Open Label Study to Test the Safety and Efficacy of Ustekinumab in Patients With Giant Cell Arteritis
Phase: PHASE1
Conditions: Giant Cell Arteritis, Temporal Arteritis, Horton's Disease
Sponsor: Massachusetts General Hospital

 
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PARTNERS HUMAN RESEARCH COMMITTEE 
DETAILED PROTOCOL 
 
Massachusetts General Hospital  
55 Fruit Street 
Boston, MA 02114 
 
Study title 
USTEKINUMAB FOR THE TREATMENT OF GIANT CELL ARTERITIS 
Study Drug 
Ustekinumab (Stelara) 
 
Study Drug and Financial Support Provided By 
Janssen Scientific Affairs, LLC 
 
Sponsor Investigator 
Sebastian Unizony, MD 
 
Co-investigators 
John H. Stone, MD, MPH 
Cory A Perugino, DO 
 
Research Manager 
Ana Fernandes 
 
Protocol Number 
2016P000932 
 
Version 3: February 20, 2019  
ClinicalTrials.Gov Number 
 NCT02955147 

 
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I. BACKGROUND AND SIGNIFICANCE 
a. Clinical background and unmet need 
Giant Cell Arteritis (GCA) is the most common form of primary vasculitis among adults 
in Western countries, with a prevalence ranging from 24 to 280 cases per 100,000 
individuals older than 50. The incidence of GCA increases progressively with age and 
peaks during the eighth decade of life. The disease has a particular predilection for 
populations of northern European ancestry and is approximately twice as common in 
women than in men [1]  
 
The main histopathologic feature of GCA comprises a chronic granulomatous 
inflammatory process that involves the aorta and its main branches, with a tendency to 
affect the extracranial carotid arteries and the ophthalmic circulation [1]. The clinical 
manifestations consist of constitutional symptoms (e.g., asthenia, fever), headaches, jaw 
pain, scalp tenderness, visual symptoms (e.g., blurry vision, amaurosis fugax, diplopia), 
shoulder and hip girdle pain and stiffness (i.e., polymyalgia rheumatica) and elevated 
acute-phase reactants. The most important complication of GCA is vision loss, which 
occurs in 15% of cases. Other possible complications include aortic aneurysm, limb 
claudication from large-artery stenosis (particularly the subclavian and axillary arteries), 
stroke, mesenteric ischemia, myocardial infarction and venous thromboembolism [1] 
 
No curative treatment currently exists for GCA. However, glucocorticoids (prednisone) 
are able to control the clinical evidence of inflammation when administered in moderate 
to high doses . Unfortunately, 40-85% of the patients experience disease relapses upon 
glucocorticoid tapering or discontinuation [2-8]. Such patients require frequent re-
treatment and most of them develop undesirable side effects form prolonged 
glucocorticoid exposure [9]. Long-term glucocorticoid therapy is associated with adverse 
events in approximately 86% of the patients, including osteoporotic fractures, diabetes 
mellitus, 
infection, 
cataracts, 
hypertension, 
femoral 
avascular 
necrosis, 
and 
gastrointestinal bleeding [9, 10]. In most cases, glucocorticoid-related toxicity becomes 
more problematic to patients than the disease itself. 
 

 
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No medication except glucocorticoids has been shown convincingly to be effective in 
suppressing the activity of GCA. The use of other immunosuppressive medications, 
including methotrexate, azathioprine, cyclophosphamide, and tumor necrosis factor 
(TNF) antagonists has been generally unsuccessful [7, 11-14]. Sudies using the 
interleukin (IL)-6 receptor inhibitor tocilizumab are ongoing [15]. There is currently a 
great unmet need for specific disease modifying agents to maintain disease remission in 
GCA, and therefore reduce the exposure to and the toxicity associated with 
glucocorticoids. 
 
b.    Pre-clinical and clinical studies leading up to and supporting the proposed 
research 
Role of interleukin (IL)-12 and IL-23 in autoimmune diseases 
IL-12 and IL-23 play important roles in regulating physiologic T-cell immune responses. 
IL-12 drives the differentiation of naïve T helper (Th) cells towards the Th1 cell 
phenotype [16], and IL-23 acts in concert with IL-6, IL-1β and transforming growth 
factor (TGF)- to promote the generation and maintenance of Th17 cells [17, 18]. Once 
differentiated, Th1 and Th17 cells produce the effector cytokine interferon (IFN)- and 
IL-17, respectively 
 
Although the activation of the Th1 and Th17 pathways is crucial for generating immunity 
against a variety of microorganisms, the deregulation of these mechanisms has been 
described in several immune-mediated diseases. IL-12 and IL-23 are important mediators 
in experimental models of psoriasis [19, 20], Crohn’s disease [21], multiple sclerosis 
(MS) [22], rheumatoid arthritis [23], and thyroiditis [24]. In humans, IL-12 and IL-23 
have been implicated in the pathogenesis of psoriasis [25], Crohn’s disease [26, 27], MS 
[28], RA, and recently GCA [29-32] (see below).  
 
Ustekinumab ameliorates Th1 and Th17 responses in vitro and in vivo  
IL-12 and IL-23 are heterodimeric cytokines that have a common p40 subunit. A 
functional IL-12 molecule consists of a p40 and a p35 subunit, and a functional IL-23 
molecule consists of a p40 and a p19 subunit. On the other hand, IL-12 and IL-23 

 
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receptors are also heterodimers that share the same IL-12Rβ1 chain. Whereas IL-12Rβ1 
is responsible of binding to p40, the second receptor component, namely IL-12Rβ2 for 
IL-12 receptor and IL-23R for IL-23 receptor, is cytokine-specific, and mediates signal 
transduction upon binding to p35 and p19, respectively  
 
Ustekinumab is a fully human IgG1-kappa monoclonal antibody that specifically binds 
with high affinity to the shared p40 subunit of the cytokines IL-12 and IL-23 (IL-
12/23p40) and blocks the cytokine-cytokine receptor coupling, thereby preventing the 
initiation of the signaling cascade that leads to the generation and activation of Th1 and 
Th17 cells, and the production of IFN- and IL-17 [33, 34] (Figure 1. IL-12 and IL-17 
pathways and ustekinumab mechanism of action).  
 
By preventing IL-12/23p40 ligation to IL-12Rβ1, ustekinumab neutralizes the following 
IL-12 (Th1) and IL-23 (Th17) mediated in vitro cellular responses: 
- 
Intracellular phosphorylation of STAT 4, STAT 6 and production of INF- (Th1) 
- 
Intracellular phosphorylation of STAT 3 and production of IL-17A, IL-22, and 
IL-17F (Th17) 
 
Ustekinumab was approved by the FDA in 2009 for the treatment of moderate to severe 
plaque psoriasis requiring systemic therapy based on 3 randomized controlled trials [35-
37]. Besides the observed clinical response, serial skin biopsies in patients with psoriasis 
treated with ustekinumab showed decreased T-cell infiltrates and reduced gene 
expression of IL-12p40, IL-23p19, and IFN- [38]. 
 
Some evidence suggests that IL-12/IL-23p40 targeted treatment may also be beneficial in 
Crohn’s disease [39], psoriatic arthritis [40, 41], and ankylosing spondylitis [42, 43] 
 
Two distinct pathways driven by Th17 and Th1 cells contribute to the pathogenesis 
of GCA.  
The etiology of GCA is not known. However, the mechanisms that perpetuate vascular 
inflammation in this disease are partially understood. In untreated patients, CD4-positive 

 
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T lymphocytes, mainly IFN-producing Th1 cells and IL-17-secreting Th17 cells, 
infiltrates large- and medium- sized arteries [29, 44-48]. Mirroring vascular 
inflammation, flow cytometry studies have demonstrated that Th1 and Th17 cell 
frequencies are also expanded in peripheral blood during periods of disease activity [29, 
45, 46].  
 
