate
FDA
Food and Drug Administration
GCA
giant cell arteritis
GI
gastrointestinal
GMR
geometric mean ratio
HBsAg
hepatitis B surface antigen
ICH
International Council for Harmonisation
IL-6
interleukin-6
IL-6R
interleukin-6 receptor
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IV
Intra Venous
LDH
lactate dehydrogenase
MRA
magnetic resonance angiography
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
PD
pharmacodynamic
PET-CT
positron emission tomography- computed tomography


Tocilizumab —F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan WP41152
Abbreviation
Definition
pH
negative logarithm of hydrogen ion concentration 
(pondus hydrogenii)
PK
pharmacokinetic
PMR
polymyalgia rheumatica
Q4W
every 4 weeks
RA
rheumatoid arthritis
RBC
Red Blood Cell
SC
subcutaneous
sIL-6R
soluble interleukin-6 receptor
sJIA
systemic juvenile idiopathic arthritis
TB
Tuberculosis
TCZ
Tocilizumab
ULN
upper limit of normal
WBC
White Blood Cell


Tocilizumab —F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan WP41152
1.
BACKGROUND
Tocilizumab (TCZ) has been evaluated in two completed randomized controlled trials in 
patients with Giant Cell Arteritis (GCA).  In the Phase III WA28119 (GiACTA) study, 149 
patients with GCA received subcutaneous (SC) TCZ (Stone et al. 2017), and based on 
the data from this trial, the SC formulation of TCZ was approved for the treatment of 
GCA in multiple countries worldwide. In a second study, the Phase II, investigator-
initiated ML25676 study, 20 patients with GCA received intravenous (IV) TCZ (Villiger et 
al. 2016).
Although the approval of SC TCZ is a significant step to improve the treatment paradigm 
for patients with GCA and reduce the burden of glucocorticoid (GC)-associated toxicity, 
important challenges remain. The availability of the IV formulation will provide another 
administration option for those patients who prefer IV infusion because of needle phobia. 
There is also a significant unmet medical need owing to a patient access issue to TCZ 
SC under U.S. medical insurance, which would not apply to TCZ IV. Furthermore, the 
patient population with GCA is older than the patient population with RA, and an unmet 
medical need exists for a subset of this elderly population for whom the IV infusion will 
be preferable, as some patients may either have difficulty administering the SC 
injections and/or may have suboptimal adherence to SC treatment. 
The ML25676 study indicated a positive benefit-risk profile for IV TCZ (8 mg/kg IV dose 
every 4 weeks (Q4W) regimen) in GCA similar to that observed for the approved SC 
route. However, PK data from the study are sparse, and although observed trough 
exposures were within the therapeutic range established in study WA28119, model 
based predictions showed that average exposures (but not peak concentrations) over a 
dosing interval at steady state are higher than those observed in the RA population at 
the same dose. Therefore, in order to supplement the pharmacokinetic (PK) data 
collected in ML25676 and to identify the optimal dose of IV TCZ that will best match the 
exposure leading to efficacy after SC TCZ administration as observed in Study 
WA28119, this study WP41152 will examine exposures achieved at steady state from 
multiple doses of 6 and 7 mg/kg IV TCZ Q4W.
This document describes the statistical methods for the analysis of the efficacy, 
pharmacokinetics, pharmacodynamics, and safety of 6 and 7 mg/kg of TCZ administered 
by IV infusion Q4W to patients with GCA.
2.
STUDY DESIGN
This is a Phase Ib, open-label, dose-ranging study designed to characterize the 
pharmacokinetics, pharmacodynamics, and safety of two dose levels of TCZ (6 and 7 
mg/kg) administered by IV infusion Q4W to patients with GCA.


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2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1. For additional details, see the Study Schema in 
Appendix 2.
2.2
ENDPOINTS
All assessments and procedures are listed with the relevant schedule detailed in the 
Schedule of Activities Table in Appendix 3. Additional information about the Schedule of 
Pharmacokinetic, IL-6, and sIL-6R Samples are provided in Appendix 4.
2.2.1
Pharmacokinetic Endpoints

Steady-state maximum serum concentration (Cmax) at specified timepoints

Ctrough at specified timepoints

AUC over the dosing interval of 4 weeks (AUC4weeks) at specified timepoints
PK samples will be obtained before and after each infusion of TCZ to characterize the 
Cmax and Ctrough of TCZ, and more intensive sampling during the last dosing cycle will be 
used to estimate the steady-state AUC4weeks at each dose level.
2.2.2
Pharmacodynamic Endpoints

Serum concentration of IL-6 at specified timepoints

Serum concentration of sIL-6R at specified timepoints

Serum concentration of C-reactive protein (CRP) at specified timepoints

Erythrocyte sedimentation rate (ESR) at specified timepoints
2.2.3
Safety Endpoints

Nature, frequency, severity, and causality of adverse events, with severity 
determined according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE).

Clinical safety laboratory results collected at specified timepoints. 
o
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, 
platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
o
Chemistry panel (serum or plasma) includes bicarbonate or total carbon 
dioxide (if considered standard of care for the region), sodium, potassium, 
chloride, glucose, BUN or urea, creatinine, total protein, albumin, 
phosphorus, calcium, total bilirubin (direct and indirect bilirubin will be 
performed if total bilirubin is greater than the ULN), ALP, ALT, AST, uric 
acid, CPK, and LDH
o
Lipid panel includes total cholesterol, LDL cholesterol, HDL cholesterol, 
and triglycerides


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o
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, 
ketones, blood) and microscopic examination only if indicated after local 
dipstick analysis (sediment, RBCs, WBCs, casts, crystals, epithelial cells, 
bacteria)
o
Viral serology includes HBsAg, total hepatitis B core antibody, and 
hepatitis C virus antibody

Vital signs: pulse rate, systolic and diastolic blood pressure, temperature collected 
at specified timepoints. Blood pressure measurements should be obtained prior to 
the infusion.

