Conditions: Still's Disease, Adult-Onset Still's Disease, Juvenile-Onset
Keywords: Interleukin 1 receptor antagonist IL-1 receptor antagonist Kineret anakinra Adult-Onset Still's Disease Systemic Juvenile Idiopathic Arthritis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 13
Healthy volunteers: no

Brief summary:
The aim of this study is to demonstrate the efficacy and to evaluate the safety, pharmacokinetics (PK) and immunogenicity of anakinra in patients with newly diagnosed Still's disease, including SJIA (Systemic juvenile idiopathic arthritis) and AOSD (Adult-onset Still's disease).

Detailed description:
The study consists of a 12-week, randomized, double-blind, placebo controlled period with two dose levels of anakinra and a 4-week safety follow-up after last dose of investigational medicinal product (IMP). The primary endpoint will be evaluated at Week 2. Sustained efficacy and time to study drug discontinuation will be evaluated during the full study period.

A screening visit is optional and may be done to identify patients that could be suitable for the study. During the study 6 visits and 2 telephone contacts are scheduled i.e., Day 1 (baseline visit), Day 4Tel, Week 1, Week 2, Week 4, Week 8, Week 12 and Week 16Tel (End of Study).

Patients will be randomly assigned to study drug, after they meet all of the inclusion criteria and none of the exclusion criteria. Patients will receive treatment for 12 weeks, either anakinra or placebo. Patients will be randomized to anakinra in a dose of either 2 or 4 mg/kg/day, with a maximum dose of 100 or 200 mg once daily, respectively. Patients will be randomized to placebo with corresponding volumes for each of the two anakinra dose levels.

Arms:
arm 1: 2 mg/kg/day (max 100 mg/day) or 4 mg/kg/day (max 200 mg/day) arm 2: Corresponding volume to anakinra 2 mg/kg/day or 4 mg/kg/day

Interventions: intervention 1: anakinra intervention 2: Placebo
Intervention descriptions: intervention 1: sub cutaneous injection intervention 2: sub cutaneous injection

Protocol document:
Prot_001.pdf: 
Study Protocol 
 
 
Protocol number: 
Sobi.ANAKIN-301 
NCT number:  
03265132 
Study title: 
A randomized, double-blind, placebo-controlled, multicenter, phase 3 
efficacy and safety study of 2 dose levels of subcutaneous anakinra 
(Kineret®) in patients with Still’s disease (SJIA and AOSD) 
Version: 
Version 4.0, Amended protocol including amendment 3 
Date: 
03 July 2018 
 
 
 
 


 
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A randomized, double-blind, placebo-controlled, multicenter, phase 3 efficacy 
and safety study of 2 dose levels of subcutaneous anakinra (Kineret®) in 
patients with Still’s disease (SJIA and AOSD)  
The anaSTILLs study 
Version 4.0, Amended protocol including amendment 3 
Sobi.ANAKIN-301 
 
Type of Study: Therapeutic Confirmatory 
Canada: CTA Control no. 200300. USA: IND no. 003611. 
 
 
 
Confidential 
This protocol contains confidential information belonging to Swedish Orphan Biovitrum. Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such information in 
confidence and not to disclose it to others (except where required by applicable law) nor use it for unauthorized 
purposes. In the event of actual or suspected breach of this obligation, Swedish Orphan Biovitrum should be 
promptly notified. 
 
 


 
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Version 4.0, Amended protocol including amendment 3, Date 03 Jul 2018 
 
 
Investigator statement 
 
I have read the protocol entitled “A randomized, double-blind, placebo-controlled, 
multicenter, phase 3 efficacy and safety study of 2 dose levels of subcutaneous anakinra 
(Kineret) in patients with Still’s disease (SJIA and AOSD)” and the accompanying current 
investigator’s brochure. I agree to conduct the clinical investigation in compliance with the 
Version 4.0, Amended protocol including Amendment 3, Date: 3 July 2018, the 
International Council for Harmonisation (ICH) harmonised guideline E6 (R2): Guideline for 
Good Clinical Practice (1), applicable regulatory/government regulations, and in accordance 
with the Ethical Principles that have their origin in the Declaration of Helsinki (2). I will not 
implement any changes to study procedures or conduct without prior approval from the 
sponsor and, when applicable, the Independent Ethics Committee/Institutional Review Board 
and Regulatory Authority. I will supervise any individual or party to whom I delegate study-
related duties and functions conducted at the study site and ensure qualification of individuals 
or parties who perform delegated tasks. 
I agree to maintain the confidentiality of this study protocol, as described on the title page. 
Further, I will not publish results of the study without authorization from Swedish Orphan 
Biovitrum AB (publ). 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 


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Table of contents 
 
Table of contents ................................................................................................................... 3 
Protocol Amendment History and Reasons for Amendment ................................................... 6 
Synopsis .............................................................................................................................. 10 
1 
Abbreviations and definition of terms .................................................................... 21 
2 
Ethics..................................................................................................................... 24 
2.1 
Institutional review board and research ethics board .......................................... 24 
2.2 
Ethical conduct of the study .............................................................................. 24 
2.3 
Patient Information and consent ........................................................................ 24 
3 
Study administrative structure ................................................................................ 24 
3.1 
Sponsor ............................................................................................................. 24 
3.2 
Academic research organization ........................................................................ 24 
3.3 
Central laboratories ........................................................................................... 25 
3.4 
MAS adjudication committee ............................................................................ 25 
3.5 
Data safety monitoring board ............................................................................ 26 
4 
Introduction ........................................................................................................... 26 
4.1 
Background ....................................................................................................... 26 
4.2 
Study rationale .................................................................................................. 28 
4.3 
Potential benefits and risks ................................................................................ 28 
5 
Study objectives and endpoints .............................................................................. 30 
5.1 
Primary objective and endpoint ......................................................................... 30 
5.2 
Secondary endpoints supporting primary objective ............................................ 30 
5.3 
Key secondary objective and endpoints ............................................................. 31 
5.4 
Secondary objectives and endpoints .................................................................. 31 
 
Secondary efficacy objectives and endpoints ................................................ 31 
 
Safety objective and endpoint ....................................................................... 32 
 
Pharmacokinetic objective and endpoint ....................................................... 32 
 
Immunogenicity objectives and endpoints ..................................................... 32 
 
Productivity objective and endpoint .............................................................. 33 
5.5 
Exploratory objectives and endpoints ................................................................ 33 
6 
Investigational plan ................................................................................................ 34 
6.1 
Overall study design and plan ............................................................................ 34 
6.2 
Discussion of study design ................................................................................ 35 
 
Rationale for selection of doses ..................................................................... 36 
 
Rationale for primary endpoint ..................................................................... 37 
6.3 
Selection of study population ............................................................................ 37 
 
Inclusion criteria ........................................................................................... 38 
 
Exclusion criteria .......................................................................................... 38 


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Study drug discontinuation and withdrawal of patients from the study .......... 39 
 
Replacement of withdrawn patients .............................................................. 40 
 
Screening failures ......................................................................................... 40 
6.4 
Treatments ........................................................................................................ 40 
 
Treatments administered ............................................................................... 40 
 
Identity of investigational medicinal products ............................................... 41 
 
Storage, preparation and administration of IMP ............................................ 41 
 
Method of assigning patients to a treatment group ........................................ 42 
 
Blinding and unblinding ............................................................................... 43 
 
Prior and concomitant therapy ...................................................................... 43 
 
Treatment compliance ................................................................................... 44 
 
