Safety, Tolerability and Efficacy of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Rejection After Kidney Transplantation - a Pilot Trial
Phase: PHASE2
Conditions: Antibody-mediated Rejection
Sponsor: Medical University of Vienna

1 
 
COVER PAGE 
 
 
Official study title: 
Safety, Tolerability and Efficacy of anti-IL-6 Antibody Clazakizumab in Late Antibody-
Mediated Rejection after Kidney Transplantation - a Pilot Trial 
 
NCT number: 
Not available yet 
 
Date of the document: 
June 25, 2017 
 
 
 
 
 
 
 
 
 
 
 

2 
 
Principal Investigator 
 
Univ.-Prof. Dr. Georg Böhmig 
Department of Medicine III, Medical University of Vienna, Austria 
 
 
_________________  
___________ 
Signature 
 
 
           Date 
 
 
Principal Investigator 
 
Univ.-Prof. Dr. Bernd Jilma 
Department of Clinical Pharmacology, Medical University of Vienna, Austria 
 
 
 
_________________  
___________ 
Signature 
 
 
           Date 
 
 
 

3 
 
 
Trial Sponsor 
Medical University of Vienna (MUW) 
Spitalgasse 23 
1090 Vienna, Austria 
Principal investigators 
MUW 
 
Prof. Dr. Georg A. Böhmig  
Medical University of Vienna 
Department of Medicine III 
Waehringer Guertel 18-20 
1090 Vienna, Austria 
Phone: +43 1 40400 43630 
Fax: + 43 1 40400 39302 
Email: georg.boehmig@meduniwien.ac.at 
Prof. Dr. Bernd Jilma 
Medical University of Vienna 
Department of Clinical Pharmacology 
Waehringer Guertel 18-20 
1090 Vienna, Austria 
Phone: +43 1 40400 29810 
Fax: + 43 1 40400 29980 
Email: bernd.jilma@meduniwien.ac.at 
Co-Investigators 
MUW 
(VIETAC lab) 
 
Dr. Farsad Eskandary  
Medical University of Vienna 
Department of Medicine III 
Waehringer Guertel 18-20 
1090 Vienna, Austria 
Phone: +43 1 40400 43630 
Fax: + 43 1 40400 39302 
Email: farsad.eskandary@meduniwien.ac.at 
PD Dr. Markus Wahrmann  
Medical University of Vienna 
Department of Medicine III 
Waehringer Guertel 18-20 
1090 Vienna, Austria 
Phone: +43 1 40400 6207 
Fax: + 43 1 40400 39302 
Email: markus.wahrmann@meduniwien.ac.at 
Prof. Dr. Gregor Bond 
Medical University of Vienna 
Department of Medicine III 
Waehringer Guertel 18-20 
1090 Vienna, Austria 
Phone: +43 1 40400 72530 
Fax: + 43 1 40400 39302 
Email: gregor.bond@meduniwien.ac.at 
Dr. Jakob Mühlbacher 
Medical University of Vienna 
Department of Surgery 
Waehringer Guertel 18-20 
1090 Vienna, Austria 
Phone: +43 1 40400 56210 
Fax: + 43 1 40400 56410 
Email: heinz.regele@meduniwien.ac.at 
Prof. Dr. Heinz Regele 
Medical University of Vienna 

4 
 
Clinical Institute of Pathology 
Waehringer Guertel 18-20 
1090 Vienna, Austria 
Phone: +43 1 40400 49730 
Fax: + 43 1 40400 51930 
Email: heinz.regele@meduniwien.ac.at 
Investigators - Second 
participating center 
Charité 
Berlin 
 
Prof. Klemens Budde 
Charité Berlin 
Department of Nephrology 
Charitéplatz 1 
10117 Berlin, Germany 
Phone: +49 30 450 514 002 
Fax: +49 30 450 514 002 
PD Dr. Johannes Waiser 
Charité Berlin 
Department of Nephrology 
Charitéplatz 1 
10117 Berlin, Germany 
Phone: +49 30 450 614 243 
Fax: +49 30 450 514 002 
Dr. Michael Dürr 
Charité Berlin 
Department of Nephrology 
Charitéplatz 1 
10117 Berlin, Germany 
Phone: +49 30 450 614 244 
Fax: +49 30 450 514 002 
Dr. Nils Lachmann 
Charité Berlin 
H&I Laboratory 
Augustenurger Platz 1 
13353 Berlin, Germany 
Phone: +49 30 450 665 098 
Fax: +49 30 450 553 918 
Co-Investigator 
(for ‘Molecular 
Microscope’, MMDx) 
University of 
Alberta 
 
Prof. Dr. Philip Halloran 
Alberta Transplant Applied Genomics Centre 
Faculty of Medicine & Dentistry 
#250 Heritage Medical Research Centre  
University of Alberta 
Edmonton, Alberta, Canada 
T6G 2S2  
Phone: (780) 492-6160 
Fax: (780) 407-7450 
Email:  phadmin@ualberta.ca 
 
 

5 
 
List of abbreviations: ADCC = antibody-dependent cellular cytotoxicity, AE = adverse 
event, ABMR = antibody-mediated rejection, ALT = Alanin-Aminotransferase, AST = 
Aspartat-Aminotransferase, BM = basement membrane, CDC = complement-dependent 
cytotoxicity, cg = transplant glomerulopathy, CNI = calcineurin inhibitor, CRF = Case-Report-
Form, CRP = C-reactive protein, CyA = cyclosporine A, CYP = cytochrome P450, DSA = 
donor-specific antibody, DSMB = data and safety monitoring board, eGFR = estimated 
glomerular filtration rate, EOS = end-of-study, GCP = Good Clinical Practice, GLP = Good 
Laboratory Practice, HLA = human leukocyte antigen, IFTA = interstitial fibrosis/tubular 
atrophy, IgG = Immunoglobulin G, IL-6 = Interleukin-6, IL-6R = Interleukin 6 receptor, IV = 
intravenous, IVIG = intravenous immunoglobulin, KTX = kidney transplantation, MFI = mean 
fluorescence intensity, mGFR = measured glomerular filtration rate, MLPTC, multilayering of 
peritubular capillary basement membranes, MMDx = molecular microscope; MMF = 
mycophenolate mofetil, mTOR = mammalian target of rapamycin, MUW = Medical University 
Vienna, PD = pharmacodynamics, PK = pharmacokinetics, PTC = peritubular capillaries, 
pSTAT3 = phosphorylated signal transducer and activator of transcription 3, RA = rheumatoid 
arthritis, SAE = serious adverse event, SAFB = single-antigen flow-beads, SC = 
subcutaneous, SD = standard deviation, STAT3 = signal transducer and activator of 
transcription 3, TTV = Torque Teno virus, ULN = upper limit of normal 
 
 
 
 
 

6 
 
1. BACKGROUND AND RATIONALE 
 
There is emerging evidence that antibody-mediated rejection (ABMR) is a leading cause of 
kidney allograft dysfunction and failure in the long-term 1-3. According to current diagnostic 
standards, the diagnosis of ABMR is based on the detection of donor-specific antibodies 
(DSA) and renal biopsy results, including characteristic acute and/or chronic morphological 
lesions in the microcirculation and, in some cases, detection of complement split product 
(C4d) deposits along peritubular capillaries (PTC) 4,5. In addition, ABMR was shown to 
associate with specific gene expression patterns 6, and distinct molecular criteria are now 
included in the Banff classification of renal allograft pathology 4,5. While a continuous 
diagnostic refinement has helped define the role of this rejection type as a major trigger of 
chronic allograft injury, treatment of late and/or chronic ABMR still represents a major 
challenge. Our current knowledge is mainly based on the results of uncontrolled 
observational studies, where a variety of different treatment strategies were evaluated, 
ranging 
from 
modifications 
in 
maintenance 
immunosuppression 
7-9 
to 
different 
immunomodulatory measures, including high dose intravenous immunoglobulin (IVIG) with or 
without CD20 antibody rituximab 10-13, the proteasome inhibitor bortezomib 14, or anti-C5 
antibody eculizumab 15. Some of these reports have pointed to potential beneficial treatment 
effects. Nevertheless, the results of recent systematic randomized controlled trials designed 
to assess the effect of specific interventions, such as eculizumab 15 or bortezomib 
(Eskandary & Böhmig, manuscript in preparation) in chronic ABMR, have failed to 
demonstrate a meaningful effect on the course of rejection. For example, in a recent double-
blind placebo-controlled phase 2 trial performed at the Medical University Vienna (MUW), we 
were unable to demonstrate a beneficial effect of two cycles of bortezomib on the 
progression of late ABMR in 44 kidney allograft recipients. These data clearly demonstrate 
that there is still an unmet need for an effective treatment of late (chronic) ABMR, and new 
innovative treatment concepts are required. 
 
The pleiotropic pro-inflammatory cytokine interleukin-6 (IL-6), which is known to play a 
pivotal role not only as a trigger of acute phase responses, but also in the activation and 
development of B cells and antibody production, may be a promising target for ABMR 
treatment 16. Monoclonal antibodies against IL-6 and the IL-6 receptor (IL-6R) have been 
proven to be effective in the treatment of various autoimmune diseases, including rheumatoid 
arthritis (RA) 17-19. More recently, targeting IL-6/IL-6 receptor has gained interest also in the 
context of organ transplantation. In a recent uncontrolled trial by Choi et al. 20 the anti-IL6R 
monoclonal antibody tocilizumab was evaluated as treatment of chronic ABMR unresponsive 
to IVIG, rituximab and/or plasmapheresis in a cohort of 36 kidney transplant recipients. The 
results of this uncontrolled trial are promising, showing a beneficial safety profile, a reduction 

7 
 
in DSA levels, and stabilization of kidney function at 2 years. A major result of this study was 
a marked reduction in the extent of microcirculation inflammation in follow-up biopsies. The 
authors noted graft losses in four recipients in whom tocilizumab was prematurely stopped. 
For these cases, a role of a rebound effect by accumulated IL-6 20. 
 