Immunogenicity assessment (anti-drug antibodies) for patients withdrawing from the 
study because of serious or non-serious hypersensitivity reaction.
2.2.4
Exploratory Efficacy Endpoints

Proportion of patients who experience a flare, defined as the recurrence of signs or 
symptoms of GCA and/or ESR 30 mm/h attributable to GCA as determined by the 
investigator, during each period

Proportion of patients in remission, defined as the absence of flare (defined above) 
and normalization of CRP (1 mg/dL), at each visit
2.3
DETERMINATION OF SAMPLE SIZE
In order to provide a precise characterization of PK parameters (Ctrough, Cmax, and 
AUC4weeks), in this study, a hybrid of two approaches was followed for sample size. The 
first of these approaches is the guidance for estimation of sample size in pediatric 
studies, which requires a study to be prospectively powered to target 95% CI within 
60%140% of the geometric mean estimates of clearance and volume of distribution for 
the drug in each pediatric sub-group with at least 80% power (Wang et al. 2012). The 
second is the sample size guidance from the Food and Drug Administration (FDA) for 
bioequivalence studies, which specifies the 90% CI for the geometric mean ratio (GMR) 
should fall within 80%–125% of the GMR estimate (U.S. FDA 2001).
Given the need to characterize the PK parameters to a higher precision than in a 
pediatric population, the sample size for this study was estimated based on achieving a 
target of 95% CI for estimates of Cmax and Ctrough at each dose level that would fall within 
80%125% of the geometric mean estimate.
In Study ML25676, observed steady-state Ctrough data were available for 18 patients 
receiving 8 mg/kg TCZ IV Q4W.  The geometric mean was 44.4 g/mL (95% CI: 37.0, 
53.4), with the 95% CI corresponding to 83% and 120% of the geometric mean estimate.
Using the variability in observed steady-state Ctrough in Study ML25676, a sample size of 
n17 will provide 80% power to characterize the geometric mean estimate of the 
observed Ctrough and Cmax so that the 95% CI falls within 80%125% of the geometric 
mean estimate of the corresponding PK parameter. A minimal sample size of n12 


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would provide 80% power for the 90% CI to fall within 80%–125% of the geometric 
mean estimate of the corresponding PK parameter.  To account for potential study 
dropouts, approximately 25 patients already receiving 8 mg/kg IV TCZ and in remission 
will be enrolled in the Period 1 of this study with the goal of obtaining robust PK 
characterization at both dose levels.
2.4
ANALYSIS TIMING
There will be final analysis and Clinical Study Report (CSR) when all patients have 
reached the end of the study: the end of this study is defined as the date when the last 
patient, last visit of Period 2 occurs, which corresponds to approximately 28 days after 
the last dose of Period 2.
3.
STUDY CONDUCT
The plan is to enroll approximately 25 patients into Period 1 in order to obtain data to 
robustly characterize the pharmacokinetics at each of the two dose levels.  If the dropout 
rate before Period 2 and/or variability are higher than planned, additional patients may 
be directly enrolled in Period 2.  Data from all patients receiving 6 mg/kg TCZ IV Q4W in 
Period 2 will be combined.
Although five doses (Q4W) at each dose level are sufficient to achieve the primary study 
objectives, if necessary to accommodate patient availability for the intensive PK 
sampling during the last dosing cycle, the dosing periods may be extended by one dose 
for a total of six doses. This will not be considered a protocol violation.
3.1
RANDOMIZATION 
The study is not randomized.
4.
STATISTICAL METHODS
Data collected during the 2 periods of treatment will be analyzed separately in general. 
Summaries of Period 2 will include patients that have completed Period 1 and may also 
include patients that have entered Period 2 directly. 
4.1
ANALYSIS POPULATIONS
Disposition summaries will be based on the All Patients population. Medical history data, 
including surgery and procedures and baseline conditions, will be summarized 
descriptively using the safety population. Analysis of safety and pharmacodynamic data 
will be based on the safety population and presented by period group. 
4.1.1
All Patients Population
The All Patients population will include all subjects enrolled in the study within any study 
period, i.e. all patients present in the clinical database .


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4.1.2
Efficacy Population
The Efficacy population will consist of all patients who received at least one dose of 
study drug and had at least one efficacy assessment in any study period.
4.1.3
Pharmacokinetic-Evaluable Population
The Pharmacokinetic (PK) analysis population will consist of patients who have received 
at least one dose of TCZ and have at least one valid PK sample in a given study period.
4.1.4
Pharmacodynamic Population
The Pharmacodynamic (PD) analysis population will consist of patients belonging to 
Safety analysis population. 
4.1.5
Safety Population
The Safety analysis population will consist of all patients who received at least one dose 
of study drug and had at least one safety assessment in any study period.
4.2
ANALYSIS OF STUDY CONDUCT
The number of patients who enroll, discontinue, or complete each study period and the
study overall will be summarized for the All Patient population.  Reasons for premature 
study drug discontinuation will be listed.  Major protocol deviations will be listed by site 
and evaluated for their potential effects on the interpretation of study results. A summary 
of all enrolled patients will be provided by country and investigator. In addition, a listing
of protocol deviations related to epidemic/pandemic will be provided in order to 
document any potential impact of the COVID-19 pandemic on the study.
4.3
SUMMARIES OF BASELINE DATA 
For baseline summaries of Period 2, for data that are only collected once at the start of 
the study, the original baseline data from Period 1 will be used for Patients entering 
Period 2 after completion of Period 1.
4.3.1
Demographics and Disease Characteristics
Demographic and baseline characteristics will be summarized using mean, standard 
deviation, median, minimum, and maximum for continuous variables and proportions for 
categorical variables, as appropriate for the Safety population.  Demographic and 
baseline characteristics will be listed.
Demographic and baseline disease characteristics will be summarized for period 1 
(separately by dose period only if any subject will be recruited directly into period 2) as 
described in the following sections. 


