Conditions: Adult-Onset Still´s Disease
Keywords: Adult-Onset Still´s Disease Canakinumab Joint involvement AOSD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
The purpose of this trial is to investigate the efficacy of the treatment with canakinumab in participants with Adult-onset Still's Disease (AOSD) and active joint involvement.

Detailed description:

Arms:
arm 1: Participants received canakinumab 4 mg/kg up to a maximum of 300 mg subcutaneous (SC) injection, once in morning on Day 0, Weeks 4, 8, and 12 in Part I of the core study. Participants with response (change in DAS score \> 1.2 at Week 12) continued to receive same dose of canakinumab in Part II for Weeks 12, 16, and 20. Participants who had remission (change in DAS score \> 1.2 and no signs of systemic activity for adult-onset Still's disease at Week 20) entered Long-term extension (LTE) phase and received same dose of canakinumab at Weeks 24 and 28, which was down titrated to 2 mg/kg if applicable from Week 28 up to Month 27. arm 2: Participants received placebo, SC injection, once in morning on Day 0, Weeks 4, 8, and 12 in Part I of the core study. Participants with response (change in DAS score \> 1.2 at Week 12) continued to receive placebo at Weeks 12, 16, and 20. Non-responders (who had change in DAS score ≤ 1.2) were unblinded to receive canakinumab 4 mg/kg (up to 300 mg maximum), SC injection, at Weeks 12, 16, and 20. Participants who had remission (change in DAS score \> 1.2 and no signs of systemic activity for adult-onset Still's disease at Week 20) entered Long-term extension (LTE) phase and received same dose of canakinumab at Weeks 24 and 28, which was down titrated to 2 mg/kg if applicable from Week 28 up to Month 27.

Interventions: intervention 1: Canakinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Canakinumab, single-dose 4 mg/kg up to 300 mg administered subcutaneously. intervention 2: Matching placebo administered subcutaneously.

Protocol document:
Prot_000.pdf: 
Study Protocol for a Multi-Centre, Placebo-Controlled Phase II Study of 
Canakinumab for the Treatment of Adult-onset Still's disease (AOSD) 
including an open-label long term extension. 
Protocol No.: 
CACZ885GDE01T / NCT02204293
EudraCT No. 
2011-001027-20 
Protocol version: 
3.1 
Short name of the protocol: CONSIDER 
(Canakinumab for treatment of adult onset Still‘s disease to 
achieve reduction of arthritic manifestation) 
Date of the protocol: 
20.10.2017 
Principal Investigator: 
Prof. Dr. med. 
 
, 
 
 
 
 
 
Tel. 
 
Fax. 
 
E-mail: 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 2 of 52 
Protocol Synopsis 
Title: 
A Multi-Centre, Placebo-Controlled Phase II Study of Canakinumab for 
the Treatment of Adult-Onset Still's Disease (AOSD)-core study, including 
an open-label long-term extension - LTE 
Acronym: 
CONSIDER 
(Canakinumab for treatment of adult onset Still‘s disease to achieve 
reduction of arthritic manifestation) 
Study drug: 
Canakinumab  
Clinical phase: 
II 
Rationale: 
Interleukin-1 antagonists such as canakinumab have been used for the 
treatment of AOSD and have had a marked influence on the activity of the 
disease, including joint mobility. Results from controlled clinical studies are 
not, however, currently available. 
Objectives of the core 
study:  
 
Primary objective: 
Investigation of the efficacy of canakinumab in patients with AOSD and 
active joint involvement in terms of the proportion of patients with a 
clinically-significant reduction in disease activity ( DAS28 > 1.2) following 
a treatment period of 12 weeks.  
 
Secondary objective: 
1. Evaluation of the safety of canakinumab in patients with AOSD 
2. Evaluation of the efficacy of canakinumab in patients with AOSD and 
joint involvement in terms of the ACR and EULAR Response Criteria for 
weeks 12 and 24 
3. Proportion of patients achieving low disease activity (< 3.2) or 
remission (< 2.6) based on DAS28, 
4. Recording of the change in joint mobility using the neutral zero 
method, 
5. Investigation of the general changes in health based on HAQ-DI and SF-
36, 
6. Improvement in the skin manifestation of AOSD and the frequency of 
fever, 
7. Reduction in inflammatory markers (CRP, ESR, ferritin), 
8. Biomarker analysis (mRNA, protein) aimed at identifying predictive 
biomarkers (for those participating in the accompanying project). 
Objectives 
of 
the 
long-term extension 
part: 
Primary objective: 
Evaluation of the long-term safety of canakinumab in patients with AOSD 
and articular involvement 
Secondary objectives: 
1. Description of the long-term efficacy of canakinumab in patients with 
AOSD according to EULAR response criteria (proportion of patients 
showing prolonged clinically improvement according to DAS28 low-
disease activity [< 3.2] and remission [< 2.6], reduction of flares and 
glucocorticoid intake). 
2. Assessment of health outcome measures (HAQ-DI, SF36), improvement 
in skin manifestation and reduction of inflammatory markers of disease 
under long-term treatment. 
3. Evaluation if a reduced dosage of canakinumab can be used to control 
disease activity by down-titration from 4mg/kg/body weight (BW) (max 
300mg)/month to 2mg/kg/BW (max 150mg)/month 
Design 
Core study: double blind, placebo-controlled 
LTE: open-label 
Number of patients: 
68 (Core phase); 35 (LTE phase) 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 3 of 52 
Number of study 
centres: 
Approx. 14 study centres in Germany 
Duration of study 
treatment: 
Core study: 6m 
LTE: 24 m 
Duration of 
participation in the 
study: 
Screening: up to 4 weeks 
Study treatment duration (see above) 
Follow-Up: up to 3 months 
Inclusion criteria: 
1. Written and signed consent from the patient to participate in the study  
2. Men and women aged ≥ 18 years and ≤ 75 years 
3. Fulfilment of AOSD classification criteria (according to Yamaguchi et al, 
J. Rheumatology, 1992) 
4. Disease activity based on DAS28 of ≥ 3.2 at screening 
5. At least 4 painful and 4 swollen joints at screening and baseline (of the 
28 joints according to DAS28) 
6. If undergoing treatment with NSAIDs, stable dose for at least 2 weeks 
prior to randomisation 
7. If undergoing treatment with glucocorticoids, stable dose of ≤10 
mg/day (prednisolone or equivalent) for at least 1 week prior to 
randomisation 
8. If undergoing treatment with conventional DMARD, stable dose for at 
least 6 weeks prior to randomisation 
9. Normalisation period for biological DMARDS (anakinra 1 week, 
etanercept 2 weeks, adalimumab, certolizumab,  abatacept s. c. and 
tocilizumab s. c. 1 month, infliximab, golimumab, abatacept and 
tocilizumab (i.v.) 3 months, canakinumab 6 months, rituximab 9 
months) prior to randomisation 
10. In patients of reproductive age, use of an effective method of 
contraception as well as negative pregnancy test prior to the study 
commencing. 
Exclusion criteria: 
 
1. Previous treatment with the study drug with repeated administration 
of canakinumab 
2. Intraarticular or intravenous administration of glucocorticoids within 4 
weeks prior to the baseline or use of narcotic analgesics except for 
analgesics permitted within the framework of the investigation 
(codeine and tramadol) 
3. Presence of another, serious chronic-inflammatory disease 
4. Positive hepatitis B antigen (HBsAg), hepatitis C antibodies and/or HIV 
antibodies. 
5. Presence of a relevant, active infection or other diseases, which entail 
a tendency towards infection.  
6. Positive screening for latent tuberculosis, in accordance with usual 
local practice. If patient is taking adequate/isoniazid prophylaxis for 4 
weeks before first IP administration, this patient may be randomized. 
7. Raised liver count (raised bilirubin; ALT or AST ≥3-fold the normal 
range)  
8. Serum-creatinine concentration >1.5 mg/dl 
9. Inadequate haematological findings (Hb ≤ 9 g/dl, neutrophils ≤ 
2,500/µl and thrombocytes ≤ 100,000/µl) 
10. Simultaneous participation in any other interventional clinical study 
within the last 30 days preceding the commencement of the study 
11. History of neoplasia with the exception of a curatively treated non-
melanoma skin tumour or carcinoma of the cervix treated in situ 
without any indication of recurrence within the last 10 years 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 4 of 52 
12. Relevant cardiac or pulmonary disorders 
13. Severe intercurrent neurological or psychiatric disorders 
14. Macrophage activation syndrome (MAS) as part of previous treatment 
with IL-1 blockade (e.g. anakinra, rilonacept) 
15. Vaccination with a live vaccine within 3 months before the baseline  
16. A history of alcohol or drug abuse in the past 12 months 
17. ≥400 ml donation or loss of blood up to 8 weeks before the baseline 
18. Pregnancy or breast-feeding 
19. Commitment of the patient to an institution at the direction of an 
authority or court 
Classification criteria 
for entering the LTE: 
1. Participation 
in 
the 
randomized, 
placebo-controlled 
trial 
(CACZ885GDE01T) (core study) 
2. Considered to be a responder with respect to articular involvement ( 
DAS28 > 1.2) as well as to systemic disease manifestation of AOSD at 
week 24 
3. In case of female patient of childbearing potential, she agrees to 
comply with effective contraceptive measures, has been using 
contraception since the last menses, will use adequate contraception 
during the study and has a negative test at week 24 
Dosage and 
administration of the 
study drug 
In the active treatment arm (n=34), the drug being investigated, 
canakinumab, will be administered while the control group (n= 34) will 
receive placebo injections. The study drug and the placebo will be 
administered subcutaneously. 
Canakinumab will be administered subcutaneously in a dose of 4mg/kg 
body weight up to a maximum of 300 mg every 4 weeks. No escalation in 
dosage is envisaged. 
A re-evaluation will take place in week 12. It is expected that at this point 
in time, approx. 75% of patients will change over from the placebo to the 
verum group, if no significant improvement has been achieved according 
to DAS28 (a significant improvement is defined as an improvement in 
DAS28 from visit 2 to visit 5 of > 1.2). 
Investigations 
regarding the safety 
of the treatment 
1. Blood count, Na, K, creatinine, ALT, AST, GGT, AP, LDH, ferritin and 
urine test sticks at each visit 
2. Recording of adverse events over the entire period 
3. Recording of vital signs and physical examination at each visit 
Pharmacokinetics 
(PK): 
The serum-canakinumab concentration will be established at all visits from 
the baseline, in episodes of illness and in the event of a macrophage 
activation syndrome (MAS) occurring. In the event of an anaphylactic 
reaction, samples will be investigated following the injection and at 
intervals of 8 weeks. 
Pharmacodynamics 
(PD): 
Overall IL-1ß (circulating IL-1ß as well as connected to canakinumab) will 
be investigated at all visits. 
Analysis of efficacy: 
 
Primary endpoint: clinically relevant reduction in DAS28 (>1.2 units) 
between baseline (mean DAS28 of visit 1 and visit 2) and week 12 (double 
blind period). 
Secondary endpoint parameters: 
Joint manifestation:  
1. DAS28 (Disease activity score)  
2. ACR (American College of Rheumatology) Response Criteria and 
EULAR response criteria for low disease activity (DAS28 < 3.2) and 
remission (DAS28 < 2,6) 
Assessment of the level of disability and of quality of life  
1. Health Assessment Questionnaire Disability Index (HAQ-DI) 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 5 of 52 
2. SF-36 health survey 
Laboratory tests 
1. Serological markers for inflammatory reactions (CRP, ESR, ferritin) 
2. Immunogenity (anti-canakinumab antibodies) will be established 
at all visits, in the case of episodes of illness and with MAS. In the 
event of an anaphylactic reaction occurring, samples will be 
investigated following the injection and at intervals of 8 weeks. 
Additional investigations 
Optional scientific accompanying project on biomarker analysis: 
1. Soluble serum protein in connection with pathomechanism 
investigated such as IL-6 and IL-18, S100 as an inflammatory 
marker; 
2. Pharmacogenomic investigations with mRNA profile in connection 
with investigated pathomechanism for the stratification of patients 
with regard to responsiveness to treatment; 
3. Investigations 
into 
mRNA 
expression 
in 
connection 
with 
macrophage activation syndrome for Perforin-, SOCS3-, MUNC 12-
4; 
4. Pharmacogenetic investigations into identifying Single Nucleotide 
Polymorphisms [SNP], as well as sequencing of the genome for the 
stratification of patients with regard to responsiveness to 
treatment. 
Statistical evaluation: 
The statistical evaluation of the safety and efficacy of canakinumab will be 
conducted according to the Intention-to-treat principle. Patients who have 
terminated the study early will be counted as non-responders. The DAS28 
response rates to week 12 (primary endpoint) will be compared by means 
of Fisher's exact test. This test will also be used to compare secondary 
binary endpoints. The comparison of mean values will be made using the t-
tests and Mann-Whitney test. 95% confidence intervals will be stated for 
all response rates and safety signals. 
Ethical aspects: 
The study will be carried out in accordance with currently valid legal 
provisions, including the Guidelines on Good Clinical Practice (GCP) and 
the ethical principles of the Helsinki Declaration. 


 
Study Procedures 
Procedures 
 
Visit 1 
Screening 
(-1 week to -4 
weeks) 
Visit 2 
baseline 
(Day 0) 
Visit BM with 
accompanying 
project  
(Day 7-10) 
Visit 3 
Week 4 
(+/- 3 days) 
Visit 4 
Week 8 
(+/- 3 days) 
Visit 5 
Week 12  
(+/- 3 days) 
(switch 2) 
Visit 6 
Week 16 
(+/- 3 days) 
Visit 7 
Week 20 
 (+/- 3 days) 
V8 
Week 24 
(+/- 3 days) 
*8 
End of core 
study (7) 
Wk 28/Wk 40 
(+/- 3 days) 
Informed consent 
X 
X (1) 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Inclusion or exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Differential blood count 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Electrolytes (Na, K) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Creatine, ALT, AST, GGT, AP, LDH, 
ferritin 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
CRP 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
ESR 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Electrophoresis protein 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
Anti-canakinumab antibodies 6 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
ANA 
X 
 
 
 
 
X 
 
 
X 
X 
HIV, Hepatitis B and C serology 
X 
 
 
 
 
 
 
 
 
 
Urine test sticks 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECG 
 
X 
 
 
 
 
 
 
 
X 
Tuberculosis screening 3 
X 
 
 
 
 
 
 
 
 
 
Joint status (28) 
X 
 
 
 
 
 
 
 
 
 
Joint status (68/66) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Joint mobility 4 
 
X 
 
 
 
X 
 
 
X 
 
PGA 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
PhGA 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
HAQ-DI 
 
X 
 
 
 
X 
 
 
X 
 
SF-36 
 
X 
 
 
 
X 
 
 
X 
 
Administration of the study drug 5 
 
X 
 
X 
X 
         X    (2) 
        X   (2) 
        X   (2) 
 
 
Pharmacodynamics 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetic properties 6 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Optional biomarker study 1 
 
X 
X 
X 
 
 
 
 
 
 
LTE 8 
 
 
 
 
 
 
 
 
 
X (8) 
 
 
 
 
 
Page 6 of 43 
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1. Additional informed consent required for the accompanying project. In the event of an episode of illness or MAS or suspected MAS.  
 
 
2. Responders (∆DAS28 > 1.2) remain under masked treatment until week 40, final injection at week 20. 
 
 Unblinding of the non-responders: non-responders in the placebo group receive canakinumab 4mg/kg body weight (max. 300 mg) subcutaneously openly at weeks 12, 16 and 20. 
 
  
 non-responders in the verum group remain without the study drug in the safety follow-up until week 28. 
 
 
NR: non-responder 
 
 
3. Chest X-ray within the last 3 months + PPD test and /or Quantiferon test 
 
 
4. Neutral zero method 
 
 
5. Subcutaneous injections of canakinumab / placebo are prepared, applied and recorded by an independent drug administrator.  
This member of staff is not permitted to carry out any further study-specific actions within the framework of this study. 
 
 
6. Is established at all visits from baseline, in the event of episodes of illness or MAS, or suspected MAS. In the event of an anaphylactic reaction occurring, samples will be 
investigated following the injection and at intervals of 8 weeks.       
 
 
7. for patients not classifying for LTE 
 
 
8. please refer to LTE-flow-chart, page 8 and study procedures graphic at page 10 
 
 
In the event of premature discontinuation or termination of the study by a decision of the sponsor, the investigating doctor or the study participant, the visit will be carried out in 
week 24. Furthermore, a concluding visit will take place while recording the adverse events with an interval of 20 weeks after the last administration of the study drug. 
Page 7 of 43 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 8 of 52 
 
Study Procedures-LTE 
Procedures 
 
Visit 8 
Week 24 (end of core study treatment) 
Entry in LTE 
Visits 9 – 31 
Week 28/ 
Month 7 – 30 
(+/- 1 week) 
V 32/EOS 
Month 33   
  
Classification criteria for LTE 
X 
 
 
Physical examination 
X 
X 
X 
Vital signs 
X 
X 
X 
Concomitant medication 
X 
X 
X 
Adverse events 
X 
X 
X 
Differential blood count 
X 
X 
X 
Electrolytes (Na, K) 
X 
X 
X 
Creatine, ALT, AST, GGT, AP, LDH 
X 
X 
X 
Ferritin 
X 
X 
X 
CRP 
X 
X 
X 
ESR 
X 
X 
X 
Electrophoresis protein 
X 
 
X 
Pregnancy test 
X 
 
 
Anti-canakinumab antibodies 6 
X 
X 
X 
ANA 
X 
X 
X 
Urine test sticks 
X 
X 
X 
ECG 
X 
 
X 
Joint status (28) 
X 
X 
 
Joint status (68/66) 9 
X 
X 9 
 
Joint mobility 9 
X 
X 9 
 
PGA 
X 
X 
 
PhGA 
X 
X 
 
Evaluation of down-titration criteria 10 
 
X 10 
 
HAQ-DI 9 
X 
X 9 
 
SF-36 9 
X 
X 9 
 
Administration of canakinumab 
X 
X 
 
Pharmacodynamics 
X 
X 
 
Pharmacokinetic properties 6 
X 
X 
 
Optional biomarker study 1 
X 
 
 
 
9. 66/68 joint count, joint mobility, HAQ-DI and SF-36 to be performed quarterly 
 
 
10. down-titration from 4 mg/kg/body weight (BW) (max 300 mg)/month to 2 mg/kg/BW (max 150 mg)/month in case of remission defined as a DAS28 < 2.6 AND no signs of systemic 
disease activity at two consecutive (monthly) visits, after (and including) visit 9 (week 28). 
In case of increasing disease activity or flare under a reduced dosage of canakinumab, up-titration to the initial dosage is possible (for details refer to 3.9). 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 9 of 52 
CONSIDER - Core Study procedures 
 
 
*1) responder (∆ DAS28 > 1.2) remains under masked treatment until week 40. Final injection at week 20. 
Unblinding of the Non-Responder: non-Responder in the placebo group receive canakinumab 4 mg/kg body weight (max. 300 mg) s.c. openly at weeks 12, 16 and 20. 
 