Doses of prednisone used in clinical practice significantly reduce the arterial infiltration 
of Th17 cells and normalize Th17 cell blood stream expansion [29, 45, 46]. Increased 
serum level of Th17-related cytokines (e.g., IL-6, IL-23, IL-1, and IL-17) rapidly 
decline with glucocorticoid treatment [29, 49]. On the other hand, reports regarding the 
effects of glucocorticoids on the abnormalities of the Th1 axis are contradicting [29, 31, 
32], with some reports describing persistance of the arterial Th1 infiltrates and the IL-12 
and IFN serum and tissue up-regulation even after 3-9 months of therapy [29] 
The pathogenesis of GCA supports the hypothesis that the down-regulation of the Th1 
and Th17 pathways by blocking IL-12 and IL-23 signaling could allow patients to stay in 
remission off glucocorticoid therapy (See figure 1) 
 
 Pre-clinical safety of ustekinumab [50] 
In cynomolgus monkeys, ustekinumab was well-tolerated following IV doses up to 45 
mg/kg/week for up to a month, and following twice weekly subcutaneous doses up to 45 
mg/kg for 6 months. Except for one case of bacterial enteritis, no ustekinumab-related 
mortality or adverse events were reported, and there was no tumor, pre-neoplastic or 
other histological abnormality in necropsy studies. Immunotoxicity evaluations showed 
no alteration on lymphoid organ weight or histology; abnormalities on blood counts or 
lymphocyte subpopulations; nor adverse effects on immune response to neoantigen 
(KLH), delayed type hypersensitivity responses, or ex vivo lymphoproliferative 
responses to T cell mitogens. No adverse events were seen in an acute asthma model 
carried out given theoretical increased risk of exacerbation of Th2-driven pathologies 
with Th1 blocking agents. Ustekinumab did not show developmental toxicity, 
teratogenicity, or reproductive toxicity. The no observed adverse effect level (NOAEL) 

 
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for ustekinumab in general, developmental and reproductive toxicity studies was 45 
mg/kg. The cumulative dose in the 6-month chronic toxicity study (45 mg/kg twice 
weekly for 26 weeks) was 2340 mg/kg. Based on the proposed dosing, a GCA participant 
who has 50 Kg of weight would receive ustekinumab doses of < 2 mg/kg  (>22-fold 
lower than the NOAEL dose). In addition, based on the proposed dosing, upon 
completing the study a GCA patient who has 50 Kg of weight would receive 12.6 mg/kg 
(cumulative dose >180-fold lower than the dose given chronic toxicity studies) 
 
 Prior clinical experience with ustekinumab 
Summary of clinical efficacy [50] 
Ustekinumab has shown efficacy with adequate safety profiles in psoriasis, and psoriatic 
arthritis (PsA) 
 
Ustekinumab was approved by the FDA in 2009 for the treatment of adults with chronic 
moderate to severe plaque psoriasis.  The psoriasis clinical development program 
consisted of 3 well-controlled Phase 2 and Phase 3 clinical trials that evaluated 
subcutaneous doses of 45 and 90 mg as monotherapy in a total of 2266 subjects [51-53]. 
In these studies, ustekinumab led to rapid, clinically significant, and sustained 
improvement of psoriatic skin lesions.  
 
At week 28, over 90% of the subjects were Psoriasis Area and Severity Index (PASI) 50 
responders in both the 45 mg and 90 mg groups, at least 70% of subjects achieved a PASI 
75 response, and approximately 50% of subjects achieved a PASI 90 response. Clinical 
response was maintained with every 12 weeks administrations through 1 year in nearly 
90% of long-term responders (PASI 75 response at 28 and 40 weeks).  
 
Summary of clinical safety [50, 54] 
Data pertaining to the safety of ustekinumab comes from 2266 exposed subjects during 
the psoriasis trials (1970 subjects received at least 6 months of ustekinumab, 1285 
subjects were exposed for at least 1 year, and 373 underwent at least 18 months of 
treatment).  

 
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The rate of adverse events was similar in the placebo (50.4%), ustekinumab 45 mg 
(57.6%) and ustekinumab 90 mg (51.6%) groups. The risk of adverse events (AE) and 
serious adverse events (SAE) did not increase with the duration of exposure. Common 
AE tended to be mild and self-limited and included nasopharyngitis, upper respiratory 
infection, and headache. Dizziness, back pain, myalgia, injection-site erythema (1.3% 
ustekinumab, 0.4% placebo), ecchymosis, diarrhea, and pharyngolaryngeal pain were 
slightly more frequent in the ustekinumab group. 
 
For all mortality causes, 8.11 deaths were expected through the data cutoff for the BLA, 
and only 1 death due to idiopathic dilated cardiomyopathy was reported. Three additional 
deaths were reported during phase 3 extension from causes unlikely related with the 
study drug (alcohol intoxication, post-operative bleeding, and metastatic renal cancer) 
 
Serious adverse events were reported in 1.4%, 1.6%, and 1.4% of the patients in the 
placebo, 45 mg, and 90 mg groups, respectively, through week 12. Serious adverse event 
rate did not increase over time.  
 
Serious infections were reported at a rate of 1.70 (95% CI, 0.35; 4.96) per hundred 
subject-years of follow up in the placebo group compared with 0.49 (95% CI, 0.01, 2.74) 
and 1.97 (95% CI, 0.54; 5.03) in subjects in the 45 mg and 90 mg ustekinumab groups, 
respectively.  
 
Malignancies were reported in 3 placebo-treated subjects (2 of 3 were non melanoma 
skin cancer), and 4 ustekinumab-treated subjects (3 of 4 were non melanoma skin 
cancer). Overall rates of malignancies per hundred subject-years of follow up were 
comparable in both groups. 
 
Through the data cutoff for the BLA, the rates of major adverse cardiovascular events 
(MACE) per hundred subject-years of follow up were comparable between groups. Rates 
of MACE were consistent with expected background rates. [55]. 

 
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The overall incidence of antibodies to ustekinumab was 3.7% in the combined Phase 3 
studies and did not differ across doses nor increase over time. There was no evidence of 
lymphocyte depletion; alteration on the proportion of naïve (CD45RA), memory 
(CD45RO), or activated T lymphocytes; or ex-vivo PBMC production of IFN- or IL-5. 
Ustekinumab did not impact in non-memory antibody response (pneumococcal vaccine) 
or antigen recall response (tetanus toxoid).  
 
Safety of ustekinumab was consistent in all subpopulations including subjects >65 years 
of age. 
 
The 120-day safety update did not show increase in the rates of adverse events, serious 
adverse events, serious infections, malignancies, and serious cardiovascular events. 
 
Multiple subsequent studies have demonstrated similar safety profiles without 
unexpected adverse events. Some of these studies have used ustekinumab doses 
equivalent or higher to the dose proposed in this GCA study [41-43]  
 
Clinical pharmacology  
The SC bioavailability of the drug is 57.2% and after a single SC dose, ustekinumab 
reaches a maximum serum concentration in 7 to 14 days. The median volume of 
distribution ranged from 57 mL/kg to 83 mL/kg (intravascular space), and through the 
endogenous gammaglobulin metabolic pathway (reticuloendothelial system) ustekinumab 
is eliminated from the system with a median half-life of 3 weeks. In population PK 
analysis, only weight, diabetes and positive immune response status to ustekinumab 
affected the systemic exposure of the drug. No formal drug-drug interaction studies were 
conducted with ustekinumab. 
 
c.    Rationale behind the proposed research, and potential benefits to patients and 
society 

 
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Given its mechanism of action, ustekinumab will specifically target important pathogenic 
pathways of GCA, and consequently may help maintain the disease in clinical remission 
while reducing the requirements of glucocorticoids (steroid-sparing effect).  
 
Remission maintenance and glucocorticoid-sparing effects may prevent or ameliorate the 
morbidity associated with GCA and the prolonged glucocorticoid exposure that this 
disease usually requires, improving the quality of life of the patients. In addition, if 
effective, the use of ustekinumab may reduce the costs of treating glucocorticoid-related 
side effects (e.g., osteoporotic fractures, diabetes mellitus, infections, cataracts, 
hypertension, femoral avascular necrosis, steroid induced myopathy, and gastrointestinal 
bleeding). Finally, ustekinumab may add to the limited therapeutic options currently 
available for GCA. 
 
II SPECIFIC AIMS 
The objective of this study is to evaluate the efficacy and safety of ustekinumab, an IL-
12/23 inhibitor, in patients with GCA 
 
Hypothesis 
IL-12/23 pathway blockade with ustekinumab maintains disease remission in patients 
with GCA  
 
Specific Aims 
 To evaluate the safety and tolerability of ustekinumab administration in 20 patients 
with GCA  
 
 To evaluate the efficacy of ustekinumab for remission maintenance and 
glucocorticoid sparing in 20 patients with GCA  
 
 
III. SUBJECT SELECTION 

 
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a. Inclusion Criteria (Subjects must meet the following criteria to be considered 
eligible for study entry): 
1) Able and willing to provide written informed consent and to comply with the 
study protocol 
 
2) Diagnosis of GCA classified according to the following criteria: 
• Age 50 years or older 
• History of ESR ≥ 50 mm/hour or CRP ≥ 10 mg/L 
 
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 (e.g., mononuclear cell infiltration or 
granulomatous inflammation). 
 
• Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study 
such as MRA, CTA, or PET-CT 
 
3) New-onset or refractory active disease defined as follows: 
• New onset: diagnosis of GCA within 6 weeks of Baseline visit 
 
• Refractory: diagnosis of GCA > 6 weeks before Baseline visit and previous treatment 
with 40 mg/day prednisone (or equivalent) for at least 2 consecutive weeks at any time 
 
AND 

 
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• Active GCA within 6 weeks of Baseline visit (active disease defined as the presence of 
clinical signs and symptoms [cranial or PMR] and ESR ≥ 30 mm/hour or CRP ≥ 10 
mg/L)* # 
 
*ESR ≥ 30 mm/hour or CRP ≥ 10 mg/L is not required if active GCA has been confirmed 
by a positive temporal artery biopsy within 6 weeks of the Baseline visit 
# Prior treatment with tocilizumab normalizes CRP and ESR values therefore these inflammatory 
markers cannot be used monitor disease activity. For patients who are failing treatment with 
tocilizumab due to flare, elevation of ESR and/or CRP is not required in the definition of active 
disease for eligibility purposes.  
 
b. Exclusion Criteria 
Patients who meet any of these criteria will not be enrolled in this study 
 Comorbidities 
- Allergies: Subjects who have history of previous severe allergic or anaphylactic reaction 
associated with the administration of monoclonal antibodies or antibody fragments or 
excipients to ustekinumab. 
- Systemic infection: Subjects who have an active systemic infection. 
- Serious infection: Subjects who have had serious infections (e.g., pneumonia, or 
pyelonephritis), or any major episode of infection requiring hospitalization or treatment 
with IV antibiotics within 4 weeks of enrollment.  
- Chronic or recurrent infection: Subjects who have chronic or recurrent bacterial, viral, 
fungal, mycobacterial (e.g., tuberculosis and other atypical mycobacterial disease), or 
protozoan infection. 
- Opportunistic infection: Subjects who have, or have had, an opportunistic infection 
(e.g., cytomegalovirus, 
coccidioidomycosis, 
Pneumocystis 
carinii, aspergillosis, 
histoplasmosis, or mycobacterium) within 6 months prior to enrollment. 
- Blood borne infection: Subjects who have active hepatitis B or active hepatitis C or a 
documented history of HIV, hepatitis B, or hepatitis C.  

 
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- Latent tuberculosis infection (LTBI): Subjects who have untreated LTBI are ineligible. 
Patients with LTBI are eligible for enrollment one month after initiating treatment for 
LTBI. 
- Malignancy: 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) 
- Uncontrolled disease: Subjects with evidence of serious uncontrolled concomitant 
cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine, immunologic, 
psychiatric (incl. drug or alcohol abuse) or gastrointestinal disease that could interfere 
with participation in the trial according to the protocol. 
- Transplanted organs: Subjects with transplanted organs (with the exception of a corneal 
transplant > 3 months prior to screening). 
- Major surgery within 8 weeks prior to Screening or planned major surgery within 12 
months after Baseline 
- Pregnancy 
 
 Prohibited medications:  
- Subjects who received immunosuppressive agents [e.g., methotrexate (MTX) > 30 mg 
weekly, azathioprine, mycophenolate mofetil, cyclophosphamide, chlorambucil, 
tacrolimus, leflunomide]; IL-1 antagonists (e.g., anakinra, canakinumab); B-lymphocyte 
stimulator (BLyS) inhibitors (e.g., belimumab); co-stimulator blockers (e.g., abatacept);  
anti IL-6R monoclonal antibodies (e.g., tocilizumab); IL-17 antagonists (e.g., 
secukinumab); or any therapeutic agent targeted at reducing tumor necrosis factor (TNF) 
activity (e.g., infliximab, etanercept, adalimumab, golimumab, certolizumab) within the 
3-month period prior to enrollment. 
- Subjects who had treatment with any anti-CD20 agent (e.g., rituximab) within the 9-
month period prior to enrolment  
- Subjects who used any investigational drug within 1 month prior to enrollment or within 
5 half-lives of the investigational agent, whichever is longer. 
- Low dose MTX: Patients on < 30 mg of MTX weekly will be eligible for enrollment 
after a 2-week washout interval before receiving ustekinumab 

 
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- Vaccines: Prior to initiating therapy with ustekinumab, patients should be up to date 
with all immunizations appropriate for age as recommended by current immunization 
guidelines. Subjects who received any live virus or bacterial vaccinations other than BCG 
within the 3 months before the first administration of the study agent, or are expected to 
receive any live virus or live bacterial vaccinations during the study, or up to 3 month 
after the last administration of ustekinumab are not eligible. Subjects who received BCG 
vaccines within the 12 months before the first administration of the study agent, or are 
expected to receive BCG vaccines during the study, or up to 12 month after the last 
administration of ustekinumab are also not eligible. Caution is advised when 
administering live vaccines to household contacts of patients receiving ustekinumab 
because of the potential risk for shedding from the household contact and transmission to 
patient. Non-live vaccinations received during a course of ustekinumab may not elicit an 
immune response sufficient to prevent disease. 
 
 Baseline laboratory abnormalities 
- Hemoglobin < 8 gr/dL 
- Platelets < 100/mm3 
- WBC < 3000/mm3 
- Absolute neutrophil count < 2.0 X 109/L (2000/mm3) 
- Absolute lymphocyte count < 0.5 X 109/L (500/mm3) 
- Serum creatinine > 1.4 mg/dL in female subjects and > 1.6 mg/dL in male subjects 
- Total bilirubin > 2 mg/dL 
- ALT or AST > 1.5 X ULN 
- Positive hepatitis B surface antigen, hepatitis B core antibody or hepatitis C antibody 
 
c.    Source of subjects and recruitment methods 
The source of patients will be the Massachusetts General Hospital Rheumatology clinic 
and the Massachusetts General Hospital Vasculitis and Glomerulonephritis Center, where 
staff physicians will be aware of this study protocol. Potential candidates will be initially 
approached by their primary provider (subjects’ physician) at these two locations, who 
will review available treatment options, including this protocol. After this step, and if the 

 
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subject is interested in participating in this study, either Dr. Unizony or Dr. Stone will go 
over the informed consent process. 
 
 
IV. SUBJECT ENROLLMENT 
Procedures for obtaining informed consent 
 Dr. Unizony or Dr. Stone will review the inform consent with the potential candidates 
 
 The diagnosis of GCA will be confirmed through appropriate evaluations that will 
include comprehensive history, complete physical exam, and review of the medical 
records for prior temporal artery biopsy, inflammatory markers level, and cross 
sectional imaging  (See Section III,  inclusion criteria, diagnosis of GCA) 
 
 Potential treatment approaches, including continued glucocorticoid monotherapy, 
conventional 
DMARDs 
(e.g., 
methotrexate), 
experimental 
biologics 
(e.g., 
tocilizumab), and this investigational protocol, will be discussed. 
 
 Patients will be given at least twenty-four (24) hours to consider their potential 
treatment options.  Adequate time will be permitted for patients to ask questions to 
Dr. Unizony or Dr Stone and to discuss treatment options further with family 
members, primary care providers, or referring physicians.   
 
 
V. STUDY PROCEDURES 
a. Study Overview 
This is a single center, open label study that will assess the efficacy and safety of 
ustekinumab plus standard of care with a taper course of prednisone in 20 patients with 
active GCA. The study will enroll 20 subjects with a diagnosis of either new onset GCA 
or relapsing GCA.  The study will consist of a screening phase (up to 6 weeks), a 
treatment phase (52 weeks) and a safety follow up phase (8 weeks). The primary efficacy 

 
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assessment will take place at week 52. The maximum duration of subject participation 
(including screening) is 66 weeks (See table 1. Schedule of events).  
 
b. Study drugs 
Treatment protocol 
All subjects will receive ustekinumab and prednisone  
1) Ustekinumab: 90 mg of ustekinumab will be administered at baseline, week 4, 
week 12, week 20, week 28, week 36 and week 44. Ustekinumab will be 
administered in a subcutaneous (SQ) injection in the rheumatology clinic by the 
physician investigator or other qualified study personnel. Ustekinumab 
interruption or withdrawal will be as per current US product insert (See attached 
ustekinumab package insert). In case of ustekinumab-related toxicities that do 
not warrant the discontinuation of the medication, the dose of ustekinumab 
will be reduced to 45 mg keeping the same dosing intervals (See section VII. 
Risks and discomforts, page 24). 
2) Prednisone: All patients will receive standard of care therapy with prednisone 
tapered according to predefined schedules (See table 2, Prednisone tapers). There 
will be 3 possible initial prednisone doses (60 mg, 40 mg and 20 mg) to fully 
capture the different requirements of prednisone for induction of remission in 
GCA. The initial dose of prednisone will be chosen by the investigators following 
best clinical judgment. The duration of the prednisone taper will be 6 months in 
all cases. A 6 month prednisone taper will allow ustekinumab to fully reach 
steady state pharmacokinetics and pharmacodynamics while patients are still on 
prednisone. Patients who presents with vision-threatening manifestations (e.g., 
amaurosis fugax) will be treated with pulse methylprednisolone (1000 mg/day) 
for up to three doses at the discretion of the physician-investigator before starting 
the study prednisone taper at a dose deemed appropriate by the physician-
investigator. Patients with severe clinical manifestations such as visual symptoms, 
jaw claudication or severe headaches will start the taper at a higher dose (e.g., 40 

 
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to 60 mg). Patients with less severe clinical manifestations such as PMR 
symptoms or mild headaches will start the taper at lower dose (e.g., 20 to 40 mg).  
Please note that patients are required to have active disease (see inclusion criteria) 
within 6 weeks of baseline visit in order to be eligible for the study. Patients may 
or may not be on prednisone by the time of the screening visit and there is no 
timeframe for prior prednisone use as far as the criteria of disease activity within 
6 weeks of baseline is met. Most of the relapsing patients and some of the new 
onset patients will be taking some prednisone by the time of the screening. For 
those who are already taking prednisone and demonstrate active disease at 
screening visit, the prednisone dose will be increased to one of the protocol initial 
doses (i.e., 20 mg, 40 mg or 60 mg) in order to control that activity. For those who 
are already taking prednisone and are in remission at screening (because the 
prednisone dose was recently modified to control disease activity), the dose will 
be kept if it is one of the protocol starting doses, and if it is not, modified in order 
to start the study on one of the protocol starting doses.  
3) Escape therapy: Patients who do not achieve the status of clinical remission by 
week 12, can not follow the study prednisone taper, or develop a disease flare 
before week 52 will be deemed failures for the primary endpoint. Those subjects 
will stop ustekinumab and be offered treatment with an investigator-defined 
prednisone rescue regimen 
 
Upon study completion, decisions on treatment options for individual subjects will be at 
the discretion of the investigator. 
 