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Demographics

Sex

Age

Height

Weight

Race

Ethnicity

Smoking history
Disease Characteristics

Patient in Clinical Remission at period day 1

Erythrocyte sedimentation rate (ESR) at period day 1

C-reactive protein (CPR) at period day 1 

Duration of Disease (GCA) at period Day 1

Steroid use with GCA indication at period Day 1 (to be derived from concomitant 
medication use for GCA)

GCA characteristics at diagnosis
o
Age ≥50 years 
o
History of ESR ≥50 mm/h
o
History of CRP ≥2.45 mg/dL
o
Localized headache
o
Scalp tenderness
o
Temporal artery tenderness
o
Temporal artery decreased pulsation
o
Ischemia-related vision loss
o
Otherwise unexplained mouth or jaw pain upon mastication
o
Symptoms of PMR
o
Positive Temporal Artery Biopsy (TAB)
o
Large vessel vasculitis

Was Temporal Artery Biopsy (TAB) performed?

Was angiography or cross-sectional imaging study performed? If yes, which imaging 
study was performed (MRA, MRI, CTA, PET-CT, OTHER).
In addition, any positive tuberculosis screening, abnormal ECG or chest X-ray results at 
screening will be listed using the safety population.


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4.3.2
Medical history 
Medical history and baseline conditions will be summarized for period 1 (separately by 
dose period only if any subjects are recruited directly into period 2) using the Safety
population. A glossary showing the mapping of investigator verbatim terms to diseases 
will be produced for the medical history data.
4.4
SURGERIES AND PROCEDURES
A listing of any previous or ongoing surgeries and procedures will be produced using 
Safety population. 
4.5
PREVIOUS AND CONCOMITANT MEDICATIONS
Descriptive summaries of any previous treatment(s) will be produced. Previous 
medication consists of any treatments that stop prior to initiation of study drug.
Concomitant medications will be summarized separately by indication (for GCA and not 
for GCA). When summarizing concomitant medications, medications taken during the 
two dose periods will be summarized together.
A glossary showing the mapping of investigator verbatim terms to medication coded 
terms will be produced for previous or concomitant medication. All Analyses will be 
presented using Safety population.
4.6
VISIT WINDOWS
Endpoints collected according to scheduled visits will be assigned to a study week 
using the actual study day of the assessment; data collected at withdrawal visits and 
any unscheduled visits will also be mapped to the scheduled time points. Time windows 
will be continuous from the midpoint between two consecutive study visits to the next 
midpoint, and will be dependent on the schedule of assessments for each variable 
independently. An example table of time windowing for the exploratory endpoints is 
shown below (Table 1) for dose Period 1. Mapping of other variables will similarly be 
based on the scheduled visits. Data will never be mapped to visits for which the 
assessment was not scheduled in the protocol.


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Table 1
Time Windows for Assigning Assessment Study Days to Study 
Visits (Weeks) for Efficacy Exploratory Endpoints, CRP, ESR
Study visit
within period
(1 or 2)
Scheduled 
study day 
± 3 days
Efficacy time windowa
Baseline
1
≤ 2
Week 4
29
> 2 to ≤ 43
Week 8
57
> 43 to ≤ 71
Week 12
85
> 71 to ≤ 99
Week 16
113
> 99 to ≤ 116
Week 17
120
> 116 to ≤ 123
Week 18
127
> 123 to ≤ 130
Week 19
134
> 130 to ≤ 137
Week 20 b
141
> 137 to ≤ 144 or day of first 6mg/kg 
dose
For patients with a sixth dose
Week 16
113
> 99 to ≤ 127
Week 20
141
> 127 to ≤ 144
Week 21
148
> 144 to ≤ 151
Week 22
155
> 151 to ≤ 158
Week 23
162
> 158 to ≤ 165
Week 24 b
169
> 165 to ≤ 172 or day of first 6mg/kg 
dose
a
Use value nearest to scheduled study day.
b
Assessments on day of first 6 mg/kg dose will also considered as the last 
assessment of period 1.
A similar scheme should be adopted for dose Period 2, restarting computation of number 
of weeks and days from baseline (first 6 mg/kg dose) of Period 2.
If more than one particular efficacy assessment occurs within the same time window, 
then the nearest non-missing assessment to the nominal timepoint will be assigned to 
that visit. If there are two (or more) efficacy assessments that occur the same time away 
from the nominal timepoint, then the latest assessment will be assigned to that visit. 
Similar approach will be applied for PD assessments.
If more than one particular safety assessment (e.g., laboratory result or vital sign) occurs 
within the same time window then the worst value will be assigned to the visit. The last 
value from screening will be used for baseline assessments of safety if there is no 
baseline (study day 1) value.
For summaries of data not collected by visit, such as AEs, medical history, and 
concomitant medications, all data up will be included.


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4.7
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
4.7.1
Pharmacokinetic Analyses
The PK analysis will be conducted by the Sponsor’s department of clinical pharmacology 
and outputs will be produced by an external vendor.
The PK analysis population will consist of patients who have received at least one dose 
of TCZ and have one valid PK sample, with patients grouped according to treatment 
received. Individual and mean serum TCZ concentration versus time data will be 
tabulated and plotted by dose level. The serum pharmacokinetics of TCZ will be 
summarized by estimating total exposure (AUC4weeks), Cmax, and Ctrough at steady state. 
Estimates for these parameters will be tabulated and summarized (mean, standard 
deviation, coefficient of variation, median, minimum, and maximum). Inter-patient 
variability and drug accumulation will be evaluated. Additional PK analyses will be 
conducted as appropriate.
4.7.2
Pharmacodynamic Analyses
The PD analyses will use the safety analysis population. 
Serum concentration data will be summarized and plotted by visit and dose level (i.e. 
study period), with dose levels in separated tables/plots. All individual patient data will be 
plotted by week of assessment and dose level will be labeled with a different color. 
Absolute and change from baseline for CRP and ESR results will be summarized (mean, 
standard deviation, coefficient of variation, median, minimum, and maximum) by visit 
and dose level. Separate summary tables for serum concentration of IL-6 and sIL-6R
(mean, standard deviation, median, minimum, and maximum) will be produced by visit 
and dose level for absolute values and change from baseline. Summary statistics will 
also be presented by day of intensive sampling after the last dose of the study period (i.e. 
by steady state day: Day 1, 8, 15, 22 and 29 for CRP and ESR, Day 1 and Day 29 for 
IL-6 and sIL-6R). Note that intensive sampling can occur after the fifth or sixth dose 
within each dosing period, according to the investigator decision.
Summary plots will be provided visit and dose level: CRP and ESR absolute value data 
will be plotted as median and interquartile ranges while IL-6 and sIL-6R will be plotted as 
mean and sample error of the mean. Summary plots will also be provided by steady 
state day and dose level.
A listing of PD data will be reported, with specification of dose period, visit, dose amount.
4.8
EXPLORATORY EFFICACY ANALYSIS
The exploratory efficacy analyses will be performed using the efficacy population. 
The proportion of subjects with flare (as collected in the CRF) will be computed at each 
visit separately for each dose period. The proportion of subjects in remission (defined as 
absence of flare and normalization of CRP, i.e. <1mg/dL at lab examination) will also be 