Direct binding and blockade of IL-6 may be an attractive alternative. Clazakizumab 
(formerly ALD518, BMS945429), is a high affinity humanized monoclonal antibody which 
binds to IL-6 and prevents interaction and signaling via IL-6R. This antibody is the most 
potent and longest acting agent in the IL-6/IL-6R blocking category, is free of antibody-
dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) and 
does not crosslink any surface receptors. Its half-life is about 30 days [subcutaneous (SC) 
administration], and monthly SC injections allow for sustained IL-6 blockade.  Its safety has 
so far been established in more than 800 subjects, many of them treated within phase 2 
studies performed in RA or psoriatic arthritis (PsA) 18,21-23. 
This 12-month pilot trial is primarily designed to evaluate the safety, tolerability, 
pharmacokinetics and pharmacodynamics of clazakizumab versus placebo in a cohort of 20 
kidney transplant recipients diagnosed with late ABMR. The design of the study, which 
includes early and late follow-up protocol biopsies to decipher the effects on microcirculation 
inflammation, gene expression profiles and features of chronic transplant injury will also allow 
for preliminary efficacy assessment (information on effect size and variability), and thus can 
be expected to provide a valuable foundation of future trials in large populations of transplant 
patients. 
 
Clazakizumab (anti-IL6 monoclonal antibody): Potential as a therapeutic agent in 
transplantation 
Clazakizumab (Vitaeris Inc., Vancouver, BC Canada) is a humanized monoclonal antibody 
aimed at the cytokine IL-6 ligand. Clazakizumab has been evaluated extensively in patients 
with arthritis 18,21-23, but has not yet been approved by the FDA for any condition. Since the 
introduction of IL-6/IL-6R blocking drugs, reports indicate that inhibition of the IL-6/IL-6R 
pathway may have significant benefits in systemic lupus erythematosus and other vasculitic 
disorders and reduces antibody producing cells in treated patients. There is currently no 
information for clazakizumab in highly sensitized patients awaiting incompatible transplants 
or for treatment of ABMR. However, preliminary data suggests that clazakizumab exhibits a 
broad range of immunomodulatory actions that could address the alloantibody response to 
allografts and be useful as a desensitization agent to improve rates of renal transplantation 
for highly-HLA sensitized patients. This is based on data obtained from clinical trials of 
clazakizumab for treatment of RA.  

8 
 
Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) 
antibody that binds to human IL-6 with an affinity of 4 pM. Using multiple assays for signaling 
and cellular functions in response to IL-6 alone (to measure classical signaling) and a 
combination of IL-6 and sIL-6R (to measure trans-signaling), it was demonstrated that 
clazakizumab is a potent and full antagonist of IL-6-induced signaling as measured by 
phosphorylation of signal transducer and activator of transcription 3 (STAT3), as well as 
cellular functions such as cell proliferation, differentiation, activation, B-cell production of 
immunoglobulins, and hepatocyte production of acute phase proteins [C-reactive protein 
(CRP) and fibrinogen]. In addition, clazakizumab is shown to be a competitive antagonist of 
IL-6-induced cell proliferation. This in vitro pharmacological profile supports the potential of 
clazakizumab to impact multiple immune and non-immune cellular processes that are central 
to disease pathogenesis, and thus, to offer a new therapeutic modality in the treatment of 
autoimmune diseases and other IL-6 mediated diseases.  
The clazakizumab development program includes a comprehensive nonclinical 
development program and clinical studies conducted in healthy subjects and in subjects with 
RA, PsA, Crohn’s disease, graft-versus-host disease, and oncology. To date, no studies with 
clazakizumab have been conducted in subjects with highly sensitized patients undergoing 
renal transplant, although supporting safety data are available from the previous clinical 
studies. 
 
Nonclinical Studies. A comprehensive nonclinical development program has been 
completed. Clazakizumab was shown to be a potent inhibitor of IL-6-induced acute phase 
proteins. In pharmacokinetic (PK)/pharmacodynamic (PD) studies, a single dose of 
clazakizumab resulted in full inhibition of IL-6 activity as measured by the inhibition of IL-6-
induced phosphorylated STAT3 (pSTAT3) activity in whole blood treated ex vivo with IL-6. 
The results of this functional PD assay correlated with drug exposures where full inhibition of 
pSTAT3 activity was observed when drug levels exceeded 50 ng/mL (approximately 0.3 nM). 
In a tissue cross-reactivity study, tissue binding of clazakizumab was observed in multiple 
tissues in both human and cynomolgus monkey, was generally cytoplasmic in nature, and 
was consistent with the known expression of IL-6 by cells and tissues. Results from both 
single- and repeat-dose nonclinical toxicology studies of up to 6 months in cynomolgus 
monkeys demonstrated an acceptable safety profile for clazakizumab. In a preliminary 
enhanced pre- and post-natal development study conducted in cynomolgus monkeys, an 
increase in the number of monkeys with retention of the placenta at parturition was observed 
at clazakizumab doses of 3 mg/kg (n=2) and 30 mg/kg (n=3), corresponding to doses 11 and 
110 times the planned human dose of 50 mg. There were no other safety findings of clinical 
concern. 

9 
 
 
Clinical studies. Clinical studies have been conducted in healthy subjects and in the 
following patient populations: RA, PsA, Crohn’s disease, graft-versus-host disease, and 
oncology. These clinical studies include a total of 1,223 subjects, of which 888 subjects were 
exposed to clazakizumab with doses ranging from 1 mg to 640 mg given by either 
intravenous (IV) or SC injection for up to 48 weeks.  
 
Clinical Pharmacology. Following the administration of clazakizumab as a 1-hour IV 
infusion, the PK of clazakizumab were linear over the dose ranges of 30 mg to 640 mg in 
healthy subjects and 80 mg to 320 mg in subjects with RA as indicated by consistent 
clearance at these dose levels. The T-half of clazakizumab at all doses was very similar in 
healthy male subjects and in subjects with RA and was consistent with that expected for a 
humanized IgG1 antibody. Across the doses studied, the mean T-half of clazakizumab 
ranged from 19.5 to 31.0 days in healthy male subjects and from 26.4 to 30.9 days in 
subjects with RA. The T-half of clazakizumab after SC administration in healthy male 
subjects was similar to the IV administration. In a Phase 1 study comparing IV and SC 
dosing in healthy male subjects, the mean T-half of clazakizumab was 30.7 days after a 
single IV dose and 31.1 to 33.6 days after SC administration. The bioavailability of 
clazakizumab after SC administration was 60% of the IV formulation. As expected, Cmax 
was lower and Tmax was longer for the SC administration relative to IV administration. 
Population PK analysis of the data from clinical studies in RA, PsA and healthy subjects 
have indicated that body weight affects the PK of clazakizumab such that both clearance and 
central volume of distribution increase with increasing body weight. Therefore, heavier 
subjects will have lower drug exposure compared with less heavy subjects. 
 
Clinical Efficacy and Safety Studies. Efficacy and safety data for clazakizumab is available 
from clinical studies conducted in RA, PsA, and oncology. Studies conducted in GVHD and 
Crohn’s disease were prematurely terminated due to safety concerns and therefore no 
efficacy conclusions are available for these studies. The GVHD study was terminated after 
only 3 subjects were enrolled, due to 2 subjects with severe GVHD experiencing similar 
serious adverse events (SAEs) (i.e., acute renal failure) which led to death. These 2 subjects 
had received single doses of clazakizumab 160mg intravenously. The Crohn’s disease study 
was terminated early because of gastrointestinal (GI) perforation in 3 subjects who had 
received clazakizumab intravenously at doses of 150 mg or greater. These subjects had 
multiple confounding medical issues, and the disease itself has an inherent risk of mucosal 
perforation. Gastrointestinal perforations were also observed during the clinical studies with 
tocilizumab in subjects with RA. 

10 
 
 
 
2. HYPOTHESIS AND OBJECTIVE OF THE STUDY 
 
Clinical data to date support that IL-6 blockade is safe and well tolerated, and we 
hypothesize that clazakizumab will have a similar safety profile in kidney transplant recipients 
on baseline immunosuppression. Moreover, we hypothesize that repeated administration of 
clazakizumab is able to counteract tissue inflammation and injury in ongoing ABMR, in 
particular, inflammation in the microcirculation, HLA antigen-specific B cell alloresponses 
and, as a consequence, alloantibody-triggered chronic graft injury. The primary objective of 
this bi-center two-step prospective pilot trial (part A: 12-week double-blind placebo-controlled 
part of the trial; part B: 40-week open-label part of the trial) is to evaluate the safety and 
tolerability of clazakizumab in a cohort of 20 kidney transplant recipients diagnosed with late 
ABMR. Secondary objectives are to evaluate the PK (including measurement of anti-
clazakizumab antibodies) and PD of this antibody (subcutaneous administration of 25 mg in 
4-weekly intervals) in the specific context of organ transplantation. Moreover, two sequential 
protocol biopsies (histomorphology, immunohistochemistry, electron microscopy, gene 
expression patterns), in addition to kidney function, urinary protein monitoring and ABMR-
associated blood biomarkers, will allow an in-depth analysis of the anti-inflammatory effect of 
clazakizumab (early biopsy in part A) and its effect on the progression of antibody-mediated 
chronic injury (late biopsy in part B). Finally, blockade of the pleiotropic cytokine IL-6 may 
potentially interfere with cytochrome P450 (CYP) metabolism and thus potentially affect the 
half-life of CYP-metabolized drugs 24. We will evaluate the impact of IL-6 blockade on the 
pharmacokinetics of CYP substrate pantoprazole. The results of this pilot trial will provide a 
valuable foundation of future systematic long-term trials to assess the efficacy of IL-6 
blockade in ABMR. 
 