 
 
 
 
non-Responder in the verum group stay receive no study drug and have a safety follow-up until week 28. 
*2) for patients not classifying for long term extension  
 
 
study visit without study drug administration 
 
study visit with study drug administration 
 
long term extension 
0 • 
i) 
Vl 
Week - 1 
to - 4 
Screening 
V2 
WeekO 
Baseline/ 
Randomisation 
blinded 
Study drug 
Canakinumab 
vs. Placebo 
Long term extension (see page 9) 
I 
Non-responder 
: 
Canakinumab 4 mg/ kg body weight 
(max. 300 mg)/ 4 wk sc. 
ti-DAS $ 1.2 at week 12 safety follow up (no stody drug) 
.......................................................................................................... ;·····························• O 
I 
Responder ti-DAS > 1.2 at week 12 
Placebo 
Responder ti-DAS > 1.2 at week 12 
"-111--------------------e-----e---------f----------+O 
Non-responder ti-DAS$ 1.2 at week 12 
V3 
V4 
Week 4 
Weeks 
study-visit 
study-visit 
with s.c. -
with s.c. -
administration 
administration 
of blinded 
of blinded 
study drug 
study drug 
Canakinumab 4 mg/ kg body weight (max. 300 ' g)/ 4 wk sc. (open) 
vs 
V6 
V7 
V8 
I End of core 1 
End of core 2 
Week 12 
Woche 16 
Week20 
Week24 
Week28 
Week40 
primary 
• 11 if applicaple, 
• 11 
secondary 
'2) 
•21 
Endpoint 
study drug 
if applicaple, 
endpoints 
End of core 
End of core 
*1) if 
study drug 
study 1 
study 2 
applicaple, 
(final 
only applies to 
study drug 
administration) 
verum 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 10 of 52 
CONSIDER - LTE Study procedures 
 
 
 
* 3) If remission criteria fulfilled: DAS28 < 2.6 AND no signs of systemic activity (Yamaguchi´s primary classification criteria for AOSD) for two consecutive visits consider down-titration: 
canakinumab open-label 2mg/kg body weight (max 150 mg) s.c. / month 
 
*4) In case of flare (see 3.9) under a reduced dosage of canakinumab, up-titration to the initial dosage is possible.  
 
One application at most can be missed during the study. 
Remission crite ria fulfilled: DAS28 < 2.6 AND no signs of systemic activity (Yamaguchi's primary classification criteria for AOSD) 
for two consecut,ive visits: downtitration (canakinumab open-label 2mg/ kg body weight (max. 150 mg) s.c. / month) 
V8 
Week 24 
Entry in 
LTE 
V 9 , 10 , 12 , 13 , 15 , 16 , 18 , 19 , 21 , 22 , 24 , 25 , 27 , 28 , 30 , 31 
Months 7 , 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, 29 
*3) and *4) 
Open label st udy drug 
0 
study visit without study drug administ ration 
0 
canakinumab open-label 4mg/kg body weight (max. 300 mg) s.c. 
0 
canakinumab open-label 2mg/kg body weight (max 150 mg) s.c. *3) 
V 11 , 14 , 17 , 20 , 23 , 26 , 29 , 32 
Months 9, 12, 15, 18, 21, 24, 27, 30 
Additionally to other visits: 
Joint status (66/ 68), Joint mobility, HAQ-DI, SF-36 
*3) and 4*) 
Open label study drug 
V33/EOS I 
Month 33 
EOS 


 
      Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.doc 
Page 11 of 52 
                                                                                                
 
 
Table of Contents 
 
1. INTRODUCTION AND RATIONALE OF THE CLINICAL STUDY 
13 
1.1.OVERVIEW OF THE CLINICAL PICTURE .............................................................................................................. 13 
1.2.CANAKINUMAB (ILARIS®) ............................................................................................................................. 14 
1.2.1 
SCIENTIFIC BACKGROUND ................................................................................................................................... 14 
1.2.2 
PHARMACOLOGY .............................................................................................................................................. 15 
1.2.3 
TOXICOLOGY ................................................................................................................................................... 15 
1.2.4 
CLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS ........................................................................................ 15 
1.2.5 
CLINICAL EXPERIENCE ........................................................................................................................................ 16 
1.2.6 
POTENTIAL RISK FACTORS ................................................................................................................................... 16 
1.3. RATIONALE FOR THE STUDY AND CHOICE OF DRUG DOSAGE ............................................................................... 17 
2. OBJECTIVES OF THE STUDY 
18 
2.1. PRIMARY ENDPOINT OF THE CORE STUDY ....................................................................................................... 18 
2.2. SECONDARY OBJECTIVE PARAMETERS OF THE CORE STUDY ................................................................................ 18 
2.3. PRIMARY OBJECTIVE PARAMETERS OF THE LONG TERM EXTENSION STUDY ........................................................... 18 
2.4. SECONDARY OBJECTIVE PARAMETERS OF THE LONG TERM EXTENSION STUDY ....................................................... 18 
3. STUDY PLAN 
19 
3.1. GENERAL DESIGN AND PLAN OF THE STUDY .................................................................................................... 19 
3.2. SELECTION OF PATIENTS (CORE) .................................................................................................................. 20 
3.2.1. INCLUSION CRITERIA .......................................................................................................................................... 20 
3.2.2. EXCLUSION CRITERIA ......................................................................................................................................... 20 
3.2.3. SELECTION OF PATIENTS FOR LTE ............................................................................................................................ 21 
3.3. STUDY TREATMENT.................................................................................................................................... 22 
3.3.1. CLINICAL STUDY DRUG AND DOSING ..................................................................................................................... 22 
3.3.2.  CLINICAL STUDY MATERIAL IN THE LONG-TERM EXTENSION ....................................................................................... 22 
3.3.3. PREPARATION, HANDLING AND STORAGE OF THE STUDY DRUG ................................................................................... 22 
3.3.4. DOWN-TITRATION, DOSE MODIFICATION AND DISCONTINUATION OF TREATMENT ......................................................... 24 
3.3.5. ALLOCATION OF THE STUDY MEDICATION / RANDOMISATION .................................................................................... 24 
3.3.5 
BLINDING, PACKAGING AND LABELLING ................................................................................................................. 25 
3.3.6 
CONCOMITANT MEDICATION .............................................................................................................................. 25 
3.4. STUDY PROCEDURES BY VISIT ....................................................................................................................... 25 
VISIT 1-SCREENING (WEEK -4 TO -1) ................................................................................................................................. 25 
VISIT 2-BASELINE (DAY 0) ............................................................................................................................................... 26 
VISIT BM (DAY 7-10) .................................................................................................................................................... 26 
VISIT 3 AND 4 (WEEK 4 AND 8 [+/-3 DAYS]) ....................................................................................................................... 26 
VISIT 6 AND 7 (WEEK 16, 20 [+/-3 DAYS]) ........................................................................................................................ 26 
VISIT 5 (WEEK 12), [+/-3 DAYS] ...................................................................................................................................... 27 
VISIT 8 (WEEK 24), [+/-3 DAYS] ...................................................................................................................................... 27 
END OF CORE STUDY 1, 2 (WEEK 28/40) [+/-3 DAYS] FOR PATIENTS NOT CLASSIFYING TO PARTICIPATE IN THE LTE ......................... 28 
VISIT 9 - 31 (WEEK 28/MONTH 7 – MONTH 30), [+/-7 DAYS] (FOR PATIENTS CLASSIFYING TO PARTICIPATE IN THE LTE) MONTHLY 
VISITS 
28 
VISIT 32/MONTH 33/EOS-LTE ...................................................................................................................................... 28 
3.5. DURATION OF TREATMENT AND PARTICIPATION OF THE PATIENTS ..................................................................... 29 
3.6. TERMINATION OF THE TREATMENT OR OF PARTICIPATION IN THE STUDY ............................................................. 29 
3.7. EFFICACY, PHARMACODYNAMICS AND PHARMACOKINETICS, ANALYSIS OF SAFETY ................................................. 29 
3.7.1. STUDY OF EFFICACY ........................................................................................................................................... 29 
3.7.2. PHARMACODYNAMICS AND PHARMACOKINETICS .................................................................................................... 30 
3.7.3. SAFETY INVESTIGATIONS .................................................................................................................................... 31 
3.8. REMISSION CRITERIA AND DOWN TITRATION .................................................................................................. 31 
3.9. DEFINITION OF FLARE OR INCREASING DISEASE ACTIVITY ................................................................................... 31 


 
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4. ADVERSE EVENTS 
32 
4.1.   DEFINITION .............................................................................................................................................. 32 
4.1.1     DEFINITION OF ADVERSE EVENTS ........................................................................................................................... 32 
4.1.2.    DEFINITION OF SERIOUS ADVERSE EVENTS ............................................................................................................... 32 
4.1.3.    DEFINITION OF AN UNEXPECTED, ADVERSE DRUG INTERACTION (SUSAR) ..................................................................... 32 
4.2.   PROCEDURES FOR REPORTING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .................................................. 32 
5. DETERMINING THE STATISTICAL EVALUATION OF THE STUDY 
33 
5.1. TESTING OF THE EFFICACY OF CANAKINUMAB .................................................................................................. 33 
5.2 CALCULATION OF THE SAMPLE SIZE ................................................................................................................. 34 
5.3. RANDOMISATION AND STRATIFICATION .......................................................................................................... 34 
5.4. "EARLY ESCAPE" ......................................................................................................................................... 34 
5.5. DEALING WITH MISSING OR INCOMPLETE DATA ............................................................................................... 35 
5.6. STATISTICAL METHODS ................................................................................................................................ 35 
5.6.1. COMPARISONS AT BASELINE ............................................................................................................................... 35 
5.6.2. ANALYSIS OF EFFICACY ....................................................................................................................................... 35 
5.6.3. EVALUATION OF SAFETY ..................................................................................................................................... 36 
5.7. INTERIM ANALYSIS ...................................................................................................................................... 36 
6. ADMINISTRATIVE PROVISIONS 
36 
6.1. GOOD CLINICAL PRACTICE .......................................................................................................................... 36 
6.2. ETHICAL PROVISIONS ................................................................................................................................. 36 
6.3. PATIENT INFORMATION AND INFORMED CONSENT .......................................................................................... 37 
6.4. PATIENT CONFIDENTIALITY .......................................................................................................................... 37 
6.5. COMPLIANCE WITH THE STUDY PROTOCOL ..................................................................................................... 37 
6.6. AUDITS AND MONITORING .......................................................................................................................... 37 
6.7. ACCOUNTABILITY ...................................................................................................................................... 37 
6.8. EARLY TERMINATION OF THE STUDY ............................................................................................................. 39 
6.9. PUBLICATION OF THE RESULTS OF THE STUDY ................................................................................................. 39 
7. REFERENCES 
40 
8. PROTOCOL SIGNATURE 
43 
9. APPENDICES 
43 
INDEX OF ABBREVIATIONS ................................................................................................................................... 44 
CLASSIFICATION CRITERIA FOR ADULT-ONSET STILL'S DISEASE (AOSD) ACCORDING TO YAMAGUCHI (1992) .................... 46 
DAS28 ........................................................................................................................................................... 47 
ACR 20 50 70 EFFICACY PARAMETERS ................................................................................................................. 48 
JOINT MOBILITY ACCORDING TO THE NEUTRAL ZERO METHOD ................................................................................... 49 
MACROPHAGE ACTIVATION SYNDROME (MAS) ..................................................................................................... 50 
GCP VERSION DATED 12.08.2004 ..................................................................................................................... 51 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ...................................................................... 51 


 
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1. Introduction and rationale of the clinical study 
 
1.1. Overview of the clinical picture 
 
Adult onset Still‘s disease (AOSD) is a rare systemic inflammatory disease. The cause of the 
disorder is unknown. The clinical picture is characterised by periodic fever attacks, usually 
accompanied by a passing, salmon-coloured rash and polyarthritis (1, 2, 3). The clinical 
picture of AOSD occurs in a similar form in systemic juvenile arthritis (JIA). The occurrence of 
fever has been described in about 95.7% of cases in retrospective studies (1, 4, 5) and in most 
cases precedes the other manifestations of the disease. The recurrent fever attacks typically 
occur once or twice a day, with the highest temperatures occurring late in the afternoon.  
The typical macular or maculopapular rash which usually accompanies the reaction to fever, 
especially in the evening and at night, is fleeting and salmon pink in colour (5, 6). The rash is 
described in approx. 73% of patients and predominantly occurs in the thigh and trunk area. 
Pruritus is sometimes reported (32% of patients in a Dutch cohort), meaning that it could be 
confused with an allergic reaction to medication (1, 7, 8). Histological findings often reveal a 
discrete perivascular inflammation on the upper dermis with infiltrates of lymphocytes and 
histiocytes (9). 
 
The mortality of the disease may have fallen in the last few years. While it was stated as still 
being at 10% up to 1990 within a period of 12 years (6, 10, 11, 12), a meta-analysis of 5 
studies published in 2008 reveals mortality of 4% within a period of 5 to 13 years (13). The 
most frequent causes of death within this are usually stated as being sepsis, hepatic failure 
and haemophagocytic syndrome (or macrophage activation syndrome, MAS). The prognosis 
for AOSD primarily depends on the visceral participation of organs (7, 8, 14), with a 
secondary amyloidosis (type AA), which considerably increases mortality. The secondary 
amyloidosis frequently occurs with the progress of refractory AOSD stretching over a number 
of years, in which the participation of the kidneys in particular plays a key prognostic role (15, 
16, 17). 
 
The cause of AOSD is still unexplained. Possible trigger factors are assumed to be infectious 
diseases caused by viruses and bacteria, but no active infectious disease can usually be 
established in terms of disease manifestations (9, 11). A genetic association with the features 
of HLA (B17, B18, B35, DR2) have been described in some studies (7, 9, 14, 18). The 
inflammatory reaction is mediated in the pathogenesis through the raised secretion of 
various cytokines, with raised serum levels of IL-1, IL-6, TNF-a and IL-18 in particular being 
measured in highly active AOSD patients (7, 8, 9, 14, 18). 
 
Epidemiological data regarding the incidence and prevalence of the disease are only 
insufficiently available. The disease occurs worldwide, with females appearing to be 
somewhat more frequently affected. AOSD usually affects young people with the age of first 
manifestation being between 16 and 35 years old in 75% of cases (7, 8). Prevalence was 
stated in 1990 as being at 0.16 to 3.4/100,000 and in 2000 at 6.9/100,000 (19, 20). The 
annual incidence in Norway was stated as being 0.4/100,000 (20). 
 
The treatment available until now has consisted in particular of measures targeted at the 
symptoms using non-steroid anti-inflammatory drugs (NSAIDs). In the case of pronounced 
systemic disease manifestation, immunosuppressive drugs such as glucocorticoids and 
disease modifying anti-rheumatic drugs (DMARDs) are also used. In cases of progress where 
there is resistance to therapy, biologicals have likewise been increasingly used, with good 


 
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results in particular for Interleukin-1 inhibitors having been published in case descriptions as 
well as in small cohort studies. In various case series, the achievement of remission of the 
disease could also be demonstrated. Furthermore, in one study, long-term remission from 
AOSD could also be shown in response to IL-1 blockade amongst patients who had previously 
had a high need for glucocorticoids and who had not responded to any other 
immunosuppressive drugs (DMARDs- and/or TNF blockers) (7, 8, 9, 14, 22). Amongst these 
patients, in addition to good clinical efficacy, a reduction in the glucocorticoid dose could also 
be achieved. Good tolerance of the treatment could be established overall. This provides 
good indications for an IL-1 blockade having good efficacy amongst patients with refractory 
AOSD (23, 24, 25, 26, 27). 
 
Still’s disease, as juvenile and adult manifestation, is considered to represent a disease 
continuum. This view is supported by a similar clinical presentation, the involved pro-
inflammatory cytokine signature and known treatment effects under IL-1 inhibitors. In this 
context, canakinumab has shown strong efficacy and beneficial safety profile for treatment of 
systemic juvenile idiopathic arthritis (SJIA or juvenile Still’s disease). The first controlled 
clinical trial of canakinumab in AOSD is performed to confirm these results in an adult 
population over a period of 24 weeks. First analyses of mRNA expression profiles, derived 
from these patients at baseline, revealed an upregulation of genes in AOSD which where 
responsive to successful canakinumab treatment in SJIA. 
 
To provide long-term data on safety and efficacy, we aim to perform an extended treatment 
period until possible approval of the drug for this indication. Since it is of interest to clarify, 
whether this promising approach for treatment of SJIA as well as AOSD does require the 
same dose regimen, we also include the option for down-titration regimen in case of disease 
remission. Taken together, the aim of this long-term extension of our IIT in AOSD, is to 
investigate, whether canakinumab can be used with maintained efficacy and beneficial safety 
profile in AOSD patients. 
 
Canakinumab is a specific IL-1ß-blocker with a good efficacy and safety profile in clinical 
applications to date with periodic fever syndromes in infantile- and adult-aged patients. 
Compared to other IL-1 blockers, fewer localised skin reactions in particular were observed 
with canakinumab. Canakinumab is approved for treatment in patients suffering from 
cryopyrin-associated periodic syndromes (CAPS) in Europe and the USA. This range of 
hereditary autoinflammatory syndromes is similar to AOSD, characterised by fever, skin 
rashes and an increase in inflammatory markers (28, 29, 30). The aim of this controlled 
clinical study in this process is to investigate the efficacy and safety of canakinumab amongst 
patients with active AOSD. 
 
1.2. Canakinumab (Ilaris®) 
 
1.2.1 
Scientific background 
 
Canakinumab (Ilaris®) is a pharmaceutical product of the class of active substances of 
immunosuppressives and is a human monoclonal anti-human-interleukin-1-beta-(IL-1-beta-) 
antibody of the IgG1/κ-isotype. Canakinumab attaches specifically to human IL-1 beta with 
high affinity and neutralises the biological activity of human IL-1 beta by inhibiting the 
interaction of this with IL-1 receptors, which means that the gene activation and formation of 
inflammatory mediators induced by IL-1 beta is prevented (32). 


 
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In clinical studies, CAPS patients responded rapidly to treatment with canakinumab, with 
pathological laboratory parameters, such as raised C-reactive protein (CRP), serum amyloid A 
(SAA), neutrophils and thrombocytes as well as leukocytosis, being normalised (32). 
 
1.2.2 
Pharmacology 
 
The efficacy and safety of canakinumab have been proven amongst CAPS patients with 
varying degrees of severity of the disease and varying CAPS phenotypes. The approval of the 
drug under the trade name Ilaris has been secured for the treatment of adults, adolescents 
and children from the age of 4 with body weight exceeding 15 kg for the treatment of 
Cryopyrin-Associated Periodic Syndromes (CAPS), including: 
1. Muckle-Wells Syndrome (MWS), 
2. Multi-systemic inflammatory disease commencing at neonate age (Neonatal Onset 
Multisystem Inflammatory Disease; NOMID) or chronic infantile neuro-dermo articular 
syndrome (Chronic Infantile Neurological, Cutaneous, Articular Syndrome; CINCA), 
3. Severe forms of Familial Cold Autoinflammatory Syndrome; FCAS)/Familial Cold Urticaria; 
FCU with indications and symptoms which go beyond a cold-induced urticarial skin rash (31). 
The recommended dose of canakinumab amounts to 150 mg for CAPS patients with a body 
weight >40 kg or 2 mg/kg for CAPS patients with a body weight ≥15 kg and ≥40 kg. This dose is 
to be administered every eight weeks as a single dose in the form of a subcutaneous injection. 
If no clinically satisfying response (complete receding of the skin rash and other general 
inflammatory symptoms) has been achieved 7 days after the initiation of treatment, a second 
administration of 150 mg or 2 mg/kg canakinumab can be considered. If complete 
responsiveness to the treatment has then been achieved, the intensified dosage regime of 
300 mg or 4 mg/kg should be maintained. No experience is available in the use of 
canakinumab at doses > 600 mg every 8 weeks. Clinical experience is limited in dosage 
intervals of less than 4 weeks (32). 
 