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computed at each visit separately for each dose period. Proportions will use the number 
of patients with valid data as the denominator for computation at each visit, as no 
imputation rule will be used for missing values.
A listing of signs and symptoms, ESR, and CRP, at the time of flare will be produced for 
patients with flare, by dose period. A listing of signs and symptoms, ESR, and CRP, by 
visit, will also be produced for all patients, by dose period.
4.8.1
Sensitivity Analyses
No sensitivity analyses are planned for this study.
4.8.2
Subgroup Analyses
No subgroup analyses are planned for this study.
4.9
SAFETY ANALYSES
The safety analysis will be performed on the safety population. Any safety analyses will 
be presented separately for each dose period.
Safety will be assessed in terms of adverse events (nature, frequency, severity, and 
causality).  Adverse events will be summarized by dose period and listed.
Values, along with change from baseline, will be summarized by visit and dose period 
using descriptive statistics for each laboratory test and vital sign parameter.  Marked 
abnormalities will be listed.
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to NCI CTCAE dictionary.
4.9.1
Exposure of Study Medication
The number of doses received will be summarized for each dose period.  A listing of 
patients in each period detailing dosing of TCZ will be prepared.
Compliance will be summarized by the number of patients with missed infusion.
4.9.2
Adverse Events
Medical Dictionary for Regulatory Activities (MedDRA) will be used as the thesaurus for 
AEs and disease codes, and the INN (International Non-Propriety Name) dictionary will 
be used for treatments. A glossary of these codes will be produced. Generally AEs will 
be classified and presented separately according to the dose period of onset.
Only treatment-emergent AEs will be summarized. Treatment-emergent events are 
defined as those AEs with observed or imputed onset date on or after the start date of 
trial treatment. Only where the most extreme intensity is greater than the initial intensity 
(or if most extreme intensity is not missing and initial intensity is missing) will events 


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with an onset date prior to the start of trial treatment be considered treatment-emergent. 
An AE with a completely missing start date will be assumed to be treatment-emergent 
unless the AE has a complete non-imputed end date that is prior to study Day 1. 
Adverse events will be coded and tabulated by system organ class (SOC) and/or 
preferred term. In tabulations, preferred terms and their associated SOC will be 
presented in order of descending frequency summed across the dose periods. Adverse 
events will also be tabulated by severity and relationship to study medication as 
indicated by the investigator. 
Adverse event rates per 100 patient-years exposure (defined as the number of
events/total duration in the study multiplied by 100) will be calculated for each AE
preferred term and SOC, along with the corresponding 95% CIs for the rates of the 
SOC (exact based on the χ2 distribution [Ulm et al. 1990]).
The following will also be summarized:

Serious adverse events

Adverse events leading to withdrawal from treatment 

Adverse Events leading to withdrawal from study

Adverse events leading to death
Adverse events of special interest will be defined using published Standard 
MedDRA Queries (SMQs) or AE Grouped Terms (AEGTs) defined by Roche Drug 
Safety. The groupings of AEs will include but may not be limited to the following:

Serious Infections (Infections and Infestations SOC filtered for serious)

Opportunistic Infections (Roche Standard AEGT Opportunistic Infections)

Hypersensitivity Reactions (AEs during or within 24 hours of TCZ treatment and 
not unrelated to study medication)

Clinically Significant Hypersensitivity Reactions (AEs during or within 24 hours of 
TCZ treatment, not unrelated to study medication and leading to study treatment 
discontinuation)

Anaphylactic reactions according to Sampson's criteria (Roche Standard AEGT 
Basket according to Sampson’s criteria (Sampson et al. 2006)

Anaphylactic Reaction (SMQ narrow)

Serious Hepatic Events (Hepatic Failure, Fibrosis and Cirrhosis and Other Liver 
Damage-Related Conditions (SMQ wide + Hepatitis, Non-Infectious SMQ wide)

Gastrointestinal Perforations (Gastrointestinal Perforation SMQ wide)

Demyelinating Disorders (Demyelination SMQ narrow)

Myocardial infarction (MI)/acute coronary syndrome (MI SMQ narrow)

Stroke (Haemorrhagic Central Nervous System Vascular Conditions SMQ 
narrow + Ischaemic Central Nervous System Vascular Conditions SMQ narrow)

Serious Bleeding (Haemorrhage Terms [Excluding Lab Terms] SMQ wide 
filtered for serious)


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
Malignancies (Malignant Tumors SMQ narrow + Tumors of Unspecified 
Malignancy SMQ narrow)

Suspected transmission of an infectious agent by the study drug (STIAMP), 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. 
The two MedDRA preferred terms to capture STIAMP AEs will be “Suspected 
transmission of an infectious agent via product” and “Transmission of an 
infectious agent via product”
Selected AEs (AEs selected for analysis but not part of protocol-defined expedited 
reporting requirements):

Infection (Infections and Infestations SOC)

Neutropenia (Roche standard AEGT for neutropenia)

Thrombocytopenia (thrombocytopenia SMQ wide)
A glossary showing the mapping of investigator verbatim terms to preferred terms 
will be produced for all AEs included in the analysis. For each AE of special interest 
table based on SMQs/AEGTs, a corresponding listing of the preferred terms that 
comprise the SMQ will be produced. 
A listing of for the following will be produced:

Deaths

Adverse events leading to dose modification or interruption

Adverse events leading to drug withdrawn

Adverse events leading to study discontinuation

Adverse events

Serious adverse events 

Serious adverse events caused by a protocol-mandated intervention prior to 
initiation of study drug, all screened patients