Concomitant medications:  
- Anti-platelet therapy All the subjects will be treated with aspirin 81 mg daily unless 
contraindicated.  

 
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- Glucocorticoid induced osteopenia/osteoporosis prevention and treatment All the 
subjects will receive oral calcium and 25-hydroxy vitamin D supplementation (Ca 1200-
1500 mg and vitamin D 800-1000 IU daily in divided doses).  Bisphosphonate therapy 
(e.g., alendronate 70 mg weekly or zolendronate 5 mg annually) will also be employed at 
the discretion of the physician-investigator for the prevention of glucocorticoid-induced 
osteoporosis. Participants with documented osteoporosis will be treated with FDA-
approved drugs for osteoporosis according to clinical guidelines [e.g., National 
Osteoporosis Foundation (NOF)].  
- Gastric prophylaxis. Prophylaxis with proton pump inhibitors or H-2 blockers will be 
employed at the discretion of the physician-investigator for the prevention of 
glucocorticoid-induced gastrointestinal side effects 
- PCP prophylaxis with an acceptable regimen which may include sulfamethoxazole and 
trimethoprim one single strength pill (80 mg / 400 mg) daily, sulfamethoxazole and 
trimethoprim one double strength pill (160 mg / 800 mg) three times a week or dapsone 
50 to 100 mg daily 
c. Study Visits (See table 1. Schedule of events). 
- Screening visit (-42 to 0 days before Baseline). Complete medical history, physical 
examination and selective laboratory investigations will be obtained for the purpose of 
confirming the diagnosis of active GCA, determining study eligibility, and assessing 
baseline values for the outcomes of interest 
 
During this visit the following procedures will be completed 
 Written Informed Consent 
 Subject Demography  
 Medical and surgical history  
 GCA history evaluation (date of disease diagnosis, date of temporal artery biopsy, 
duration of prednisone treatment, prednisone-related adverse events) 
 Inclusion/Exclusion Criteria  
 Concomitant Medications  
 Assessment of signs and symptoms of GCA/PMR activity 

 
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 Vital signs and Physical exam 
 Screening laboratory tests including complete blood count (CBC), creatinine, 
BUN, AST, ALT, total bilirrubin, alkaline phosphatarse, ESR, CRP level, urine 
analysis, HCV antibody, HBV superficial antigen, and HBV anti core antibodies. 
 Chest x-ray (CXR) 
 Electrocardiogram (ECG) 
 Urine or serum pregnancy testing will be completed for female patients who 
report their last menstrual period within 12 months of the screening visit  
 Evaluation for latent TB infection with interferon gamma releasing assay (e.g., 
quantiferon test or T spot). 
 Blood samples for optional research studies (DNA/RNA/flow cytometry/serum 
biomarkers)  
 
 
Following the Screening period, eligible subjects will proceed with a 52-week treatment 
phase 
- Baseline-Week 52 visits 
Subjects will start the treatment phase of the study only if all eligibility criteria are met. 
The treatment phase of the study will consist of a Baseline visit, and subsequent visits at 
week 4, week 12, week 20, week 28, week 36, week 44 and week 52. 
Ustekinumab will be administered in site by the principal investigator or designated 
trained personnel at Baseline, and at visits week 4, week 12, week 20, week 28, week 36, 
and week 44. In addition, the patients will follow a pre-specified prednisone taper  (See 
table 2. Prednisone taper protocol). 
During Baseline through week 52 visit the following procedures will be completed 
 Vital signs and Physical exam 
 Concomitant Medications  
 Adverse Events Assessments 
 Assessment of signs and symptoms of GCA/PMR activity 
 Ability to adhere to the pre-specify prednisone taper 
 Ustekinumab administration (baseline, w4, w12, w20, w28, w36, w44) 

 
19 
 Laboratories (CBC, creatinine, BUN, AST, ALT, total bilirrubin, alkaline 
phosphatarse, ESR, CRP level, and lipid profile) 
 Blood samples for optional research studies (RNA/flow cytometry/serum 
biomarkers)  
 
The main efficacy and safety endpoint will be measured at 52 weeks (See below section 
IV.) 
 
- Safety follow up visit. The participants will undergo a safety follow up visit at week 60 
During the safety follow up the following procedures will be completed 
 Vital signs and Physical exam 
 Concomitant Medications  
 Adverse Events Assessments 
 Assessment of signs and symptoms of GCA/PMR activity 
 Laboratory assessments (CBC, creatinine, BUN, AST, ALT, total bilirrubin, 
alkaline phosphatarse, ESR, and CRP level) 
 Blood samples for optional research studies (RNA/flow cytometry/serum 
biomarkers)  
d.    Toxicity Grading Scale 
All adverse events will be recorded and classified according to the most recent version of 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), published May 28, 2009 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf) 
 
Adverse events will be recorded and graded 1 to 5 according to the CTCAE grades 
provided below: 
Grade 1 = Mild adverse event 
Grade 2 = Moderate adverse event 
Grade 3 = Severe and undesirable adverse event  

 
20 
Grade 4 = Life-threatening or disabling adverse event 
Grade 5 = Death 
e. Optional research studies (DNA, RNA and flow cytometry analyses) 
Optional research samples will be collected from patients who give specific consent to 
participate in this optional research. The Informed Consent Form will contain a separate 
section that addresses participation in the optional research studies 
 
A blood sample will be collected for genetic analysis as follows: Blood (approximately 6 
mL in K3 EDTA) for DNA isolation will be collected as shown table 1 (Schedule of 
events). The sample may be processed using techniques such as array-based hybridization 
or PCR  
Blood samples will be collected for RNA expression analysis as follows: Blood (1 × 
approximately 2.5 mL collected in PAXgene vacutainers) for RNA isolation will be 
obtained as shown in table 1 (Schedule of events). The samples may be tested using 
techniques such as microarray profiling, RNA sequencing, and/or reverse transcriptase − 
polymerase chain reaction (RT-PCR)  
 
Blood samples will be collected for serum assays for biomarkers as follows: Blood (one 
sample of approximately 6.0 mL) for serum isolation will be obtained at various time 
points as shown in table 1. (Schedule of events). The samples may be tested using 
techniques such as ELISA and Luminex. Biomarkers to be determined may include 
cytokines (e.g., IL-17, IFN gamma, IL-12, IL-6, etc), chemokines (e.g., CXCL-9, CXCL-
10, etc), and other soluble molecules (e.g., VGEF) 
 
Blood samples will be collected for determination of cell subpopulations as follows: 
Blood (approximately 15 mL) for peripheral blood mononuclear cell (PBMC) and 
lymphocyte purification and determination of cell subpopulations by flow cytometry will 
be collected as shown table 1 (Schedule of events). Subpopulation of cells to be analyzed 
include T-helper (Th)1 cells, Th17 cells, and regulatory T cells. 
 