Within the framework of the examination of canakinumab in studies involving systemic 
juvenile arthritis (JIA, Still's Disease), a dosage of 4 mg/kg subcutaneously every 4 weeks has 
been established to be the optimum dosage.  
 
1.2.3 
Toxicology 
 
The most frequent side effects of treatment with canakinumab among patients with CAPS 
have been described as injection site reactions (20%), nausea, headaches, dizziness (11%), 
weight gain, muscle pains (10%), changes in blood count, liver count increases, as well as an 
increased risk of suffering slight and severe infections (nasopharyngitis, urinary tract 
infection, infection of the upper airways, viral infection) (30, 31). 
 
1.2.4 
Clinical pharmacokinetics and pharmacodynamics 
 
In clinical studies, CAPS patients usually already respond to treatment with canakinumab after 
the first dose has been administered (28). Among adult CAPS patients, the peak 
concentrations of canakinumab in the serum (Cmax) occurred approximately 7 days after a 
one-off subcutaneous administration of 150 mg. The average terminal half-life period stood at 
26 days. On the basis of a pharmacokinetic analysis, the absolute bioavailability of 
subcutaneous canakinumab was estimated at 70%. The clearance (CL) and the distribution 
volume (Vss) of canakinumab turned out differently depending on body weight and have been 


 
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estimated for a typical CAPS patient with a body weight of 70kg at 0.174 l/day or 6.01 litres. 
The accumulation ratio to be expected amounted after a subcutaneous administration of 150 
mg canakinumab every 8 weeks to 1.3-fold. The exposition parameters (such as AUC and Cmax) 
rose proportionately to the dose within a dosage range of 0.30 to 10.0 mg/kg as an 
intravenous infusion or from 150 to 300 mg as a subcutaneous injection. After repeated 
application, there were no indications of any accelerated clearance or changes in the 
pharmacokinetic properties of canakinumab depending on time. Following correction for 
body weight, no gender- or age-specific pharmacokinetic differences could be observed (32). 
 
1.2.5 
Clinical experience 
 
Canakinumab is approved for the treatment of adults, adolescents and children from the age 
of 4 with body weight exceeding 15kg with Cryopyrin-Associated Periodic Syndromes (CAPS), 
gout arthritis and systemic juvenile idiopathic arthritis (31, 32). Canakinumab is being 
investigated in clinical studies in patients with juvenile idiopathic arthritis (JIA, Still's disease) 
as well as gout. Case reports have been published regarding treatment for Schnitzler's 
syndrome, Behcet disease, relapsing polychondritis, Sweet's syndrome, type 2 diabetes and 
AOSD (31). 
NSAIDs, glucocorticoids and DMARDs (such as MTX, azathioprine, Cyclosporine A or 
cyclophosphamide) are usually administered in the treatment of AOSD. In the case of 
refractory forms of AOSD, biologicals (such as infliximab, adalimumab, etanercept, rituximab 
or tocilizumab) have been used with varying success in individual cases. Predominantly good 
treatment effects and persisting remission have been observed with the anakinra IL-1 blocker 
(23, 24, 25, 26, 27). 
 
1.2.6 
Potential risk factors 
 
The use of canakinumab can be linked to increased occurrence of infections and serious 
infections (32). Patients should therefore be carefully monitored during and after treatment 
with canakinumab for any indications and symptoms of infections. Prior to initiating any 
treatment with a biological, it is recommended to boost the vaccination status, including 
pneumococci and influenza vaccinations. In about 12% of CAPS patients undergoing a PPD 
test (tuberculin skin test) in clinical studies, a positive test result was obtained in response 
to treatment with canakinumab during the follow-ups, without any indications of latent or 
active tuberculosis (32).  
Further potential risk factors in response to the use of canakinumab can include changes in 
blood counts, including neutropenia. Increases in liver enzyme values while undergoing 
treatment are also possible (28). The risk of developing malignant diseases in connection 
with anti-interleukin (IL-) 1 therapy is unknown, but a potential risk cannot definitely be 
excluded (32).  
Treatment with an IL-1 inhibitor such as canakinumab can lead to an increased expression 
of cytochrome P450. Patients undergoing co-medication with other drugs metabolised 
through the cytochrome P450 and with a narrow therapeutic range should therefore be 
monitored in terms of efficacy or the concentration of active substances (some 
antiepileptics, antimycotics, antidepressives, Leflunomide, Warfarin, etc.) (32). 
There is limited literature available regarding reproduction toxicity and fertility. The use of 
effective contraception methods is therefore recommended during any treatment with 
Ilaris and for up to three months before commencing any such treatment (32). 
The ability to drive can be impaired through potential side-effects such as light-headedness 
(31). 


 
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1.3. Rationale for the study and choice of drug dosage 
 
No approved treatment options are currently available for the treatment of musculoskeletal 
manifestations with AOSD which have not responded to NSAIDs, glucocorticoids and 
DMARDs. Based on the good therapeutic effects which have been published with persisting 
remission reported in response to the IL-1 blocker anakrinra in cases of AOSD therapy 
resistance, this therapeutic approach is very promising. As, however, using the daily 
subcutaneous application of anakrina required is frequently accompanied by local reactions at 
the injection site, treatment with canakinumab promises to provide a sensible alternative due 
to a considerably longer application interval and fewer local reactions (32). 
Canakinumab is an anti-IL-1-beta antibody with proven efficacy and a good safety profile with 
auto-inflammatory syndromes and is approved for the treatment of CAPS patients (32). This 
human, monoclonal antibody therefore appears to be suitable for the treatment of AOSD and 
is to be investigated within the framework of this study. 
 
Within the framework of the examination of canakinumab in studies involving systemic 
juvenile arthritis (SJIA, Still's Disease), a dosage of 4 mg/kg body weight subcutaneously every 
4 weeks has been established to be the optimum dosage. In the present study protocol for 
the treatment of AOSD, a dosage adjustment of canakinumab 4 mg/kg body weight up to a 
maximum dosage of 300 mg subcutaneously is envisaged, which is to be carried out every 4 
weeks. The dose of canakinumab used in the process will continue to exceed the dose 
approved for the treatment of CAPS patients. As justification for the selection of the higher 
canakinumab dose, reference is made to the similarity of the clinical pictures of Still's disease 
in juvenile and adult age groups, while CAPS and Still's disease differ in clinical and 
pathogenetic terms. For this reason, an identical treatment dose as for Still's disease cannot 
definitely be inferred from proceeding from a dose of canakinumab known to be effective 
with CAPS. According to current knowledge gained from pharmacokinetic investigations, a 
higher dose with canakinumab is required in patients with SIJA compared to juvenile and 
adult CAPS patients. These data (33, 34) accepted for publication revealed that a dosage of 
canakinumab at 4 mg/kg body weight at an interval of four weeks was required in order to 
achieve a therapeutically effective plasma concentration of canakinumab. 
 
The data available from the phase II clinical studies on the use of canakinumab (study 
A2203) with a dose of 4 mg/kg body weight at an interval of 4 weeks among patients with 
SIJA provide a basis for a dosage adjustment with regard to age (1-19 years). Furthermore, 
there are no indications of any excessive over- or under-dosing in the AUC vs. age analysis. 
It can therefore be assumed that a higher dose of canakinumab needs to be selected for the 
treatment of AOSD than for CAPS, based on the efficacy shown with SIJA. A relevant 
accumulation of canakinumab is not to be expected in this process due to the dosage 
corresponding to body weight and the limitation of the maximum dose.  


 
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2. Objectives of the study 
 
2.1. Primary endpoint of the core study 
 Investigation of the efficacy of canakinumab in patients with AOSD and active joint 
involvement. Primary endpoint: clinically relevant reduction in DAS28 of more 
than 1.2 between baseline (mean DAS28 of visit 1 and visit 2) and week 12 
(double blind treatment period of 12 weeks). 
 
2.2. Secondary objective parameters of the core study 
 
 Evaluation of the safety of canakinumab in patients with AOSD 
 Evaluation of the efficacy of canakinumab in patients with AOSD and joint 
involvement according to ACR and EULAR response criteria at weeks 12 and 24 
 Improvement in skin manifestations, the frequency of fever and reduction in the 
inflammatory markers of the disease 
 Proportion of patients achieving low disease activity (< 3.2) or remission (< 2.6) 
according to DAS28 
 Investigation of general changes in health based on HAQ-DI and SF-36 
 Recording of the change in joint mobility based on the neutral zero method 
2.3. Primary objective parameters of the long term extension study 
 
 Evaluation of the long-term safety of canakinumab in patients with AOSD 
and articular involvement 
 
2.4. Secondary objective parameters of the long term extension study 
 
 Description of the long term efficacy of canakinumab in patients with AOSD 
according to EULAR response criteria (proportion of patients showing prolonged 
clinically improvement according to DAS28 low-disease activity [< 3.2] and 
remission [< 2.6], reduction of flares and glucocorticoid intake) 
 Assessment of health outcome measures (HAQ-DI, SF-36), improvement in skin 
manifestation, the frequency of fever and reduction of inflammatory markers of 
disease under long-term treatment. 
 Evaluation if a reduced dosage of canakinumab can be used to control disease 
activity by down-titration from 4mg/kg/body weight (BW) (max 300mg)/month to 
2mg/kg/BW (max 150mg)/month. 
 
 


 
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3. Study plan 
 
3.1. General design and plan of the study 
 
Patient population 
Patients with AOSD and active joint manifestation are included in the study.  
 
Centres and number of patients participating: 
The study will be carried out at approx. 14 different centres under the supervision of the 
Department for Rheumatology and Clinical Immunology of the Charité. The inclusion of 68 
patients with AOSD is envisaged. 
 
Study design and methodology 
Multi-centre, randomised, double blind, place-controlled phase II study for patients with 
AOSD and active joint involvement in response to stable symptomatic treatment with 
NSAIDs and DMARD. Having undergone previous treatment with biologicals is permitted, 
with attention being paid to the respective normalisation times prior to the conclusion of 
the study. Having undergone treatment with the study drug through the repeated 
administration of canakinumab represents a criterion for exclusion. In the event of 
canakinumab having been administered on a one-off basis, inclusion is possible based on 
the placebo-controlled study design, if the interval amounts to more than 6 months. 
During the masked study phase, patients receive canakinumab at 4mg/kg body weight (up 
to a maximum of 300 mg subcutaneously vs. placebo subcutaneously) as study medication 
at baseline, in weeks 4 and 8. In the event of a response being obtained, further 
administration of the study medication of canakinumab 4mg/kg body weight up to a 
maximum of 300 mg subcutaneously vs. placebo subcutaneously is to be carried out at 
weeks 12, 16 and 20.  
Non-responders will be unblinded at week 12. For patients in the placebo group showing no 
significant change in disease activity at week 12, an open administration of canakinumab 
4mg/kg body weight up to a maximum of 300 mg will be carried out subcutaneously at 
week 12 as well as at weeks 16 and 20. Non-responders at week 12 from the canakinumab 
arm will not undergo further treatment with the study drug. 
 
Long term extension 
Patients who enter long-term extension: 
A down-titration from 4mg/kg/BW (max. 300mg)/month to 2mg/kg/BW (max 
150mg)/month can be considered after week 28 (visit 9) if the patient fulfils remission 
criteria defined as: a DAS28 < 2.6 AND no signs of systemic activity (Yamaguchi´s primary 
classification criteria for AOSD) for two consecutive visits. 
In case of increasing disease activity or flare (see 3.9) under a reduced dosage of 
canakinumab, up-titration to the initial dosage is possible.  
 


 
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3.2. Selection of patients (Core) 
 
3.2.1. 
Inclusion criteria 
1. Written and signed consent from the patient to participate in the study  
2. Men and women aged ≥ 18 years and ≤ 75 years 
3. Fulfilment of the classification criteria of AOSD (according to Yamaguchi et al, J. 
Rheumatology, 1992) 
4. Disease activity according to DAS28 of ≥ 3.2 at screening  
5. At least 4 painful and 4 swollen joints at screening and baseline (of the 28 joints 
according to DAS28) 
6. If undergoing treatment with NSAIDs, stable dose for at least 2 weeks prior to 
randomisation 
7. If undergoing treatment with glucocorticoids, stable dose of ≤ 10 mg/day (prednisone 
or equivalent) for at least 1 week prior to randomisation 
8. If undergoing treatment with conventional DMARD, stable dose for at least 6 weeks 
prior to randomisation 
9. Normalisation period for biological DMARDS (anakinra 1 week, etanercept 2 weeks, 
adalimumab, tocilizumab s.c. and certolizumab 1 month, infliximab, golimumab, 
abatacept (i. v.) and tociluzumab (i.v.) 3 months, rituximab 9 months, canakinumab 6 
months) prior to randomisation 
10. In patients of reproductive age, use of an effective method of contraception as well as 
negative pregnancy test prior to the study commencing. 
 
3.2.2. 
Exclusion criteria 
 
1. Previous treatment with the study drug with repeated administration of canakinumab 
2. Intraarticular or intravenous administration of glucocorticoids within 4 weeks prior to 
the baseline or use of narcotic analgesics except for analgesics permitted within the 
framework of the study (codeine and tramadol) 
3. Presence of another, serious chronic-inflammatory disease 
4. Positive hepatitis B antigen (HBsAg), hepatitis C antibodies and/or HIV antibodies. 
5. Presence of a relevant, active infection or other diseasees, which entail a tendency 
towards infection, including HIV-positive upon screening (ELISA and Western blot) 
6. Positive screening for latent tuberculosis, in accordance with usual local practice. If 
patient is taking adequate/isoniazid prophylaxis for 4 weeks before first IP 
administration, this patient may be randomized. 
7. Raised liver count (raised bilirubin; ALT or AST ≥ 3-fold of normal range)  
8. Serum-creatinine concentration > 1.5 mg/dl  
9. Inadequate haematological findings (Hb ≤ 9 g/dl, neutrophils ≤ 2,500/µl and 
thrombocytes ≤ 100,000/µl) 
10. Simultaneous participation in any other interventional clinical study within the last 30 
days preceding the commencement of the study 
11. History of neoplasia with the exception of a curatively treated non-melanoma skin 
tumour or carcinoma of the cervix treated in situ without any indication of recurrence 
within the last 10 years 
12. Relevant cardiac or pulmonary disorders 
13. Severe intercurrent neurological or psychiatric disorders 


 
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14. Macrophage activation syndrome (MAS) within the framework of a previous treatment 
with IL-1 blockade (e.g. anakinra, rilonacept) 
15. Vaccination with a live vaccine within 3 months before baseline  
16. Alcohol or drug abuse in the past 12 months 
17. ≥ 400 ml donation of blood or –loss up to 8 weeks before baseline 
18. Pregnancy or breast-feeding 
19. Commitment of the patient to an institution at the direction of an authority or court 
 
3.2.3. Selection of patients for LTE 
 
1. Participation in the randomized, placebo-controlled trial (CACZ885GDE01T) (core-study) 
2. Considered to be a responder with respect to articular involvement (according to EULAR 
response criteria) as well as to systemic disease manifestation of AOSD 
3. If the patient is of childbearing potential, she agrees to: comply with effective 
contraceptive measures, has been using adequate contraception since the last menses, 
will use adequate contraception during the study, and has a negative pregnancy test 
within one week of study entry 


 
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3.3. Study treatment 
 
3.3.1. 
Clinical study drug and dosing 
 
Canakinumab 150 mg/ 1ml solution for injection will be used as the study substance in a dose 
of 4mg/kg body weight up to a maximum of 300 mg subcutaneously. Individual 
administration dose will be calculated based on the subject’s body weight as measured at the 
baseline and subsequent scheduled visits. A fixed dose level of 4mg/kg (to a maximum of 300 
mg) will be used for the calculation. 
 
Example of calculation (patient requiring 4mg/kg): 
- 
Subject weight = 60 kg 
- 
Dose level = 4mg/kg 
- 
Calculated dose (mg) = 60 kg x 4mg/kg = 240 mg 
- 
Calculated volume of solution for s.c. injection (mL): 240 mg/150 mg/mL = 1.6 mL 
- 
Number of vials to be used: 2 
 
The placebo will be administered as an identical injection. 
3.3.2.  
Clinical study material in the long-term extension 
 
In the LTE, open-label canakinumab will be used for treatment.  
 
 
 
3.3.3. 
Preparation, handling and storage of the study drug 
Canakinumab / placebo for subcutaneous injection 
 
Novartis will provide canakinumab  as solution to prepare a subcutaneous injection.  
 
The canakinumab 150mg/ 1mL solution for injection is provided in 2mL glass vial filled with 
1.0 mL of solution, plus 15% overfill (0.15 mL) to allow a complete withdrawal of 1.0mL of 
solution from each vial. Packs and vials will be provided as both blinded and open label 
presentations. 
Canakinumab 150mg/ 1mL solution for injection is a clear to opalescent, colorless to 
yellowish, ready to use solution formulated in L-histidine buffered mannitol solution 
containing polysorbate 80. 
As canakinumab is a protein, the solution can contain some translucent particles. 
 
Each vial is intended to be used for a single application. All residues of canakinumab remain 
in the vials. Any remaining quantities of the study substance must not be used for 
application in other study participants/ patients.  
The sponsor will provide study sites with supplemental material. 
 
 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 23 of 52 
Placebo 
 
Novartis will provide placebo solution for injections in 2mL glass vial filled with 1.0 mL of 
solution plus a  15% overfill (0.15 mL) to allow a complete withdrawal of 1.0mL of solution 
from each vial. Packs and vials will be provided as blinded presentations. 
Placebo solution for injection is a clear to opalescent, colorless to yellowish, ready to use 
solution formulated in L-histidine buffered mannitol solution containing polysorbate 80. 
 
Each vial is intended to be used for a single application. All residues remain in the vials. Any 
remaining quantities must not be used for application with other study participants/ 
patients. 
 
Instructions regarding the preparation of canakinumab / placebo solution for 
subcutaneous injections 
 
An independent qualified member of staff is not necessary; each trained staff member can 
prepare and administer the study drug.  
 
The vials with solution have an overfill of 15% above the nominal quantity. No more than 
1.0 ml may be drawn. 
Materials required: 
 
Canakinumab 150mg /1mL or  placebo solution for injection 
 
Sterile 1 mL (10μL graduated) disposable syringes for withdrawal and injection of 
the solution for s.c. injection. 
 
Sterile disposable needles 21G x 2” for withdrawal of investigational treatment 
solution from the vial; if not available, needles with larger inner diameter can also 
be used. 
 
Sterile disposable needles 27G x 0.5” for s.c. injections. 
 
Remove the plastic flip off cap from the vials and disinfect the rubber stopper with an alcohol 
swab. Using a clean 1.0mL syringe to withdraw the calculated volume of solution from each 
vial. 
 
 
Administration 
Canakinumab injection solution or placebo is to be injected subcutaneously with a 
27Gx0.5"needle. The dose adapted according to body weight is to be injected 
subcutaneously on each dosage day. Dosage should be made in the morning so as to have 
time for taking blood samples and well as processing and despatching the blood samples. The 
patients must be observed for 30 minutes after the administration of the study drug at the 
test centre.  
In the LTE (i.e. after week 24), the medication will be administered open-label. In the LTE 
placebo will not be applied. 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 24 of 52 
 
 
Storage of the study drug 
The study drug is to be stored at temperatures between 2 and 8° C in the refrigerator of the 
respective participating centres. If not used immediately (within 15 minutes) after 
preparation the solution should be kept at 2-8 °C, and allowed to come to room 
temperature for approximately 20 minutes before administration. ACZ885 solution for 
injection can be stored at 2-8 °C for up to 24 hours. Do not freeze.  It will be administered to 
the patients in the masked part of the study at baseline as well as at weeks 4, 8, 12, 16 and 
20 at the study centre.  
 