Overdose management .................................................................................. 44 
6.5 
Efficacy, safety, pharmacokinetic, and exploratory assessments ........................ 44 
 
Study schedule .............................................................................................. 44 
 
Medical history ............................................................................................. 48 
 
Demographics ............................................................................................... 48 
 
Efficacy assessments .................................................................................... 48 
 
Safety assessments ........................................................................................ 52 
 
Pharmacokinetic assessments ........................................................................ 61 
 
Exploratory laboratory assessments .............................................................. 63 
7 
Quality control and quality assurance ..................................................................... 64 
8 
Statistical plan ....................................................................................................... 64 
8.1 
Determination of sample size ............................................................................ 64 
8.2 
Definition of study populations ......................................................................... 65 
8.3 
Overall statistical and analytical plan ................................................................. 65 
 
General statistical issues ............................................................................... 65 
 
Demographics and baseline characteristics .................................................... 66 
 
Analysis related to primary objective ............................................................ 66 
 
Analysis related to secondary endpoints supporting the primary objective .... 67 
 
Analysis related to key secondary objective .................................................. 67 
 
Analysis related to secondary objectives ....................................................... 68 
 
Analysis of safety and tolerability data .......................................................... 69 
 
Analysis of pharmacokinetics ....................................................................... 70 
 
Analysis related to productivity objective ..................................................... 70 
 
Analysis related to exploratory objectives ..................................................... 70 
 
Interim analysis ............................................................................................ 71 
 
Multiple comparison/multiplicity .................................................................. 71 
 
Exploratory subgroup analyses ..................................................................... 71 
8.4 
Data standards ................................................................................................... 72 
 
Handling of missing data .............................................................................. 72 


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Sensitivity analyses ....................................................................................... 72 
9 
Data collection, handling and record keeping ......................................................... 73 
9.1 
Case report form ................................................................................................ 73 
9.2 
Patient diary ...................................................................................................... 73 
9.3 
Source data ........................................................................................................ 73 
9.4 
Protocol Deviations ........................................................................................... 74 
9.5 
Database closure ............................................................................................... 74 
9.6 
Record retention ................................................................................................ 74 
10 
End of study .......................................................................................................... 76 
11 
Sponsor’s discontinuation criteria .......................................................................... 76 
12 
Dissemination and publication of results ................................................................ 76 
13 
References ............................................................................................................. 77 
 
Diagnose criteria ........................................................................................... 82 
 
Guidance for MAS diagnosis ........................................................................ 84 
 
Dosing instructions ....................................................................................... 85 
 
Guidance for glucocorticoid tapering ............................................................ 86 
 
Schedule of assessments ............................................................................... 87 
 
Schedule of repeated PK assessments Week 12 ............................................. 89 
 
Physician global assessment of disease activity ............................................. 90 
 
Patient/parent global assessment of overall well-being .................................. 91 
 
Physical function (CHAQ/SHAQ) ................................................................ 92 
 
Global assessment of the patient disease related pain .............................. 100 
 
Joint count JADAS27 ............................................................................. 101 
 
Additional Protocol Signatures ............................................................... 102 
 
 
 


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Protocol Amendment History and Reasons for Amendment 
 
Version 
Date 
Reason for Amendment  
Version 1.0 
05 Sep 2016 
Original Protocol 
Version 2.0  
Non-substantial 
amendment 1 
08 Nov 2016 
All changes are administrative and updates are minor. The amendment is 
considered as non-substantial.  
 
Method of ICF collection updated.  
 
Highlighted that MAS adjudication committee is an independent blinded 
committee.  
 
Updated exclusion criterion #18 as part of the criterion already stated in 
exclusion criterion #6. 
 
Updated prior and concomitant therapy section in order to clarify that after 
the final IMP dose at Week12 the patient can be treated according to 
standard of care. 
 
Age cut-off updated for the CHAQ/SHAQ assessments including the overall 
well-being VAS scale.  
o 
Updated that CHAQ will be assessed for children <18 years 
of age.  
o 
Updated that SHAQ will be assessed for subject ≥18 years of 
age.  
 
Updated CHAQ assessment section and appendix to clarify that the 
interview or self-reporting assessment for children ≥8 years of age will not 
be used. Only the parent or guardian version of CHAQ will be used.  
 
Vital signs section updated as height will only be measured at the baseline 
visit.  
 
Physical examination section updated to clarify that presence or absence of 
signs of joint inflammation such as swelling or tenderness will be captured 
in joint assessments part of ACR and JADAS27. Other abnormal findings 
related to the musculoskeletal system should be recorded in the physical 
examination and reported as medical history or as AEs.  
 
Added section regarding local laboratory assessments in order to clarify 
which samples are required for assessing patient eligibility. 
 
Clarified for which data variables the CRF will be regarded as source.  
 
Added footnote in the schedule of assessment regarding how to proceed 
with PK blood draws if exceeding maximum blood volume.  
Version 3.0 
Amendment 2 
12 May 2017 
The amendment is considered as substantial. 
In addition to clarifications, changes to format and wording the following 
changes have been made to the study design:  
 
Open-label (OL) period removed due to preventing escape to investigational 
product (anakinra) – all sections related to OL period updated.   
 
Double-blind (DB) period extended to 12 weeks, but primary endpoint at 
Week 2 remains. 
 
Added Day 4Tel for additional follow-up and for retention reasons. 
 
Updated secondary endpoints supporting primary objective and key 
secondary endpoints  
o 
Added Patient/Parent global assessment of disease activity 
(key secondary endpoint) 
o 
Full ACR at Week 1 (supporting primary objective) 
o 
Moved time point from Day 4 to Week 1 
 
Clarification regarding primary endpoint to be evaluated at Week 2 and 
sustained efficacy to be evaluated in responders during the remaining study 
period. 

Added objective/endpoint to evaluate time to early termination of anakinra 


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Version 
Date 
Reason for Amendment  
versus placebo.  
 
Updated glucocorticoid tapering objective/endpoint.  
 
Escape criteria updated - removed persistent fever from list of criteria 
 
Clarification regarding if not fulfilling the escape criteria, i.e. worsening 
between Week 1 visit and Week 2 visit, the patient can withdraw. 
 
Highlighted that escape therapy is only standard of care, at the discretion of 
the investigator. 
 
Added a treatment arm of 4 mg/kg/day, max 200 mg/day.  
 
Applied a concept of “corresponding volume of placebo” in order to 
minimize number of injections/day.  
 
Removed possibility to dose escalate from 2 mg/kg/day to 4 mg/kg/day as 
OL period not present. 
 
Removed exclusion criteria #17 (alcohol or substance abuse) as covered in 
exclusion criteria #18 (inability to cooperate with given instructions or study 
procedures) and #19 (presence of any medical or psychological condition 
that can interfere with the patient’s ability to comply with the protocol 
requirements).  
 
Updated exclusion criteria with wash-out periods for prohibited concomitant 
therapies prior randomization.  
 
Optimized the background therapy with liberalization of background 
steroids - maximum allowed dose has been increased from 40 mg/day at  
60 mg/day. 
 
Clarification regarding the process and evaluation of the interferon- gamma 
release assay or PPD test results at the Baseline visit, Day 1.   
 
Clarification regarding how fever or rash attributable to the disease should 
be evaluated by investigator at site visits - patient diary will support the 
evaluation. 
 
Clarification regarding if patient is on glucocorticoid treatment tapering can 
start earliest at the week 2 visit 
 
Added rash assessment and description how to collect information regarding 
rash.  
 