 
21 
Optional research samples will be destroyed no later than 15 years after the date of 
informed consent signature. These samples will be de-indentified and stored in the 
Division of Rheumatology, Allergy and Immunology (Dr Andrew Luster’s Laboratory) 
 
Optional research samples will be used to achieve the following objectives: 
- 
To study genetic variants associated with GCA and treatment response to the 
study medication 
- 
To study the association of biomarkers with efficacy, adverse events, or other 
disease-related outcomes 
- 
To increase knowledge and understanding of disease biology 
 
Patients will be told that they are free to refuse to participate in the optional research 
studies, and may withdraw their specimens at any time and for any reason during the 
storage period.  
VI. BIOSTATISTICAL ANALYSIS   
Signs and symptoms of GCA activity, compliance with the prednisone taper, specific 
laboratory parameters (e.g., ESR, CRP) and the occurrence of adverse events will be 
assessed over time for the analysis of the efficacy and safety endpoints. 
Study endpoints 
Primary efficacy endpoint: 
1) Percentage of patients in glucocorticoid-free remission at 52 weeks 
 
The definition of glucocorticoid-free remission contains 3 elements: 
- Absence of clinical signs or symptoms of active GCA and PMR along with the 
normalization of the ESR (<40 mm/hour) and CRP (<10 mg/L) 
- Completion of the pre-specified prednisone taper protocol  
- Absence of disease flare (relapse) since the induction of remission 
 

 
22 
Definition of flare: Re-appearance of unequivocal signs or symptoms of active GCA or 
PMR (with or without elevation of ESR and CRP) that requires increase in the prednisone 
dose in order to be controlled 
 
Secondary efficacy endpoint 
1) Percentage of patients in clinical remission on prednisone ≤ 5 mg/day at 52 weeks  
 
Clinical remission is defined as the absence of clinical signs or symptoms of active GCA 
and PMR along with the normalization of the ESR (<40 mm/hour) and CRP (<10 mg/L) 
regardless of the treatment being received 
2) Time to disease flare 
3) Number of disease flares at 6 and 12 months 
4) Cumulative prednisone dose 
5) ESR and CRP 6 and 12 months 
Safety endpoints 
1) The number, nature and severity of adverse events (AE) at week 52 and 60 
2) The number, nature and severity of serious AE (SAE) at week 52 and 60 
3) Number of glucocorticoid-related adverse events at week 52 and 60 
 
 Statistical Methods  
Continuous data will be summarized using descriptive statistics (e.g., means, standard 
deviations, medians, interquartile ranges).  Categorical data will be summarized as 
numbers and corresponding percentages. Descriptive statistics and two-sided 95% 
confidence intervals will be calculated to assist the interpretation of efficacy outcomes.  
The remission rate of patients treated with Ustekinumab in this study will be compared to 
the remission rate by week 52 of historical controls treated with prednisone monotherapy 
in clinical trials (~15% in Jover et al. MTX trial 2001 [3]; 10% in Hoffman el al. MTX 
trial 2001 [4]; 50% in Hoffman el al. Infliximab trial 2007 [6] [early stop before 52 
weeks due to inefficacy]; 22% in Martinez-Taboada et al. Etanercept trial [8]; 30% in 

 
23 
Seror et al. Adalimumab trial [7]) Setting up the probability of type I error at 0.05 and 
type II error at 0.2, and assuming a 40% remission rate by 52 week in historical controls, 
a sample size of 20 patients will provide more than 80% power to detect a difference in 
the proportion of patients in remission between the ustekinumab group  and the historical 
controls of 30% if that difference actually exists. 
 
We will complete an interim analysis after 5 patients from each stratum (i.e., new onset 
and relapsed disease) have completed 12 months of treatment. In case the flare rate 
within any of the strata is ≥ 60%, that strata will be terminated 
VII. RISKS AND DISCOMFORTS 
With the exception of ustekinumab administration, which is experimental, all the 
procedures performed in this study are consistent with the SOC for a patient with GCA.   
a.   Complications of Subcutaneous Medication Administration 
The injection of subcutaneous medications is associated with a mild degree of discomfort 
at the injection site for a short period of time.  Small degrees of bleeding or bruising may 
occur at the injection site.  Skin irritation (erythema) and rarely cellulitis can result at the 
site of injection.   
 
To minimize this risk, we have experienced infusion nurses who are experts in the 
administration of subcutaneous medications commonly used in the rheumatology practice 
(e.g., etanercept, adalimumab).   
 
b.    Potential Side-effects of Ustekinumab [56] 
Ustekinumab has been approved by the FDA in 2009 for adults with chronic moderate to 
severe plaque psoriasis. Thus, there is substantial clinical experience with this drug and 
the adverse effect profile is well defined. 
 
 Common mild and self-limited side effects include  
- Dizziness 
- Headache 

 
24 
- Back pain 
- Myalgias 
- Injection site erythema 
- Diarrhea 
- Upper airway infection 
 
 Potential serious side effects 
- Infections 
Ustekinumab may increase the risk of infections and reactivation of latent infections. 
Serious bacterial, fungal, and viral infections were observed in subjects receiving 
ustekinumab.  
 
As a risk mitigation strategy, patients will be screened for latent TB infection (LTBI), and 
undergo close monitoring for prompt diagnosis and treatment of any potential infection. 
Patients will be instructed to seek medical advice if signs or symptoms suggestive of an 
infection occur. Ustekinumab will not be given to patients with any clinically important 
active infection. Ustekinumab will not be administered until any clinically important 
active infection resolves or is adequately treated. Should a patient have a serious or 
opportunistic infection, ustekinumab will be discontinued and the patient will not be re-
challenged with the drug. 
 
- Malignancy 
Controlled trials have not shown increased risk of cancer associated with ustekinumab. 
However, given its immunosuppressive effects, surveillance for malignancy is required. 
Appropriate age and gender cancer screening will be recommended as per current 
national guidelines, and patients will be closely monitored during the study. Any sign or 
symptom suggestive of malignancy will be properly investigated. If a neoplastic 
condition were diagnosed, ustekinumab will be discontinued, and patients will be referred 
to oncology (or other pertinent specialist) for appropriate evaluation and treatment. 
 
- Cardiovascular events 

 
25 
Phase 2 psoriasis studies showed an imbalance in the incidence of cardiovascular events, 
which were more frequent in the ustekinumab treated patients. Increased cardiovascular 
morbidity was not confirmed in phase 3 studies.  
 
Sensitivity analysis showed an incidence of serious and non serious cardiovascular AE of 
4.5%, 3.8% and 4.3% in the placebo, ustekinumab 45 mg and ustekinumab 90 mg, 
respectively. The rates of myocardial infarction and stroke seen in clinical trials were 
consistent with or lower than the rates expected in the general population. 
 
The presence of cardiovascular risk factors will not exclude a subject from participating 
in this study.  However, to minimize cardiovascular risks and following the standards of 
our practice, there will be communication with the subjects’ primary care physician to 
have cardiovascular risk factors (e.g., hypertension, dylipidemia, smoking, diabetes) 
addressed according to national guidelines. 
 
- Hypersensitivity reactions 
No anaphylaxis or serum sickness events were reported in clinical trials, but serious 
allergic reactions (including angioedema, dyspnea and hypotension), and hypersensitivity 
reactions (including rash and urticaria) have been reported post-marketing. 
 
Subjects will be monitored for hypersensitivity reactions and treated accordingly. If a 
serious hypersensitivity reaction occurs (e.g., analphylaxis), ustekinumab will be 
discontinued and subjects will not be re-challenged with the drug. 
 
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
RPLS has been rarely reported in patients treated with ustekinumab. If RPLS is suspected 
in patients presentating with headache, seizures, confusion, or visual disturbances, 
ustekinumab will be discontinued, and patients will be properly evaluated and treated. 
- Th-2 related disease exacerbation 

 
26 
No exacerbation of Th2 driven pathologies such as asthma or airway allergies were 
reported during clinical trials. Patients will be monitored for exacerbation of 
hypersensitivity conditions, and treated accordingly if indicated. 
 
- Laboratory abnormalities 
Markedly abnormal changes in hematology and chemistry laboratory values were 
infrequent during clinical trials, with comparable rates among ustekinumab and placebo 
treated patients. The ustekinumab manufacturer does not recommend any type of 
laboratory monitoring during ustekinumab treatment. 
 
Selected labs will be checked at different times during the study (See table 1. Schedule of 
events). If a marked laboratory abnormality is detected (See below section IX.b. Criteria 
for dropping a subject from the study), the study drug will be discontinued and the patient 
will not be re-challenged. 
Ustekinumab dose may be reduced to 45 mg for any of the following reasons: 
1) Recurrent non-serious infections 
2) Other non-serious adverse events deemed to be secondary to ustekinumab that 
justify a dose reduction 
 
VIII POTENTIAL BENEFITS 
a.    Potential benefits to Subjects 
The Subjects may benefit from having their disease controlled more effectively than with 
prednisone monotherapy or prior immunosuppressive regimens. They may also benefit 
from requiring less treatment with prednisone, and thereby incurring in fewer side effects 
associated with this treatment (e.g., hypertension, diabetes, osteoporosis, gastrointestinal 
bleeding, glaucoma, cataracts, other).   
 
b.    Potential benefits to Society 
There is great unmet need for the treatment of GCA. Glucocorticoids are still the main 
agents used to control disease activity and prevent complications. However, 
glucocorticoid treatment is invariably associated with undesirable side effects that impair 
quality of life of patients and increase costs to society. 

 
27 
 
Ustekinumab may prove to be effective in controlling GCA activity and exerting 
glucocorticoid-sparing effects. Therefore, ustekinumab may increase the quality of life of 
the patients, and reduce the costs of treating glucocorticoid -related morbidity. On the 
other hand, ustekinumab may increase the options to treat GCA in patients refractory to 
or unable to take glucocorticoids due to contraindications (uncontrolled hypertension, 
uncontrolled diabetes, severe osteoporosis, cataracts, mood disorders, gastrointestinal 
bleeding), or toxicity.  
 