After and including week 24, administration of study drug will be performed in an open-
label setting. 
 
3.3.4. 
Down-titration, dose modification and discontinuation of treatment 
 
The patients will be treated with canakinumab at a dose of 4mg/kg body weight up to a 
maximum of 300 mg or the placebo at 4-week intervals with no dose modification being 
foreseen until week 20. One application at most can be missed during the core study 
period. 
 
 
Long term extension 
 
There will be the possibility of a down-titration from 4mg/kg/BW (max. 300mg)/month to 
2mg/kg/BW (max 150mg)/month that might be performed after week 28 (visit 9) if the 
patient fulfils remission criteria defined as: a DAS28 < 2.6  AND no signs of systemic activity 
(Yamaguchi´s primary classification criteria for AOSD) for two consecutive visits. 
In case of increasing disease activity or flare under a reduced dosage of canakinumab, up-
titration to the initial dosage is possible.  
 
 
3.3.5. 
Allocation of the study medication / randomisation 
 
34 patients will receive treatment with the study substance (canakinumab) and 34 patients 
will receive treatment with a placebo. The patient's report will be made by FAX 
randomisation form. Randomisation will be made on the basis of a documented 
randomisation list. 
A re-evaluation will take place in week 12. It is expected that at this point in time, approx. 
75% of patients will change over from the placebo to the verum group, if no significant 
improvement has been achieved according to the DAS28 (a significant improvement is 
defined as improvement in the DAS28 from the commencement of the study (=average of 
visits 1 and 2) to visit 5 of more than 1.2 points). 
 
During the LTE all patients will receive canakinumab open-label. 
 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 25 of 52 
 
3.3.5 
Blinding, packaging and labelling 
 
Blinding, packaging and labelling will be performed by Novartis Pharma. 
There will be 1,008 complete, packed and marked samples of canakinumab (Ilaris®) 150 mg 
and 768 complete, packed and marked samples with placebo for the placebo-controlled 
core-study. 
 
There will be approx. 1440 - 1680 fully packed and labelled samples of canakinumab (Ilaris®) 
150 mg for the LTE. 
 
3.3.6 
Concomitant medication 
 
Concomitant systemic treatment with glucocorticoids is excluded in a dose of 10 mg/day of 
prednisolone-equivalent or biologicals (infliximab, adalimumab, etanercept, abatacept, 
rituximab, tocilizumab, anakinra). In cases of existing DMARD treatment, this must have 
been stable for 3 months. The use of narcotic analgesics, with the exception of analgesics 
permitted within the framework of the study (codeine and tramadol), is not permitted. 
NSAIDs and oral glucocorticoids (≤ 10 mg/day Prednisolone-equivalent) must be taken at a 
stable dose at least 1 week before baseline and should not be changed within the period of 
participation in the study, as far as possible.  
Concomitant medication taken for the treatment of other illnesses will be recorded at every 
visit in regards to dose, type of application and indication. 
 
3.4. Study procedures by visit 
Visit 1-Screening (week -4 to -1) 
 
Informed consent, including accompanying project, if applicable 
 
Demographic data 
 
Medical history 
 
Physical examination and vital signs 
 
Concomitant medication 
 
Inclusion and exclusion criteria 
 
Differential blood count, Na, K, crea, ALT, AST, GGT, AP, LDH, ferritin, CRP 
 
ESR 
 
Protein electrophoresis 
 
Pregnancy test 
 
ANA 
 
HIV, hepatitis B and heptitis C serology (HBsAg, Anti-HCV) 
 
Urine test sticks 
 
Tb screening (chest X-ray ≤ 3months, PPD skin test and/or IGRA) 
 
Joint status (68) 
 
PGA 
 
PhGA 
 
Pharmacodynamics 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 26 of 52 
 
Visit 2-Baseline (day 0) 
 
Informed consent for accompanying project§ 
 
Physical examination and vital signs 
 
Concomitant medication 
 
Inclusion and exclusion criteria 
 
Adverse events 
 
Differential blood count, Na, K, crea, ALT, AST, GGT, AP, LDH, ferritin, CRP 
 
ESR 
 
Anti-canakinumab antibodies 
 
Urine test sticks 
 
ECG 
 
Joint status (68) 
 
Joint mobility 
 
PGA 
 
PhGA 
 
HAQ-DI, SF-36 
 
Pharmacodynamics 
 
Pharmacokinetic properties  
 
Administration of the study drug 
 
Biomarkers (with supplementary informed consent for the accompanying project) 
 
Randomisation FAX 
 
Visit BM (day 7-10)  
 
Adverse events 
 
Biomarkers (with supplementary informed consent for the accompanying project) 
 
Visit 3 and 4 (week 4 and 8 [+/-3 days]) 
 
Physical examination and vital signs 
 
Concomitant medication 
 
Adverse events 
 
Diff. blood count, Na, K, crea, ALT, AST, GGT, AP, LDH, ferritin, CRP 
 
ESR 
 
Anti-canakinumab antibodies 
 
Joint status (68) 
 
PGA 
 
PhGA 
 
Pharmacodynamics 
 
Pharmacokinetic properties 
 
Administration of the study drug  
 
Biomarkers (visit 3 with supplementary informed consent for the accompanying 
project) 
 
Visit 6 and 7 (week 16, 20 [+/-3 days]) 
 
Physical examination and vital signs 
 
Concomitant medication 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 27 of 52 
 
Adverse events 
 
Diff. blood count, Na, K, crea, ALT, AST, GGT, AP, LDH, ferritin, CRP 
 
ESR 
 
Anti-canakinumab antibodies 
 
Joint status (68) 
 
PGA 
 
PhGA 
 
Pharmacodynamics 
 
Pharmacokinetic properties 
 
Administration of the study drug, if applicable  
 
Visit 5 (week 12), [+/-3 days] 
 
Physical examination and vital signs 
 
Concomitant medication 
 
Adverse events 
 
Diff. blood count, Na, Ka, crea, ALT, AST, GGT, AP, LDH, ferritin, CRP 
 
ESR 
 
ANA 
 
Anti-canakinumab antibodies 
 
Joint status (66/68) 
 
Joint mobility 
 
PGA 
 
PhGAHAQ-DI, SF-36 
 
Pharmacodynamics 
 
Pharmacokinetic properties 
 
Re-evaluation of treatment (DAS28 > 1.2) 
 
Fax to sponsor for re-randomisation in case of DAS difference ≤ 1.2 
 
Administration of the study drug, if applicable  
 
Visit 8 (week 24), [+/-3 days] 
 
Physical examination and vital signs 
 
Concomitant medication 
 
Adverse events 
 
Diff. blood count, Na, K, crea, ALT, AST, GGT, AP, LDH, ferritin, CRP, ESR 
 
Electrophoresis 
 
Pregnancy test 
 
ANA 
 
Urin test stick 
 
ECG 
 
Anti-canakinumab antibodies 
 
Joint status (68) 
 
Joint mobility 
 
PGA 
 
PhGA 
 
HAQ-DI 
 
SF-36 
 
Pharmacodynamics 
 
Pharmacokinetic properties 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 28 of 52 
 
Pharmacodynamics 
 
Pharmacokinetic properties  
 
Biomarkers (with supplementary informed consent for the accompanying project) 
 
For patients eligible for LTE, administer open-label canakinumab 
 
End of core study 1, 2 (week 28/40) [+/-3 days] for patients not classifying to participate in 
the LTE 
 Physical examination and vital signs 
 Concomitant medication 
 Adverse events 
 Diff. blood count, Na, K, crea, ALT, AST, GGT, AP, LDH, ferritin, CRP, ESR 
 ANA 
 Anti-canakinumab antibodies 
 
Long term extension 
Visit 9 - 31 (week 28/month 7 – month 30), [+/-7 days] (for patients classifying to participate 
in the LTE) monthly visits 
 
Physical examination and  
 
vital signs 
 
Concomitant medication 
 
Adverse events 
 
Diff. blood count, Na, K, crea, ALT, AST, GGT, AP, LDH, ferritin, CRP, ESR 
 
Anti-canakinumab antibodies 
 
PGA 
 
PhGA 
 
Pharmacodynamics 
 
Pharmacokinetic properties 
 
Administration of the study drug, if applicable 
 
Joint count (28)  
 
Joint count (66/68) 
 
Joint mobility 
 
 
to be performed every 3 months and at month 30 
 
HAQ-DI  
 
 
(months 9, 12, 15, 18, 21, 24, 27) 
 
SF-36 
Visit 32/Month 33/EOS-LTE  
 
Physical examination and vital signs 
 
Concomitant medication 
 
Adverse events 
 
ECG 
 
Diff. blood count, Na, K, crea, ALT, AST, GGT, AP, LDH 
 
Ferritin 
 
CRP 
 
ESR 
 
Electrophoresis 
 
ANA 
 
Anti-canakinumab antibodies 
 
Urin test stick 
} 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 29 of 52 
 
3.5. Duration of treatment and participation of the patients 
Participation in the core study and LTE, including screening and subsequent observation, 
will involve a maximum of 34 months (4 weeks screening, 30 months study-drug treatment, 
3 months FU). The study substance will be taken through a maximum of 30 applications 
over a period of a maximum of 30 months. 
 
3.6.  Termination of the treatment or of participation in the study 
Criteria for discontinuing the treatment or participation in the study in individual cases:  
1. Withdrawal of consent to participate 
2. Adverse events which make it appear that continuation of the treatment/participation 
can no longer be seen as medically justifiable 
a. Parameters which can be measured medically (derived from the safety profile/side-
effects of the study medicine) 
I. Appearance of recurrent and/or severe infectious diseases 
II. Occurrence of serious adverse events which are not compatible with the 
further administration of the study drug 
III. Occurrence of a malignant neoplasm 
IV. Occurrence of macrophage activation syndrome (MAS) 
V. Occurrence of pregnancy 
VI. Rise in liver function values (incl. bilirubin; ALT or AST  > 5-fold normal range)  
VII. Rise in creatinine > 30%  
VIII. Neutropenia < 1,000/µl  
IX. Leukocytopenia < 2000/µl 
X. Thrombocytes < 50,000/µl 
b. High activity of the AOSD persisting or newly occurring since the inception of the 
study 
 
In the event of premature discontinuation or termination of the study through a decision by 
the sponsor, the investigating doctor or the study participant, the visit will be carried out at 
week 28. Furthermore, a concluding visit will be held, recording the adverse outcomes with 
an interval of 20 weeks after the last administration of the study drug. 
The participants in the study will be transferred for further rheumatological treatment to 
the respective responsible/referring treatment institution after the study has been 
concluded. 
 
3.7. Efficacy, pharmacodynamics and pharmacokinetics, analysis of safety 
3.7.1. 
Study of efficacy 
The following investigations will be conducted in order to study the efficacy of 
canakinumab: clinical and also serological tests will be conducted in order to assess joint 
involvement and the disease activity of AOSD. Efficacy with regard to joint involvement will 
be studied on the basis of the findings about the joints. The following are envisaged as valid 
methods for examining tolerance of the study drug: 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 30 of 52 
 
Joint status: 
Number of tender joints (68 joints) 
Number of swollen joints (66 joints) 
Global patient’s assessment regarding disease activity and pain (numerical rating scale 
(NRS) 0-10) 
Global physician’s assessment regarding disease activity (NRS 0-10) 
Illness activity with regard to joint involvement (DAS28 and ACR response criteria) 
Joint mobility based on the neutral zero method 
 
Assessment of functionality and life quality 
Health Assessment Questionnaire - Disability Index (HAQ-DI) 
SF-36 health survey 
 
Laboratory tests 
Serological markers for inflammatory reactions (ESR, CRP, ferritin) 
 
Further optional investigations 
The optional scientific accompanying project on biomarker analysis includes the following 
investigations: 
  
1)      Investigations into soluble serum proteins 
at baseline, day 7-10 and week 4 and during an episode of illness, macrophage 
activation syndrome (MAS), or suspected MAS: 
-          IL-6 (2 ml blood in the serum test tube for 600 µl serum) 
-          IL-18 (2 ml blood in the EDTA test tube for 600 µl plasma)  
-          IL-18, IL-18-BP and IL-18/IL18-BP complex (5 ml blood in the Heparin test 
tube for 2ml plasma and 5ml blood in the serum test tube for 2 ml serum) 
at baseline, day 7-10 and week 4 and during an episode of illness 
-          S100 protein (4 ml blood in the serum test tube for 2 ml serum) 
2)      Investigations into the mRNA-expression 
at baseline, day 7-10 and week 4 and during an episode of illness, macrophage 
activation syndrome (MAS), or suspected MAS: 
-          PAXgene (2.5 ml blood in the PAXgene test tube) 
-          Mononuclear cells of the peripheral blood [PBMC] (8 ml blood in the 
Vacutainer®CPT™ cell preparation test tube with sodium citrate) 
3)      Pharmacogenetic investigations (10 ml whole blood) 
at baseline: 
-          Identification of genome sequencing and Single Nucleotide Polymorphisms 
[SNP]. 
 
3.7.2. 
Pharmacodynamics and pharmacokinetics 
The serum-canakinumab concentration will be established at all visits and during episodes of 
illness (2 ml serum test tubes). In the event of an anaphylactic reaction, samples will be 
investigated following the injection and at intervals of 8 weeks. 
 
Overall, IL-1ß (circulating IL-1ß as well as attached to canakinumab) will be investigated at all 
visits (3 ml serum small tubes).  


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 31 of 52 
 
3.7.3. 
Safety investigations 
The following investigations will be carried out in order to ensure the safety of the 
application of canakinumab: 
 
a. Blood count, electrolyte levels, (Na, K), blood chemistry (ALT, AST, GGT, AP, 
ferritin, LDH, creatinine and urine test sticks at each visit) 
b. Recording of adverse events over the entire period 
c. Recording of vital signs and physical examination at each visit 
d. Immunogenity (anti-canakinumab antibodies and ANA) (1 ml serum test tubes) 
 
Clinically significant outcomes of examinations of the laboratory diagnostic investigations will 
be evaluated as an adverse event and recorded in the case report form (CRF). Clinically not 
significant examination results from laboratory diagnostic investigations will be recorded in 
the source documents (patient records). 
 
Treatment with canakinumab will be discontinued in the event of: the occurrence of a 
pronounced renal function disorder (increase exceeding 5-fold of the norm), increase in 
creatinine by > 30%, leukocyptopenia of < 2.0 x 109/l, neutropenia of < 1.0 x 109/l and 
thrombocytopenia < 50.0 x 109/l, occurrence of an allergic reaction, occurrence of 
macrophage activation syndrome, occurrence of pregnancy. 
Therapy with canakinumab will be suspended in the event of liver counts increasing between 
3- and 5-fold of the norm. 
 
3.8. Remission criteria and down titration 
There will be the possibility of a down-titration from 4mg/kg/BW (max. 300mg)/month to 
2mg/kg/BW (max 150mg)/month after week 28 (visit 9) if the patient fulfils remission 
criteria. 
 
Remission criteria are defined as:  
DAS28 < 2.6 
AND 
no signs of systemic activity defined as any of Yamaguchi´s primary classification criteria for 
AOSD for two consecutive visits. 
 
3.9. Definition of flare or increasing disease activity 
 An increasing disease activity or flare is defined as the onset of signs of systemic activity 
defined as any of Yamaguchi´s primary classification criteria for AOSD and the elevation of 
the CRP-value and/or ferritin-value ≥ 3x upper normal range. 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 32 of 52 
 
4. Adverse events 
 
4.1.   Definition 
 
4.1.1     Definition of adverse events 
An adverse event (AE) is every adverse medical event which occurs in a patient or a 
participant in a clinical study following the administration of a drug and which is not 
necessarily in a causal relationship with this treatment. 
An adverse event can therefore mean every unfavourable and unintended reaction 
(including an abnormal laboratory test finding), every symptom or every illness temporarily 
accompanying the administration of a drug (of a study drug in this case), whether this is 
connected to the study drug or not. 
 
4.1.2.    Definition of serious adverse events 
A serious adverse event (SAE) is every adverse medical event which:  
 
- 
Leads to death 
- 
Is life-threatening 
- 
Requires inpatient treatment of the study participant or which 
- 
Makes an extension of the in-patient stay necessary 
- 
Leads to permanent or significant damage/disabilities, or which  
- 
Represents an innate malformation or a congenital abnormality 
 
4.1.3.    Definition of an unexpected, adverse drug interaction (SUSAR) 
A SUSAR is a serious adverse event in which a causal connection exists between the 
administration of the study drug and the event and in which the type and severity of the 
event does not correspond with the information already known about the study drug. 
4.2.   Procedures for reporting adverse events and serious adverse events 
 
The investigating physician will regularly monitor all patients with respect to the occurrence 
of adverse events in clinical and laboratory chemical terms. 
 
If a serious adverse event occurs, then this is to be reported to the sponsor within 24 hours. 
The investigating physician will evaluate and record every adverse event in detail, with at 
least the patient number, (pseudo-) initials, causal connection with the study drug, degree 
of severity, start and end dates and medication, as well as other therapies for the 
treatment of the adverse event being recorded. In addition, the age, alternative aetiology, 
relevant previous and concomitant diseases, concomitant medication / treatments will be 
recorded, together with any laboratory results of relevance to this event. 
 
If adverse, serious and at the same time unexpected drug interactions (SUSAR) occur, the 
sponsor (simultaneously principal investigator) will inform all participating investigating 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 33 of 52 
physicians without delay. Furthermore, the responsible ethics committee, authority (PEI) 
and manufacturer of the study drug will be informed within the regular periods of time. 
 
 
5. Determining the statistical evaluation of the study 
 
Statistical evaluation will be conducted according to the intention-to-treat (ITT) principle. 
All patients who are included in the CONSIDER (CACZ885GDE01T) double blind, placebo-
controlled clinical study will have been allocated to one of the two study arms on a 
randomised basis, and have received at least one dose of the study drug (modified ITT 
population) will be included in the statistical evaluation of the study into the safety and 
efficacy analysis of canakinumab in patients with AOSD and active joint symptomatology. 
 
5.1. Testing of the efficacy of canakinumab 
 
The primary objective consists in comparing the proportion of DAS28 responders at week 
12 between the two treatment arms. A DAS28 responder is a patient whose DAS28 score 
has improved by more than 1.2 points between the commencement of the study and week 
12. Patients who have terminated participation in CONSIDER (CACZ885GDE01T) before 
week 12 will be counted as non-responders. As the starting value which forms the base for 
calculating the improvement, the mean value of the DAS28 scores from visits V1 (screening 
visit) and V2 (week 0) will be used. Comparison of the response rates will then be made by 
using R.A. Fisher’s exact test with a two-tailed level of significance of α = 0.05. 95% 
confidence intervals for the proportion of responders will be calculated using the Blyth-Still-
Casella method. 
 