AESIs (listed above)

Selected AEs (listed above)
Pregnancy data will be listed. Pregnancies will be identified using the urine test results.
4.9.3
Laboratory Data
All laboratory data will be converted to SI units. The International Standard for the 
Handling and Reporting of Laboratory Test Data (Data Analysis Guidance) will be used 
to implement reference ranges and marked abnormalities for laboratory data where 


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possible. Summary tables will detail the actual values and changes from baseline of the 
laboratory parameters over visits by period. 
Summaries of the number of patients by highest CTC grade post-baseline for 
hematology, chemistry, hepatic lab parameters (liver enzymes, alkaline phosphatase 
and total bilirubin) and lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and 
triglycerides) will be produced (for summaries referring to NCI CTCAE grading). 
For neutrophils, platelets, hepatic lab parameters and lipids, the number of patients will 
be summarized by category for baseline and worst post baseline result.
For neutrophils, a categorical analysis of the pattern of elevations Grade 3 or higher will 
be produced (i.e. % patients with no depression, depressions at a single timepoint, 
consecutive depressions, consecutive depressions sustained, non-consecutive 
depressions).
For lipids, a categorical analysis of the pattern of elevations in total cholesterol (>=240 
mg/dL) and a categorical analysis of the pattern of elevations in LDL (>=160 mg/dL) will 
be produced (i.e. % patients with no elevation, elevation at a single timepoint, 
consecutive elevations, consecutive elevations sustained, non-consecutive elevations).
Similar categorical analysis of the pattern of elevations will be produced liver enzymes 
and total bilirubin.
Listing will be produced for patients who had simultaneous elevations ≥3 x ULN in ALT 
or AST and ≥2 x ULN in total bilirubin (laboratory criteria for Hy’s Law).
Patients with marked abnormalities will be listed. 
Any analysis will be performed separately by dose period.
Lipid Data
Fasting lipids consist of total cholesterol, triglycerides, HDL, and LDL, and these will be
summarized separately from the other laboratory parameters when referencing gradings
or shifts.
Threshold for the presentation of lipid data are defined by the National Cholesterol
Education Program Adult Treatment Panel III (2001) and are shown in Table 2.


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Table 2
National Cholesterol Education Program (ATPIII) Thresholds
4.9.4
Vital Signs
Summary tables will detail the actual values and changes from baseline of the laboratory 
parameters over visits and by dose period for pulse rate, systolic blood pressure, 
diastolic blood pressure, body temperature, body weight and body mass index.
Blood pressure will also be summarized by visit using the following JNC 7 (Joint National 
Committee) categories reported in Table 3.
Table 3
Blood Pressure JNC 7 Category Criteria
4.9.5
Immunogenicity Assessment
Blood samples for the presence of anti-TCZ antibodies should be obtained for all 
patients at baseline and for any patients withdrawing from the study because of serious 
or non-serious hypersensitivity reaction, including anaphylaxis, at the time of occurrence 
of the event and approximately 8 weeks after the last dose. 
All samples will be tested by screening assay, and those samples that are positive will 
be further analyzed by a confirmation assay to confirm antibodies’ specificity. If the 
confirmation assay is positive, two additional tests will be performed: a neutralizing 
assay to measure the antibodies’ neutralizing potential and an IgE assay to confirm if the 
anti-TCZ antibodies are of IgE isotype. 
Given the testing strategy, for the purpose of the summary tables, if the results of the 
confirmation or neutralizing assays are missing for a sample, then they will be assumed 
negative if the screening assay is negative. If the screening assay is positive and the 


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confirmation assay is negative, then the neutralizing assay will be assumed negative if 
missing.
A listing of all patients who have a positive immunogenicity assay result at any timepoint 
will be produced for safety population flagging the dose period.
4.10
MISSING DATA
Partial dates for concomitant medications, exposure and AEs (AE start date) will be 
imputed.
4.11
INTERIM ANALYSES
No efficacy interim analysis is planned. 
PK data will be analyzed on an ongoing basis, but interim results will not be included in 
the final clinical study report; only the final analysis will be included. 
An evaluation of the data at the end of Period 1 will be undertaken. If the dropout rate 
and/or variability are higher than expected, additional patients on 8 mg/kg TCZ IV Q4W 
(who have received at least five consecutive doses and are in remission) may be directly 
enrolled into Period 2.
5.
REFERENCES
Common Terminology Criteria, Version 5.0, National Cancer Institute, USA, Published 
November 27, 2015.
Data Analysis Guidance: International Standard for the Handling and Reporting of
Laboratory Test Data, Roche Global Data Standards Repository, version 1.1, 19 
APR 2018.
Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. 2001. 
Available from https://www.fda.gov/downloads/drugs/guidances/ucm070244.pdf.
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report – Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol 2006;117:391-7.
Stone JH, Tuckwell K, Dimonaco S, et al. Trial of Tocilizumab in Giant-Cell Arteritis. 
N Engl J Med 2017;377 ;31728.
Ulm K. A simple method to calculate the confidence interval of a standardized mortality 
ratio (SMR). Am J Epidemiol 1990;131:373−5.
Villiger PM, Adler S, Kuchen S, Wermelinger F, Dan D, Fiege V, et al. Tocilizumab for 
induction and maintenance of remission in giant cell arteritis: a phase 2, 
randomised, double-blind, placebo-controlled trial. Lancet 2016;387:1921–7.


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Wang Y, Jadhav PR, Lala M, et al. Clarification on precision criteria to derive sample 
size when designing pediatric pharmacokinetic studies. J. Clin Pharmacol 
2012;52:1601–6.