Physical examination section updated to clarify how to handle signs and 
symptoms related to the disease under study. Also a clarification how to 
collect information regarding the endpoint Inactive disease was added.    
 
Added in laboratory assessment section that patients with a body weight 
<15kg, hematology and coagulation samples should not be repeated at visit 
Week 1, if not clinically indicated, in order to preserve blood volume.  
 
Removed single dose pharmacokinetic in patients <6 years of age (separate 
group of 6 patients) as OL period not present. Repeated-dose PK sampling 
(4-5 time points) will be conducted at Week 12 visit at a selected number of 
sites in approximately 30 patients.  
 
Updated proposed sensitivity analyses and overall statistical analysis - a 
sensitivity analysis was added for both the primary analysis of ACR30 
(+ absence of fever) at Week 2 and the supportive analysis of ACR30 
(+ absence of fever) at Week 1.   
 
Updated glucocorticoid tapering steps in appendix 4.  
Version 4.0  
Amendment 3 
03 July 2018 
The amendment is considered as substantial. 
In addition to clarifications, changes to format, and wording, changes have been 
made to the study design regarding data collection for patients that discontinue 
study drug early. The possibility to escape from Week 1 visit to the Week 2 visit 
has been replaced with a Study Drug Discontinuation visit which can take place 
any time during the study before the Week 12 visit in order to be able to capture 
data at the timepoint when the study drug is discontinued. Furthermore, changes 
have been made to comply with ICH GCP addendum:  
 
3.2 Catalent is changed to Almac for IMP depot and logistics 

4.1 Updated current  approval for Kineret i.e. Still’s disease, including SJIA 


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and AOSD, in EU (2018) 
 
4.3 Added text: Hepatic events during postmarketing use have been more 
commonly reported in predisposed patients, including patients with Still's 
disease, than for patients treated for RA and CAPS. 
 
Early termination is changed to study drug discontinuation throughout the 
protocol in order to clarify that early termination is defined as when study 
drug was discontinued. 
 
5.4.1 The objective “To evaluate time to early termination of anakinra 
versus placebo” is changed to “To evaluate time to study drug 
discontinuation in anakinra versus placebo treated patients”. The 
corresponding endpoints are changed to “Time to study drug discontinuation 
for any reason” and “Time to study drug discontinuation due to lack of 
efficacy or progressive disease”. 
 
6.1 Escape between Week 1 visit and Week 2 visit is deleted. Added that if 
a patient discontinues study drug before the Week 12 visit, a Study Drug 
Discontinuation visit should be performed as soon as possible and before 
standard of care treatment is initiated if possible. If the study drug is 
discontinued on a scheduled visit, the Study Drug Discontinuation visit 
should be performed instead of the scheduled visit unless the study drug is 
discontinued at the Week 12 visit. For a patient that discontinue study drug 
before the Week 2 visit, the Week 2 visit should still be performed 
according to the original schedule of assessments, see 6.3.3. If the Study 
Drug Discontinuation visit is performed within 3 days prior to the Week 2 
visit, the scheduled Week 2 visit should be omitted. 
 
6.1 Escape criteria is defined as being a subcategory of patients that has 
discontinued study drug due to progressive disease 
 
6.2 Updated text with: In order to be able to evaluate the primary endpoint 
at week 2, patients that discontinue study drug before week 2 will be 
encouraged to do a Study Drug Discontinuation visit as well as the Week 2 
visit. 
 
6.3.2 Exclusion criteria changed: 
o 
6.  Wash-out periods for prior medication have been updated 
based on terminal half-life for non-immunosuppressive 
agents (4 x t½) and protracted effects on immunocompetent 
cells and toxicity for immunosuppressant agents 
o 
12. Changed to “Presence or suspicion of MAS at baseline” 
o 
14. Added “within 5 years” 
6.3.3 Section title has been changed from “Withdrawal of patients from 
study” to “Study drug discontinuation and withdrawal of patients from the 
study”. Furthermore, the section has been updated to the following: If the 
patients discontinues study drug, a Study Drug Discontinuation visit 
should be performed before standard of care treatment is initiated, when 
possible. If the study drug is discontinued on a scheduled visit, the Study 
Drug Discontinuation visit should be performed instead of the scheduled 
visit unless the study drug is discontinued at the Week 12 visit.  For patients 
that discontinue study drug before the Week 2 visit, a Week 2 visit should 
still be performed according to the original schedule of assessments unless 
consent is withdrawn. However, if the Study Drug Discontinuation visit is 
performed within 3 days prior to the Week 2 visit, the scheduled Week 2 
visit should be omitted. For patients who discontinue study drug and are 
unable to visit the clinic before initiation of standard of care treatment 
appropriate assessments should be performed to substantiate the reason for 
study drug discontinuation, e.g. local lab results. 
 
6.4.6 The list of not allowed concomitant treatments has been updated to 
describe classes of treatments rather then only specific treatments 
 
6.5.1 JADAS27 is removed as a separate assessment since the JADAS27 
components are collected and derived through other assessments.  
 
6.5.1.4 Sentences deleted about that the Investigator should evaluate escape 
criteria.  

6.5.1.9 “Unscheduled escape visit” replaced by “Study drug discontinuation 


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Version 
Date 
Reason for Amendment  
visit” and the text is rewritten.  
 
6.5.5. Definition of SUSAR added and how they will be reported. 
 
6.5.5.6 Added “All laboratory assessments should be performed also for 
patients <15 kg body weight at the Study Drug Discontinuation visit. If the 
Week 2 visit is peformed after the Study Drug Discontinuation visit, central 
lab should also be collected at the Week 2 visit, if not exceeding the 
maximum allowed blood volume collection according to limitations in 
relation to the body-weight of the patient. In case any of the safety central 
lab assessments cannot be analysed from the Week 12 visit the patient 
should be asked to return for an unscheduled visit to ensure that results are 
available for all lab assessments.” 
 
6.5.6.2 Added text about Guidelines that are followed regarding validation 
of  immunoassay.  
 
Section 7 is updated to comply with ICH GCP addendum with regards to 
sponsor’s responsibility to monitor quality management of the study. 
Sentences added: “Sobi will systematically review the study quality 
management to identify, evaluate and control risks to study critical 
processes and data which would affect subject safety and reliability of study 
data. 
Sobi will establish a systematic, prioritized, risk-based approach to 
monitoring and has chosen a combination of on-site and centralized 
monitoring.” 
 
8.2 Text added: “Patients randomized to anakinra who incorrectly received 
only placebo will be included in the placebo group.“    
 
8.3.6.2 Text updated regarding how to present results.  
 
8.3.6.3 Text updated to reflect the change from “early termination” to 
“study drug discontinuation”. 
 
8.4.2 Text updated how the sensitivity analyses are effected by the change 
to Study Drug Discontinuation visit from the previous definition of 
withdrawal 
 
9.4 Protocol deviations section is added to comply with ICH GCP 
addendum.  
 
9.6 Record retention is updated to comply with ICH GCP addendum 
 
Section 12 is updated to comply with the International Committee of 
Medical Journal Editors.  
 
Appendix 5-Schedule of assessments has been updated to reflect the 
changes in the protocol.  
 
 


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Synopsis  
STUDY IDENTIFIERS 
Title of study: 
A randomized, double-blind, placebo-controlled, multicenter, phase 3 efficacy and safety 
study of 2 dose levels of subcutaneous anakinra (Kineret®) in patients with Still’s 
disease (SJIA and AOSD)  
The anaSTILLs study 
Clinical study 
number: 
Sobi.ANAKIN-301 
 
Investigators: 
Pediatric and adult rheumatologists in North America.  
 