Comparison of the secondary endpoints will be performed in a similar way: ACR 20, ACR 50, 
ACR 70 (EULAR good response) DAS28 remission (DAS28 < 2.6), low disease activity (DAS28 
< 3.2) at week 12. In this process, the ACR response criteria will be examined on the basis of 
the 68/66 joint scores, the HAQ-DI, the erythrocyte sedimentation rate, the patient’s 
assessment of pain and disease activity and the physician's assessment of disease activity. 
Mean values will be compared by means of a t-test or, if required due to the skewness of 
distribution (in part. laboratory data such as ESR, CRP, ferritin), the Mann-Whitney test. 
The outcomes of treatment at week 24 will be compared with the values achieved at week 
12 in the patients randomised into the verum group. The McNemar test for binary outcome 
parameters and the paired t-Test or Wilcoxon test will be used for this purpose. Evaluation 
will be performed in a similar way within the 2 sub-groups of the placebo group: of patients 
who have been switched due to insufficient responsiveness to canakinumab as well as of 
patients who have been treated for 24 weeks with the placebo. For the latter sub-group, 
the proportion of patients who were in DAS28 remission at week 24 as well as overall 
between week 12 and 24 will be of particular interest. This proportion will be given as a 
percentage of all placebo patients, with the associated 95% confidence intervals being 
calculated according to the Blyth-Still-Casella method. 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 34 of 52 
 
5.2 Calculation of the sample size 
 
The primary objective consists in proving - in comparison with patients treated with 
placebos - a significantly increased DAS28 response by patients with AOSD and joint 
involvement who have been treated for 12 weeks with canakinumab. 
The HO zero hypothesis assumes that treatment with canakinumab will not have any 
significant influence upon joint involvement in AOSD. The H1 alternative hypothesis 
assumes that treatment with canakinumab will lead to a clinically significant improvement 
in joint involvement in patients with AOSD. 
The studies and case reports of AOSD patients who have been treated with an IL-1 inhibitor 
(anakinra) which have been available to date lead to the expectation that a very high 
response rate will be produced in the verum group. Laskari et al. report that in 21/25 (84%) 
AOSD patients "the clinical activity resolved completely". We found a similar result in a 
study of our own on 8 AOSD patients treated with anakinra, who all achieved remission. 
There is, unfortunately, no valid data regarding the assessment of the DAS28 responses in 
response to placebos. Based on our experience in treating Still's Disease patients, a placebo 
response rate of a maximum of 25% can be assumed. With the cautious assumption of a 
verum response of at least 67%, 34 patients per group would accordingly be sufficient to 
achieve an at least 90% power of Fisher's exact test. This number of cases would also be 
sufficient if the placebo responses amount to 33% and we would assume a slightly 
increased verum response of at least 70% in this case. The total of 34 patients per group 
would then still correspond to an 80% power. i.e. lead to a significant result with at least 
80% probability, a two-tailed Fisher test with an alpha of 5%. As a result, the number of 
patients is set at 34 per treatment arm. 
 
Participants from the randomized, placebo-controlled trial can continue treatment with 
canakinumab in the LTE study. Taking into account an estimated drop-out rate of about 
30% of the remaining 43 patients to be enrolled, approx. n=30 - 35 patients from the RCT 
will continue treatment in the LTE. 
 
5.3. Randomisation and stratification 
 
Randomisation will take place centrally at the 
 
(
), Berlin following previous treatment with 
biologicals (yes/no) by means of permuted block randomisation. After week 12, a re-
allocation of the treatment arm will be required for a portion of the patients. This is 
described in more detail in "early escape". 
 
5.4. "Early escape" 
 
Patients who have been randomised into the placebo group and have improved in week 12 
by less than 1.2 points based on DAS28 compared with the start of the study (DAS28 non-
responders) will be treated with canakinumab after week 12. This requires that for every 
patient who has completed visit 5 (week 12), the corresponding CRF pages of visits V1, V2, 
V5 on which the details are stated which are required to calculate the DAS28 be sent to the 
randomisation office in the 
 A calculation of the DAS28 response for the patients will 
then be made there and the re-allocation of the medication will be derived from this. 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 35 of 52 
Patients in both the placebo and verum groups will remain in their respective treatment 
arms upon achieving a DAS28 response in week 12. 
DAS28 non-responders of the placebo group in week 12 will openly receive canakinumab at 
weeks 12, 16 and 20. 
DAS28 non-responders in the verum group in week 12 will not receive any further study 
medication and will be continued until the concluding visit in week 28. 
 
5.5. Dealing with missing or incomplete data 
 
Patients who have terminated the study prematurely will be regarded as non-responders 
with regard to all parameters of efficacy from the time they end the study (see above). 
Missing values for individual visits preceding a drop-out visit (if available) will be replaced 
by the SAS procedure, PROC MI by means of the Markov Chain Monte Carlo method and 
the criteria derived will then be re-calculated. Should the number of variables and group to 
be replaced in each case not exceed 15%, then repeated replacements will not be made. In 
order to then be able to make comparisons of mean values, the replacement of missing 
values from visits will be made according to drop-out. Replacement is likewise made by 
means of PROC MI with the use of regression techniques, with repeated substitution if 
necessary.  
 
5.6. Statistical methods 
5.6.1. 
Comparisons at baseline 
A comparative examination at baseline is required. 
5.6.2. 
Analysis of efficacy 
 
Primary endpoint 
- 
Fisher’s exact test will be applied to compare the number of patients with a 
clinical relevant reduction of the DAS28 (> 1.2 units, primary endpoint) within 
the mITT population between the treatment groups at week 12. (See 5.1) 
 
The secondary endpoints of the core study: 
- 
Evaluation of the safety of canakinumab in patients with AOSD 
- 
Evaluation of the efficacy of canakinumab in patients with AOSD and joint 
involvement according to the ACR response criteria at weeks 12 and 24 
- 
Proportion of the patients achieving low disease activity (DAS28 < 3.2) or 
remission (DAS28 < 2.6)  
- 
Examination of the changes in health status based on HAQ-DI and SF-36 
- 
Improvement in skin manifestation of AOSD  
- 
Reduction in inflammatory markers (CRP, ESR, ferritin), 
- 
Biomarker analysis (mRNA, proteins) with the aim of enabling a prognostic 
statement to be made regarding responsiveness to the treatment. 
- 
Regarding the statistical methods see 5.1. 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 36 of 52 
 
The primary objective parameter of the long term extension study is: 
- 
The evaluation of long-term safety of canakinumab in patients with AOSD and 
articular involvement. Safety analysis will consider the exposure time. Event 
rates per 100 patient years and their corresponding 95% confidence intervals 
will be calculated. 
 
The secondary objective parameters of the long term extension study are: 
- 
First results will be provided on the disease course of AOSD patients treated 
with canakinumab under a treatment strategy which allowed down-titration of 
the canakinumab dose as described above. 
- 
The long-term efficacy of canakinumab in patients with AOSD will be described 
according to EULAR response criteria (proportion of patients showing 
prolonged clinically improvement according to DAS28 low-disease activity        
[< 3.2] and remission [< 1.2], reduction of flares and glucocorticoid intake) 
- 
Assessment of health outcome measures (HAQ-DI), improvement in skin 
manifestation and reduction of inflammatory markers of disease under long-
term treatment 
- 
The impact of the change in the dosage of canakinumab on the disease course 
will be examined.. 
5.6.3. 
Evaluation of safety 
Data relating to safety will be evaluated after the incidence and type of adverse events 
occurring have been s 
ummarised. All patients will be included in the evaluation of the safety data. 
Evaluation of long-term safety of canakinumab in patients with AOSD and articular 
involvement is the primary objective of LTE study. 
5.7. Interim analysis 
A primary endpoint analysis is planned when all patients finish week 24 of the core study. 
 
A safety interim analysis is planned one year after LPFV in LTE. 
 
6. Administrative provisions 
 
6.1. 
Good Clinical Practice  
 
This study will be conducted in accordance with the guidelines of the International 
Conference for Harmonisation (ICH), "Good Clinical Practice" (GCP) as well the federal and 
regional laws of the authorities. The principal investigator will be entrusted with the 
appropriate use of the study drug in the ways described in the protocol or in the technical 
information. The consistent collection of essential clinical documents will ensure the integrity 
and validity of the entire data. A primary study file (referred to as the master file) will be 
opened when the study commences, be updated during the study and stored according to 
the guidelines following the study. 
 
6.2. 
Ethical provisions 
 
This study will be conducted in accordance with the basic ethical principles of the Helsinki 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 37 of 52 
Declaration (of 1996). An independent ethics committee will review the entire study 
documentation in order to ensure the protection of the patient, his rights and his well-
being. The study protocol, patient information, patients' informed consent forms and data 
collection questionnaire will be submitted to an independent ethics committee, together 
with updates of any information on safety, advertisements (if applicable), interim reports 
and revisions of these documents.  
 
6.3. 
Patient information and informed consent 
 
Following extensive discussion, informed consent will be collected in written form from 
each patient or their legal representative. The procedure for collecting the informed 
consent and its documentation and contents will correspond to the GCP / ICH Guidelines 
and federal or regional legal provisions. 
6.4. 
Patient confidentiality 
 
In order to uphold the patient's right to confidentiality, all data to be recorded, such as lists 
of medication, study reports and all forms of communication within the study, will be 
encoded using an allocated patient number as well as pseudo-initials (e.g. A-A, B-B, etc.). 
6.5. 
Compliance with the study protocol  
 
The principal investigator will carry out this study in adherence with the protocol for which 
he has approval/positive opinion from an independent ethics committee and the 
corresponding regional authorities (PEI). Any amendments to the protocol require the 
written approval of an independent ethics committee or of the corresponding regional 
authority (PEI). Exceptions are only permitted in order to avoid a directly hazardous 
situation to the patient occurring. The independent ethics committee can, if the applicable 
authorisations allow this, bring about an accelerated approval of/ positive opinion on small 
changes to protocols in on-going studies, if an accelerated approval/ positive opinion has 
already been made available on the part of an independent ethics committee. The principal 
investigator will present all amendments to the protocol to the corresponding regional 
authorities in accordance with legal regulations. Any deviation from the study protocol 
must be recorded in full in the source data. 
 
6.6. 
Audits and monitoring 
 
The responsible regional and federal authorities and the ethics committee can demand 
access to all source data, data media and other study documents within the framework of 
an audit or an inspection. Direct access to these documents must be guaranteed by the 
principal investigator at all times. 
 
In order to monitor this clinical study appropriately, an independent monitor will be 
commissioned to undertake a review of its due implementation and documentation. Six 
monitoring visits are scheduled to take place in the course of the core study. 
 
Six visits for each active centre are scheduled to take place in the course LTE, i. e. initiation 
visit, ongoing monitoring every 6 months during study course and close out visit. 
6.7. 
Accountability 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 38 of 52 
Liability for the study drug lies within the area of responsibility of the principal investigator. 
He will ensure that the study drug will only be used in accordance with the study protocol. 
The whereabouts of the study medication will be recorded at the test centre. Accordingly, 
the receipt, administration to patients and destruction of the drug will be recorded in lists. 
Notes will be made of the date, number, batch number, shelf life and patient number. All 
materials containing canakinumab will be despatched separately to the respective test 
centres via the central pharmacy.  


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 39 of 52 
 
6.8. 
Early termination of the study 
The study can be terminated early by the principal investigator for compelling reasons. 
However, the justification for this decision must be made in writing. Circumstances which 
can lead to premature discontinuation are, e.g. (not an exhaustive list): 
 
 Unexpected, significant, unreasonable risk for the health of the patients 
 Insufficient patients having been recruited 
 Grave violations of the study protocol 
 
6.9. 
Publication of the results of the study 
The data collected for this study are to be treated confidentially. The participating 
investigating physicians agree that all of the information solely serves the purpose of the 
study and is not allowed to be used in any other way without the consent of the sponsor. It is 
envisaged that the results of this study will be presented at scientific events and will be 
published in peer-reviewed scientific or medical journals. The list of authors has been agreed 
with the authors prior to publication and confirmed by the principal investigator. 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 40 of 52 
 
7. References 
 
1. Bagnari V et al (2010) Adult-onset Still´s disease. Rheumatol Int.; 30(7): 855-62 
 
2. Efthimiou P, Paik PK, Bielory L (2006) Diagnosis and management of adult-onset Still´s 
disease. Ann Rheum Dis 65: 564-572. 
 
3. Pouchot J, Vinceneux P (2004) Manifestations cliniques et biologiques de la maladie de Still 
de ládulte. Presse Med 33:1012-1018. 
 
4. Wouters JM, van de Putte LB (1986) Adult-onset Still´s disease; clinical end laboratory 
features, treatment and progress of 45 cases. Q J Med 61: 1055-1065 
 
5. Pouchot J, Sampalis JS, Beaudet F et al (1991) Adult Still´s disease: manifestations, disease, 
course, and outcome in 62 patients. Medicine 70: 118-136. 
 
6. Ohta A, Yamaguchi M, Tsunematsu T et al (1990) Adult Still´s disease: a multicenter survey 
of Japanese patients. J Rheumatol 17: 1058-1063. 
 
7. Owlia MB, Mehrpoor G (2009). Adult-onset Still´s disease: a review. Indian J Med Sci. 2009 
May;63(5):207-21. 
 
8. Fautrel B (2008). Adult-onset Still disease. Best Pract Res Clin Rheumatol. 2008 
Oct;22(5):773-92. Review. 
 
9. Kontzias A, Efthimiou P (2008). Adult-Onset Still´s Disease-Pathogenesis, Clinical 
Manifestations and Therapeutic Advances. Drugs. 2008;68(3):319-37. Review. 
 
10. Ohta A, Yamaguchi M, Kaneoka H, Nagayoshi T, Hilda M (1987) Adult Still´s disease: review 
of 228 cases from the literature. J Rheumatol 14: 1139-1146. 
 
11. Kim HA, Sung JM, Suh CH (2011). Therapeutic responses and prognosis in adult-onset Still´s 
disease. Rheumatol Int 2011 Jan 29. [Epub ahead of print] 
 
12. Zeng T, Zou YQ, Wu MF, Yang CD (2009). Clinical features and prognosis of adult-onset Still's 
disease: 61 cases from China. J Rheumatol. 36(5):1026-31. 
 
13. Manger B. 2008. Der adulte Morbus Still. Zeitschrift für Rheumatologie 5.2008- S. 415-423. 
 
14. Efthimiou P, Georgy S (2006). Pathogenesis and Management of Adult-Onset Still´s Disease. 
2006 Dec; 36(3):144-52. Epub 2006 Sep 1.  
 
15. Wendling D, Humbert PG, Billerey C, Fest T, Dupond JL (1990) Adult onset Still´s disease  
and related renal amyloidosis. Ann Rheum Dis. 1991 Apr;50(4):257-9. 
 
16. Harrington TM, Moran JJ, Davis DE (1981) Amyloidosis in adult onset Still´s disease. J 
Rheumatol. 1981 Sep-Oct;8(5):833-6 
 
17. Oh YB, Bae SC, Jung JH, Kim TH, Jun JB, Jung SS, Lee IH, Yoo DH, Park MH, Kim SY (2000). 
Secondary renal amyloidosis in adult onset Still's disease: case report and review of the 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 41 of 52 
literature. Korean J Intern Med. 2000 Jul;15(2):131-4. Review. 
 
18. Efthimiou P, Kontzias A, Ward CM, Ogden NS (2007). Adult-onset Still’s disease: can recent 
advances in our understanding of its pathogenesis lead to targeted therapy? Nature Clinical 
Practice Rheumatology 2007 Jun; 3 (6): 328-335. 
 
19. Magadur-Joly G, Billaud E, Barrier JH, et al (1995). Epidemiology of Adult Still´s disease: 
estimate of the incidence by a retrospective study in west France. Ann Rheum Dis 1995; 
20:1608. 
 
20. Evensen KJ, Nossent HC (2006), Epidemiology and outcome of adult-onset Still´s disease in 
Northern Norway. Scand J Rheumatol. 2006 Jan-Feb; 35 (1): 48-51. 
 
21. Masson C, Le Loët X, Liote F et al (1995) Adult Still´s Disease: part I. Manifestations and 
complications in sixty-five cases in France. Rev Rheum Engl Ed 62: 748-757. 
 
22. Masson C, Le Loët X, Liote F et al (1995) Adult Still´s Disease: part II. Management, 
outcome, and prognostic factors. Rev Rheum Engl Ed 62: 758-65. 
 
23. Laskari K, Tzioufas AG, Moutsopoulos HM (2011) Efficacy and long-term follow-up of IL-1R 
inhibitor anakinra in adults with Still´s disease a case-series study Arthritis Research & 
Therapy 13:R91 
 
24. Kötter I, Wacker A, Koch S et al (2007) Anakinra in Patients with treatment-resistant adult-
onset Still´s disease: four case reports with serial cytokine measurements and a review of 
the literature. Semin Arthritis Rheum 37:189-197. 
 
25. Naumann L, Feist E, Burmester GR et al (2010) IL-1-receptor antagonist anakinra provides 
long-lasting efficacy in the treatment of refractory adult-onset Still´s disease. Ann Rheum 
Dis 69: 466-467. 
 
26. Vasques Godinho FM, Parreira Santos MJ, Canas da Silva J (2005) Refractory adult Still´s 
disease successfully treated with anakinra. Ann Rheum Dis 64: 647-648. 
 
27. Fitzgerald AA, LeClercq SA, Yan A et al (2005) Rapid responses to anakinra in patients with 
refractory adult onset Still´s disease. Arthr Rheum 52: 1794-1803. 
 
28. Nirmala N, Brachat A, Feist E, et al. Gene-expression analysis of adult-onset Still's disease 
and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease 
entity. Pediatr Rheumatol Online J 2015;13(1):50. 
 
29. Rachel L, Glaser MD, Goldbach-Mansky R (2008) The spectrum of monogenic 
Autoinflammatory syndromes: understanding disease mechanisms and use of targetes 
therapies Curr Allergy Asthma Rep 8: 288-298. 
 
30. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, Gitton 
X, Widmer A, Patel N, Hawkins PN (2009) Use of Canakinumab in the Cryopyrin-Associated 
Periodic Syndrome. N Engl J Med. 360(23):2416-25. 
 
31. Feist E, Burmester GR (2010) Canakinumab for treatment of cryopyrin-associated periodic 
syndrome Exp Opin Biol Ther 10: 1631-1636. 
 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 42 of 52 
32. Fachinformation Ilaris® Novartis Pharma (Mai 2010) 
 
33. Ruperto N, Quartier P, Wulffraat N, Woo P, Loy A, Mouy R, et al. A phase II trial with 
canakinumab, a new IL-1beta blocking monoclonal antibody (ACZ885), to evaluate 
preliminary dosing, safety and efficacy profile in children with systemic Juvenile Idiopathic 
arthritis (sJIA) 15thPaediatric Rheumatology European Society (PreS) Congress London UK. 
14–17 September 2008, Pediatric Rheumatology. 2008; 6:2. 
 
34. Ruperto N, Quartier P, Wulffraat N, Woo P, Ravelli A, Mouy R, Bader-Meunier B, Vastert SJ, 
Noseda E, D'Ambrosio D, Lecot J, Chakraborty A, Martini A, Chioato A; Paediatric 
Rheumatology International Clinical Trials Organisation. A phase II, multicenter, open-
label study evaluating dosing and preliminary safety and efficacy of canakinumab in 
systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum. 
2012;64(2):557-67. 
 