In randomized controlled trials (mostly including newly diagnosed GCA subjects), the 
flare rate within 12 months in patients only receiving glucocorticoids has been between 
50% and 85% [6-8, 19]. If  ≥ 60% of the subjects in this cohort of GCA patients achieve 
the primary outcome (glucocorticoid-free remission) at 12 months, then this will be 
considered a successful pilot study, and an adequately powered randomized controlled 
trial would be indicated. 
IX. MONITORING AND QUALITY ASSURANCE 
Drs. Unizony and Stone will monitor study data to ensure the safety of patients.   
 
a.    Specific elements related to the safety of study subjects that will be examined 
include: 
 Deaths 
 Hospitalizations from any cause 
 Infections 
 Injection site reactions 
 Other unexpected and serious adverse events 
 
b.    Criteria for dropping a subject from the study 
 A disease flare while on ustekinumab (treatment failure) as defined by the principal 
investigator 
 The occurrence of any malignancy,  
 The occurrence of major cardiovascular event (e.g., stroke, acute coronary syndrome)  

 
28 
 The occurrence of reversible posterior leukoencephalopathy syndrome (RPLS) 
 The occurrence of a severe hypersensitivity reaction, (e.g., anaphylaxis, 
bronchospasm, angioedema) 
 The worsening of any Th2 related pathology (e.g., asthma) 
 The occurrence of a serious, systemic, opportunistic, chronic/recurrent or blood-borne 
infection 
 The occurrence of any marked laboratory abnormality including: Hemoglobin < 8 
gr/dL, Platelets < 100/mm3, WBC < 3000/mm3, Absolute neutrophil count < 2.0 X 
109/L (2000/mm3), Absolute lymphocyte count < 0.5 X 109/L (500/mm3), Serum 
creatinine > 1.4 mg/dL  in female subjects and > 1.6 mg/dL in male subjects, Total 
bilirubin > 2 mg/dL, ALT or AST > 1.5 X ULN 
 
c.    Specific elements of efficacy that will be examined include: 
 Improvement of active GCA symptoms, as judged by medical history, physical 
examination, and laboratory tests (ESR, CRP) 
 Ability to followed the pre-specified glucocorticoid taper  
 Ability of maintain remission off glucocorticoids 
 Glucocorticoid-sparing effects by analyzing the incidence of glucocorticoid-related 
side effects  
 
d.    Adverse event reporting guidelines: 
Adverse events and unanticipated problems involving risks to subjects or others will be 
reported to the PHRC in accordance with PHRC adverse event and unanticipated 
problems reporting guidelines.  
Regarding safety data collection and reporting also refer to Addendum 1 (Interventional 
IIS Janssen Scientific Affairs Requirements for Safety Data Collection and Reporting) 
The investigator may share coded safety information with Janssen Scientific Affairs, LLC so 
it may conduct additional reviews of the coded information in order to study the safety and 
effectiveness of the study drug, to develop a better understanding of disease, or to improve 
the efficiency of future clinical trials. 

 
29 
 
 
 
 
 
 

 
30 
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Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, Sands BE, 
Hanauer SB, Targan S, Rutgeerts P et al: Ustekinumab induction and 
maintenance therapy in refractory Crohn's disease. The New England journal 
of medicine 2012, 367(16):1519-1528. 
44. 
Espigol-Frigole G, Corbera-Bellalta M, Planas-Rigol E, Lozano E, Segarra M, 
Garcia-Martinez A, Prieto-Gonzalez S, Hernandez-Rodriguez J, Grau JM, 
Rahman MU et al: Increased IL-17A expression in temporal artery lesions is a 
predictor of sustained response to glucocorticoid treatment in patients with 
giant-cell arteritis. Ann Rheum Dis 2012. 
45. 
Samson M, Audia S, Fraszczak J, Trad M, Ornetti P, Lakomy D, Ciudad M, 
Leguy V, Berthier S, Vinit J et al: Th1 and Th17 lymphocytes expressing 
CD161 are implicated in giant cell arteritis and polymyalgia rheumatica 
pathogenesis. Arthritis Rheum 2012, 64(11):3788-3798. 
46. 
Terrier B, Geri G, Chaara W, Allenbach Y, Rosenzwajg M, Costedoat-Chalumeau 
N, Fouret P, Musset L, Benveniste O, Six A et al: Interleukin-21 modulates Th1 
and Th17 responses in giant cell arteritis. Arthritis Rheum 2012, 64(6):2001-
2011. 
47. 
Weyand CM, Hicok KC, Hunder GG, Goronzy JJ: Tissue cytokine patterns in 
patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med 
1994, 121(7):484-491. 
48. 
Visvanathan S, Rahman MU, Hoffman GS, Xu S, Garcia-Martinez A, Segarra M, 
Lozano E, Espigol-Frigole G, Hernandez-Rodriguez J, Cid MC: Tissue and 
serum markers of inflammation during the follow-up of patients with giant-
cell arteritis--a prospective longitudinal study. Rheumatology (Oxford) 2011, 
50(11):2061-2070. 
49. 
Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ: Treatment of 
giant cell arteritis: interleukin-6 as a biologic marker of disease activity. 
Arthritis Rheum 2000, 43(5):1041-1048. 

 
34 
50. 
Briefing Document for Ustekinumab (CNTO 1275). Food and Drug 
Administration Dermatologic and Ophthalmologic Drugs Advisory 
Committee. 2008. 
51. 
Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, 
Dooley LT, Gordon KB: Efficacy and safety of ustekinumab, a human 
interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week 
results from a randomised, double-blind, placebo-controlled trial (PHOENIX 
1). Lancet 2008, 371(9625):1665-1674. 
52. 
Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, Guzzo 
C, Hsu MC, Wang Y, Li S et al: Efficacy and safety of ustekinumab, a human 
interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week 
results from a randomised, double-blind, placebo-controlled trial (PHOENIX 
2). Lancet 2008, 371(9625):1675-1684. 
53. 
Tsai TF, Ho JC, Song M, Szapary P, Guzzo C, Shen YK, Li S, Kim KJ, Kim TY, 
Choi JH et al: Efficacy and safety of ustekinumab for the treatment of 
moderate-to-severe psoriasis: A phase III, randomized, placebo-controlled 
trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci 2011. 
54. 
Scherl EJ, Kumar S, Warren RU: Review of the safety and efficacy of 
ustekinumab. Therap Adv Gastroenterol 2010, 3(5):321-328. 
55. 
Reich K, Langley RG, Lebwohl M, Szapary P, Guzzo C, Yeilding N, Li S, Hsu 
MC, Griffiths CE: Cardiovascular safety of ustekinumab in patients with 
moderate to severe psoriasis: results of integrated analyses of data from 
phase II and III clinical studies. Br J Dermatol 2011, 164(4):862-872. 
56. 
Ustekinumab [package insert]. Janssen Biotech Inc.; 2009. 
http://www.stelarainfo.com/pdf/PrescribingInformation.pdf. 
 
 
 
 
 
 
 
 
 
 
 
 

 
35 
Table 1. Schedule of events 
EVALUATION 
STUDY VISIT (week +/- 5 days) 
Screen 
 (-42 to 
0 days) 
BL 
4 
12 
20 
28 
36 
44 
52 
608,9 
Safety 
FU / 
EW 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics, 
medical and surgical 
history  
X 
 
 
 
 
 
 
 
 
 
GCA history 
evaluation 1 
X 
 
 
 
 
 
 
 
 
 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluation for LTBI3  
X 
 
 
 
 
 
 
 
 
 
Ustekinumab 
Administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Signs and Symptoms 
of GCA/PMR activity4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry5 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile6 
 
X 
 
X 
 
X 
 
 
X 
 

 
36 
HBsAg, anti-HBc Ab 
and anti-HCV Ab 
X 
 
 
 
 
 
 
 
 
 
UA 
X 
 
 
 
 
 
 
 
 
 
CXR 
X 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test7 
X 
 
 
 
 
 
 
 
 
 
DNA 
X 
 
 
 
 
 
 
 
 
 
Serum, RNA and Flow 
X 
 
X 
 
X 
 
X 
 
X 
 
 
1. Date of diagnosis, date of temporal artery biopsy, duration of prednisone treatment, initial prednisone dose, prednisone-related adverse 
events.  
2. Complete examination, including assessments of the skin, head, eyes, throat, neck, lungs, heart, abdomen, lymph nodes, and 
musculoskeletal (MSK) system 
3. Tuberculin test (PPD) and/or interferon gamma releasing assay (IGRA) 
4. Temporal artery or scalp tenderness with palpation; unequivocal jaw claudication; visual changes such us transient diplopia, transient 
blurry vision, amaurosis fugax, or new/worsening decrease visual acuity; or unequivocal evidence of active PMR as manifested by 
shoulder and/or pelvic girdle pain and stiffness (e.g. morning stiffness)  
5. Creatinine, BUN, eGFR, AST, ALT, alkaline phosphatase, total bilirubin 
6. Total cholesterol, LDL cholesterol, HDL cholesterol, triglicerides 
7. If last menstrual period within 12 months of screening visit 
8. Week 60 visit will be a safety follow up visit. During this visit, GCA treatment options moving forward will be discussed with the 
subjects. Treatment from this time point will be guided as per best clinical judgment. 
9. In case of early withdrawal, an early withdrawal visit will take place 8 weeks after the last visit before the early withdrawal 
 