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Appendix 1 Protocol Synopsis
TITLE:
A PHASE Ib, OPEN-LABEL, DOSE-RANGING STUDY TO 
EVALUATE THE PHARMACOKINETICS, PHARMACODYNAMICS, 
AND SAFETY OF TOCILIZUMAB ADMINISTERED BY 
INTRAVENOUS INFUSION TO PATIENTS WITH GIANT CELL 
ARTERITIS
PROTOCOL NUMBER:
WP41152
VERSION NUMBER:
1
EUDRACT NUMBER:
2018-004718-17
IND NUMBER:
113,654
TEST PRODUCT:
Tocilizumab (RO4877533)
PHASE:
Phase Ib
INDICATION:
Giant cell arteritis
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the pharmacokinetics, pharmacodynamics, and safety of 6 and 7 mg/kg 
of tocilizumab (TCZ) administered by IV infusion every 4 weeks (Q4W) to patients with giant cell 
arteritis (GCA).  Specific objectives and corresponding endpoints for the study are outlined 
below.
Pharmacokinetic Objectives
The primary pharmacokinetic (PK) objective for this study is to characterize the 
pharmacokinetics of two dose levels of TCZ administered by IV infusion to patients with GCA, 
on the basis of the following endpoints:

Steady-state maximum serum concentration (Cmax) at specified timepoints

Trough concentration (Ctrough) at specified timepoints

Area under the concentrationtime curve (AUC) over the dosing interval of 4 weeks 
(AUC4weeks) at specified timepoints
Pharmacodynamic Objectives
The pharmacodynamic (PD) objective for this study is to assess the pharmacodynamics of two 
dose levels of TCZ administered by IV infusion to patients with on the basis of the following 
endpoints:

Serum concentration of interleukin-6 (IL-6) at specified timepoints

Serum concentration of soluble interleukin-6 receptor (sIL-6R) at specified timepoints

Serum concentration of C-reactive protein (CRP) at specified timepoints

Erythrocyte sedimentation rate (ESR) at specified timepoints
Safety Objectives
The safety objective for this study is to evaluate the safety and tolerability of two dose leves of 
TCZ administered by IV infusion to patients with GCA on the basis of the following endpoints:

Nature, frequency, severity, and causality of adverse events, with severity determined 
according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0


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
Clinical safety laboratory results
Exploratory Objective
The exploratory objective for this study is to monitor the efficacy of two dose levels of TCZ 
administered by IV infusion to patients with GCA on the basis of the following endpoints:

Proportion of patients who experience a flare, defined as the recurrence of signs or 
symptoms of GCA and/or ESR 30 mm/h attributable to GCA as determined by the 
investigator, during each period

Proportion of patients in remission, defined as the absence of flare (defined above) and 
normalization of CRP (1 mg/dL), at each visit
Study Design
Description of Study
This is a Phase Ib, open-label, dose-ranging study designed to characterize the 
pharmacokinetics, pharmacodynamics, and safety of two dose levels of TCZ (6 and 7 mg/kg) 
administered by IV infusion Q4W to patients with GCA.  This study will enroll patients with GCA 
from at least two sites in Switzerland who have received at least five consecutive doses of 
8 mg/kg TCZ IV Q4W prior to baseline in clinical practice and who have reached remission, 
defined as the absence of flare and normalization of CRP (1 mg/dL). 
The study is divided into two periods:  In Period 1, approximately 25 patients who have been 
receiving 8 mg/kg TCZ IV Q4W for a minimum of five consecutive doses and who are in 
remission will receive five consecutive doses of 7 mg/kg TCZ IV Q4W.  Subsequently, if a 
patient is still in remission at the end of Period 1, the patient will enter Period 2 and receive five 
consecutive doses of 6 mg/kg TCZ IV Q4W.  Although five doses at each dose level are 
sufficient to achieve the primary study objectives, if absolutely necessary to accommodate 
patient availability for the intensive PK sampling during the last dosing cycle, the dosing periods 
may be extended by one dose for a total of six doses.  This will not be considered a protocol 
violation. 
The plan is to enroll approximately 25 patients into Period 1 in order to obtain data to robustly 
characterize the pharmacokinetics at each of the two dose levels.  Guidance from a statistical 
evaluation of the variability in PK parameters from IV dosing established a minimum of 
12 patients would be adequate.  Given the open-label nature of the study design, an evaluation 
of the data at the end of Period 1 will be undertaken.  If the dropout rate and/or variability are 
higher than planned, additional patients may be directly enrolled in Period 2.  Data from all 
patients receiving 6 mg/kg TCZ IV Q4W in Period 2 will be combined.
PK samples will be obtained before and after each infusion of TCZ to characterize the Cmax and 
Ctrough of TCZ, and more intensive sampling during the last dosing cycle will be used to estimate 
the steady-state AUC4weeks at each dose level.  
The usage of glucocorticoids during the study is at the discretion of the investigator.  Only 
patients in remission at the end of Period 1 will be eligible for Period 2.
Number of Patients
The study will enroll approximately 25 adult patients with a diagnosis of GCA who are being 
treated with 8 mg/kg TCZ IV Q4W in clinical practice and have reached remission at the time of 
enrollment.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 50 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Diagnosis of GCA per the 1990 American College of Rheumatology criteria fulfilled at the 
time of diagnosis 


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
For patients entering Period 1, patients must be receiving treatment with TCZ 8 mg/kg IV 
Q4W and received at least five consecutive doses prior to baseline and be in remission at 
baseline

For patients entering Period 2, prior to the first dose of 6 mg/kg TCZ IV, patients must be in 
remission at the end of Period 1

For women:  not of childbearing potential.  A woman is considered to be not of childbearing 
potential if she has reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause) or has undergone surgical 
sterilization (removal of ovaries and/or uterus).  The definition of non-childbearing potential 
may be adapted for alignment with local guidelines or requirements.