35. Yamaguchi, M., et al., Preliminary criteria for classification of adult Still’s disease.J 
Rheumatol, 1992. 19(3): p. 424-30. 
http://dgrh.de/fileadmin/media/PraxisKlinik/Kriterien/PDFs/Stillsyndrom/Still.pdf 
 
36. http://dgrh.de/fileadmin/media/Praxis___Klinik/Kriterien/PDFs/01-ra-10.pdf 
 
37. Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, Viola S, Martini A. 
Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic 
juvenile idiopathic arthritis. J Pediatr. 2005 May; 146(5): 598-604. Review. PMID: 15870661 
[PubMed - indexed for MEDLINE]  
 
38. http://www.gesetze-im-internet.de/gcp-v/BJNR208100004.html 
 
39. http://www.aerzteblatt.de/v4/plus/down.asp?typ=PDF&id=5324 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 43 of 52 
 
8. Protocol signature 
 
I hereby confirm the correctness of this protocol, together with all attachments which are 
enclosed with it. I undertake to conduct this study in adherence with the protocol, 
according to the currently valid guidelines and the statutory provisions currently in force. 
 
 
 
Principal investigator  
____________ ______________ 
___ : ___ : __________ 
 
 
 
Name  
Signature 
 
Date 
 
9.  Appendices 
 
a. Index of abbreviations 
b. Classification criteria for adult-onset Still's disease 
c. DAS28 
d. ACR score 
e. Joint mobility neutral zero method 
f. Macrophage Activation Syndrome (MAS) and MAS adjudication committee 
g. GCP ordinance (version dated 9.8.2004) 
h. Helsinki declaration (English version , including latest revision of October 2008)  


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 44 of 52 
Index of abbreviations 
ACR 
American College of Rheumatology 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT (GPT) 
Alanine aminotransferase 
AMG 
German medicinal product act (Ger.: Arzneimittelgesetz) 
ANA 
Anti-nuclear antibodies 
AOSD 
Adult-onset Still´s disease 
AP 
Alkaline phosphatase 
AST (GOT) 
Aspartate aminotransferase 
BfArM 
Federal institute for drugs and medical devices (Ger.: Bundesinstitut für 
Arzneimittel und Medizinprodukte)  
BM 
Biomarker 
CAPS 
Cryopyrin-associated periodic syndromes 
CINCA 
Chronic infantile neurological, cutaneous, articular syndrome 
Crea 
Creatinine 
CRF 
Case report form 
CRP 
C-reactive protein 
DAS28 
Disease Activity Score 28 
DMARDs 
Disease modifying anti-rheumatic drugs 
ESR 
ESR - erythrocyte sedimentation rate [Ger.: Blutsenkungsgeschwindigkeit (BSG)] 
EOC 
End of core study 
EOS 
End of study 
FCAS 
Familial cold auto-inflammatory syndrome 
FCU 
Familial cold urticaria 
GCP 
Good Clinical Practice  
GGT 
Gamma-glutamyl transpeptidase 
HAQ-DI 
Health Assessment Questionnaire-Disability Index 
Hb 
Haemoglobin 
ICH 
International Conference on Harmonisation 
IgG 
Immunoglobulin G 
ITT 
Intention to treat 
K 
Potassium 
BW 
Body weight 
LTE 
Long-term extension 
LPLV 
Last patient last visit 
MAS 
Macrophage activation syndrome 
mg 
Milligram 
mmHg 
Millimetre of mercury 
MWS 
Muckle Wells syndrome 
Na 
Sodium 
NOMID 
Neonatal onset multisystem inflammatory disease 
NRS 
Numerical rate scale 
NSAR 
Non-steroid anti-inflammatory drugs (NSAIDs) 
PD 
Pharmacodynamics 
PGA 
Patient global assessment 
PhGA 
Physician global assessment 
PK 
Pharmacokinetic properties 
s.g. 
salutis gratia   
r 
I 
L__ f---
-
I 
-
-
---+----======== 
:: 
========--_ 
'-
-
L__ 
-
I 
-
'-
-
I 
-
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f------- >-
======== 
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-
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--~ 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 45 of 52 
SAE 
Serious adverse event 
SF36 
Short Form 36 - Questionnaire on state of health 
SNP 
Single nucleotide polymorphism 
SUSAR 
Suspected unexpected serious adverse reaction 
VAS 
Visual analogue scale 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 46 of 52 
Classification criteria for Adult-onset Still's Disease (AOSD) according to Yamaguchi (1992) 
 
Primary criteria 
Fever attacks 39 °C, duration >1 week 
Arthralgia 
Salmon red, maculate, urticarial or maculo-papular rash 
Leukocytosis of > 10 000/mm3 with > 80% neutrophils 
 
Secondary criteria 
Sterile pharyngitis 
Lymphadenopathy and/or splenomegaly 
Hepatic enzymes increased 
Negative rheumatoid factors and negative ANA 
 
Exclusion criteria 
I. Infection (esp. sepsis or mononucleosis syndrome) 
II. Neoplasia (esp. lymphoma) 
III. Rheumatic diseases or collagen disorders 
 
According to the criteria published by Yamaguchi in 1992, 5 or more criteria must be met for 
classification, with at least 2 primary criteria needing to be fulfilled (sensitivity 96.2%, specificity 
92.1%). Diagnoses I-III must be excluded. The criteria encompass clinical and laboratory chemical 
special features (17, 18, 34). 
 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 47 of 52 
DAS28 
The following parameters are included in DAS28: 
 
Number of joints tender to pressure (0-28; measurement of 28 in each case from the EULAR 
defined joints)  
 
Number of swollen joints (0-28)  
 
Erythrocyte sedimentation rate (mm/h)  
 
Assessments of disease activity by the patient (0-10 mm NRS)  
DAS28 is calculated according to the following formula: 
 
 
A value between 0 and 2.6: disease remission 
 
A value between 2.6 and 3.2: low disease activity  
 
A value between 3.2 and 5.1: moderate disease activity  
 
Values > 5.1: high disease activity  
Standardised data entry forms and calculation aids are available for DAS28. 
(http://www.das-score.nl/) 
tender to pressure joints+0.28 
swollen joints+0.70 in (ESR)+0.014 illness state 
DAS28 = 0.56-


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 48 of 52 
ACR 20 50 70 Efficacy parameters  
from http://dgrh.de/fileadmin/media/Praxis___Klinik/Kriterien/PDFs/01-ra-10.pdf (37) 
≥ 20 (50/70)% improvement in the number of joints tender to pressure (68 joints) 
and 
≥ 20 (50/70)% improvement in the number of swollen joints (66 joints) 
plus 
≥ 20 (50/70)% improvement in 3 of the 5 following criteria: 
 
Statement of pain by the patient (NRS 0- 10) 
 
Assessment of disease activity of the patient (NRS 0- 10) 
 
Assessment of disease activity by the physician (NRS 0- 10) 
 
Patient questionnaire HAQ 
 
Acute phase reaction (ESR) 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 49 of 52 
Joint mobility according to the neutral zero method 
 
 
Right 
Left 
Reference range 
(degree) 
Shoulder joints 
External / internal rotation 
(upper arm contiguous) 
/           / 
/           / 
40-60 / 0 / 40-60 
Ante- / retroversion 
/           / 
/           / 
150-170 / 0 / 40 
Abduction / adduction 
/           / 
/           / 
160-180 / 0 / 20-40 
Elbows 
Extension / flexion 
/           / 
/           / 
10 / 0 / 150 
Pronation / supination 
/           / 
/           / 
60-90 / 0 / 80-90 
Wrists 
Extension / flexion 
/           / 
/           / 
35-60 / 0 / 50-60 
Radial / ulnar abduction 
/           / 
/           / 
25-30 / 0 / 30-40 
Hip joints 
Extension / flexion 
/           / 
/           / 
0-10 / 0 / 120-140 
Abduction / adduction  
/           / 
/           / 
30-45 / 0 / 20-30 
External / internal rotation  
(90° bent hip) 
/           / 
/           / 
40-50 / 0 / 30-40 
Knee joints 
Extension / flexion 
/           / 
/           / 
5-10 / 0 / 120-150 
Upper ankle 
Dorsal extension / 
plantar flexion 
/           / 
/           / 
20-30 / 0 / 40-50 
Pronation / supination 
/           / 
/           / 
30-45 / 0 / 45-60 
 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 50 of 52 
 
Macrophage Activation Syndrome (MAS)  
Occurrence of biologic features of MAS such as haemorrhages, central nervous 
system dysfunction, hepatomegaly, serum fibrinogen level < 2.5 g/L, cytopenia, 
hypertriglyceridaemia, decreased platelet count, increased aspartate transaminase, 
hyperferritinaemia (Ravelli, Magni-Manzoni and Pistorio 2005) must be carefully 
monitored by the investigator. Significant findings which meet the definition must 
be recorded in the Adverse Event eCRF. See following section for the description of 
the MAS Adjudication Committee. 
 
MAS Adjudication Committee 
An independent Adjudication Committee will review and adjudicate information on 
all cases of MAS. Occurrence of MAS may be reported by investigators or through 
systematic database search of specified terms. The Committee will review cases as 
they are identified. The committee will be blinded to treatment if the patient has 
entered the blinded part of the study. A report of the adjudication outcome will be 
provided to the DMC and the Sponsor. As part of the adjudication process, a 
request for supplemental data collection will be sent to the investigator. The 
supplemental package will include standardized follow-up questions. If biological 
specimens (e.g. bone marrow aspirate, bronchoalveolar lavage, etc.) were collected 
as part of customary diagnostic work-up, samples, such as tissue slides, may be 
requested by the committee for their review and/or for specialized analysis such as 
immunohistochemical staining for biomarkers associated with MAS. As part of 
follow-up additional blood specimens for biomarker analyses may also be collected. 
Patients will provide written informed consent for providing additional specimens. 
The MAS Adjudication Committee Charter provides detail on the committee 
composition, adjudication process, database search terms and supplemental data 
package. The outcome of the adjudication will be reported on the MAS adjudication 
CRF (37). 


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 51 of 52 
GCP Version dated 12.08.2004  
 
from http://www.gesetze-im-internet.de/gcp-v/BJNR208100004.html(38) 
 
 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI  
 
from HYPERLINK "http://www.aerzteblatt.de/v4/plus/down.asp?typ=PDF&id=5324" 
http://www.aerzteblatt.de/v4/plus/down.asp?typ=PDF&id=5324


 
Protokoll_CACZ885GDE01T_Version 3.1_2017_10_20.docPage 52 of 52 
 

SAP_001.pdf: 
Multi-Centre, Placebo-Controlled Study of Canakinumab for the 
Treatment of Adult-onset Still's disease (AOSD) 
CONSIDER 
(Canakinumab for treatment of adult onset Still 's disease to achieve 
reduction of arthritic manifestation) 
Statistical analysis plan (SAP) 
Study drug: 
Comparator drug: 
Indication: 
Version 1: Date: 9. May 2018 
Canakinumab. 
Placebo 
Treatment of adult-onset Still's disease with active joint 
involvement 
Duration of the core study: 24 weeks 
Clinical phase: 
EudraCT No. 
Protocol No.: 
Duration of long-term 
extension study 
Approved by: 
Principal Investigator: 
 
SAP CONSIDER 
II 
2011-001027 -20 
CACZ885GDE01 T / NCT02204293
24 months 
Professor Dr. med. 
 
Dr. 
t.f
page 1 


1 
General remarks .............................................................................................................................. 4 
1.1 
General principles .................................................................................................................... 4 
1.2 
Clinical parameters .................................................................................................................. 4 
1.3 
Abbrevations ............................................................................................................................ 4 
2 
Rationale of the CONSIDER study .................................................................................................... 5 
3 
Objective of the trial ........................................................................................................................ 5 
4 
Design .............................................................................................................................................. 6 
4.1 
Core study ................................................................................................................................ 6 
4.2 
Treatment assignment ............................................................................................................. 6 
4.3 
Long-term extension ( L TE) study ............................................................................................. 6 
5 
Primary outcome (core study) ......................................................................................................... 6 
6 
Secondary outcomes (core study) ................................................................................................... 7 
6.1 
Efficacy ..................................................................................................................................... 7 
6.2 
Health related quality of life .................................................................................................... 9 
6.3 
Safety ....................................................................................................................................... 9 
6.4 
Biomarker analysis ................................................................................................................. 10 
7 
Handling of missing values ............................................................................................................ 10 
7.1 
7.1.1 
7.1.2 
7.2 
7.3 
Missing response criteria and missings in other binary outcomes ........................................ 10 
Primary outcome ........................................................................................................... 10 
Missing secondary endpoints core study ...................................................................... 10 
Missing items of the HAQ-DI or the SF36 .............................................................................. 11 
Missing continuous efficacy parameters ............................................................................... 11 
7.4 
Safety ..................................................................................................................................... 11 
8 
Power considerations in the case of a premature termination of the CONSIDER trial. ................ 11 
9 
Statistical efficacy analysis double blinded part of the core study (weeks (4,8) and 12) .............. 11 
9.1 
Analysissets ........................................................................................................................... 11 
9.2 
Analysis of the primary outcome ........................................................................................... 12 
9.2.1 
Null hypothesis .............................................................................................................. 12 
9.2.2 
9.3 
9.4 
9.5 
Statistica I analysis .......................................................................................................... 12 
Binary secondary endpoints .................................................................................................. 12 
Non-binary secondary endpoints .......................................................................................... 12 
Dropout analyses ................................................................................................................... 13 
9.6 
Subgroup analyses ................................................................................................................. 13 
9.7 
Sensitivity analyses ................................................................................................................ 14 
SAP CONSIDER 
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10 
Statistica I efficacy analysis of the second part of the core study (weeks 16, 20, 24) ............... 15 
10.1 
Description of patients included ............................................................................................ 15 
10.2 
Comparison of the outcome of patients randomized to ca nakinumab with patients who 
switched from placebo to canakinumab ........................................................................................... 15 
10.2.1 
Comparison of response rates and remission rates ...................................................... 15 
10.2.2 
Comparisons by means of disease activity parameters, HAQ-DI and SF-36 .................. 16 
10.3 
Duration of persistent response ............................................................................................ 16 
10.4 
Risk of deterioration in patients in remission ........................................................................ 16 
11 
Safety analysis of the core study ............................................................................................... 16 
12 
Objective of the long-term extension study .............................................................................. 17 
13 
Safety a na lys is L TE study ........................................................................................................... 17 
14 
Specifications with regard to unmasking ................................................................................... 17 
15 
Description of tables, flow charts, figures ................................................................................. 18 
15.1 
Flow chart of patients enrolled and analyzed ....................................................................... 18 
15.2 
Baseline characteristics ......................................................................................................... 18 
15.3 
Primary outcome ................................................................................................................... 18 
15.4 
Binary secondary outcomes at week 4, 81 and 12 ................................................................. 18 
15.5 
Non-binary secondary outcomes at week 4, 8, and 12 ......................................................... 19 
15.6 
Safety results core study ........................................................................................................ 19 
16 
References ................................................................................................................................. 20 
SAP CONSIDER 
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1 General remarks 
1.1 General principles 
The procedures of the statistical analysis plan follow accepted guidelines especially 
ICH E9: Note for Guidance on Statistical Principles in Clinical Trials. If a procedure 
does not describe a detail and causes an open problem in the analysis then ICH E9 
or other details sufficiently described here should be used to solve this problem. 
1.2 Clinical parameters 
The following SAP refers to names of parameters assessed in the CRF and to 
parameters calculated from the original CRF parameters. 
All of these parameters follow one general nomenclature: varname_t. "varname" is 
a string in italic letters which identifies the parameter and which is valid for all 
time points. The suffix "_t" indicates the point in time to which the parameter 
refers. E.g. the parameter name of patients assessment of disease activity 
reported at screening is "PATUR_01". The corresponding names at baseline, week 
4. week 8, week 12 are "PATUR_Ol", "PATUR_03", "PATUR_04", "PATUR_05" 
respectively. "varnames" idendifying parameters assessed in the CRF are explained 
in the annex. Names of calculated parameters are explained in the SAP. In the case 
that only "varname_" is given here in the SAP this text or this formula is then valid 
for all time points at which this parameter is valid. Only in cases in which the 
varname refers to a specific point in time the complete varname is given. 
Time point 
Suffix of the parameters 
Screening 
01 
Baseline 
02 
Week4 
_03 
Week 8 
04 
Week 12 
05 
-
Week 16 
06 
Week 20 
07 
Week 24 
08 
-
Table 1: Used suffixes of parameters (core study) 
For the visits of the LTE study, the suffixes of parameters are assigned similarly in 
ascending order. A list is not given, since no direct reference is created in this SAP. 
1.3 Abbrevations 
ACR 
ACR20 
AE 
AOSD 
American College of Rheumatology 
American College of Rheumatology response criterion (see p.4) 
adverse event 
adult onset Still's disease 
SAP CONSIDER 
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BW 
95% Cl 
CRP 
DAS28 
body weight 
95% confidence interval 
(-reactive protein 
disease activity score based on 28 joint counts and ESR 
DAS28(CRP) disease activity score based on 28 joint counts and CRP 
 