Study sites: 
Approximately 40 study sites 
 
Type of study: 
Therapeutic confirmatory, Phase 3 
 
 
 
BACKGROUND INFORMATION AND STUDY RATIONALE 
Adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (SJIA) are rare systemic 
disorders and their pathogenesis is still not completely understood, but is believed to be of autoinflammatory 
nature. Laboratory and clinical observations suggest an inappropriate activation of the innate immune system, 
with hypersecretion of the proinflammatory cytokines interleukin 1 (IL-1) and interleukin 6 (IL-6). They share 
common clinical manifestations such as daily spiking fever, typical transient cutaneous rash, arthritis, 
lymphadenopathy, hepatosplenomegaly and serositis, and laboratory manifestations such as high erythrocyte 
sedimentation rate (ESR), C-reactive protein (CRP), platelet and neutrophil counts. The two diseases also 
share the increased risk for macrophage activation syndrome (MAS), a severe, potentially fatal, complication. 
The principal difference between SJIA and AOSD is the patient's age at the time of onset; childhood and 
young/middle aged adults, respectively. The two groups of patients are typically treated by pediatricians 
(SJIA) and by adult rheumatologists (AOSD) separately as if they are two separate diagnostic entities. 
There is a growing understanding that SJIA and AOSD are one single disease representing an age continuum 
of a single biologic disease entity. If symptoms appear during the late teens it appears arbitrary whether a 
diagnosis of SJIA or AOSD is used. Therefore we will refer to Still’s disease as the overarching name when 
describing the disease in both the pediatric and adult population.  
Although the disease manifestations and treatment approach are similar irrespective of age of symptom onset 
of the disease, there is presently no drug approved for treatment at all ages in USA and Canada. To date, 
nonsteroidal anti-inflammatory drug, glucocorticoids, methotrexate and IL-1/IL-6 inhibitors are used in the 
treatment of Still’s disease. In USA and Canada the long acting IL-1 inhibitor canakinumab and the IL-6 
inhibitor tocilizumab are approved for treatment of SJIA, but no treatments are approved for AOSD. In 
Europe both anakinra and canakinumab are approved for treatment of Still’s disease including SJIA and 
AOSD.   
Existing publications indicate that IL-1 inhibitor treatment early in the disease process is beneficial since it is 
particularly efficacious in treating the systemic symptoms, which are prominent early during disease 
progression. Early treatment with an IL-1 inhibitor may also reduce the risk for a later development of 
arthritis, and enable tapering of glucocorticoids to avoid the risk of dependency and the associated risks of 
osteoporosis, diabetes, serious infections and growth disturbances in children. 


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There is an unmet medical need for an IL-1 blocking agent with a short half-life which allows quick 
modification or withdrawal of treatment should untoward effects occur. This is particularly important since 
there is no diagnostic test for SJIA or AOSD which may mimic other severe diseases, such as infections and 
malignancy. Therefore it is an advantage to be able to quickly terminate IL-1 blocking therapy in case of 
infections or other clinical reasons for discontinuation. Anakinra, with a short half-life (approximately 
6 hours), could be an alternative treatment to the currently approved therapies. 
In both the consensus treatment plans developed by the Childhood Arthritis and Rheumatology Research 
Alliance and the treatment pathways published by American College of Rheumatology anakinra is presented 
as an alternative first line treatment for patients with SJIA although it is not approved for the indication. This 
is a reflection of how important a short-acting IL-1 blocking therapy is for the treatment of the disease. IL-1 
and IL-6 blocking therapies are also included as treatment options in the published treatment 
recommendations for AOSD. 
Anakinra is a recombinant IL-1 receptor antagonist (IL-1Ra) that blocks the biological activity of cytokine 
IL-1 (IL-1 and IL-1) by competitively inhibiting its binding to the IL-1 type I receptor and thereby 
controlling active inflammation. Anakinra has a short half-life and is self-administered as a daily 
subcutaneous injection.  
There is evidence that IL-1 plays an important role in the systemic features of Still’s disease and that 
inbibition of IL-1 can be an effective treatment strategy for this condition.  
The aim of this phase 3 study is to demonstrate the efficacy and to evaluate the safety, pharmacokinetics (PK) 
and immunogenicity of anakinra in patients with newly diagnosed Still’s disease, including SJIA and AOSD. 
 
 
STUDY OBJECTIVES AND ENDPOINTS 
Primary 
objective 
The primary objective of this study is to demonstrate efficacy of anakinra versus placebo in 
Still’s disease as assessed by ACR30 response including absence of fever. 
Primary 
endpoint 
- 
The primary endpoint is ACR30 response at Week 2 with absence of fever 
attributable to the disease during the 7 days preceding Week 2. 
 
 
Definition of ACR30 response: An improvement of ≥ 30% from baseline in at least 3 of any 
6 variables listed below. Also, no more than 1 of the 6 variables may worsen by > 30% from 
baseline. 
1. Physician global assessment of disease activity (VAS) 
2. Patient/parent global assessment of overall well-being (VAS) 
3. Number of joints with active arthritis 
4. Number of joints with limitation of motion 
5. Assessment of physical function (CHAQ/SHAQ) 
6. CRP (mg/L) 
Definition of fever: Body temperature ≥ 38.0 °C (100.4 °F) attributable to the disease 
Secondary 
endpoints 
supporting 
primary 
objective  
- 
ACR30 response at Week 1 with absence of fever attributable to the disease during 
24 hours preceding Week 1. 
- 
ACR50, ACR70 and ACR90 response at Week 1 and Week 2 with absence of fever 
attributable to the disease during 24 hours before Week 1 and 7 days preceding 
Week 2. 
- 
Response in the individual components of ACR at Week 1 and Week 2. Response is 
defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline.  
o 
Physician global assessment of disease activity (VAS) 
o 
Patient/parent global assessment of overall well-being (VAS) 
o 
Number of joints with active arthritis 


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o 
Number of joints with limitation of motion 
o 
Assessment of physical function (CHAQ/SHAQ)  
o 
CRP (mg/L) 
- 
Absence of fever during the 7 days preceding Week 2. 
Key secondary objective and endpoints 
Objective 
To demonstrate early onset of efficacy of anakinra versus placebo in Still’s disease. 
Endpoints 
- 
Absence of fever during the 24 hours preceding Week 1. 
 
- 
Change from baseline in physician global assessment of disease activity (VAS) at 
Week 1. 
 
- 
Change from baseline in patient/parent global assessment of overall well-being 
(VAS) at Week 1. 
 
- 
Change from baseline in CRP at Week 1. 
 
 
Secondary efficacy objectives and endpoints 
Objective 
To evaluate sustained efficacy of anakinra versus placebo in patients that reached at least 
ACR30 response at Week 2.  
Endpoint 
- 
Sustained ACR response at Week 4, Week 8 and Week 12 compared to ACR 
response at Week 2. 
 
 
Objective 
To evaluate efficacy of anakinra versus placebo during 12 weeks treatment. 
Endpoints 
- 
ACR30, ACR50, ACR70 or ACR90 response with absence of fever 24 hours before 
Week 1 or during the 7 days preceding the visit at  Week 2, Week 4, Week 8 and 
Week 12.  
 
- 
Absence of rash 24 hours before Week 1 or during the 7 days preceding Week 2, 
Week 4, Week 8 and Week 12. 
 
- 
Change from baseline in CRP, Hb, platelet count and ferritin at Week 1, Week 2, 
Week 4, Week 8 and Week 12. 
 