 
3. STUDY DESIGN 
 
This bi-center study (MUW, Charité Berlin) is an investigator-driven pilot trial designed to 
assess the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy 
(preliminary assessment) of humanized anti-IL-6 monoclonal antibody clazakizumab in 
kidney transplant recipients with late ABMR. This study, a phase 2 trial, has two subsequent 
sub-parts, a randomized placebo-controlled trial (part A) of 12 weeks, where recipients are 
allocated to receive either clazakizumab (n=10) or placebo (n=10), followed by an open-label 
prospective study, where all 20 study patients will receive clazakizumab for a period of 40 

11 
 
weeks. In this second part, treatment will be offered to all subjects for two major reasons: (i) 
in a recent uncontrolled preliminary observational study, interference with IL-6/IL-6R 
blockade in ABMR patients using tocilizumab was reported to be safe and well tolerated, and 
first results have suggested stabilization of kidney function in many of the treated patients; (ii) 
two subsequent protocol biopsies planned in our trial, which are necessary for an in-depth 
analysis of the early and late effects of IL-6 blockade, would not be justified for long-term 
placebo treatment. After completion of part A, the randomization sequence will be unblinded 
for a first analysis of data. A simplified flow chart of the trial is shown in Figure 1: 
 
Figure 1. Trial overviw 
 
 
 
 
 
Part A: Patients will be randomized to receive either clazakizumab (25 mg subcutaneous 
[SC] administration) or placebo (1:1 randomization) for a period of 12 weeks (administration 
of clazakizumab/placebo at day 0, and after 4 and 8 weeks). After 12 weeks, patients will be 
subjected to a first follow-up biopsy. Primary goals of this part of the trial are to assess the 
safety, pharmacokinetics and pharmacodynamics of a short course of treatment. Moreover, 
part A will allow for a first preliminary assessment of the impact of clazakizumab on ABMR-
associated inflammation detected in peripheral blood and in the rejecting organ allograft, on 
the pharmacokinetics of pantoprazole as a probe drug to investigate influence of IL-6 
blockade on cytochrome P450-dependent drug metabolism, and on the short-term course of 
DSA MFI and kidney allograft function (eGFR, urinary protein excretion). The randomization 

12 
 
sequence will be unblinded for a first data analysis after the last patient has completed the 
12-week follow-up period. 
 
Part B: After 12 weeks, all study patients will enter an open-label part of the study. All 20 
subjects will receive clazakizumab (25 mg SC injection) in 4-weekly intervals until the end-of-
study (EOS) visit after 52 weeks and will then be subjected to a second protocol biopsy. 
Major goals of part B are to evaluate the safety and tolerability of a prolonged period of 
treatment with clazakizumab and the long-term impact of this antibody on the evolution of 
ABMR, rejection-associated biomarkers and kidney allograft function and survival over a 
period of 12 months. 
 
We expect a recruitment phase of 18 months, and thus completion of the trial after 30 
months.  
 
Inclusion/exclusion criteria 
 
We will include kidney transplant recipients with circulating anti-HLA DSA and biopsy 
features of ABMR (ABMR according to the Banff 2013 scheme) in an indication biopsy (index 
biopsy; performed for a positive post-transplant DSA result and/or slow deterioration of 
allograft function and/or proteinuria. Other key inclusion criteria are a functioning graft at 
≥365 days post-transplantation and an eGFR above 30 ml/min/1.73 m2. This eGFR threshold 
has been chosen to avoid inclusion of transplants with a high degree of irreversible chronic 
damage (for patients with very advanced graft injury a sustainable treatment benefit can no 
longer be expected). Inclusion and exclusion criteria are listed in Table 1. 
 
 
 
 
 
 
 
 
 
 
 
 

13 
 
 
 
 
Table 1. Inclusion and exclusion criteria 
INCLUSION CRITERIA 
Voluntary written informed consent 
Age >18 years 
Functioning living or deceased donor allograft after ≥365 days post-transplantation 
eGFR >30 ml/min/1.73 m2 
Detection of HLA class I and/or II antigen-specific antibodies (preformed and/or de novo 
DSA). 
Acute/active or chronic/active ABMR (±C4d in PTC) according to Banff 2013/2015  
Molecular ABMR score (ABMRpm) ≥0.2  
EXCLUSION CRITERIA 
Patients actively participating in another clinical trial 
Age ≤18 years 
Female subject is pregnant or lactating 
Index biopsy results: 
T-cell-mediated rejection classified Banff grade ≥I 
De novo or recurrent severe thrombotic microangiopathy 
Polyoma virus nephropathy 
De novo or recurrent glomerulonephritis 
Acute rejection treatment <3 month before screening 
Acute deterioration of graft function (eGFR decline within 1-3 months >25%) 
Nephrotic range proteinuria >3500 mg/g protein/creatinine ratio 
Active viral, bacterial or fungal infection precluding intensified immunosuppression 
Active malignant disease precluding intensified immunosuppressive therapy 
Abnormal liver function tests (ALT, AST, bilirubin > 1.5 x upper limit of normal) 
Other significant liver disease 
Latent or active tuberculosis (positive QuantiFERON-TB-Gold test, Chest X-ray) 
Administration of a live vaccine within 6 weeks of screening 
Neutropenia (<1 G/L) or thrombocytopenia (<100 G/L) 
History of gastrointestinal perforation, diverticulitis, or inflammatory bowel disease 
Allergy against proton pump inhibitors 
History of alcohol or illicit substance abuse 
Serious medical or psychiatric illness likely to interfere with participation in the study 
 
Random allocation 
For part A of the trial, patients will be centrally randomized by computer assignment between 
two 
study 
arms 
(part 
A 
of 
the 
study: 
clazakizumab 
versus 
placebo) 
using 
http://www.randomization.com (1:1 randomization). Stratification according to acute/active 
ABMR and chronic/active ABMR will be used to ensure a balance of patients with these two 
histological types between the two arms. For each patient, a study ID will be assigned. The 
participating investigators and the patients will be blinded to group allocation until the 
completion of part A of the study. 
 
Blinding and unblinding 

14 
 
The first part (A) of the study is designed as a double-blinded trial, in order to minimize bias. 
Investigational drug (clazakizumab) and placebo (normal 0.9% saline) are prepared by non-
blinded pharmacists and formulated to have identical appearance. Neither study participants 
nor medical staff interacting with patients or data know the assigned treatment (clazakizumab 
versus placebo). The randomization sequence will be unblinded after the last patient has 
completed the 12-week follow-up period. Premature unblinding may be necessary in cases of 
medical emergencies or serious medical conditions, where participants cannot be treated 
adequately unless the medical staff knows the allocated treatment. Unblinding can, if 
necessary, be requested by the DSMB. 
 
 
4. INTERVENTIONS 
 
Treatment with clazakizumab/placebo: 
Clazakizumab or placebo will be administered as single SC injection of 1 mL each by blinded 
qualified study personnel during the double blind phase. All study drug administrations will be 
documented in the subject’s source documents and in the CRF. 
 
Clazakizumab will be supplied in single-dose vials (25 mg/mL) for injection and provided by 
Vitaeris Inc. The placebo medication will be administered with normal saline for injection 
(commercially available in country) and will be provided by the Investigator. Prepared 
syringes may be stored for up to 24 hours in a refrigerator, 2°C to 8°C, and up to 4 hours of 
the 24 hours may be at room temperature, 15°C to 25°C. The prepared syringes will be 
protected from light. Prior to administration, clazakizumab/placebo injection must reach room 
temperature by storing unrefrigerated for 30 to 60 minutes before use. 
 
Storage and Accountability. Clazakizumab will be stored at -20C or colder, with protection 
from light. Placebo will be stored at controlled room temperature and should not be frozen. 
Study product disposition and accountability will be documented on the subject level, 
whereby all study product dispositions will be listed (drug accountability log). In a stock 
record, overall bulk study product supplies and accountability will be recorded. 
 
The following medications are prohibited during the study: 
Rituximab, eculizumab, proteasome inhibitors, IVIG, plasma exchange or immunoadsorption, 
other investigational drugs/treatments including commercially available anti-IL-6/sIL-6R 
monoclonal antibody drugs such as tocilizumab (Actemra®). 
The following concomitant medications are permitted during the study: 

15 
 
Calcineurin inhibitors (CNI, tacrolimus or cyclosporine A), mammalian target of rapamycin 
(mTOR) inhibitor (everolimus or rapamycin), Mycophenolate mofetil (MMF)/mycophenolate 
sodium; low dose corticosteroids (prednisolne ≤ 5mg/day) 
 
 
Baseline immunosuppression: Upon diagnosis of ABMR, baseline immunosuppressive 
treatment will be adjusted according to the standard of the Vienna transplant unit. Upon 
diagnosis of late ABMR, all recipients (both arms in part A) on therapy with a CNI (tacrolimus 
or cyclosporine A, CyA) or a mTOR inhibitor (everolimus or rapamycin), without azathioprine 
or MMF/mycophenolic acid, will receive MMF (initially 2 x 500 mg per day; stepwise increase 
to 2 x 1000 mg per day if tolerated) to avoid under-immunosuppression. Tacrolimus will be 
adjusted to achieve target trough levels between 5 and 10 ng/mL, CyA to 80-120 ng/mL. 
Recipients weaned off steroids will receive low dose prednisolone (5 mg/day).  
 