BL = baseline; EW = early withdrawal; I/E = inclusion/exclusion; AE = adverse events; Con Meds = concomitant medications; LTBI = 
latent tuberculosis infection;  ESR = erythrocyte sedimentation rate, CRP = C-reactive protein; CBC = complete blood count; HBsAg = 
hepatitis B superficial antigen; anti-HBc Ab = anti Hepatitis B core antibody; anti-HCV Ab = anti Hepatitis C virus antibody; UA = 
urinalysis; CXR = chest x-ray; EKG = electrocardiogram 
 
 

 
37 
Table 2. Prednisone taper protocol 
 
Week 
Initial prednisone dose (*) 
60 mg 
40 mg 
20 mg 
Daily dose 
(mg/day) 
Cumulative 
dose (mg) 
Daily dose 
(mg/day) 
Cumulative 
dose (mg) 
Daily dose 
(mg/day) 
Cumulative 
dose (mg) 
1 
60 
  
40 
  
20 
  
2 
60 
  
40 
  
20 
  
3 
50 
  
30 
  
17.5 
  
4 
40 
1470 
25 
945 
15 
507.5 
5 
30 
  
20 
  
12.5 
  
6 
25 
  
17.5 
  
10 
  
7 
20 
  
17.5 
  
10 
  
8 
17.5 
2117.5 
15 
1435 
9 
798 
9 
17.5 
  
15 
  
8 
  
10 
15 
  
12.5 
  
7 
  
11 
15 
  
12.5 
  
6 
  
12 
12.5 
2537.5 
10 
1785 
6 
987 
13 
12.5 
  
10 
  
5 
  
14 
10 
  
9 
  
5 
  
15 
10 
  
8 
  
4 
  
16 
9 
2828 
7 
2023 
3 
1106 
17 
8 
  
6 
  
3 
  
18 
7 
  
5 
  
3 
  
19 
6 
  
4 
  
2 
  
20 
5 
  
3 
  
2 
  
21 
4 
  
2 
  
2 
  
22 
3 
  
2 
  
1 
  
23 
2 
  
1 
  
1 
  
24 
1 
3080 
1 
2191 
1 
1211 

 
38 
 
(*) Rational for allowing patients to enter the prednisone taper at different initial 
doses. New onset patients usually require doses of prednisone between 40 to 60 mg for 
induction of remission. In contrast, the prednisone dose required for induction of 
remission in patients with relapsed disease is variable. Relapses characterized by cranial 
symptoms (e.g., headaches, jaw claudication, visual manifestations) usually require 
higher prednisone doses (40 to 60 mg). In contrast, a relapse characterized by 
polymyalgia rheumatica (PMR) symptoms, typically responds to lower prednisone doses 
(e.g., 20 mg). In addition, other patient’s comorbidities (e.g., diabetes, hypertension, etc) 
may influence the prednisone dose selection as lower prednisone doses are associated 
with lower prednisone-induced toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
39 
 
Figure 1. IL-12 and IL-17 pathways and proposed mechanism of action of 
ustekinumab in GCA 
 
 
 
 
 
 
 
 
 
 
 
 

 
40 
Addendum 1. Interventional IIS Janssen Scientific Affairs Requirements for 
Safety Data Collection and Reporting 
   
 
1. OVERVIEW 
As the sponsor of the Study, INSTITUTION and PRINCIPAL INVESTIGATOR 
shall be solely responsible for complying, within the required timelines, any safety 
reporting obligation to competent Health Authorities, IRB/ECs and any participating 
(co or sub) investigators, as defined in applicable laws and regulations.  For the 
purposes of this EXHIBIT, safety data includes adverse events, product quality 
complaints (PQCs), and special situations including pregnancies. 
 
The INSTITUTION and PRINCIPAL INVESTIGATOR will provide safety 
information to Janssen Scientific Affairs on adverse events, special situations 
including pregnancies and product quality complaints as defined within this 
EXHIBIT. 
 
2. Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse 
events regardless of causality and special situations excluding those from subjects not 
exposed to a Janssen Medicinal Product and product quality complaints with or 
without an adverse event as described in this Exhibit will be reported from the time a 
subject has signed and dated an Informed Consent Form (ICF) until completion of the 
subject’s last study-related procedure (which may include contact for follow-up 
safety).  Serious adverse events will be reported for 30 days after the last dose of 
study drug. 
   
3. Definitions 
3.1. Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An adverse 

 
41 
event does not necessarily have a causal relationship with the treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational or non- investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition, or abnormal results of diagnostic procedures, 
including laboratory test abnormalities. 
 
3.2. Adverse Events of Special Interest  
Adverse events of special interest are events that Janssen Scientific Affairs 
is actively monitoring as a result of a previously identified signal (even if 
non-serious).  The adverse events of special interest for ustekinumab are:  
 
 
 Malignancies  
 Tuberculosis (TB)  
 Serious infections including Opportunistic infections  
 Severe Hypersensitivity reactions (including anaphylactic reactions and 
angioedema) 
 Neurologic 
events 
(eg, 
demyelination, 
progressive 
multifocal 
leukoencephalopathy (PML), facial palsy, reversible leukoencephalopathy 
syndrome (RPLS)) 
 MACE events (Non fatal Stroke, Non fatal MI, CV death)  
 Erythrodermic psoriasis 
 Pustular psoriasis 
 
Adverse Events of Special Interest will be reported on a Serious Adverse Event 
Report Form and be reported to Janssen Scientific Affairs within 24 hours of 
becoming aware of the event. 

 
42 
 
 
3.3. Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
 an identifiable subject (but not disclosing personal information such as the 
subject’s name, initials or address) 
 an identifiable reporter (investigational site) 
 a Janssen medicinal product 
 an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
 suspected Janssen medicinal product (doses, indication) 
 date of therapy (start and end date, if available) 
 batch or lot number, if available 
 subject details (subject ID and country) 
 gender 
 age at AE onset 
 reporter ID 
 adverse event detail (AE verbatim in English), onset date, relatedness, 
causality, action taken, outcome, (if available) 
 Janssen protocol ID 
 
3.4. Product Quality Complaint (PQC) 
A product quality compliant is defined as any suspicion of a product defect 
related to a potential quality issue during manufacturing, packaging, release 
testing, stability monitoring, dose preparation, storage or distribution of the 
product, or delivery system.  Not all PQCs involve a subject.  Lot and batch 
numbers are of high significance and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 

 
43 
 Functional Problem: e.g., altered delivery rate in a controlled release 
product 
 Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
 Potential Dosing Device Malfunction: e.g.,  autoinjector button not 
working, needle detaching from syringe 
 Suspected Contamination 
 Suspected Counterfeit 
 
3.5. Serious Adverse Event (SAE) 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any 
dose: 
 
 
Results in death 
 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to 
an event that hypothetically might have caused death if it were more severe.) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a suspected transmission of any infectious agent via a medicinal product 
 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is also appropriate in other situations, such as important 
medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above. These should 
usually be considered serious. 
 

 
44 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A 
SERIOUS ADVERSE EVENT. 
 
3.5.1.  Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs 
during the study must be reported as a serious adverse event, except 
hospitalizations for the following: 
 Hospitalizations not intended to treat an acute illness or adverse event 
(e.g., social reasons such as pending placement in long-term care facility) 
 Surgery or procedure planned before entry into the study. [Note: 
Hospitalizations that were planned before the start of data collection and 
where the underlying condition for which the hospitalization was planned 
has not worsened will not be considered serious adverse events. Any 
adverse event that results in a prolongation of the originally planned 
hospitalization is to be reported as a new serious adverse event.] 
 
3.5.2.  Life-Threatening Conditions 
The cause of death of a subject in a study within 30-days of the last dose of 
Stelara (ustekinumab), whether or not the event is expected or associated with the 
study drug, is considered a serious adverse event. 
 
Disease progression should not be recorded as an adverse event or serious adverse 
event term; instead, signs and symptoms of clinical sequelae resulting from 
disease progression/lack of efficacy will be reported if they fulfill the serious 
adverse event definition. 
 
4. Unlisted (Unexpected) Adverse Event/Reference Safety Information 
 

 
45 
An adverse event is considered unlisted if the nature or severity is not consistent 
with the applicable product reference safety information. For a medicinal 
product(s) with a marketing authorization, the expectedness of an adverse event 
will be determined by whether or not it is listed in the applicable product 
information.  
 