- 
Change from baseline in patient/parent global assessment of disease related pain 
(VAS) at Week 1, Week 2, Week 4, Week 8 and Week 12. 
 
- 
Inactive disease at Week 12. 
 
- 
Change from baseline in JADAS27 at Week 2 and Week 12.   
 
 
Objective 
To evaluate time to study drug discontinuation inanakinra versus placebo treated patients.  
Endpoints 
- 
Time to study drug discontinuation for any reason. 
 
- 
Time to  study drug discontinuation due to lack of efficacy or progressive disease.  
 
 
Objective 
To evaluate glucocorticoid tapering in anakinra and placebo treated patients. 
Endpoints 
- 
Number of patients who have initiated tapering of glucocorticoids at Week 12. 


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- 
Number of patients with decreased dose of glucocorticoids by at least 50% at 
Week 12 compared to baseline. 
 
- 
Percentage decrease of glucocorticoid dose at Week 12 compared to baseline. 
 
 
Objective 
To evaluate the efficacy of anakinra in the 2 separate dose groups. 
Endpoint 
- 
Efficacy endpoints as described above. 
 
 
Safety objective and endpoint 
Objective 
To evaluate the safety of anakinra.  
Endpoint 
- 
Adverse events (AEs) (including MAS), vital signs and laboratory safety 
assessments. 
 
 
Pharmacokinetic objective and endpoint 
Objective 
To evaluate the PK of anakinra. 
Endpoint 
- 
Anakinra trough plasma concentrations and repeated-dose PK parameters at 
Week 12. 
 
 
Immunogenicity objectives and endpoints 
Objective 
To evaluate occurrence of ADAs, NAbs and cross-reactivity.  
Endpoint 
- 
Occurrence of ADAs, NAbs, and cross-reactivity and titer levels of ADA and NAbs 
at baseline, Week 1, Week 2, Week 4, Week 8 and Week 12. 
 
 
Objective 
To evaluate ADAs in relation to safety. 
Endpoint 
- 
Occurrence and titer levels of ADAs in relation to AEs at Week 1, Week 2, Week 4, 
Week 8 and Week 12. 
 
 
Objective 
To evaluate ADAs, and NAbs in relation to efficacy.  
Endpoint 
- 
Occurrence and titer levels of ADA, including NAb in relation to ACR response and 
CRP at Week 1, Week 2, Week 4, Week 8 and Week 12.  
 
 
Productivity objective and endpoint 
Objective 
To evaluate absenteeism from school or work. 
Endpoint 
- 
Number of days off school or work due to Still’s disease.  
 
 
Exploratory objectives and endpoints 
Objective 
To explore PK/PD relationship between IL-1Ra/anakinra serum concentrations and selected 
efficacy and safety parameters.  
Endpoint 
- 
Population PK/PD parameter estimates and associated covariates describing intra- 
and inter-individual variability in respective parameter estimate. 
 
 
Objective 
To explore the PK properties of anakinra using population analysis. 
Endpoint 
- 
Population PK parameter estimates and associated covariates describing intra-and 
inter-individual variability in respective parameter estimate.  
 
 


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Objective 
To explore the effect of anakinra on the exploratory inflammatory biomarkers (IL-6, IL-18, 
calprotectin and neopterin) in the treatment of patients with Still´s disease. 
Endpoint 
- 
Change from baseline in exploratory inflammatory biomarkers at Week 1, Week 2 
and Week 12. 
 
 
Objective 
To collect a blood sample for future analysis for genetic factors potentially contributing to the 
patient's response to anakinra, safety and tolerability. Will be reported separately.  
 
STUDY DESIGN AND METHODS 
 
 
Study design:  
The study consists of a 12-week, randomized, double-blind, placebo controlled period 
with two dose levels of anakinra and a 4-week safety follow-up after last dose of 
investigational medicinal product (IMP). The primary endpoint will be evaluated at 
Week 2. Sustained efficacy and time to study drug discontinuation will be evaluated 
during the full study period.  
A screening visit is optional and may be done to identify patients that could be suitable 
for the study. During the study 6 visits and 2 telephone contacts are scheduled i.e., Day 1 
(baseline visit), Day 4Tel, Week 1, Week 2, Week 4, Week 8, Week 12 and Week 16Tel 
(End of Study).  
Patients will be randomly assigned to study drug, after they meet all of the inclusion 
criteria and none of the exclusion criteria. Patients will receive treatment for 12 weeks, 
either anakinra or placebo. Patients will be randomized to anakinra in a dose of either 2 
or 4 mg/kg/day, with a maximum dose of 100 or 200 mg once daily, respectively. 
Patients will be randomized to placebo with corresponding volumes for each of the two 
anakinra dose levels.  
To be able to evaluate the primary objective of the study it is important that the patient 
remains in the study until the Week 2 visit whenever possible. All patients included in 
the study will be carefully monitored by the investigator and if there is a need, patients 
can withdraw from the study drug at any time. If the patients discontinues study drug, a 
Study Drug Discontinuation visit should be performed before standard of care treatment 
is initiated if possible.  
 


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For patients that discontinue Study drug before the Week 2 visit, the Week 2 visit should 
be performed according to original schedule of assessements. However, if the Study 
Drug Discontinuation visit is performed within 3 days prior to the Week 2 visit, the 
scheduled Week 2 visit should be omitted. 
A final follow-up call will be conducted 4 weeks after the last IMP administration 
according to the assessments described for the Week 16Tel visit.  
If the patient is on glucocorticoid treatment the dose can be tapered starting earliest at the 
Week 2 visit. The patient must have reached at least ACR50 response with no fever in 
the preceding 7 days at the visit initiating tapering.  
If a patient develops MAS, the patient will terminate the study treatment and will be 
treated according to standard of care. If the MAS event occurs before the Week 2 visit it 
is preferred, if possible, that the patient returns to conduct the Week 2 visit according to 
the schedule of assessments. For all patients that are diagnosed with MAS, irrespective 
of timepoint in the study, a follow-up call should be conducted 4 weeks after the last 
IMP administration according to the assessments described for the Week 16Tel visit 
before the patient is withdrawn from the study. MAS is defined as an event of special 
interest in this study and must be reported as a serious adverse event (SAE). 
PK sampling will be conducted in all patients at all study visits. In addition, repeated-
dose PK sampling (4-5 time points) will be conducted at Week 12 at a selected number 
of sites in approximately 30 patients. All patients at these pre-selected sites will be asked 
to participate in the repeated PK sampling until the target number of patients have 
completed the repeated PK sampling. If a patient declines to participate in the repeated 
PK sampling, he/she will still be eligible to participate in the main study. When the 
overall number of 81 patients has been reached in the study the enrollment will be 
stopped regardless of whether the target number of repeated-dose PK patients has been 
reached. 
Number of 
patients: 
 