 
5. OUTCOME MEASURES 
 
Study endpoints are listed in Table 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary and secondary outcomes in part A and part B of the trial 
PRIMARY OUTCOME 
Safety and tolerability 
SECONDARY OUTCOMES (PART A AND B) 
PK of clazakizumab (every visit; measurement of anti-Claza antibodies included) and of 
pantoprazole (0, 12, 52 weeks) 

16 
 
PK/PD of clazakizumab (clazakizumab levels and CRP suppression) (every visit) 
Cytokines patterns and endothelial activation/injury markers in serum (0, 12, 52 weeks) 
Effect on leukocyte subsets in peripheral blood 
Effect on IL-6 and IL-6R gene expression in peripheral blood cells 
HLA antibody levels (0, 12, 52 weeks) 
 
Maximum and sum of mean fluorescence intensity (MFI) of DSA 
 
Number of DSA 
 
Broadness of sensitization (virtual PRA) 
Total Ig classes (IgG, IgA, IgM) and IgG subclasses (IgG1, 2, 3, 4) 
Protocol biopsy results at 11 and 51 weeks 
    ABMR category 
    Microcirculation inflammation (g+ptc score) 
    Transplant glomerulopathy (cg) and interstitial fibrosis/tubular atrophy (IFTA) scores 
    Molecular ABMR score (molecular microscope, MMDx) 
    Archetype analysis of gene expression profiles (molecular microscope, MMDx) 
eGFR (every visit) 
Protein excretion (protein/creatinine ratio) (every visit) 
1-year graft and patient survival 
Occurrence of biopsy-proven acute rejection necessitating rejection treatment (52 weeks) 
 
 
 
 
 
 

17 
 
The schedule of events is provided in Table 3. 
 
Table 3. Schedule of events 
 
Part A 
Part B 
Visit 
Screen 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
Week 
up to -4 
0 
1 
2 
3 
4 
8 
11 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
51 
52 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination and 
medical history 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test 
x 
 
 
 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Quantiferon test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Clazakizumab/placebo 
 
x 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clazakizumab 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Safety Lab 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
LDL/HDL cholesterol, 
triglycerides 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CMV PCR 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x 
Evaluation of PK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clazakizumab concentration 
and anti-clazakizumab 
antibodies 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Evaluation of PD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ultrasensitive CRP 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Preliminary efficacy 
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsies (incl. MMDx) 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
DSA detection 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Ig (sub)classes 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Cytokine patterns 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Endothelial markers 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Leukocyte subpopulations 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
TTV copy number 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
eGFR 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Protein/creatinine ratio 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Liver metabolism 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pantoprazol i.v. 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Pantoprazol concentration 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Immunosuppression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CNI trough level 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Biobanking 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Long visits (approx. 6-9 hours) in grey 
 
 
Primary outcome measures are the safety and tolerability of clazakizumab, evaluated 
throughout the study period (19 visits until EOS visit at 52 weeks). Secondary endpoints are 
pharmacokinetics (clazakizumab concentration) and pharmacodynamics (suppression of 
CRP). For preliminary efficacy assessment, blood-derived biomarkers of ABMR (HLA/DSA 
antibody levels, cytokines and markers of endothelial injury, patterns of peripheral blood 
leukocyte subpopulations) and IL-6/IL-6R gene expression will be assessed at day 0, and 
after 12 and 52 weeks. The study will include two protocol biopsies, an early biopsy after 11 
weeks (end of part A) to primarily dissect the effect of IL-6 blockade on microcirculation 
inflammation in direct comparison to placebo, and a late biopsy after 51 weeks to assess the 

18 
 
effect of clazakizumab on the progression of chronic injury (cg score, IFTA score). All 
biopsies will in addition be evaluated for ABMR-typical gene expression patterns (ATAGC, 
Alberta University, Edmonton; major read-out: molecular ABMR score). We will in addition 
monitor kidney function, protein excretion and graft survival over the whole study period. 
Finally, we will assess the impact of IL-6 blockade (as compared to placebo) on 
pharmacokinetics of pantoprazole reflecting CYP-dependent liver metabolism. At day 0, 
week 12 and week 52, pantoprazole will be administered at a dosage of 20 mg intravenously, 
and drug levels will be determined every hour over a period of 6 hours. In patients on 
continuous proton pump inhibitor therapy, oral treatment will be paused for 3 days before 
pharmacokinetic testing, and re-started one day thereafter. 
 
 
6. METHODOLOGY 
 
HLA antibody detection. For assessment of the course of DSA levels, serum samples will 
be evaluated after completion of the study (part A and B). If detailed data on preformed DSA 
are not available, stored pre-transplant sera will be tested retrospectively for the presence or 
absence of DSA. Sera will be heat-inactivated to preclude complement-dependent in vitro 
artifacts (prozone phenomenon) and subjected to single-antigen flow-bead testing 
(LABscreen Single Antigen assays; One Lambda). Test results will be documented as mean 
fluorescence intensities, and MFI >1000 will be considered positive. Donor-specificity will be 
defined according to donor and recipient HLA typing results. Virtual panel-reactive antibody 
(PRA) levels will be calculated using specific software tools (http://www.eurotransplant.eu). 
 
Transplant biopsies. Biopsies will be performed after exclusion of a coagulation disorder or 
platelet counts below 80%. Anticoagulants or inhibitors of thrombocyte aggregation will be 
transiently paused. The biopsy will be performed under local anaesthesia (lidocain) using 
ultrasound-guided percutaneous techniques (1-2 cores per biopsy, 16 gauge needle). After 
biopsy, patients will be monitored closely for 5 to 8 hours for any complications (serial blood 
pressure measurements, monitoring for hematuria, haemoglobin check 4 hours after biopsy). 
Histomorphology will be evaluated on paraffin-embedded sections applying standard 
methodology. For immunohistochemical C4d staining, we will use a polyclonal anti-C4d 
antibody (BI-RC4D, Biomedica; Vienna, Austria), and, following the rules of the Banff 
scheme 4, minimal immunohistochemical staining (C4d Banff score ≥1) along peritubular 
capillaries will be considered positive. Biopsies will in addition evaluated by electron 
microscopy for detection of multilayering of peritubular capillary basement membranes 
(MLPTC).  All biopsies will be analyzed using microarrays, as proposed by the Banff scheme. 

19 
 
For each biopsy, a 3 mm portion of one core will be placed immediately in RNAlater, stored 
at -20°C and shipped at ambient temperature or dry ice to the Alberta Transplant Applied 
Genomics Centre (ATAGC, University of Alberta, Edmonton, AB, Canada) for gene array 
analysis. Thoroughly validated molecular scores based on machine-learning derived lesion-
based classifiers related to rejection (ABMRpm, TCMRt, all Rejection) will be generated 
using the Edmonton reference set of >1200 biopsies. Moreover, gene expression patterns 
will be evaluated using unbiased archetype analysis. Morphological results will be evaluated 
by experienced renal transplant pathologists blinded for treatment allocation. For 
classification of ABMR according to the Banff 2013 scheme, all biopsy results will be 
analyzed in the context of the molecular results. ABMR categories and morphological single 
lesions will be defined and scored following the 2013/2015 update of the Banff classification 
4. ABMR will be defined on the basis of both morphological (histomorphology, 
immunohistochemistry, electron microscopy) and thoroughly validated molecular criteria: (i) 
evidence of acute or chronic tissue injury, (ii) evidence of current/recent antibody interaction 
with the vascular endothelium, and (iii) serological evidence of DSA. 
 
Kidney function. eGFR will be assessed using the CKD-EPI formula. Protein excretion will 
be documented as protein/creatinine ratio. 
 
Pantoprazole pharmacokinetics will be determined by liquid chromatography tandem mass 
spectrometry. 
 
Cytokine and markers of endothelial activation/injury. Sera collected at week 0, 12 and 
52 will be analysed for IL-6, soluble IL-6 receptor, soluble VCAM-1, soluble P-Selectin and 
DARC in order to document IL-6 decrease in the clazakizumab arm and to monitor 
endothelial activation and injury. Analysis will be carried out on FlowELISA beads in a 
multiplex approach (where possible) in a Luminex 200 or ELISA technology (DARC). In 
parallel, markers of inflammation and endothelial cell activation will be evaluated in urine.  
 
Leukocyte subpopulations. The underlying mechanisms of chronic antibody mediated 
rejection, especially the role of peripheral T- and B-cell subsets are not fully clarified. Thus, 
the prospective monitoring of immune phenotype under therapy with clazakizumab is a 
promising approach to further elucidate the impact on immune-regulatory pathways when IL-
6 signal is blocked. For monitoring of leukocyte (sub)populations we will use reproducible 
immune monitoring (IM) panels for phenotyping. Recently, the international "The ONE study" 
consortium has designed a standardized panel (DuraClone®) for flow cytometry based 
immune phenotyping that demonstrated robust results 25 26. In the DuraClone IM kits pre-

20 
 
defined assay tubes contain a layer with the dried-down antibody panel ready to use. Up to 
10 different monoclonal antibodies per tube allows the identification of leukocyte (e.g. T cell, 
B cell, NK cell subsets) subpopulations present in whole blood samples. 
 