EULAR 
ESR 
HAQ-DI 
ICH 
 
 
European League Against Rheumatism 
erythrocyte sedimentation rate 
Health Assessment Questionnaire disabiity index 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
intention-to-treat 
Coordinating Center for Clinical Studies at the Charite Berlin 
last observation carried forward 
long-term extension 
modified ITT 
patient-years 
ITT 
KKS 
LOCF 
LTE 
mlTT 
PYRS 
SAE 
serious adverse event 
2 Rationale of the CONSIDER study 
lnterleukin-1 antagonists such as canakinumab have been used for the treatment of 
adult-onset Still's disease (AOSD) and have had a marked influence on the activity 
of the disease, including joint mobility. However, results from controlled clinical 
studies are currently not available. 
3 Objective of the trial 
Investigation of the efficacy of treatment with canakinumab in patients with AOSD 
and active joint involvement. 
SAP CONSIDER 
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4 
Design 
4.1 Core study 
The core study is performed as a multi-centre double-blinded randomized placebo 
controlled trial in patients with AOSD and active joint involvement. 
4.2 Treatment assignment 
Randomization stratified by pre-treatment status with biologic DMARDs and study 
centre is performed at the
in a ratio of 1 :1 to the canakinumab or the placebo 
arm according to Atkinsons's DA-optimal biased coin algorithm [1]. Responsible for 
the randomization is one statistician from the
who is not otherwise involved 
in the CONSIDER trial. 
4.3 Long-term extension (L TE) study 
Patients who participated in the core study, fulfilled the DAS28 response 
criterion(~ DAS28 [das28diff _08] > 1.2) at week 24 and had no systemic disease 
manifestations of AOSD at this point in time were eligible for participation in the 
L TE part of the trial. All patients receive canakinumab open-label during the LTE 
period. The duration of the LTE part is 24 months. During the LTE period a down-
titration of canakinumab from 4mg/kg BW to 2mg/kg BW is allowed in patients who 
fulfill DAS28 remission criteria (das28_ < 2.6) and have no signs of systemic activity 
according to Yamaguchi's primary classification criteria (see study protocol for 
further details). 
5 Primary outcome (core study) 
Primary outcome: Proportion of patients with a clinically-relevant reduction in 
disease activity at week 12. The reduction is measured by the change in the 
disease activity score (DAS28). The DAS28(ESR) hereinafter referred to as DAS28 
only is based on 28 joint counts, the erythrocyte sedimentation rate (mm/h) (ESR) 
and patient assessment of disease activity [2]. A change (11 DAS28) > 1.2 is 
considered to be clinically relevant. The calculation of 11 DAS28 is shown below: it 
is the difference between the mean of the DAS28 scores assessed at screening and 
baseline and the DAS28 score assessed at week 12. 
SAP CONSIDER 
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Calculation of the DA528 score: 
DAS28_ = 0.56* ,Jgs28sum _ +0.28* .Jgw28sum_ +0.7 * ln(lbbsg _) + 0.14* patur _ 
gs28sum _: 28 tender joint count, gw28sum _: 28 swollen joint count (see CRF e.g. p.6) 
lbbsg _: ESR rnm/h (see e.g. CRF p. 7), patur _: patient global of disease activity (e.g. CRF p.9) 
Mannequins which included more than 28 painful or swollen joints (e.g. p. 14) 
always include these 28 joints which were used for the calculation of the DAS28 
scores. Patient global of disease activity is measured on a O to 10 numerical rating 
scale. Of note, DAS28 scores based on ESR and DAS28 scores based on CRP are not 
exchangeable. In the case of a missing ESR value the missing DAS28(ESR) will not be 
replaced by a DAS28(CRP) .. 
Calculation of 11 DAS28 at week 12 
1'1D AS2 8: das 2 8diff _ 05 - das2& - O I ; das2S - 02 - da,,28 05 
Therefore: Primary outcome: Proportions of patients with das28diff_05 > 1.2. 
6 Secondary outcomes (core study) 
6. 1 Efficacy 
The following secondary outcomes will be investigated at weeks 4, 8, 12 and as 
appropriate at visits thereafter. (Varna mes which are needed for the calculation 
are given in parenthesis). 
disease activitv measured by 
DAS28 (DAS28_) 
68 tender joint count (GS68sum_: sum of GS6801_ to GS686B_, o if GS68_ = 2) 
66 swollen joint count (GW66surn_: sum of GW6801_ to GW6836_, GW6839_ to 
GW6868_, 0 if GW68_ = 2, see e.g. CRF p.14) 
28 tender joint count and 28 swollen joint count (see chapters.) 
acute phase parameters CRP and ESR (lbcrp_ tbbsg_) 
Ferri tin (lbfer _} 
fever episodes 
Physician assessment of disease activity (KRAKT_, see e.g. CRF p. 14) 
Patient's assessment of disease activity (PATUR_, see e.g. CRF p. 17) 
SAP CONSIDER 
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Patient's assessment of pain (SCHMRZ_, see e.g. CRF p. 17) 
DAS28(CRP) 
DAS28CRP _ = 0.56* Jgs28sum_ +0.28*,Jgw28sum_ +0.36*ln(lbcrpsi _ +l)+0.14* patur _ + 0.96 
with lbcrpsi_ C-reactive Protein in SI-units that is in mg/L (calculated 
from /bcrp_ which is assessed in mg/L or mg/dL) 
functional caoacity measured by 
the Health Asssessment Questionnaire disability index (HAQ-DI). [3] [4] [5] 
The HAQ -DI is a validated measure of physical disability and functional 
status. The disability dimension consists of 20 multiple choice items 
concerning difficulty in performing eight common activities of daily living; 
dressing and grooming, arising, eating, walking, reaching, personal hygiene, 
gripping and activities. Subjects choose from four response categories, 
ranging from 'without any difficulty' to 'unable to do'. (In CONSIDER the 
parameters HAQ11_ to HAQHM 14_ [e.g. p. 18, 19] will be used to calculate the haq_ scores 
as described in [3] [4]) Details of the calculating are given in the appendix. 
American College of Rheumatology (ACR) and European League Against Rheumatism 
(EULAR) response criteria developed for rheumatoid arthritis are applied.[6] 
ACR20, (ACR30, ACRS0, ACR70, ACR90, ACR100) response criteria are defined as 
follows: 
20% reduction (ACR 30: 30% reduction; ACR 50: 50% reduction ACR70 70% 
reduction; ACR90 90% reduction; ACR100 100% reduction) between baseline 
and follow-up in: 
68 tender joint count 
66 swollen joint count 
and in three of the following five parameters 
erythrocyte sedimentation rate (ESR) 
functional capacity (HAQ-DI) 
Physician assessment of disease activity 
Patient's assessment of disease activity 
Patient's assessment of pain 
(varnames of the criteria: ACR20_, ACR30_, ACR50_, ACR70_, ACR90_, ACR100_} 
Modified adapted ACR variable 
SAP CONSIDER 
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In addition to the above ACR variable, a modified adapted ACR 30 response 
will be calculated using the above definition (for ACR 30) and requiring 
additinally no intermittent fever (i.e. oral or rectal body temperature > 
38 "C) in the preceding week and no more than one variable 1-7 worsening by 
more than 30%. 
EULAR response based on~ DAS28[7]: 
Good response: das28diff _ > 1.2 and DAS28_ at follow-up$ 3.2 
Moderate response: das28diff _> 1.2 and DAS28_ at follow-up > 3.2 
or 0.6 < das28diff _ $ 1.2 and DAS28_ at follow-up$ 5.1 
No response: das28diff _ $ 0.6 or 
0.6 < das28diff_ 5 1.2 and DAS28_ at follow-up> 5.1 
Note: For week 4, 8, 16 etc. the das28diff _ parameters are calculated in 
the same way as described above (see 5.) for week 12. Reference is always 
the mean of the DAS28 parameters DAS28_01 and DAS28_02. 
low disease activitv: 
Criterion for low disease activity: DAS28_ < 3.2 
remission: 
Criterion for DAS28 remission: DAS28_ < 2.6 
Criterion for extended remission: DAS28_ < 2.6 AND no signs of systemic 
activity defined as any of Yamaguchi, s primary classification criteria [8] for 
AOSD for two consecutive visits 
Change in joint mobility using the neutral zero method and will also be explored. 
6.2 Health related quality of Ufe 
SF-36 sum scores for physical and mental health will be calculated as described by 
the developer of the SF-36 health survey (Ware et al).[9]. The determinations and 
recommendations made there will followed (see annex for further details). 
6.3 Safety 
The occurrence of adverse events (AE) will be described in detail. An AE is an 
adverse medical event which occurs in a patient of the study and which is not 
necessarily in a causal relationship with the treatment the patient receives. AEs 
include symptoms of illnesses, as well as every unfavourable and unintended 
reaction. Clinical significant abnormal laboratory test finding are also included. 
SAP CONSIDER 
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Serious adverse events (SAEs) are AEs leading to death, are life-threatening, 
require hospitalizations or prolongation of hospitalizations, represent an innate 
malformation or a congenital abnormality. (See study protocol for further details.) 
Adverse events will be coded using the MedDRA dictionary (version 21.0) that 
provides the primary system organ class and preferred term information. 
6.4 Biomarker analysis 
An accompanying project aimed at identifying predictive biomarkers (mRNA, 
protein). False positive discovery rates will be considered. Details are not laid 
down in this SAP. 
7 Handling of missing values 
The best method for handling of missing data is to prevent it. Since this is usually 
not achievable, methods for handling of missing data needs to be pre-specified. To 
minimize the possible bias and to allow an understandable interpretation of the 
main findings dropouts were deemed to be non-responders in the case of the 
primary endpoint and binary secondary endpoints. In the case of continues outcome 
parameters mixed linear models are the preferred method. 
7.1 Missing response criteria and missings in other binary outcomes 
Two cases were considered: 
A) Patients who discontinued the study prior to the visit at which the 
response criterion is evaluated 
B) Patients with missing data of the response criterion for other reasons. 
7. 1. 1 Primary outcome 
Patients with missing DAS28 scores at week 12 were considered as non-responders. 
(We do not expect missing data according to case 8) described above for the 
primary outcome at week 12. However, even if this happens we cannot exclude an 
information bias by the treating physician. We do not differentiate case B) from 
case A) for that reason.) 
7.1.2 Missing secondary endpoints core study 
The following is defined for all secondary endpoints (assessed at week 4 to 24) 
Case A (see above): Non-response or non•fulfillment of the criterion will be 
imputed for the secondary endpoint. 
Case 8 (see above): Provided at least two of the parameters which are needed to 
calculate the response criterion or binary outcome measure are available: 
SAP CONSIDER 
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the last observation carried forward method (LOCF) will be used to impute 
the remaining missing components. Based on these imputed data the 
secondary endpoint will be calculated. 
If none or only one parameter is available non-fulfillment or non-response will be 
imputed for the secondary endpoint. 
7.2 Missing items of the HAQ-DI or the SF36 
Specific rules apply for dealing with missing items in both questionnaires. These 
rules follow suggestions of the rheumatology and immunology department of 
Stanford university for the HAQ-D 1[5] (and personal communication) as well as the 
SF36 manual. Both rules are described in detail in the annex. 
7.3 Missing continuous efficacy parameters 
Mixed linear models will be applied to deal with missing continuous parameters. In 
the case of the following heavily skewed outcome parameters CRP, ESR, Ferritin, 
joint counts the analysis will be based on non-parametric tests. The LOCF method 
will be used for that reason to replace missing data. 
7.4 Safety 
Event rates will be calculated as rates per 100 observed patient-years. Missing data 
will not be considered in this analysis. 
8 Power considerations in the case of a premature termination of 
the CONSIDER trial 
The recruitment of the patients was slower than expected. Therefore, the 
following power considerations were made for the case that the CONSIDER trial has 
to be terminated and the analysis has to be based on 36 patients randomized prior 
to April 1st. 2018. Under the assumptions made in the study protocol (verum 
response: 67%, placebo response 25%) an analysis based on n=18 patients per 
treatment arm would have a power of 66% to detect a significant difference 
between the treatment arms. 
However, these assumptions were possibly too 
cautiously. A somehow higher difference {verum response: 70% vs. placebo 
response 20%) would already lead to a power of 83% of the Fisher test. 
9 Statistical efficacy analysis double blinded part of the core study 
(weeks (4,8) and 12) 
9. 1 Analysis sets 
The statistical evaluation of the safety and efficacy of canakinumab will be 
conducted according to the Intention-to-treat principle (ITT). The safety analyses 
will be based on all patients randomized who received at least one dose of the 
study drug. All of these patients who did not violate one of the following important 
inclusion criteria: 
SAP CONSIDER 
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diagnosis of adult onset Still's disease 
disease activity based on DAS28 of.::: 3.2 at screening 
will be included in the efficacy analysis (mlTT population). 
No per-protocol analysis set will be considered. 
9.2 Analysis of the primary outcome 
9.2.1 Null hypothesis 
Objective: To show superiority of treatment with canakinumab compared to 
placebo at week 12. 
Null hypothesis: Presponse placetlo = Presponse canakinurnab 
HA: Presponse placebo 
Presponse canakinumab 
Two-sided type I error rate a= 0.05. 
9.2.2 Statistical analysis 
The two-sided Fisher's exact test will be applied to compare the response rates 
observed in both treatment groups at week 12. 
Mid -P 95% confidence intervals of the response rates will be calculated to describe 
the uncertainty in the estimates. Of note, the decision on the null hypothesis will 
be based only on the Fisher test but not on the confidence intervals. 
The analysis will be based on a SAS macro. The resulting table is described in 15. 3 
below. 
9.3 Binary secondary endpoints 
Fisher's exact test will be applied to compare binary secondary outcome measures 
at weeks 4, 8, and 12 between the treatment groups (see 6.1 above for the 
corresponding list). Improvement according to the criterion t.. DAS28 > 1.2 will 
additionally be explored at week 4 and 8. Tables with frequencies and percentages 
of response rates, results of the Fisher test and mid-P 95% confidence intervals 
(95%CI) of the response rates within both groups will be provided. Week 12 results 
are presented in the form shown in Table 3. See also the description of Table 4 
(par. 15.4) below. Graphical presentations of the final results for lectures and 
publications will also be available in consultation with the Pl. 
9.4 Non-binary secondary endpoints 
Mixed linear models (in some applications also called mixed models for repeated 
measures) will be used to compare treatment effects between the verum and the 
SAP CONSIDER 
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placebo group by taking repeated measures of the outcome parameter into 
account. 
These models include the following fixed and random effects: 
Fixed effects: treatment group, time, treatment by time interaction 
Random effects: patient. 
Taking the rather limited number of available patients into account a 
restriction regarding the covariance structure will be made. 
The analysis is performed using the SAS procedure PROC MIXED. The repeated 
statement will be used to account for the repeated measurement design and the 
type = TOEP to specify a Toeplitz structure of the R-side covariance matrix. The 
lsmeans statement of the SAS procedure PROC MIXED will be applied to calculate 
least square means of the outcome parameter per treatment group and time point. 
95% Cl of these least square means will also be calculated. Simple means and SDs of 
the outcome parameter (as observed) will also be provided. 
In the case of heavily skewed outcome parameters (CRP, ESR, Ferritin, joint 
counts) Brunner's non-parametric test for repeated measures will be used. The SAS 
macro provided and validated by the authors will be applied. The resulting p-values 
of these non-parametric analyses will be used for interpretation. For description 
purposes the LSmeans values (and their SEMs) based on the original parameters will 
be provided additionally. Of note, the ranks have to be calculated based on mid· 
ranks of a vector which contains all observed parameter values which should be 
included in the analysis [10]. 
9.5 Dropout analyses 
Usually dropouts do not differ from completers in their baseline characteristics. 
They however frequently differ in their disease characteristics at follow-up and 
especially at their last visit. It is planned to examine this possible bias for two 
important outcomes. 
Patients of the mlTT population withdrawn or lost to follow-up between screening 
and week 12 will be compared with their last valid DAS28 and their last valid HAQ 
score with the DAS28 and HAQ scores respectively of the completers at the 
corresponding visit. This analysis will be done separately for each treatment group. 
A non-parametric dropout test with a sufficient power also in small samples will be 
applied. The parametric version of this test will be used to estimate the mean 
difference and to visualize the findings [11]. In case of low drop rate, the 
additional analysis will not be performed. 
9.6 Subgroup analyses 
Patients will be stratified according to their treatment history with biologicals at 
enrollment. Group A consists of patients who were previously treated with biologic 
SAP CONSIDER 
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DMARDs and group B consists of bio-nai·ve patients. Provided both subgroups 
consists of nsubgroup 
6 patients verum vs. placebo response rates will be compared 
within both subgroups. Strata-specific 95% Cl will be provided for primary and 
major secondary response criteria (ACR30, adapted modified ACR30, ACR50, EULAR 
response, DAS28 remission). Of note, CONSIDER is not powered to detect possible 
differences in the verum or placebo responses in bio-nai"ve vs. with bDMARDs 
previously treated patients. If the data suggest a different response to 
canakinumab in bionaive and non-naive patients, this must be verified by means of 
an interaction test (provided sufficient data per subgroup are available). PROC 
LOGISTIC will be used for that purpose in the case of binary outcomes, PROC MIXED 
in the case of continuous outcomes. The results of these interaction tests can then 
be evaluated with caution in the discussion. 
9. 7 Sensitivity analyses 
Patients will be stratified in patients with / without a previous treatment with 
biologic DMARDs and the Cochran-Mantel-Haenszel test will be applied to 
investigate the primary objective in a sensitivity analysis. In the case of a 
significant interaction according to 9.6 above the findings of this logistic regression 
analysis with no additional covariates will be used for interpretation rather than 
the findings of the Cochran-Mantel-Haenszel test which investigated general 
speaking whether the averaged odds ratio significantly differs from 1. 
In dependency on the number of patients lost to follow up further sensitivity 
analyses will be made. In these sensitivity analyses multiple imputation methods 
will be used to deal with missing data. The DAS28 responses, ACR responses and 
remission rates will be re-calculated if more than 20% of patients were lost to 
follow-up in one treatment arm during the first 12 weeks or if the dropout test 
(described above (see 9.5)) shows a significant result in at least one treatment 
arm. 
Missing data will be replaced 10 times. That is 10 values (10 imputations) will be 
calculated for each missing value. The SAS procedure PROC Ml will be used in two 
steps. In the first step the Markov Chain Monte Carlo (MCMC) method will be 
applied to generate a monotone missingness pattern. In the second step linear 
regression in the case of continuous variables and logistic regression in the case of 
binary variables will be specified as methods in the PROC Ml procedure to replace 
missing values of dropouts. All imputations will be done strata specific with strata 
defined by treatment group. To impute a parameter x at visit t parameter values of 
x preceeding t will be included as predictors of x at t (=co-variables). Pre-
treatment with bDMARDs prior to enrollment will be used as another co-variable. 
Depending on the findings of paragraph 9.5 DAS28 and/or HAQ scores of previous 
visits will also be included as co-variables. 
SAP CONSIDER 
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10 Statistical efficacy analysis of the second part of the core study 
(weeks 16, 20, 24) 
10.1 Description of patients included 
All patients who completed the visit at week 12 and who were not withdrawn at 
week 12 because of non-response to canakinumab were included in the efficacy 
analysis at weeks 16, 20, and 24. Three groups of patients were considered: 
Group I: canakinumab responders (patients randomized to canakinumab who 
were primary outcome responders at week 12) 
Group II: placebo responders (patients randomized to placebo who were 
primary outcome responders at week 12), 
Group Ill: placebo non-responders at week 12 who switched to canakinumab. 
Patients disposition from week 12 to week 24 will be shown by means of a flow 
chart. Number of dropouts and reasons for lost to follow-up will be given. Baseline 
and week 12 characteristics of the three groups described above as well as of the 
4th group of canakinumab non-responders will be provided. 
10.2 Comparison of the outcome of patients randomized to canakinumab with 
patients who switched from placebo to canakinumab 
The outcome assessed in mlTT patients randomized to canakinumab at week 4, 8, 
12 will be compared with the outcome at week 16, 20, 24 of placebo patients who 
switched to canakinumab at week 12. In a first step the proportion of patients 
treated with biologic DMARDs (prior to enrollment) will be compared between both 
groups. Two cases are considered: 
Case A: 
Case B: 
the portions differ by more than 20% or even significantly (Fisher test) 
otherwise. 
10.2. 1 
Comparison of response rates and remission rates 
Taking determinations above (non-responder imputations see 7.1.2) into account 
number of responders and percentage of responders will be calculated for all 
secondary endpoints of interest (change in DAS28 > 1.2, ACR response rates, EULAR 
response, DAS28 remission). Case B: Mid-P 95% confidence intervals will also be 
calculated to allow an interpretation on the precision of the estimated rate. Case 
A: Logistic regression will be used to calculate adjusted rates and their 
corresponding 95% Cl for the response rates in both groups. Adjustment will be 
made by the pre-treatment status with bDMARDs. 
Response rates and 95% Cl of group I described above (10.1) will additionally be 
provided. 
SAP CONSIDER 
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10. 2. 2 
Comparisons by means of disease activity parameters, HAQ-DI and 
SF-36 
Analysis will be based on mixed linear models. Specifications made above for the 
double blinded period (up to week 12) are also applicable here with two 
exceptions: 1. In the case of the verum group, the time variable is set for baseline, 
week 4, 8, 12 equals 0, 4, 8, 12 as before. In the case of the placebo group, week 
12 equals time=O, week 16 equals time=4 ... weeks 24 equals time=12. Secondly: 
the pre-treatment status with bDMARDs needs to be included as an additional co-
variable in case A above. 
10.3 Duration of persistent response 
Kaplan-Meier method will be used to estimate the duration of DAS28 response 
("non-response free survival" with das28diff _ > 1.2) in DAS28 placebo and DAS28 
canakinumab responders. 
10.4 Risk of deterioration in patients in remission 
A simple definition of deterioration will be considered here: worsening in DAS28 > 
1.2. Kaplan-Meier method will be applied to calculate the likelihood of 
deterioration in patients of group I and group II. No adjustment for a possible 
selection bias will be made. 
11 Safety analysis of the core study 
MedDRA will be used to code adverse events. The pt-level is used for coding and 
presentation of uncompiled results. The primary path is used to summarize pt 
terms to system organ classes. Adverse events will be summarized by presenting, 
for each treatment group in part I and II of the core study, the number and 
percentage of patients having any adverse event, having any adverse event in each 
primary system organ class and having each individual adverse event based on the 
preferred term. Since the exposure time to the randomized treatment differed 
between both treatment arms AE and SAE event rates per treatment exposure time 
will be calculated as rates per 100 patient-years (PYRS) of treatment exposure. 95% 
Poisson confidence intervals of these rates /100 PYRS will be calculated for events 
of interest and the total number of AEs, SAEs per treatment group. Events of 
interest are: infections, macrophage activation syndrome, anaphylactic reaction, 
fever episodes, AOSD typical rash (Salmon red, maculate, urticarial or maculo-
papular rash), Leukocytosis of> 10 000/mm3 with> 80% neutrophils. 
SAP CONSIDER 
page 16 