A total of 81 patients will be randomized, 54 patients to anakinra and 27 patients to 
placebo treatment. At least a third of the randomized patients should have had a disease 
onset before the age of 16, and at least a third of the randomized patients in the study 
should have had a disease onset at the age of 16 or above.  
Criteria for 
inclusion/ 
exclusion: 
Inclusion criteria 
A patient must fulfill all of the following criteria in order to be included in the study: 
1. Signed informed consent. 
2. Male and female patients with a body weight ≥ 10 kg. 
3. Diagnosis of Still’s disease:  
a. 
If < 16 years of age at disease onset, according to adapted ILAR 
criteria i.e., CARRA-criteria for SJIA.  
b. If ≥16 years of age at disease onset, according to Yamaguchi criteria.  
4. If currently on glucocorticoid treatment, a stable dose for at least 1 week prior 
to randomization. Maximum dose allowed is 1 mg/kg/day, up to a maximum of 
60 mg/day.  
5. If currently on methotrexate treatment, a stable dose for at least 8 weeks prior to 
randomization. Maximum dose allowed is 20 mg/m2/week. If prior treatment 
with methotrexate, discontinuation is required to be at least 4 weeks prior to 
randomization. 
6. Active disease confirmed by the following three signs and symptoms: 
a. 
Active arthritis in ≥1 joint 
b. CRP >30 mg/L 
c. 
At least one fever episode attributable to the disease within one week 
before randomization.  
(Definition of fever: body temperature ≥38.0°C)


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7. Female patients of childbearing potential must use an effective method of 
contraception during the study (abstinence being a possible option) as well as 
present a negative pregnancy test prior to randomization. 
8. Negative interferon-gamma release assay or PPD test within 2 months prior to 
randomization. If not available, a test should be performed at day of 
randomization  
Exclusion criteria 
The presence of any of the following will exclude a patient from inclusion in the study: 
1. Diagnosis of Still’s disease more than 6 months prior to randomization.  
2. Previous randomization into this study  
3. Participation in another concurrent clinical interventional study within 30 days 
of randomization. 
4. Treatment with an investigational drug within 5 half-lives prior to 
randomization. 
5. Previous or current treatment with anakinra, canakinumab or any other IL-1 
inhibitor.  
6. Use of the following therapies prior to randomization:  
 
Narcotic analgesics within 24 hours prior to randomization  
 
Dapsone or etanerceptwithin 3 weeks prior to randomization  
 
Intraarticular, intramuscular or intravenous administration of 
glucocorticoids or intravenous immunoglobulin within 4 weeks prior 
to randomization 
 
Intravenous immunoglobulin with proven Still’s disease modifying 
effect, leflunomide, infliximab or adalimumab within 8 weeks prior to 
randomization 
 
Thalidomide, cyclosporine, mycophenolate mofetil, 6-mercaptopurine, 
azathioprine, cyclophosphamide,chlorambucil or any other 
immunosuppressant within 12 weeks prior to randomization 
 
Tocilizumab within 12 weeks prior to randomization or any other 
immunomodulatory medication within 4 half-lives prior to 
randomization 
 
Rituximab within 26 weeks prior to randomization 
7. Live vaccines within 1 month prior to randomization. 
8. Known presence or suspicion of active, chronic or recurrent bacterial, fungal or 
viral infections, including tuberculosis, HIV infection or hepatitis B or C 
infection. 
9. Clinical evidence of liver disease or liver injury as indicated by presence of 
abnormal liver tests 
 
AST or ALT >5 x ULN, or  
 
AST or ALT >3 x ULN accompanied by elevated bilirubin >2 x ULN. 
10. Presence of severe renal function impairment CKD stages 4 and 5 (estimated 
creatinine clearance < 30 mL/min/1.73m2). 
11. Presence of neutropenia (ANC < 1.5 x 109/L). 
12. Presence or suspicion of MAS at baseline.  
13. A diagnosis of MAS within the last 2 months prior to randomization.  
14. History of malignancy within 5 years. Exceptions are basal cell skin cancer, 
carcinoma-in-situ of the cervix or low-risk prostate cancer after curative 
therapy. 
15. Known hypersensitivity to E coli-derived proteins, or any components of 
Kineret (anakinra). 
16. Pregnant or lactating women.  
17. Foreseeable inability to cooperate with given instructions or study procedures. 
18. Presence of any medical or psychological condition or laboratory result that in 
the opinion of the investigator can interfere with the patient’s ability to comply 
with the protocol requirements or makes the patient not appropriate for 
inclusion to the study and treatment with IMP.


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Assessments: 
Screening visit (optional): Obtain signed informed consent, evaluate eligibility based on 
the inclusion and exclusion criteria. Local laboratory results are valid for evaluation of 
eligibility criteria. 
 
Visit 1 (Day 1, baseline):  Obtain signed informed consent (if not collected at a screening 
visit), evaluate eligibility based on the inclusion and exclusion criteria. (Laboratory 
results are valid for evaluation of eligibility criteria for 36 hours.) Assess medical 
history, demographics, prior and concomitant medication, vital signs, physical 
examination and ECG. Assess the ACR variables, which include physician global 
assessment of disease activity (VAS), patient/parent global assessment of overall well-
being (VAS), number of joints with active arthritis, number of joints with limitation of 
motion, assessment of physical function (CHAQ/SHAQ) and CRP. Additionally evaluate 
global assessment of the patient disease related pain (VAS). Collect blood for central 
laboratory assessments, immunogenicity, IL-1Ra/anakinra serum concentration and 
inflammatory biomarker assessments. Administer IMP and dispense IMP to cover the 
period until next visit. Record any AE that has occurred. Instruct the patient/patient’s 
caregiver how to complete the diary. Collect sample for exploratory pharmacogenetics 
markers at any visit after randomization. 
 
Tel f-up (Day 4Tel): Record any AE.  
 
Visit 2 (Week 1): Assess vital signs, physical examination and concomitant medication. 
Assess all the ACR variables and the global assessment of the patient disease related 
pain (VAS). Collect blood for central laboratory assessments, immunogenicity, 
IL-1Ra/anakinra serum concentration and inflammatory biomarker assessments. Record 
any AE and absenteeism from school or work. Finally dispense IMP.  
 
Visit 3 (Week 2): Assess vital signs, physical examination and concomitant medication. 
Assess all the ACR variables and the global assessment of the patient disease related 
pain (VAS). Collect blood for central laboratory assessments, immunogenicity, 
IL-1Ra/anakinra serum concentration and inflammatory biomarker assessments. Record 
any AE and absenteeism from school or work. Finally dispense IMP.  
 
Visit 4 and 5 (Week 4 and 8): Assess vital signs, physical examination and concomitant 
medication. Assess all the ACR variables and the global assessment of the patient 
disease related pain (VAS). Collect blood for central laboratory assessments, 
immunogenicity and IL-1Ra/anakinra serum concentration. Record any AE and 
absenteeism from school or work. Finally dispense IMP.  
 
Visit 6 (Week 12): Assess vital signs, physical examination and concomitant medication. 
Assess all the ACR variables and the global assessment of the patient disease related 
pain (VAS). Collect morning stiffness for the evaluation of inactive disease. Collect 
blood for central laboratory assessments, immunogenicity, IL-1Ra/anakinra serum 
concentration and inflammatory biomarker assessments. Record any AE and absenteeism 
from school or work. Finally all IMP should be collected from the patient and accounted 
for.  
For patients enrolled in the repeated-dose PK sampling the visit is scheduled on the day 
of the last IMP dose and the IMP is administered at site. PK blood samples will be 
collected at 5 time points between pre-dose and 8 hours after IMP administration. 
  
Tel f-up (Week 16Tel): Record any AE and concomitant medication.  
 
Study Drug Discontinuation visit: Assess vital signs, physical examination and 
concomitant medication. Assess all the ACR variables and the global assessment of the 
patient disease related pain (VAS). Collect morning stiffness for the evaluation of 


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inactive disease. Collect blood for central laboratory assessments, immunogenicity, 
IL-1Ra/anakinra serum concentration and inflammatory biomarker assessments. Record 
any AE and absenteeism from school or work. Finally all IMP should be collected from 
the patient and accounted for.  
 