Gene expression analysis. For gene expression analysis, 5 mL of blood will be collected in 
PAXgene Blood RNA tubes and stored at -80°C until retrospective analysis. These tubes are 
designed for stabilization of RNA in blood during long-term storage at ultra-low temperature. 
After thawing, RNA will be isolated and transcribed into cDNA. The amount of RNA/cDNA of 
IL-6 or IL-6R will be determined by quantitative real-time-PCR using the TaqMan assay. 
Thereby, - on top of a common PCR reaction (amplification of template cDNA between two 
primer sequences by a DNA polymerase) - IL-6 or IL-6R-specific probes will be placed 
between the two PCR primers. These probes will be labelled with a fluorochrome which is 
released upon polymerase action. This released fluorochrome will be measured and 
compared to another fluorochrome that is released in parallel from a house-keeping gene like 
G3PDH. 
 
Torque Teno virus (TTV) quantification. TTV DNA will be quantified retrospectively in 
stored plasma samples obtained at week 0, 12 and 52 using real time PCR. 
 
Collection of biological material (outside routine monitoring). Plasma (10 mL; cytokines, 
endothelial markers, TTV load), serum (10 mL; HLA antibodies, cytokines, endothelial markers), whole 
blood (10 mL; flow cytometry, RNA for gene expression analysis) and urine (10 mL) will be collected 
before study initiation (day 0), after 12 and after 52 weeks (3x25 mL peripheral blood). For 
pantoprazole kinetics, peripheral blood samples will be collected serially (6 x 5 mL per day) at day 0, 
week 12 and week 52, respectively. Finally, for measurement of clazakizumab concentrations and 
anti-clazakizumab reactivity, serum will be obtained at every study visit (5 mL peripheral blood per 
visit; total of 17 visits). Biological material will be aliquoted and stored for testing (clazakizumab 
concentration, anti-clazakizumab antibody detection, HLA antibody detection, detection of cytokines 
and endothelial markers, TTV quantification) at the Department of Clinical Pharmacology. 
 
 
 
 
7. SAMPLE SIZE AND STATISTICAL ANALYSIS 
 
For this pilot study, no exact sample size estimation can be performed, because the effect 
size is unknown (there is no prior information to base a sample size on). The primary 
endpoint will be safety and tolerability. A preliminary assessment of efficacy outcomes in 20 

21 
 
kidney transplant recipients with late ABMR will provide first data on the effect of 
clazakizumab on clinical, morphological, immunological and molecular endpoints. The 
respective results (e.g. comparison between clazakizumab and placebo with respect to 
microcirculation inflammation and molecular rejection scores; course of chronic injury from 3 
to 12 months), including an assessment of variability, can be expected to provide a valuable 
foundation of the design of future trials. Analyses will be conducted according to the 
intention-to-treat principle. Continuous data (e.g. group comparisons in part A for DSA-MFI, 
g+ptc score, IF/TA score, molecular ABMR score, eGFR and protein/creatinine ratio after 3 
months) will be analysed using parametric and non-parametric (independent/dependent 
data) tests. These include the Mann Whitney U test or the t-test, as appropriate. Nominal 
data (e.g. occurrence of AEs in the two treatment groups in part A of the study) will be 
compared using the Fisher’s exact test, when appropriate. Transplant and patient survival or 
AE (SAE)-free survival will be evaluated using Kaplan Meier analysis and the log rank test 
will be applied for group comparisons. For paired data (e.g. difference in IF/TA score 
between month 3 and month 12 in the overall cohort - part B), paired t test or Wilcoxon test 
will be used as appropriate. Analysis of pharmacokinetics of clazakizumab and pantoprazol 
will include a description of the time evolution of antibody/drug concentration. Elimination 
half-life, Tmax, Cmax, clearance and volume of distribution will be computed using standard 
software. For some study endpoints, data on variability and center (median) that can be 
expected also for the present study, are available from a recent interventional randomized 
controlled trial performed at our unit, which included a similar cohort of kidney transplant 
recipients diagnosed with late ABMR (BORTEJECT, NCT01873157; unpublished data; 
protocol described in: Eskandary et al., Trials. 2014 Apr 3;15:107). The respective data 
obtained in study groups are listed in the table below: 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4. Median and variability of key endpoints – results of the BORTEJECT study 

22 
 
Endpoints 
All patients 
n 
Placebo (n=23) 
Bortezomib (n=21) 
HLA DSA after 1 yr 
 
 
 
 
Immunodominant DSA 
3553 
(1012-10365; 163-16284) 
39 
4360 
(1080-10226; 778-16284) 
2054 
(918-10968; 163-14461) 
Sum of DSA MFI 
4605 
(1119-12009; 273-33855) 
39 
 
5410 
(1354-13612; 778-28828) 
3479 
(929-12009; 273-33855) 
Follow-up biopsy (24 mo) 
 
 
 
 
g+ptc score 
2 (1-5; 0-6) 
38 
2 (1-5; 0-6) 
4 (0-5; 0-6) 
IF/TA score 
3 (2-5; 0-6) 
38 
3 (2-4; 0-6) 
3 (2-5; 0-6) 
Molecular ABMR score 
0.61 
(0.30-0.89; 0.05-0.99) 
37 
0.58 
(0.24-0.89; 0.08-0.99) 
0.77 
(0.41-0.90; 0.05-0.97) 
 
 
 
 
 
Kidney parameters after 1 yr 
 
 
 
 
eGFR, ml/min/1.73 m2 
44 
(23-72; 15-95) 
43 
53 
(23-81; 15-95) 
42 
(25-69; 15-89) 
Protein/creatinine ratio, mg/g 
201 
(86-1249; 0-4863) 
44 
194 
(82-959; 0-4863) 
208 
(100-1427; 0-2972) 
 
 
8. INTERIM ANALYSES 
 
This study will be monitored by an independent data and safety monitoring board (DSMB) to 
assess the safety and data quality. To timely detect major differences between groups in 
terms of safety aspects, the board members will be instructed to perform interim analyses 
after 10 and 20 patients have finalized part A of the study. The DSMB will analyze recorded 
AEs and safety lab results in relation to the randomization sequence. The trial will be 
terminated prematurely in the following cases: (i) if adverse events occur which are so 
serious that the risk-benefit ratio is not acceptable, and (ii) if the number of dropouts is so 
high that proper completion of the trial cannot realistically be expected. For this pilot trial, 
exact statistical definitions of criteria for premature study termination are not defined. 
 
 
 
 
 
 
 
 
 
DSMB - Members 

23 
 
Prof. Dr. Nina Worel 
Department of Serology and Transfusion Medicine 
Medical University of Vienna 
Waehringer Guertel 18-20 
1090 Vienna, Austria 
Prof. Dr. Marcus Säemann 
Nephrology and Dialysis 
Department of Medicine 6 
Wilhelminen Hospital 
Montleartstraße 37 
1160 Vienna, Austria 
 
Department of Medicine III 
Medical University of Vienna 
Waehringer Guertel 18-20 
1090 Vienna, Austria 
Prof. Dr. Daniel Aletaha 
Division of Rheumatology 
Department of Medicine III 
Medical University of Vienna 
Waehringer Guertel 18-20 
1090 Vienna, Austria 
 
 
 
9. ADVERSE DRUG REACTIONS 
 
Clazakizumab 
From previous studies, results obtained in approximately 900 clazakizumab-treated 
patients/subjects are available for assessment of safety patterns. Overall, adverse events 
(AEs) reported for clazakizumab treatment are consistent with IL-6 blockade.  In previous 
studies, e.g. in RA and PsA 18,22,23, clazakizumab was administered at doses up to 320 mg, 
and many patients have received this antibody as an add-on to treatment with methotrexate. 
However, until now, no data obtained in transplant patients on dual or triple 
immunosuppression are available, so that safety assessment remains a major objective of 
this pilot trial. However, preliminary data obtained with the IL-6R antibody tocilizumab in 
transplant recipients point to a beneficial safety profile of targeting of IL-6/Il-6R also in 
patients on calcineurin inhibitor (CNI)-based immunosuppression. 
Reported AEs caused by clazakizumab are abnormalities in liver function parameters, 
which are commonly mild to moderate in severity [<3 x upper limit of normal (ULN) in most 
cases] and were more frequent under concomitant methotrexate treatment. Clinically 
significant increases in liver function parameters were shown to occur only in a few patients.  
Clazakizumab was shown to decrease neutrophil counts, whereby the majority of observed 
cases were mild/moderate in severity, without clinical sequelae. In phase 2 studies 
evaluating clazakizumab in arthritis, reported infection rates under repeated administration of 
clazakinumab were low and comparable to patients allocated to control groups 18,22,23. 
Nevertheless, intensified immunosuppression, in addition to standard dual or triple baseline 

24 
 
immunosuppression, can be expected to be associated with an increased infection risk. 
Hence, a careful patient follow-up will include a close monitoring for infectious complications 
(bacterial, viral and fungal infections). In trials of arthritis, no case of gastrointestinal 
perforation was reported. However, given the low, but significantly increased risk of 
gastrointestinal perforation in other large studies evaluating IL-6/IL-6R blockers, patients with 
a history of gastrointestinal perforation, diverticulitis or inflammatory bowel disease will not be 
included in the trial. Clazakizumab, as other agents interfering with IL-6/IL-6R, was shown to 
increase total cholesterol and LDL levels. Moreover, in some patients, a mild decrease in 
platelet counts was observed. Serious infusion reactions have not been described in any of 
the published trials, but clazakizumab may cause injection site reactions, apparently in a 
dose-dependent fashion. Safety results obtained for prolonged treatment with subcutaneous 
clazakizumab at 25 mg (with or without methotrexate) in two recent phase 2 trials, one in RA 
18, the other in PsA 23, are summarized in Table 5 (in both trials also higher doses of 
clazakizumab were evaluated; some events, such as injection site reactions or liver enzyme 
elevations, were thereby more frequently observed at higher dosages). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5. Summary of AEs reported for clazakizumab at 25 mg - phase 2 trials in 
arthritis 