For men:  not of reproductive potential (i.e., infertile or sterilized) or agreement to remain 
abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain 
from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for at least 28 days 
after the final dose of TCZ.   Men must refrain from donating sperm during this same 
period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of preventing drug exposure.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Lack of peripheral venous access

Major surgery within 8 weeks prior to screening, or planned major surgery during the study 

Organ transplant (except corneal transplant performed more than 3 months prior to 
screening)

Major ischemic event, related or unrelated to GCA, within 12 weeks prior to screening

Treatment with any other investigational agent besides TCZ within 12 weeks (or 5 half-lives 
of the investigational drug, whichever is longer) prior to 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

Treatment with IV gamma globulin or plasmapheresis within 6 months prior to baseline 
(Day 1)

Previous treatment with alkylating agents, such as chlorambucil, or with total lymphoid 
irradiation

Immunization with a live or attenuated vaccine within 4 weeks prior to baseline

Treatment with hydroxychloroquine, cyclosporine A, azathioprine, or mycophenolate mofetil 
within 4 weeks prior to baseline (Day 1)

Treatment with other biologics (e.g., etanercept, infliximab, certolizumab, golimumab, 
abatacept, adalimumab, anakinra) or targeted synthetic disease-modifying anti-rheumatic 
drug (e.g., tofacitinib, baricitinib) within 12 weeks prior to baseline (Day 1)

Treatment with cyclophosphamide within 6 months of baseline (Day 1)

History of severe allergic or anaphylactic reactions to human, humanized, or murine 
monoclonal antibodies (including history of discontinuation of TCZ due to any 
infusion-related reaction or hypersensitivity) 

Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary 
(including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled 
diabetes mellitus), psychiatric, osteoporosis or osteomalacia, glaucoma, corneal ulcers or 
injuries, or gastrointestinal (GI) disease


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
Current liver disease, as determined by the investigator

History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative 
lower GI disease such as Crohn 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 should be screened for latent TB and, if positive, treated according to local 
practice guidelines prior to baseline.
Patients treated for TB with no recurrence within the last 3 years and patients treated 
for latent TB within last 3 years are eligible.

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)

History of alcohol, drug, or chemical abuse within 1 year prior to screening

Body weight 150 kg
At screening:

Serum creatinine 1.4 mg/dL (124 mol/L) in female patients and 1.6 mg/dL (141 mol/L) 
in male patients

ALT or AST 1.5 upper limit of normal (ULN)

Total bilirubin ULN 

Platelet count 100 x109/L (100,000/mm3)

Hemoglobin 85 g/L (8.5 g/dL; 5.3 mmol/L)

WBCs 3.0 109/L (3000/mm3)

ANC 2.0 109/L (2000/mm3)

Absolute lymphocyte count 0.5 109/L (500/mm3)

Positive hepatitis B surface antigen test or positive hepatitis C antibody test
End of Study
The end of this study is defined as the date when the last patient, last visit occurs, which 
corresponds to approximately 28 days after the last dose.  The end of the study is expected to 
be approximately 10 months after enrollment of the last patient into Period 1. 
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 12 months.
In addition, the Sponsor may decide to terminate the study at any time.
Investigational Medicinal Products
The investigational medicinal product for this study is TCZ.
Test Product (Investigational Drug)
TCZ will be administered by IV infusion at doses of 7 or 6 mg/kg Q4W.  The maximum dose of 
TCZ that will be administered is 800 mg. The dose of TCZ infusion will be calculated on the 
basis of body weight measured prior to each infusion.


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Statistical Methods
Primary Analysis
Given the small sample size, the short duration of the study, and open-label design without a 
control arm, a dose-related effect on flares is not expected to be observed.  Sample size 
estimates are entirely based on PK data.  PK, PD, safety, and efficacy data will be summarized 
descriptively. No formal statistical hypothesis testing is planned. A database lock will occur 
when the last patient has completed the final visit 28 days after the final dose.
The primary PK variables in this study are estimates of steady-state Ctrough, Cmax, and AUC4weeks
at the two dose levels of TCZ IV therapy (7 mg/kg Q4W and 6 mg/kg Q4W). For each dose 
level, Ctrough and Cmax will be summarized at each timepoint for each dose administered and 
AUC4weeks estimated for the last dosing cycle will be summarized as geometric means, medians, 
ranges, and standard deviations.
Determination of Sample Size  
In order to provide a precise characterization of PK parameters (Ctrough, Cmax, and AUC4weeks), in 
this study, a hybrid of two approaches will be followed. The first of these approaches is the 
guidance for estimation of sample size in pediatric studies, which requires a study to be 
prospectively powered to target 95% CI within 60%140% of the geometric mean estimates of 
clearance and volume of distribution for the drug in each pediatric sub-group with at least 80% 
power. The second is the sample size guidance from the Food and Drug Administration for 
bioequivalence studies, which specifies the 90% CI for the geometric mean ratio (GMR) should
fall within 80%–125% of the GMR estimate.
Given the need to characterize the PK parameters to a higher precision than in a pediatric 
population, the sample size for this study was estimated based on achieving a target of 95% CI 
for estimates of Cmax and Ctrough at each dose level that would fall within 80%125% of the 
geometric mean estimate.
In Study ML25676, observed steady-state Ctrough data were available for 18 patients receiving 
8 mg/kg TCZ IV Q4W.  The geometric mean was 44.4 g/mL (95% CI: 37.0, 53.4), with the 
95% CI corresponding to 83% and 120% of the geometric mean estimate.
Using the variability in observed steady-state Ctrough in Study ML25676, a sample size of n 17 
will provide 80% power to characterize the geometric mean estimate of the observed Ctrough
and Cmax so that the 95% CI falls within 80%125% of the geometric mean estimate of the 
corresponding PK parameter. A minimal sample size of n 12 would provide 80% power for 
the 90% CI to fall within 80%–125% of the geometric mean estimate of the corresponding PK 
parameter.  To account for potential study dropouts, approximately 25 patients already receiving 
8 mg/kg IV TCZ and in remission will be enrolled in the Period 1 of this study with the goal of 
obtaining robust PK characterization at both dose levels. 


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Appendix 2 Study Schema
EOS end of study; PDpharmacodynamic; PI Principal Investigator; PKpharmacokinetic; 
pts patients; Q4W every 4 weeks; TCZtocilizumab.
Note:  Vertical arrows indicate TCZ administration and numbers denote the dose number.