 
Test product; 
dose and mode of 
administration: 
 
anakinra 2 mg/kg/day (max 100 mg/day) sc administration or 
 
anakinra 4 mg/kg/day (max 200 mg/day) sc administration.  
 
The dose will be adjusted according to actual body weight (rounded to the nearest kg) 
and will remain the same throughout the study.  
 
Reference 
product;  
dose and mode of 
administration: 
The placebo will be given in a corresponding volume to any of the two different anakinra 
doses, once daily as sc administration. 
Restricted 
concomitant 
medication: 
Intraarticular, intramuscular and intravenous administration of glucocorticoids are 
prohibited within 4 weeks prior to randomization and during the study. Other 
administration of glucocorticoid treatment is allowed as concomitant medication during 
the study if the patient has had a stable dose for at least 1 week prior to randomization. 
Maximum dose allowed is 1 mg/kg/day (max 60 mg/day). If the patient is on 
glucocorticoid treatment, the dose can be tapered starting earliest at the Week 2 visit. 
The patient must have reached at least ACR50 response with no fever in the preceding 7 
days at the visit initiating tapering. All other glucocorticoid treatment is prohibited 
during the study except topical and inhaled.  
Methotrexate is allowed as concomitant medication during the study if the patient has 
had a stable dose for at least 8 weeks prior to randomization. The dose should remain 
stable throughout the study as long as it is well tolerated. If prior treatment with 
methotrexate, discontinuation is required to be at least 4 weeks prior to randomization.  
Initiation of continuous NSAID treatment is prohibited during the study. However on 
demand treatment is allowed. 
Narcotic analgesics are not allowed 24 hours prior any study visit. 
Use of the following treatments are not allowed concomitantly with the IMP (wash-out 
periods before randomization are stated in the exclusion criteria):  
 
Intraarticular, intramuscular or intravenous administration of glucocorticoids 
 
Intravenous immunoglobulins 
 
Canakinumab or any other IL-1 inhibitor 
 
Tocilizumab, rituximab or any other immunomodulatory medication  
 
Etanercept, adalimumab, infliximab, or any other TNF inhibitor (investigational 
or marketed) 
 
Dapsone or mycophenolate mofetil 
 
Leflunomide, thalidomide, or cyclosporine 
 
6-Mercaptopurine, azathioprine, cyclophosphamide, chlorambucil or any other 
immunosuppressant 
 
Use of any other investigational drug 
Live vaccines is not allowed within 1 month prior to randomization and until after 1 
month following the last study dose. Inactivated vaccines may be permitted according to 
the investigator’s discretion.  The investigator should instruct the patient to notify the 
study site about any new medications he/she takes after the start of the study drug. All 
medications and significant non-drug therapies administered after the patient starts 


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treatment with study drug until Week 16Tel must be listed on the concomitant medication 
CRF page.  
Following the 12 week double blind treatment, the patient will be treated at the 
discretion of the investigator according to standard of care.  
Duration of 
treatment(s): 
12 week double-blind, placebo-controlled, anakinra treatment period. 
Randomization 
The different treatment groups are; 
 
placebo (corresponding volume of anakinra 2 mg/kg/day [max 100 mg/day]), or 
 
placebo (corresponding volume of anakinra 4 mg/kg/day [max 200 mg/day]), or 
 
anakinra 2 mg/kg/day (max 100 mg/day) or  
 
anakinra 4 mg/kg/day (max 200 mg/day)  
The ratio between the treatment groups is 1:1:2:2, i.e. the ratio placebo:ankinra is 1:2.  
The randomization numbers will be generated in blocks. Each block will include the four 
treatment groups per the ratio described above.  
The randomization will be stratified by age at onset of disease (< 16 years, ≥ 16 years) 
and glucocorticoid use at inclusion (yes, no) with a requirement to randomize at least a 
third of the patients with an age at onset of disease < 16 years and a third of the patients 
with an age at onset ≥ 16 years.  
Sample size 
determination:  
Assuming that the ACR30 response rate is 65 % in patients receiving anakinra and 25 % 
in placebo patients, 81 evaluable patients (54 anakinra and 27 placebo) are required to 
ensure 90 % power in demonstrating that anakinra improves clinical features of Still’s 
disease using a two-sided test at a 5 % significance level.  
Statistical 
methods: 
The comparison of primary interest is between anakinra (2 mg and 4 mg combined) and 
placebo. The two dose levels of anakinra will be evaluated descriptively. 
The primary endpoint ACR30 response with absence of fever at Week 2 will be analyzed 
using a logistic regression model with treatment, age at onset of disease (< 16 years, ≥ 16 
years) and glucocorticoid use (yes, no) as explanatory variables. Patients who have 
discontinued study drug prior to Week 2 will be treated as non-responders in the primary 
analysis. The estimated probability of ACR30 response in each treatment group, the 
estimated odds ratio of anakinra to placebo, the corresponding 95 % confidence interval 
and the p-value from the model will be presented. 
The binary key secondary endpoint absence of fever at Week 1 will be analyzed using a 
logistic regression model with treatment, age at onset of disease and glucocorticoid use 
as explanatory variables. Patients who discontinue study drug prior to Week 1 will be 
treated as having a presence of fever in the analysis. The estimated probability of 
absence of fever in each treatment group, the estimated odds ratio of anakinra to placebo, 
the corresponding 95 % confidence interval and the p-value from the model will be 
presented. 
The continuous key secondary endpoints; change from baseline at Week 1 in physician’s 
global assessment of disease activity, patient/parent global assessment of overall well-
being and CRP will be analyzed using a mixed model repeated measurement with the 
measurements on the individual time points as responses and with treatment, age at onset 
of disease and glucocorticoid use, visit and treatment-visit interaction as fixed effects. 
For the comparison between treatment groups for each endpoint, the estimated 
difference, the associated 95 % confidence interval and the p-value from the model will 
be presented. 
A multiple testing procedure, combining fixed sequence testing and Hochberg procedure, 
will be used to ensure an overall significance level of 0.05 for the primary endpoint and 
key secondary endpoints. 


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Supportive analyses in sub-groups defined by the stratification variables (< 16 years, 
≥ 16 years of age at disease onset) and glucocorticoid use at inclusion (yes, no) will be 
performed in order to examine the consistency of the treatment effect. For each sub-
group, the estimated probability of ACR30 response in each treatment group, the 
estimated odds ratio of anakinra to placebo and the corresponding 95 % confidence 
interval will be presented. 
 