12 Objective of the long-term extension study 
The primary objective of the LTE study is to investigate the long•term safety of 
canakinumab for the treatment of AOSD patients with joint pain over a period of 
two years. 
13 Safety analysis LTE study 
MedDRA (version 21.0) will be used to code adverse events. The SOC and pt·level 
are used for coding and presentation of uncompiled results. For each treatment 
group the number and percentage of patients having any adverse event, having any 
adverse event in each primary system organ class and having each individual 
adverse event based on the preferred term. Similarly as described above (chapter 
11) AE and SAE event rates will be calculated as rates per 100 patient-years (PYRS) 
of treatment exposure from first dose to end of follow-up. 95% Exact Poisson 
confidence intervals of these rates / 100 PYRS will be calculated for events of 
interest and the total number of AEs, SAEs per treatment group. Events of interest 
are: infections, macrophage activation syndrome, anaphylactic reaction, fever 
episodes, AOSD typical rash (Salmon red, maculate, urticaria[ or maculo-papular 
rash), Leukocytosis of > 10 000/ mm3 with > 80% neutrophils. 
14 Specifications with regard to unmasking 
Rules for unmasking during the course of the study are laid down in the study 
protocol and are not repeated here. To perform the statistical analysis the 
following additional regulations are defined. 
The study physicians, the Pl, the KKS staff remain blind until the core study is 
completed. To calculate the primary outcome and important secondary outcomes 
at week 12 (DAS28, ACR-responses, HAQ-DI) SAS syntax and SAS macros will be 
developed and checked by a second SAS programmer under blind conditions. 
An unmasking of the statisticians (AW, JL) will be performed after database lock 
and completion of validation measures. After unmasking of the statisticians the 
Novartis team will be unmasked on request. 
Scientists Novartis SGS Cephac Europe (www.sgs.com) who perform the pk/pD 
analysis of blood samples of the patients will be unmasked on request. 
SAP CONSIDER 
page 17 


15 Description of tables, flow charts, figures 
15.1 Flow chart of patients enrolled and analyzed 
According to the CONSORT statement a flow chart of patients screened, 
randomized, withdrawn or lost to follow-up and analyzed at week 12 and 24 will be 
provided. A similar flow chart including the visits 9 to 33 will be shown in the case 
of the LTE analysis. 
1 5. 2 Base Ii ne cha racte ri st ics 
Baseline characteristics of both treatment groups and the total group will be shown 
in the baseline table for the following parameters 
Number (percent) of female patients and mean (SD) values for: 
age, disease duration, 68 tender joint count, 66 swollen joint count, ESR, CRP, 
DAS28, physician global, patient global, pain, HAQ, SF36 physical health, SF36 
mental health. 
15.3 Primary outcome 
In the statistical analysis table 2 below will be calculated by means of a SAS macro. 
n 
n 
two-sided 
of 
of 
Response 
Response 
p-value 
Group 
patients responder! 
(%) 
95%CI 
Fisher test 
Placebo 
xx 
X> 
xx.x 
[xx.x; xx.x] 
Canakinumab 
xx 
xx 
xx.x 
[xx.x; xx.x] 
x.xxxxx 
Table 2: Statistical analysis of the primary outcome at week 12 
15.4 Binary secondary outcomes at week 4, 8, and 12 
Similar to table 2 above findings of binary secondary outcomes at week 12 will be 
summarized in table 3. Again number of responders or patients in remission, 
percentage of response/of remission its 95% Cl and the p·value of the Fisher test 
will be shown. This means table 3 summarizes the findings at week 12. 
SAP CONSIDER 
page 18 


two-sided 
Response 
p-value 
Outcome 
nof 
n of 
Response 
Fisher test 
parameter 
Group 
patients 
responders 
{%} 
95%CI{%) 
ACR 20 
Placebo 
ACR 20 
Canakinumab 
.... 
.... 
~· .. 
.... 
. ... 
.... 
. ... 
-
-
DAS28 
Placebo 
remission 
DAS28 
Canakinumab 
remission 
Table 3: Secondary outcomes at week 12. 
Table 4 is an extension of table 3 showing now outcomes at week 4, 8, 12. Table 4 
describes the course in response for the different criteria. 
15.5 Non-binary secondary outcomes at week 4, 8, and 12 
Similar to the binary outcomes two types of tables will be provided. Table 5 with 
week 12 results only and table 6 with findings at week 4, 8, 12. 
For each outcome and time point the following data are provided: n of patients 
with valid data, mean (SD} of the observed data, least square means (LSmeans) and 
their 95% Cl. For the calculation of the LSmeans see 9.4 above. 
15.6 Safety results core study 
A list of all MedDRA coded (SOC and pt-term level) SAEs with corresponding event 
rates (n, n/100 PYRS) will be provided for each exposure group. MedDRA terms of 
non-serious AEs will also be listed in a detailed (SOC and pt-term) level and a 
summarized level. 
SAP CONSIDER 
page 19 


16 References 
Bibliography 
1. 
Atkinson AC. Optimum biased coin designs for sequential clinical trials with prognostic 
factors. Biometrika. 1982; 69{1):61-67. 
2. 
Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified 
disease activity scores that include twenty-eight-joint counts. Development and validation in a 
prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995 1995; 
38:44-48. 
3. 
Lautenschlager J, Mau W, Kohlmann T, Raspe HH, Struve F, Bruckle W, et al. (Comparative 
evaluation of a German version of the Health Assessment Questionnaire and the Hannover 
Functional Capacity Questionnaire]. Z Rheumatol. 1997 May-Jun; 56(3):144-155. 
4. 
Fries JF. The Assessment of Disability - from lSt to Future Principles. Br J Rheumatol. 1983 
1983; 22(3 ):48-58. 
5. 
Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: dimensions and practical 
applications. Health Qual Life Outcomes. 2003 Jun 9; 1:20. 
6. 
Felson DT, Anderson J, Boers M, et al. American College of Rheumatology preliminary criteria 
for improvement in rheumatoid arthritis patients. Arthritis Rheum. 1995 1995; 38:727-735. 
7. 
van Gestel AM, Haagsma CJ, van Riel PL. Validation of rheumatoid arthritis improvement 
criteria that include simplified joint counts. Arthritis Rheum. 1998 Oct; 41(10):1845-1850. 
8. 
Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, et al. 
Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992 Mar; 19(3):424-430. 
9. 
Ware JE, New England Medical Center H, Health I. SF-36 physical and mental health summary 
scales: a user's manual. Boston: Health Institute, New England Medical Center, 1994. 
10. 
Brunner E, Domhof S, Langer F. Nonparametric analysis of longitudinal data in factorial 
experiments: J. Wiley, 2002. 
11. 
Listing J, Schlittgen R. A Nonparametric Test for Random Dropouts. Biom J. 2003 2003; 
45(1):113-127. 
SAP CONSIDER 
page 20 


Annex B: Calculation of the HAQ-DI 
Within each of the 8 categories only the item indicating the most severe 
impairment contributes to the category score. 
In the first step the HAQ-DI Items have to be recoded. 
• 
Without ANY Difficulty 
• 
With SOME Difficulty 
• 
With MUCH Difficulty 
• 
UNABLE to do 
will be recoded in 0 
will be recoded in 1 
will be recoded in 2 
will be recoded in 3 
In the second step the maximum of the items within each of the eight categories 
will be taken. SAS-code: 
haq1_=MAX(haq11_,haq12_); 
haq2_ = MAX(haq21_,haq22_) ; 
haq3_ = MAX(haq31_,haq32_, haq33_); 
haq4_ = MAX(haq41_,haq42_); 
haq5_ = MAX(haq51_,haq52_, haq53_); 
haq6_ = MAX(haq61_,haq62_); 
haq7 _ = MAX(haq71_,haq72_, haq73_); 
haq8_ = MAX(haq81_,haq82_, haq83_); 
There is no condition on the completeness of the items. The maximum of several 
variables will result in a non-missing value if at least one valid value is available. 
Missing scores and scores of O or 1 in a category are increased to 2 if the patient 
uses devices or help from another person to carry out the corresponding 
activities. 
If at least six out of the eight parameters are valid (not missing) the HAQ-DI 
parameter will be calculated 
SAS-code: haq_scor_ = Mean(haq1, haq2,haq3,haq4,haq5,haq6, haq7,haq8); 
SAP CONSIDER 
page 22 


Annex C: Calculation of the SF36 scales 
The scoring of the SF36 scales is dearly and unambiguously described in the manual 
of Ware JE (1994). In the following only some key issues are repeated. 
The following varnames of the items are used SF3601_ to SF3636_. In the first step 
the items 1 (SF3601_), 6 (SF3620_), 7 (SF3621_), 8 (SF3622_), 9a (SF3623_), 9d 
(Sf3626_), 9e (5FJ627_), 9h (SF3630_), 11 b (SF3634_), 11d (SF3636_) have to be 
recoded as described in the manual. 
SAP CONSIDER 
page 23 


Item 
Response 
Precoded Value 
Final value 
1 (SF3601_) 
Excellent 
1 
5 
Very good 
2 
4.4 
Good 
3 
3.4 
Fair 
4 
z 
Poor 
5 
1 
6 (SF3620_) 
Not at all 
1 
5 
Slightly 
z 
4 
Moderately 
3 
3 
Quite a bit 
4 
2 
Extremely 
5 
1 
7 (SF3621_) 
None 
1 
6 
Very mild 
2 
5.4 
Mild 
3 
4.2 
Moderate 
4 
3.1 
Severe 
5 
2.2 
Very severe 
6 
1 
8 (SF3622_)if item 7 
Not at all 
1 (7: 1 ) 
6 
(SF3621_) is answered 
Not at all 
1 (7: 2 - 6) 
5 
(response to item 7 is 
A little bit 
2 (7: 1 - 6) 
4 
given in parentheses) 
Moderately 
3 (7: 1 - 6) 
3 
Quite a bit 
4 (7: 1 - 6) 
2 
Extremely 
5 (7: 1 - 6) 
1 
8 (SF3622_) if item 7 
Not at all 
1 
6 
(SF3621_) is not 
A little bit 
2 
4.75 
answered 
Moderately 
3 
3.5 
Quite a bit 
4 
Z.25 
Extremely 
5 
1 
9a (SF3623_) & 9e 
Almost of the time 
1 
6 
(5F3627_) 
Most oft he time 
2 
5 
A good bit of the time 
3 
4 
Some oft he time 
4 
3 
A little bit of the time 
5 
2 
None of the time 
6 
1 
9d (5FJ626_)&. 9h 
All of the time 
1 
6 
(SF3630_) 
Most of the time 
2 
5 
A good bit of the time 
3 
4 
Some of the time 
4 
3 
A little of the time 
5 
2 
None of the time 
6 
1 
11b (SF3634_) £t 11d 
Definitely true 
1 
5 
(SF3636_) 
Mostly true 
2 
4 
Don't know 
3 
3 
Mostly false 
4 
2 
Definitely false 
5 
1 
Table: Recoding values of SF36 items 
SAP CONSIDER 
page 24 


In the second step the eight subscales physical functioning (SF36_PF_), role 
physical (SF36_RP_), bodily pain (SF36_8P_), general health (SFJ6_GH_), vitality 
(5f36_VT_), social functioning (SFJ6_SF_), role emotional (SF36_RE_), mental 
health (SF36_MH_) will be calculated as described in the manual. Of note, Ware JE 
(1994) recommended to calculate the score of the subscale if a "respondent 
answered at least half of the items ... or half plus one in the case of scales with an 
odd number of items". Ware JE (1994) further recommended imputing missing 
items by the average score of the remaining items of the subscale. These 
recommendations will be followed here. In the case of missing data the raw score 
of the corresponding subscale needs to be re-calculated after the handling of the 
missing items. 
In the next step the corresponding standardized subscales will be calculated. This 
standardization is done by using means and standard deviations observed in the US 
general population. 
SF36_PF_Z_ = (SF36_PF_ - 84.5240452)/22.8948992; 
SF36_RP _Z_ = (SF36_RP_ - 81.1990721 )/33.7972923; 
SF36_BP_Z_ = (SF36_BP_ - 75.4919631 )/23.5587879; 
SF36_GH_Z_ = (SF36_GH_ - 72.2131559)/20.1696447; 
SF36_VT _Z_ = (SF36_VT_ - 61.0545296)/20.8694255; 
SF36_SF_Z_ = (SF36_SF _ - 83.5975259)/22.3764186; 
SF36_RE_Z_ = (SF36_RE_ · 81.2946729)/33.0271727; 
SF36_MH_Z_ = (SF36_MH_ - 74.8421239)/18.0118961; 
ln the last step the Physical and Mental Component Summary Scores will be 
calculated as weighted and T-transformed sums of the eight subscales. 
agg__phys_ = (SF36_PF _Z_ * .42402)+( SF36_RP _Z_ * .35119)+( SFJ6_BP _Z_ * 
.31754)+( SF36_SF_Z_ * -.00753)+ (5F36_MH_Z_ * -.22069)+( SF36_RE_Z_ * -
.19206)+( SF36_ VT _Z_ * .02877)+( 5f36_GH_Z * .24954); 
agg_ment_ = (SFJ6_PF _Z_ • -.22999)+( 5F36_RP _Z_ * -.12329)+( 5F36_BP _Z_ * -
.09731 }+( SF36_SF _Z * .26876)+ (SFJ6_MH_Z_ * .48581 )+( 5FJ6_RE_Z_ * .43407)+( 
SF36_VT_Z_ * .23534)+( SF36_GH_Z_ * -.01571); 
SF36_PCS_ = 50 + (agg_phys_*10); 
SF36_MCS_ = 50 + (agg_ment_*1 O); 
SF36_PCS_ and SF36_MCS_ Scores are not necessarily missing if single items are 
missing (see above) but only if at least the score of one subscale is missing. 
SAP CONSIDER 
page 25 


A Multi-Centre, Placebo-Controlled Phase II Study of Canakinumab for the 
Treatment of Adult-Onset Still's Disease (AOSD)-core study, including an 
open-label long-term extension – LTE 
NCT02204293 
Official Title: 
NCT Number: 
Document Date: 
Amendment : 2 October 2018 


Amendment 
Statistical analysis plan (SAP) 
Multi-Centre, Placebo-Controlled Study of Canakinumab for the 
Treatment of Adult-onset Still's disease (AOSD) 
CONSIDER 
Rationale: Considering the limited sample size (n=35) and taking the 
low numbers of patients with missing week 12 data (n=4) into account 
the following changes will be made to improve the power of the 
analysis of continuous secondary endpoints. These changes are made 
prior to unblinding of the statistical analysis team
 
but after being aware of the findings of a recent RCT in 
adult-onset Still's disease (Kaneko Y, et al. Ann Rheum Dis 2018;0:1 -10. 
doi:10.1136). Taking advantage of the low number of dropouts the 
application of the last observation carried forward (LOCF) method can 
be regarded as justified. This allows the application of the analysis of 
covariance (ANCOVA), which increases the power not only compared to 
the t-test but in general also in comparison the time*group interaction 
test of a mixed linear model. For this reason the following changes are 
made: 
Paragraph 7.3 Missing continuous efficacy parameters (page 10) 
For CRP values where only <2mg/L or< 1 mg/Lis specified, the center 
of the range (for< 2mg/L i.e. 1 mg/L) is imputed. 
In applications described in paragraph 9.4 below the last observation 
carried forward method (LOCF) will be used to replace missing values 
of continuous efficacy parameter. In addition Mmixed linear models 
will be applied to deal with missing continuous parameters (see 9.4 
below). In the case of the follo1Ning heavily skewed outcome 
parameters CRP, ESR, Ferritin, joint counts the analysis will be based 
on non parametric tests. The LOCF method will be used for that reason 
to replace missing data. 


Paragraph 9.4 Non-binary secondary endpoints (page 12-13) 
Analysis of covariance (ANCOVA) will be applied to compare the 
outcome of continuous or non-binary parameters at week 12 between 
the verum and the placebo group after adjustment for the baseline 
status (covariable). For parameters assessed at screening and at the 
baseline visit the average of both values will be used as covariable. The 
last observation carried forward method (LOCF) will be used to impute 
missing values of the outcome at week 12. The statistical comparison 
of the groups is carried out using type 3 test of the ANCOVA model. In 
addition baseline (covariable) adjusted least square means (LSmeans) 
of the outcome parameter and their corresponding 95% Cl will be 
calculated. 
In order to be able to compare the course of the secondary efficacy 
parameter in both groups over the period of 12 weeks, a Mmixed linear 
models (in some applications also called mixed models for repeated 
measures) will be calculated. These models allow comparisons of ¼:lseG 
to compare treatment effects between the verum and the placebo 
group by taking repeated measures of the outcome parameter into 
account. 
These models include the following fixed and random effects: 
Fixed effects: treatment group, time, treatment by time 
interaction 
Random effects: patient. 
Taking the rather limited number of available 
patients into account a 
restriction regarding the covariance structure will be made. 
The analysis is performed using the SAS procedure PROC MIXED. The 
repeated statement will be used to account for the repeated 
measurement design and the type = TOEP to specify a Toeplitz 
structure of the R-side covariance matrix. The lsmeans statement of 
the SAS procedure PROC MIXED will be applied to calculate least square 
means of the outcome parameter per treatment group and time point. 
95% Cl of these least square means will also be calculated. The 
LSmeans and their 95% Cl calculated for baseline and for week 12 can 
then be compared with the LSmeans and their 95% Cl calculated by 


ANCOVA to discuss a possible impact of LOCF. To discuss this impact in 
the case of noticeable differences in the baseline status between the 
groups a further mixed linear model with the baseline status as 
covariable can be applied. In this case missing week 4 data of dropouts 
have to be replaced by LOCF to include those patients in the analysis 
and to calculate the corresponding LSmeans. Simple means and SDs of 
the outcome parameter (as observed) will also be provided. 
In the case of heavily skewed outcome parameters (CRP, ESR, Ferritin, 
joint counts) a non-parametric ANCOVA proposed by Brunner and 
colleagues will be used. Brunner's non parametric test for repeated 
measures will be used. The SAS macro npar provided and validated by 
the authors will be applied. The resulting p-values of these non-
parametric analyses will be used for interpretation. For description 
purposes the LSmeans values (and their ~95% Cl) based on -tAe 
original parametersparametric ANCOVA will be provided additionally. 
Of note, the ranks have to be calculated based on mid-ranks of a vector 
which contains all observed parameter values which should be included 
in the analysis. 
Berlin, October 2, 2018 
Approved by: 
Principal Investigator: 
: 
Prof. Dr. med. 
 
......
............ . 
Dr.