For Stelara (ustekinumab), the link to the package insert is:  
http://www.stelarainfo.com/pdf/PrescribingInformation.pdf 
 
5. Special Reporting Situations  
Safety events of interest for a Janssen medicinal product that require expediting 
reporting and/or safety evaluation include, but are not limited to: 
 
Drug exposure during pregnancy (maternal and paternal) 
 
Overdose of a Janssen medicinal product  
 
Exposure to a Janssen medicinal product from breastfeeding  
 Suspected abuse/misuse of a Janssen medicinal product 
 Inadvertent or accidental exposure to a Janssen medicinal product  
 Failure of expected pharmacological action (i.e., lack of effect) of a Janssen 
medicinal product 
 Medication error involving a Janssen medicinal product (with or without 
patient exposure to the Janssen medicinal product, e.g., name confusion) 
 Suspected transmission of any infectious agent via administration of a 
medicinal product 
 Unexpected therapeutic or clinical benefit from use of a Janssen medicinal 
product 
 
These safety events may not meet the definition of an adverse event; however, 
from a Janssen Scientific Affairs perspective, they are treated in the same manner 
as adverse events. Special situations should be recorded on the Adverse Event 
page of the CRF. 
 

 
46 
Any special situation that meets the criteria of a serious adverse event should be 
recorded on a Serious Adverse Event Report Form and be reported to Janssen 
Scientific Affairs within 24 hours of becoming aware of the event. 
 
6. Pregnancy  
The effect of ustekinumab on human sperm, pregnant women, and women making breast 
milk, unborn babies or breast feeding infants is not known. Pregnant women and women 
making breast milk to feed infants cannot participate in this study. Urine and/or blood 
pregnancy tests will be conducted for female participants who are capable of getting 
pregnant. It is very important that men taking part in this study do not get a woman 
pregnant while taking part in this study. 
 
Contraceptive recommendation will be given to all women participants who could 
become pregnant and all men participants who may father a child as follows: 
 During this study and for 4 months after the last dose of study drug, you must use 
proven birth control methods.  
 If you are using a hormone birth control method (such as oral contraception [“the 
pill”], a patch, injections, etc.), you must also use a second method of birth control, 
such as a condom or diaphragm. It is not known if ustekinumab affects the 
effectiveness of hormonal birth control methods. However, ustekinumab may lower 
the concentration/amount of active ingredients of the hormonal birth control methods. 
 If you are planning to donate eggs (ova, oocytes) during the study and for 4 months 
after your last dose of study drug, you must notify your study doctor or healthcare 
team and discuss the associated risks. 
Pregnancies in women participants and pregnancies in partners of male subjects exposed 
to ustekinumab will be reported by the PRINCIPAL INVESTIGATOR within 24 hours 
of their knowledge of the event using the Serious Adverse Event Form.  Depending on 
local legislation this may require prior consent of the partner. Follow-up information 

 
47 
regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be 
required. 
 
7. Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. The 
INSTITUTION and PRINCIPAL INVESTIGATOR shall provide all adverse events, 
both serious and non-serious, in report format. However, in certain circumstances 
more frequent provision of safety data may be necessary, e.g. to fulfill a regulatory 
request, and as such the data shall be made available within a reasonable timeframe at 
Janssen Scientific Affairs’request. 
 
8. Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) 
for Janssen Medicinal Products to the COMPANY 
All adverse events and special situations, whether serious or non-serious, related or 
not related, following exposure to a Janssen medicinal product are to be documented 
by the investigator and recorded in the CRF and in the subject’s source records. 
Investigators must record in the CRF their opinion concerning the relationship of the 
adverse event to a Janssen medicinal product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal product 
should be followed-up in accordance with clinical practice. 
 
8.1. SAEs and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that 
have not resolved upon discontinuation of the subject's participation in the study, 
must be followed until any of the following occurs: 
 The event resolves 
 The event stabilizes 
 The event returns to baseline, if a baseline value/status is available 
 The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 

 
48 
 It becomes unlikely that any additional information can be obtained (subject 
or health care practitioner refusal to provide additional information, lost to 
follow-up after demonstration of due diligence with follow-up efforts) 
 
The INSTITUTION and the PRINCIPAL INVESTIGATOR) will transmit all 
SAEs and special situations following exposure to a Janssen product under study 
in a form provided by Janssen Scientific Affairs in English within 24-hours of 
becoming aware of the event(s). 
 
In the event the study is blinded, the PRINCIPAL INVESTIGATOR will submit 
an unblinded SAE or pregnancy exposure report to Janssen Scientific Affairs. 
 
All follow-up information for serious adverse events that are not resolved at the 
end of the study or by the time of patient withdrawal must be reported directly by 
the PRINCIPAL INVESTIGATOR, within 24 hours becoming aware, to the 
Janssen Scientific Affairs using Janssen Scientific Affairs’Serious Adverse Event 
Report  
 
All available clinical information relevant to the evaluation of a related SAE, 
serious ADR or special situation is required. 
 
 The INSTITUTION and/or PRINCIPAL INVESTIGATOR are responsible 
for ensuring that these cases are complete and if not are promptly followed-
up. A safety report is not considered complete until all clinical details needed 
to interpret the case are received. Reporting of follow-up information should 
follow the same timeline as initial reports. 
 
 Copies of any and all relevant correspondences with regulatory authorities and 
ethics committees regarding any and all serious adverse events, irrespective of 
association with the Janssen Product under study, are to be provided to 

 
49 
Janssen Scientific Affairs within 24 hours of such report or correspondence 
being sent to applicable health authorities. 
 
8.2. Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs 
according to the timeframe outlined in the Research Funding Agreement section 
entitled Reporting of Data. 
 
8.3. PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, 
accurate, and complete reporting and analysis of PQC information from studies 
are crucial for the protection of patients, investigators, and Janssen Scientific 
Affairs, and are mandated by regulatory agencies worldwide. Janssen Scientific 
Affairs has established procedures in conformity with regulatory requirements 
worldwide to ensure appropriate reporting of PQC information. Lot and/or Batch 
#s shall be collected or any reports failure of expected pharmacological action 
(i.e., lack of effect). The product should be quarantined immediately and if 
possible, take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be 
reported to Janssen Scientific Affairs by the PRINCIPAL INVESTIGATOR 
within 24 hours after being made aware of the event. The Janssen contact will 
provide additional information/form to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either 
a serious adverse event or non-serious adverse event, the PRINCIPAL 
INVESTIGATOR must report the PQC to Janssen Scientific Affairs according to 
the serious adverse event reporting timelines.  A sample of the suspected product 
should be maintained for further investigation if requested by Janssen Scientific 
Affairs. 
 

 
50 
9. Reporting Procedures for Reporting Safety Data and Product Quality 
Complaints (PQCs) for Non-Janssen Medicinal Products  
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen 
medicinal product under study, the PRINCIPAL INVESTIGATOR should notify the 
appropriate regulatory/competent authority or the manufacturer of that medicinal 
product (in the absence of appropriate local legislation) as soon as possible. 
 
10. Transmission Methods 
The following methods are acceptable for transmission of safety information to the 
Janssen Scientific Affairs: 
 Electronically via Janssen SECURE Email service (preferred) 
 For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax 
transmission report 
 Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen 
Scientific Affairs 
 
11. Reconciliation of SAEs 
At a minimum, on a quarterly basis and at the end of the Study, Janssen Scientific 
Affairs will provide to the INSTITUTION and/or PRINCIPAL INVESTIGATOR, a 
listing of all SAEs reported to the Janssen Scientific Affairs.  SPONSOR and/or 
PRINCIPAL INVESTIGATOR will review this listing and provide any discrepancies 
to Janssen Scientific Affairs. 
 
Upon request, INSTITUTION and PRINCIPAL INVESTIGATOR shall provide 
Janssen Scientific Affairs with a summary list of all SAEs, and AEs of Special 
Interest and Special Reporting Situation reports to date, for reconciliation purposes. 
 

 
51 
12. Dissemination of Safety Information from COMPANY to 
INSTITUTION/PRINCIPAL INVESTIGATORS 
PRINCIPAL INVESTIGATOR will be responsible for submitting IND safety reports 
for the Study Product to INSTITUTION’s IRB in accordance with Federal 
regulations 21 CFR 312.66.  The PRINCIPAL INVESTIGATOR will provide a copy 
of each IND safety report to sub-investigators where the study design is either a 
multi-center or cooperative study. 
 
Janssen Scientific Affairs agrees to provide to the PRINCIPAL INVESTIGATOR 
IND safety reports for the Janssen Medicinal Product as they become available until 
all subjects in the Protocol have completed their last Study visit according to the 
Protocol (i.e. Last Subject Last Visit has occurred).  
 
13. Contacting Janssen Scientific Affairs Regarding Safety 
The names (and corresponding contact information) of the individuals who should be 
contacted regarding safety issues will be provided separately by Janssen Scientific 
Affairs. 
 
14. Final Study Report 
The INSTITUTION/PRINCIPAL INVESTIGATOR will prepare a final report 
including a complete and full summary of all adverse events, special situations and 
pregnancy reports according to the timeframe outlined in the pertinent Research 
Funding Agreement section.