25 
 
Disease entity 
Psoriatic arthritis 
Rheumatoid arthritis 
Author, year 
Mease et al, 201623 
 
Weinblatt et al, 201518 
 
Treatment 
Placebo 
±MTX 
Clazakizumab 25 
mg 
±MTX 
Placebo 
+MTX 
Clazakizumab 25 mg 
+MTX 
Patient number 
41 
41 
61 
59 
Deaths 
0% 
0% 
0% 
0% 
GI perforations 
0% 
0% 
0% 
0% 
Malignancies 
0% 
0% 
0% 
0% 
SAEs 
4.9% 
4.9% 
3.3% 
8.5% 
Discontunation (SAEs) 
4.9% 
0% 
0% 
0% 
AEs 
65.9% 
73.2% 
60.7% 
84.7% 
Discontinuation (AEs) 
7.3% 
2.4% 
0% 
0% 
Infections 
48.8% 
36.6% 
total infection rate not reported 
Liver parameters 
 
 
 
 
ALT >1-3 x ULN 
24.2% 
52.6% 
21.6% 
46% 
ALT >3-5 x ULN 
0% 
5.3% 
2% 
3.7% 
ALT >5-8 x ULN 
2.0% 
0% 
0% 
3.7% 
AST >1-3 x ULN 
13.5% 
50% 
14.8% 
40% 
AST >3-5 x ULN 
0% 
0% 
0% 
3.6% 
AST >5-8 x ULN 
0% 
2.6% 
0% 
0% 
Total bilirubin 
 
 
 
 
  >1.0-1.5 x ULN 
0% 
10.8% 
0% 
8.8% 
  >1.5-2.0 x ULN 
0% 
5.4% 
0% 
1.8% 
  >2.0-3.0 x ULN 
0% 
2.7% 
0% 
0% 
Cases of Hy’s law 
0% 
0% 
0% 
0% 
Lipids 
 
 
 
 
LDL 
no details (lipids elevated) 
Increase from <130 to ≥130 mg/dL  
 
 
 
28.3% 
61.9% 
Neutrophil counts 
Mean decrease by about 2 G/L  
 
 
0.5-1.0 x 109/liter 
no details 
0% 
1.8% 
1.0-1.5 x 109/liter 
no details 
3.8% 
14.3% 
Anti-clazakizumab Ab 
- 
4.9% 
- 
5.1% 
Injection site reaction 
- 
9.8% 
- 
13.6% 
 
Adverse drug reactions - specific considerations 
 
Opportunistic Infections and Serious Infections  
Physicians should exercise caution when considering the use of clazakizumab in patients 
with a history of recurring infection or with underlying conditions (eg, diabetes) which may 
predispose patients to infections. Clazakizumab should not be administered in patients with 
active infection. The effects of clazakizumab on CRP, neutrophils, and the signs and 
symptoms of infection should be considered when evaluating a patient for a potential 
infection.  
 
Vigilance for timely detection of serious infection is recommended for transplant patients 
receiving biologic agents as signs and symptoms of acute inflammation may be lessened 
due to suppression of the acute phase reaction. Patients must be instructed to contact their 
physician immediately when any symptoms suggesting infection appear, in order to assure 
rapid evaluation and appropriate treatment.  

26 
 
 
If a patient develops a serious infection, administration of clazakizumab is to be 
interrupted until the infection is controlled. The clinician should consider the benefit-risk 
before resuming treatment with clazakizumab. 
 
Gastrointestinal Perforations   
Timely diagnosis and appropriate treatment may reduce the potential for complications of 
diverticulitis and thus reduce the risk of GI perforations. Therefore, patients should be made 
aware of the symptomatology potentially indicative of diverticular disease, and they should 
be instructed to alert their healthcare provider as soon as possible if these symptoms arise. 
In patients with a history of symptomatic diverticulosis, diverticulitis or chronic ulcerative 
lower GI disease such as Crohn’s disease, ulcerative colitis or other chronic lower GI 
conditions that might predispose to perforations, the clinician should consider the benefit-risk 
before using clazakizumab.  Discontinuation of clazakizumab is necessary for patients who 
develop GI perforations. 
 
Hematologic Abnormalities and Bleeding Events 
Decreases in neutrophil and platelet counts have been observed following treatment with 
clazakizumab in combination with MTX. In addition, there may be an increased risk of 
neutropenia in patients who have previously been treated with a TNF antagonist. For patients 
with concomitant medications associated with hematologic toxicity, the reduction or 
interruption of the suspected medication is recommended prior to modifying clazakizumab. 
Dosing guidance for neutropenia and thrombocytopenia are described in Tables 6 and 7. 
 
Table 6. Neutropenia risk mitigation 
ANC (cells/mm3) 
Action 
> 1000 
Maintain dose. 
500 – 1000 
Interrupt clazakizumab dosing. 
When ANC increases to > 1000, resume clazakizumab 
25mg SQ monthly 
< 500 
Discontinue clazakizumab. 
ANC = absolute neutrophil count 
 
Table 7. Thrombocytopenia risk mitigation 
Platelet count (cells/mm3) 
Action 
> 100,000 
Maintain dose. 
50,000 – 100,000 
Interrupt clazakizumab dosing.  
When platelet count increases to > 100,000, resume 
Clazakizumab at 25mg SQ monthly  
< 50,000 
Discontinue clazakizumab. 
 
Dosing recommendations for events of elevated liver enzymes are described in Table 8. 

27 
 
Elevated Liver Enzymes and Hepatic Events 
Elevations in ALT and AST have been observed during treatment with the study medications 
Table 8. Elevated liver enzymes – risk mitigation 
Lab Value 
Action 
> 1 to 3x ULN 
Dose modify concomitant transplant immunosuppressive 
drugs if appropriate 
For persistent increases in this range, interrupt clazakizumab 
until ALT/AST have normalized 
Restart with 25mg SC monthly as clinically appropriate 
> 3 to 5x ULN 
(confirmed 
by 
repeat 
testing) 
Interrupt clazakizumab dosing until < 3x ULN and follow 
recommendations above for >1 to 3x ULN 
For persistent increases > 3x ULN, discontinue clazakizumab 
Discontinue clazakizumab if total bilirubin >2 x ULN  
> 5x ULN 
Discontinue clazakizumab 
 
Cardiovascular Events and Elevated Lipids 
Kidney transplant recipients may have an increased risk for cardiovascular disorders, 
therefore, risk factors for cardiovascular disease (eg, hypertension, hyperlipidemia) should 
be managed as part of their standard of care.  See section on Drug Interactions.   
For patients with LDL cholesterol ≥160 mg/dL, it is strongly recommended that investigators 
advise therapeutic lifestyle changes that may include initiation lipid-lowering agents. Lipid-
lowering agents should also be considered for patients with lower LDL cholesterol levels as 
part of their therapeutic lifestyle changes depending on their overall risk as defined in NCEP 
ATP III or other national guidelines. 
 
Malignancies 
The impact of immunosuppression on the development of malignancies is not known, 
however an increased rate of some malignancies, notably lymphoma, has been observed in 
RA patients. Although no imbalance of malignancies was observed in clinical trials of 
Clazakizumab, malignancies have been identified as a concern for other biologics.  It is 
recognized that identification of such events in clazakizumab-treated patients may require a 
longer period of surveillance. Clazakizumab should be discontinued in patients with 
malignancies (with the exception of local basal or squamous cell carcinoma of the skin that is 
completely excised with free margins). 
 
Demyelinating Disorders  
The impact of treatment with clazakizumab on demyelinating disorders is not known; events 
were rarely reported.  Patients should be closely monitored for signs and symptoms 
potentially indicative of central demyelinating disorders. Physicians should exercise caution 
in considering the use of clazakizumab in patients with pre-existing or recent onset 
demyelinating disorders. Treatment with clazakizumab should be interrupted during 

28 
 
assessment of a potential demyelination event and only resumed if the benefit of continuing 
study drug is favorable.   
 
Hypersensitivity or Anaphylaxis 
An infusion/dose reaction is defined as an adverse event occurring during and within 24 
hours after the infusion or SC injection of clazakizumab. This may include hypersensitivity 
reactions or anaphylactic reactions.  
Signs of a possible hypersensitivity reaction include but are not limited to:  
 
fever, chills, pruritus, urticaria, angioedema, and skin rash. 
 
cardiopulmonary reactions, including chest pain, dyspnea, hypotension or hypertension. 
Healthcare professionals administering clazakizumab should be trained in the appropriate 
administrative procedures, be able to recognize the symptoms associated with potential 
anaphylactic or hypersensitivity reactions, and have the appropriate medication available for 
immediate use in case of anaphylaxis or hypersensitivity reaction during or after 
administration of clazakizumab. Healthcare professionals should also instruct patients to 
seek medical attention if they experience symptoms of a hypersensitivity reaction outside of 
the clinic. 
If a patient has symptoms of anaphylaxis or serious hypersensitivity, or requires an 
interruption of the study drug because of symptoms of anaphylaxis or hypersensitivity, 
administration of clazakizumab must be discontinued permanently.  The patient should be 
treated according to the standard of care for management of the hypersensitivity reaction.  A 
blood sample for the presence of anti-clazakizumab antibodies should be obtained. 
 