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Appendix 3 Schedule of Activities
Period
Scrn 
(D28 
to
1) a
Period 1
Period 2
Early 
WD b
Month
1
2
3
4
5
6
7
8
9
10
Week
1
4
8
12
16
17
18
19
20
24
28
32
36
37
38
39
40 
(EOS)
Day
1
29
57
85
113
120
127
134
141
169
197
225
253
260
267
274
281
Visit window (days)
3
3
3
3
1
1
1
1
3
3
3
3
1
1
1
1
3
Informed consent c
x
Demographic data
x
Medical history and 
baseline conditions
x
Physical 
examination d
x
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
x
x
x
x
x
Chest X-ray f
x
ECG g
x
Tuberculosis 
screening h
x
Hematology i
x
x
x
x
x
x
x
Chemistry panel j
x
x
x
x
x
x
x
Viral serology k
x
Lipid panel l
x
x
x
x


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Appendix 3 Schedule of Activities (cont.)
Period
Scrn 
(D28 
to
1) a
Period 1
Period 2
Early 
WD b
Month
1
2
3
4
5
6
7
8
9
10
Week
1
4
8
12
16
17
18
19
20
24
28
32
36
37
38
39
40 
(EOS)
Day
1
29
57
85
113
120
127
134
141
169
197
225
253
260
267
274
281
Visit window (days)
3
3
3
3
1
1
1
1
3
3
3
3
1
1
1
1
3
Pregnancy test m
x
x
x
Urinalysis n
X
x
x
x
ESR
X
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
CRP
X
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IL-6 and sIL-6R
See Appendix 4
x o
TCZ PK
See Appendix 4
x o
Anti-TCZ Ab 
x
x o
Adverse events p
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications q
X
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Clinical 
assessment of 
GCA signs and 
symptoms
X
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
TCZ administration 
(7 mg/kg IV)
x
x
x
x
x
TCZ administration 
(6 mg/kg IV)
x
x
x
x
x


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Appendix 3 Schedule of Activities (cont.)
Abantibody; BLbaseline; CRP C-reactive protein; EOS end of study; ESR erythrocyte sedimentation rate; GCAgiant cell arteritis; 
HBcAbtotal hepatitis B core antibody; HBsAghepatitis B surface antigen; HCVhepatitis C virus; IL-6 interleukin 6; LDH lactate 
dehydrogenase; NA not applicable; sIL-6Rsoluble IL-6 receptor; PDpharmacodynamic; PK pharmacokinetic; Q4W every 4 weeks; 
Scrnscreening; TCZ tocilizumab; ULNupper limit of normal; WDwithdrawal.
Notes: Laboratory samples should be drawn at least 30 minutes before clinical assessment.  If any patients enter Period 2 directly, the Period 1 
assessments should be followed with the exception that patients should receive 6 mg/kg TCZ IV instead of 7 mg/kg.
a Screening applies to all patients enrolling in Period 1 or directly into Period 2.  Results of standard-of-care tests or examinations performed prior 
to obtaining informed consent and within 28 days prior to Day 1 may be used; such tests do not need to be repeated for screening.
b Patients will return to the clinic for a study discontinuation visit at 28 (3) days after the final dose of study drug.
c Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 28 days before 
initiation of study treatment.
d Physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurologic systems.  Limited, symptom-directed physical examinations may be performed at 
unscheduled post-baseline visits as clinically indicated per the investigator’s discretion.  
e Vital signs include pulse rate, systolic and diastolic blood pressure (after patient has been seated for at least 5 minutes), and temperature.  
f
Not required if a normal chest X-ray has been obtained within 6 months prior to screening.
g ECG recordings will be obtained at screening and subsequently as clinically indicated. An ECG is not required if a normal ECG has been 
obtained within 6 months prior to screening.
h Tuberculosis screening will be performed according to local guidance.
i
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
j
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin (direct and indirect bilirubin will 
be performed if total bilirubin is greater than the ULN), ALP, ALT, AST, uric acid, CPK, and LDH. 
k Patients will be screened for HBsAg, total HBcAb, and HCV antibody.
l
Lipid panel includes total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides.  Patients are required to fast overnight (8 hours). 
m All women will have a urine pregnancy test at screening and the end of study. If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test.  Pregnancy test on freshly voided urine may be performed at any visit at the investigator’s discretion.
n Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination only if indicated after local 
dipstick analysis (sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria).


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Appendix 3 Schedule of Activities (cont.)
o For any patients withdrawing from the study because of a serious or non-serious hypersensitivity reaction, including anaphylaxis, blood samples 
for the presence of anti-TCZ antibodies and PK/PD assessments should be obtained at the time of occurrence of the event and approximately 
8 weeks after the last dose. 
p After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated
intervention should be reported.  After initiation of study drug, all adverse events will be reported until the end of study/early withdrawal visit.
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to 
prior study drug treatment.
q
Medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient in 
addition to protocol-mandated treatment from 28 days prior to initiation of study drug until the end of study visit. 


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Appendix 4 Schedule of Pharmacokinetic, IL-6, and sIL-6R 
Samples
Study visit 
(Weeks)
Study Visit (Days)
Timepoint a
PK
IL-6 and 
sIL-6R 
Week 1
Day 1
Predose
x
x
EOI
x
Week 4
Day 29 (3 d)
Predose
EOI
Week 8
Day 57 (3 d)
Predose
x
EOI
x
Week 12
Day 85 (3 d)
Predose
x
x
EOI
x
Week 16
Day 113 (3 d)
Predose
x
x
EOI
x
Week 17
Day 120 (1 d)
At visit
x
Week 18
Day 127 (1 d)
At visit
x
Week 19
Day 134 (1 d)
At visit
x
Week 20
Day 141 (1 d)
Predose
x
x
EOI
x
Week 24
Day 169 (3 d)
Predose
EOI
Week 28
Day 197 (3 d)
Predose
x
EOI
x
Week 32
Day 225 (3 d)
Predose
x
x
EOI
x
Week 36
Day 253 (3 d)
Predose
x
x
EOI
x
Week 37
Day 260 (1 d)
At visit
x
Week 38
Day 267 (1 d)
At visit
x
Week 39
Day 274 (1 d)
At visit
x
Week 40 
(EOS)
Day 281 (1 d)
At visit
x
x
Dday; EOI = end of infusion; IL-6interleukin-6; PKpharmacokinetic; 
sIL-6Rsoluble interleukin-6 receptor.
a Predose PK, IL-6, and sIL-6R assessments will be obtained from a single 
specimen and should be taken 03 hours before the start of infusion.  EOI 
samples should be taken 015 minutes after the saline flush marking the end of 
infusion and should be obtained from the patient’s opposite arm relative to the 
dosing arm.