Clazakizumab should not be administered to subjects who have had any previous allergic 
reactions to monoclonal antibodies. To date, no infusion reactions have been associated with 
clazakizumab administered by IV infusion. Injection site reactions have been reported with 
SC administration. Reactions have been mild or moderate and have resolved without 
treatment. Both allergic reactions and injection site reactions should be treated with standard 
of care. Subjects who have developed significant allergic reaction to study drugs should not 
be re-challenged. 
 
Viral Reactivation 
Though rarely reported within the clazakizumab program due to exclusion criteria at study 
entry, reactivation of viral and other serious infections (e.g. EBV or TB) has been observed 
with biologic therapies. 
 
Drug Interaction 

29 
 
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (eg, 
IL-6) during chronic inflammation. Therefore, it is expected that for molecules that antagonize 
cytokine activity, such as clazakizumab, the formation of CYP450 enzymes could be 
normalized. When starting or stopping therapy with clazakizumab, patients taking 
medications which are individually dose-adjusted and metabolized via CYP450, 3A4, 1A2, or 
2C9 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, 
cyclosporine, or benzodiazepines) should be monitored as doses may need to be adjusted to 
maintain their therapeutic effect. Given its long elimination half-life (t1/2), the effect of 
clazakizumab on CYP450 enzyme activity may persist for several weeks after stopping 
therapy. 
 
Pregnancies and Women of Child Bearing Potential 
There are no adequate well-controlled studies in pregnant or lactating women. In nonclinical 
studies, an increase in the number of monkeys with retention of the placenta at parturition 
was observed at clazakizumab doses corresponding to 22 and 220 times the planned human 
dose of 25 mg. In 3 of the 5 monkeys with retained placentas, the resulting excessive uterine 
hemorrhage led to moribund status in the mothers. 
Three pregnancies have been reported to date in subjects taking clazakizumab. The 
outcomes included one spontaneous abortion (outcome unknown for the other 2 
pregnancies). 
All subjects of child bearing potential being treated with clazakizumab (and their partners) 
must be informed of this risk, and use highly effective birth control, as defined in the study 
protocol. Administration of clazakizumab may decrease the efficacy of hormonal oral 
contraceptive. 
Under no circumstances shall clazakizumab injection be administered to women known to be 
pregnant or lactating. All pregnancies must be reported to Vitaeris within 24 hours and in 
accordance with SAE reporting procedures.  
 
 
 

30 
 
Pantoprazole 
The most common reported side effects of pantoprazole are headache, diarrhea and 
injection site thrombophlebitis. Other common side effects are rash, tiredness, flu-like 
symptoms, nausea, vomiting, abdominal pain/discomfort, constipation, dry mouth, loose 
stools, and flatulence. While some patients show increases in liver enzymes, hepatic failure 
is very rare. Rare events are fever, taste disorders, gynecomastia, agranulocytosis, 
thrombocytopenia, severe skin reactions or allergic reactions. Occurrence of interstitial 
nephritis is very rare. 
 
 
10. SAFETY ASSESSMENT AND REPORTING 
 
Definition of adverse events 
An AE is any untoward adverse change from the subject's baseline condition, i.e., any 
unfavorable and unintended sign including an abnormal laboratory finding, symptom or 
disease which is considered to be clinically relevant by the physician that occurs during the 
course of the study, whether or not considered related to the study drug. 
 
Adverse events include: 
 
Exacerbation of a pre-existing disease. 
 
Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
 
Disease or medical condition detected or diagnosed after study drug administration 
even though it may have been present prior to the start of the study. 
 
Continuous persistent disease or symptoms present at baseline that worsen following 
the start of the study. 
 
Lack of efficacy in the acute treatment of a life-threatening disease. 
 
Events considered by the investigator to be related to study-mandated procedures. 
 
Abnormal assessments, e.g., ECG and physical examination findings, must be 
reported as AEs if they represent a clinically significant finding that was not present at 
baseline or worsened during the course of the study. 
 
Laboratory test abnormalities must be reported as AEs if they represent a clinically 
significant finding, symptomatic or not, which was not present at baseline or 
worsened during the course of the study or led to dose reduction, interruption or 
permanent discontinuation of study drug. 
 
Adverse events do not include:  

31 
 
 
Pre-planned interventions or occurrence of endpoints specified in the study protocol 
are not considered AE´s, if not defined otherwise (eg.as a result of overdose) 
 
Medical or surgical procedure, e.g., surgery, endoscopy, tooth extraction, transfusion. 
However, the event leading to the procedure is an AE. If this event is serious, the 
procedure will be described in the SAE narrative. 
 
Pre-existing disease or medical condition that does not worsen. 
 
Situations in which an adverse change did not occur, e.g., hospitalizations for 
cosmetic elective surgery or for social and/or convenience reasons. 
 
Overdose of either study drug or concomitant medication without any signs or 
symptoms. However, overdose must be mentioned in the Study Drug Log. 
 
Serious Adverse Events (SAEs) 
A Serious Adverse Event (SAE) will be defined by the International Conference on 
Harmonization (ICH) guidelines and WHO GCP guidelines as any AE fulfilling at least one of 
the following criteria: 
 
Results in deaths. 
 
Life-threatening – defined as an event in which the subject was, in the judgment of 
the investigator, at risk of death at the time of the event; it does not refer to an event 
that hypothetically might have caused death had it been more severe. 
 
Requiring subject's hospitalization or prolongation of existing hospitalization – 
inpatient hospitalization refers to any inpatient admission, regardless of length of stay. 
 
Resulting in persistent or significant disability or incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions). 
 
Congenital anomaly or birth defect. 
 
Is medically significant or requires intervention to prevent at least one of the 
outcomes listed above. 
Life-threatening refers to an event in which 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. Important medical events that may not immediately result in death, be life-
threatening, or require hospitalization may be considered as SAEs when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definitions above. 
 
Hospitalization – Prolongation of existing hospitalization 
Hospitalization is defined as an overnight stay in a hospital unit and/or emergency room. An 
additional overnight stay defines a prolongation of existing hospitalization. 
 

32 
 
The following is not considered an SAE and will be reported as an AE only: 
 
Treatment on an emergency or outsubject basis for an event not fulfilling the 
definition of seriousness given above and not resulting in hospitalization. 
 
The following reasons for hospitalizations are not considered AEs, and therefore not SAEs: 
 
Hospitalizations for cosmetic elective surgery, social and/or convenience reasons. 
 
Standard monitoring of a pre-existing disease or medical condition that did not 
worsen, e.g., hospitalization for coronary angiography in a subject with stable angina 
pectoris. 
 
Elective treatment of a pre-existing disease or medical condition that did not worsen, 
e.g., hospitalization for chemotherapy for cancer, elective hip replacement for arthritis. 
 
SAEs related to study-mandated procedures 
 
Such SAEs are defined as SAEs that appear to have a reasonable possibility of causal 
relationship (i.e., a relationship cannot be ruled out) to study-mandated procedures 
(excluding administration of study drug) such as discontinuation of subject's previous 
treatment during a washout period, or complication of a mandated invasive procedure (e.g., 
blood sampling, heart catheterization), or car accident on the way to the hospital for a study 
visit, etc. 
 
Suspected unexpected serious adverse reactions (SUSARs) 
 
SUSARs are all serious adverse reactions with suspect causal relationship to the study drug 
that is unexpected (not previously described in the Investigator’s brochure) and serious.  
 
Pregnancy 
Pregnancy itself is not an AE/SAE; the outcome of a pregnancy can be a SAE. Any 
pregnancy that occurs during study participation will be reported to the investigator/sponsor. 
To ensure subject safety, each pregnancy will be reported to the investigator/sponsor 
immediately. The pregnancy will be followed up to determine outcome (including premature 
termination) and status of mother and child.  Pregnancy complications and elective 
terminations for medical reasons will be reported as an AE or SAE.  Spontaneous abortions 
will be reported as an SAE. Any SAE occurring in association with a pregnancy brought to 
the investigator’s attention after the subject has completed the study and considered by the 
investigator as possibly related to the investigational product, will be promptly reported to the 
principal investigator/sponsor. In addition, the investigator will attempt to collect pregnancy 

33 
 
information on any female partners of male study subjects who become pregnant while the 
subject is enrolled in the study. Pregnancy information will be reported to the 
investigator/sponsor as described above. 
 
Severity of adverse events 
The severity of clinical AEs will be graded on a three-point scale: mild, moderate, severe, 
and reported on specific AE pages of the CRF. If the severity of an AE worsens during study 
drug administration, only the worst intensity should be reported on the AE page. If the AE 
lessens in intensity, no change in the severity is required.  If an AE occurs during a washout 
or placebo run-in phase and afterwards worsens during the treatment phase, a new AE page 
will be filled in with the intensity observed during study drug administration.  
 
Mild: Event may be noticeable to subject; does not influence daily activities; the AE resolves 
spontaneously or may require minimal therapeutic intervention;  
 
Moderate: Event may make subject uncomfortable; performance of daily activities may be 
influenced; intervention may be needed; the AE produces no sequelae. 
 
Severe: Event may cause noticeable discomfort; usually interferes with daily activities; 
subject may not be able to continue in the study; the AE produces sequelae, which require 
prolonged therapeutic intervention. 
A mild, moderate or severe AE may or may not be serious. These terms are used to describe 
the intensity of a specific event (as in mild, moderate, or severe myocardial infarction). 
However, a severe event may be of relatively minor medical significance (such as severe 
headache) and is not necessarily serious. For example, nausea lasting several hours may be 
rated as severe, but may not be clinically serious. Fever of 39°C that is not considered 
severe may become serious if it prolongs hospital discharge by a day. Seriousness rather 
than severity serves as a guide for defining regulatory reporting obligations. 
 
Relationship to study drug 
For all AEs, the investigator will assess the causal relationship between the study drug and 
the AE using his/her clinical expertise and judgment according to the following algorithm that 
best fits the circumstances of the AE: 
 
Unrelated 
 
May or may not follow a reasonable temporal sequence from administration of the 
study product 

34 
 
 
Is biologically implausible and does not follow known response pattern to the suspect 
study drug (if response pattern is previously known). 
 
Can be explained by the known characteristics of the subject’s clinical state or other 
modes of therapy administered to the subject. 
 
Unlikely 
 
May or may not follow a reasonable temporal sequence from administration of the 
study product 
 
Is biologically not very plausible  
 
May be explained by the known characteristics of the subject’s clinical state or other 
modes of therapy administered to the subject. 
 
Possible related 
 
Follows a reasonable temporal sequence form administration of the study drug. 
 
May follow a known response pattern to the study drug (if response pattern is 
previously known). 
 
Could not be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject, if applicable. 
 
Probable 
 
Follows a reasonable temporal sequence form administration of the study drug. 
 
Follows a known response pattern to the study drug (if response pattern is previously 
known). 
 
other causes for the event are unlikely 
 
Definitely related 
 
Follows a reasonable temporal sequence form administration of the study drug. 
 
Follows a known response pattern to the study drug (if response pattern is previously 
known). 
 
No other reasonable cause is present. 
 
Reporting procedures 
A special section is designated to adverse events in the case report form. The following 
details must thereby be entered: 
 
Type of adverse event 
 
Start (date and time) 
 
End (date and time) 
 
Severity (mild, moderate, severe) 

35 
 
 
Serious (no / yes) 
 
Unexpected (no / yes)  
 
Outcome (resolved, ongoing, ongoing – improved, ongoing – worsening) 
 
Relation to study drug (unrelated, possibly related, definitely related) 
Adverse events are to be documented in the case report form in accordance with the above 
mentioned criteria. 
 
Reporting procedures for SAEs  
In the event of serious, the investigator has to use all supportive measures for best patient 
treatment.   A written report is also to be prepared and made available to the clinical 
investigator immediately. The following details should at least be available: 
 
Patient initials and number 
 
Patient: date of birth, sex, ethical origin 
 
The suspected investigational medical product (IMP) 
 
The adverse event assessed as serious 
 
Short description of the event and outcome 
If applicable, the initial report should be followed by the Follow up report, indicating the 
outcome of the SAE. 
 
 
 
All SAEs for which there is a reasonable possibility the experience may have been caused by 
clazakizumab (this applies to both expected and unexpected events) will be recorded on a 
CIOMS Form and submitted to: 
 
SAE Reporting  
Contact Information  
Vitaeris Drug Safety: Dr Edward Chong   
This must be reported to Vitaeris within 
24 hours.   
Tel: 604 638 1582 (0ffice), 250 216 6371 (cell) 
email: eddie.chong@vitaerisbio.com 
For submission of SAE report information:  
By email: safety@vitaerisbio.com or  Fax: 800-518-
5253  
 
Reporting procedures for SUSARs 
It must be remembered that the regulatory authorities, and in case of SUSARs which could 
possibly concern the safety of the study participants, also the Institutional Review Board / 
Independent Ethics Committee (IRB / IEC) are to be informed. Such reports shall be made 
by the study management and the following details should be at least available: 

36 
 
 
Patient initials and number 
 
Patient: date of birth, sex, ethical origin 
 
Name of investigator and investigating site 
 
Period of administration 
 
The suspected investigational medical product (IMP) 
 
The adverse event assessed as serious and unexpected, and for which there is a 
reasonable suspected causal relationship to the IMP 
 
Concomitant disease and medication 
 
Short description of the event: 
 
Description 
 
Onset and if applicable, end 
 
Therapeutic intervention 
 
Causal relationship 
 
Hospitalization of prolongation of hospitalization 
 
Death, life-threatening, persistent or significant disability or incapacity 
Electronic reporting should be the expected method for reporting of SUSARs to the 
competent authority. 
 
The Development Safety Update Report (DSUR) 
The DSUR will be provided by the principal investigator at least once a year. 
This report will also be presented annually to the Independent Ethics (IEC) and to the 
competent authorities by the sponsor. 
 
 
11. STUDY TERMINATION, WITHDRAWAL AND REPLACEMENT OF SUBJECTS 
 
Criteria for withdrawal 
Subjects may prematurely discontinue from the study at any time. Premature discontinuation 
from the study is to be understood when the subject did not undergo EOS examination and / 
or all pivotal assessments during the study. 
 
Subjects will be withdrawn under the following circumstances: 
 
 
at their own request 
 
if the investigator feels it would not be in the best interest of the subject to continue 

37 
 
 
if the subject violates conditions laid out in the consent form / information sheet or 
disregards instructions by the study personal 
 
In all cases, the reason why subjects are withdrawn will be recorded in detail in the CRF and 
in the subject’s medical records. Should the study be discontinued prematurely, all study 
materials (complete, partially completed and empty CRFs) will be retained. 
 
Follow-up of patients withdrawn from the study 
In case of premature discontinuation after study drug intake, the investigations scheduled for 
the EOS visit will be performed 7 days after study drug discontinuation. The subjects will be 
advised that participation in these investigations is voluntary. Furthermore, they may request 
that from the time point of withdrawal no more data will be recorded and that all biological 
samples collected in the course of the study will be destroyed. 
 
Premature termination of the study 
The sponsor has the right to close this study at any time. The IEC and the competent 
regulatory authority must be informed within 15 days of early termination. 
The trial or single dose steps will be terminated prematurely in the following cases: 
 
If adverse events occur which are so serious that the risk-benefit ratio is not 
acceptable. 
 
If the number of dropouts is so high that proper completion of the trial cannot 
realistically be expected. 
 
 
12. ETHICAL ISSUES 
 
The study will be conducted in accordance with the principles of the Declaration of Helsinki 
2008. Ethical committee approval will be obtained for all aspects of the study. All study 
participants will be asked to sign the informed consent to participate in the study (patient 
insurance included). 
 
 
13. REGULATORY REQUIREMENTS 
 
We will adhere to all the trial-related requirements, Good Clinical Practice (GCP) 
requirements (ICH GCP), Good Laboratory Practice (GLP) and the applicable regulatory 
requirements. 

38 
 
 
14. PERIODIC MONITORING 
The designated monitor (Dr. Peter Matzneller, Department of Clinical Pharmacology, Medical 
University Vienna; Tel. 01 40400 29810) will contact and visit the investigator regularly and 
will be allowed to have access to all source documents needed to verify the entries in the 
CRFs and other protocol-related documents provided that subject confidentiality is 
maintained in agreement with local regulations. It will be the monitor's responsibility to 
inspect the CRFs at regular intervals according to the monitoring plan throughout the study, 
to verify the adherence to the protocol and the completeness, consistency and accuracy of 
the data being entered on them. The monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation 
of SAEs and the recording of the main efficacy, safety, and tolerability endpoints. The 
monitor will be working according to SOPs and will provide a monitoring report after each 
visit. The investigator will resolve discrepancies of data. Source data will be checked by the 
monitor (which means 100% SDV). 
 
 
15. AUDIT AND INSPECTIONS 
Upon request, the investigator will make all study-related source data and records available 
to a qualified quality assurance auditor mandated by the sponsor or to competent authority 
inspectors. The main purposes of an audit or inspection are to confirm that the rights and 
welfare of the subjects have been adequately protected, and that all data relevant for 
assessment of safety and efficacy of the investigational product have appropriately been 
reported to the sponsor. 
 
 
16. INVESTIGATOR TRAINING 
All investigators and their study personnel will receive training regarding the study 
procedures and GCP/regulations specific to the conduct of clinical trials. This training will be 
documented and will take place prior to enrollment and throughout the study as necessary. 
 
 
17. RECORD RETENTION 
Essential documents will be retained as required by the applicable regulatory requirements 
or by an agreement with Vitaeris.  
 
 

39 
 
 
 
18. STUDY REGISTRATION 
 
The study is planned to be approved by the Austrian regulatory authority (Federal Office for 
Safety in Health Care, Austrian Agency for Health and Food Safety) and German regulatory 
authority (The Paul-Ehrlich-Institut, PEI). We plan to register the study to the European 
Clinical 
Trials 
Database 
(EUDRACT) 
and 
a 
public 
clinical 
trial 
database 
(http://clinicaltrial.gov). The study protocol will be submitted for publication to Trials 
(http://www.trialsjournal.com/). 
 
 
19. MODIFICATIONS TO THE PROTOCOL 
 
Protocol Amendments 
Protocol amendments, except where necessary to eliminate an immediate hazard to 
patients, will be made with the prior approval of Vitaeris. Each applicable Regulatory 
Authority/IRB/EC/IEC will review and approve amendments prior to their implementation. 
Regulatory Authority/IRB/EC/IEC approval need not be obtained prior to removal of an 
immediate hazard to patients. 
 
Protocol Violations and Deviations 
Protocol waivers will not be permitted except where necessary to eliminate an immediate 
hazard to patients. The Principal Investigator or designee must document and explain in the 
subject’s source documentation any deviation from the approved protocol. A deviation from 
the protocol is an unintended and/or unanticipated departure from the procedures and/or 
processes approved by the Sponsor and the IEC and agreed to by the Principal Investigator. 
Protocol violations and deviations will be documented by the clinical monitor throughout the 
course of monitoring visits. Principal Investigator will be notified of violations and/or 
deviations in writing by the monitor. The IEC will be notified of all protocol violations and 
deviations according to IEC reporting requirements.  
 
 
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