 
 


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1 
Abbreviations and definition of terms 
 
ACR 
American College of Rheumatology 
ACR30 
An improvement of ≥ 30% from baseline in at least 3 of any 6 
variables listed below. Also, no more than 1 of the 6 variables 
may worsen by >30% from baseline. 
1. Physician global assessment of disease activity VAS) 
2. Patient/parent global assessment of overall well-being 
(VAS) 
3. Number of joints with active arthritis 
4. Number of joints with limitation of motion 
5. Assessment of physical function (CHAQ/SHAQ) 
6. CRP (mg/L) 
ACR50 
An improvement of ≥ 50% from baseline in at least 3 of any 6 
variables described in ACR30. Also, no more than 1 of the 6 
variables may worsen by > 30% from baseline. 
ACR70 
An improvement of ≥ 70% from baseline in at least 3 of any 6 
variables described in ACR30. Also, no more than 1 of the 6 
variables may worsen by > 30% from baseline. 
ACR90 
An improvement of ≥ 90% from baseline in at least 3 of any 6 
variables described in ACR30. Also, no more than 1 of the 6 
variables may worsen by > 30% from baseline. 
ADA 
Anti-drug antibodies 
ARO 
Academic research organization 
AE 
Adverse event 
ANA 
Antinuclear antibody 
AOSD 
Adult-onset Still’s disease 
baseline 
Before administration of IMP at Day 1 
BW 
Body weight 
CAPS 
Cryopyrin-associated periodic syndromes 
CARRA 
The Childhood Arthritis and Rheumatology Research Alliance 
CDASH 
Clinical data acquisition standards harmonization 
CDISC 
Clinical data interchange standards consortium 
CHAQ 
Childhood health assessment questionnaire 


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CRP 
C-reactive protein 
CRF 
Case report form 
DAS 
Disease activity score 
DCRI 
Duke Clinical Research Institute  
DMARD 
Disease modifying anti-rheumatic drug 
DSMB 
Data safety monitoring board 
ECG 
Electrocardiogram 
Escape criteria 
 symptomatic serositis, or 
 flare i.e., a worsening of >30% from baseline in at least 3 of 
any 6 components part of ACR. 
Patients fulfilling the escape criteria are a subcategory of patients 
that discontinue study drug due to progressive disease. 
ESR 
Erythrocyte sedimentation rate 
GCP 
Good clinical practice 
Hb 
Hemoglobin  
HDL 
High-density lipoprotein 
ICF 
Informed consent form  
ICH 
International council for harmonization 
Ig 
Immunoglobulin 
IgM 
Immunoglobulin M 
IL-1 
Interleukin 1 
IL-1Ra 
Interleukin 1 receptor antagonist 
IL-6 
Interleukin 6 
IL-18 
Interleukin 18 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
IRS 
Interactive response system 
ISR 
Injection site reactions 
ITT 
Intention-to-treat 
JADAS 
Juvenile arthritis disease activity score 
JIA 
Juvenile idiopathic arthritis 
ka 
Absorption rate constant 
LDL 
Low-density lipoprotein 


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MAS 
Macrophage activation syndrome 
MedDRA 
Medical dictionary for regulatory activities 
MCP 
Metacarpophalangeal joints 
MSD-ECL 
Meso Scale Discovery Electrochemiluminescence 
NAb 
Neutralizing antibodies 
NSAID 
Nonsteroidal anti-inflammatory drug 
NOMID 
Neonatal onset multisystem inflammatory disease 
PD 
Pharmacodynamics 
PIP 
Proximal interphalangeal joints 
PK 
Pharmacokinetics 
PP 
Per-protocol 
PPD 
Purified protein derivative 
PRO 
Patient reported outcome 
RA 
Rheumatoid arthritis 
REB 
Research ethics board 
RF 
Rheumatoid factor 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
s.c. 
Subcutaneous 
SJIA 
Systemic juvenile idiopathic arthritis 
SHAQ 
Stanford Health Assessment Questionnaire 
SDTM 
Study data tabulation model 
Sobi 
Swedish Orphan Biovitrum AB (publ) 
SOP 
Standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
 
 


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2 
Ethics 
2.1 
Institutional review board and research ethics board 
It is the responsibility of the investigator to obtain approval of the study protocol, possible 
amendments and the written patient information and ICF from the IRB/REB. The investigator 
should file all correspondence with the IRB/REB. Copies of IRB/REB correspondence and 
approvals should be forwarded to DCRI, the ARO. 
2.2 
Ethical conduct of the study 
This study will be conducted in compliance with this protocol, the ICH GCP (1), applicable 
regulatory requirements, and in accordance with the latest revision of the Ethical Principles 
for Medical Research Involving Human Patients (the Declaration of Helsinki) (2). 
2.3 
Patient Information and consent 
It is the responsibility of the investigator to give each patient, and if applicable the patient’s 
legally authorized representative or parent/guardian, full and adequate verbal and written 
information regarding the objective and procedures of the study and the possible risks 
involved prior to any study-related activities. Declining to participate in specific assessments 
such as genotyping, PK and/or parent’s absenteeism from work will in no way affect the 
patient’s ability to participate in the main study. The patient and, if applicable, their legally 
authorized representative or parent/guardian must be informed about their right to withdraw 
from the study at any time. 
It is the responsibility of the investigator to obtain signed informed consent from all patients 
and, if applicable, child assent according to local regulations prior to any study-related 
activities. If required a signed informed consent must also be obtained from the patient’s 
legally authorized representative or parent/guardian. The patient will receive a copy of the 
patient information and signed ICF. 
The patient information and/or consent form must not be changed without prior discussion 
with DCRI or Sobi. Before any revisions are implemented, the revised written patient 
information and/or consent form must be approved by the IRB/REB. 
3 
Study administrative structure 
3.1 
Sponsor 
The sponsor of the study is Sobi, Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden. 
3.2 
Academic research organization 
The conduct of the study will be outsourced to the ARO DCRI, Durham, North Carolina, 
USA. Site evaluation, monitoring, development of master patient information and ICF, data 


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management, investigational product management and vendor management are some of the 
study-related activities and responsibilities that are transferred to DCRI. DCRI has selected 
Almac Clinical Services, LLC for IMP depot and IMP logistics. DCRI selected Medidata 
Solutions, Inc. to provide: Rave for the eCRF, Patient Cloud for electronic diaries and 
Balance for randomization and trial supply management.   
Statistical analysis and development of the clinical study report will remain the responsibility 
of Sobi.  
Handling of SAE reporting will be a shared responsibility between Sobi and DCRI. 
3.3 
Central laboratories 
Central laboratories will be used for all study-specific laboratory assessments except those 
laboratory assessments required to confirm the eligibility of the patient at baseline, evaluate 
escape criteria (CRP), glucocorticoid tapering or reason for study drug discontinuation. All 
central laboratories are compliant with Good Laboratory Practice. 
ICON Laboratory Services, Inc., 123 Smith Street, Farmingdale, NY 11735, US will be 
responsible for analyses of clinical chemistry and hematology.  
Pacific Biomarkers, 645 Elliott Ave W. Suite 300, Seattle, WA 98119, is responsible for 
analysis of the exploratory biomarkers in the study. 
The analyses of ADA, including validation of the MSD-ECL bridging method to be used, and 
the analysis of IL-1Ra/anakinra concentrations including validation of the MSD-ECL based 
method to be used for the purpose are assigned to York Bioanalytical Solutions Limited, 
Cedar House, Northminster Business Park, Upper Poppleton, York YO26 6QR, United 
Kingdom.  
The analysis of neutralizing ADA including development and validation of the cell-based 
method to be used will be performed by Euro Diagnostica, Lundavägen 151, 212 24 Malmö 
Sweden.  
3.4 
MAS adjudication committee 
MAS is the term used to describe a potentially life-threatening complication of systemic 
inflammatory disorders, which occurs in approximately 10% of patients with SJIA (3) and in 
similar incidence in AOSD (4). MAS is characterized by an overwhelming inflammatory 
reaction due to an uncontrolled and dysfunctional immune response involving the continual 
activation and expansion of T-lymphocytes and macrophages, which results in massive 
hypersecretion of proinflammatory cytokines. 
There will be an independent blinded adjudication committee assigned to enable uniform 
assessment of MAS cases after all patients have completed the study. The committee will be 
independent of the sponsor and the investigators, and information from the committee will 
not be available during the conduct of the study. The adjudication committee will be 
comprised of clinicians that have experience  treating patients with Still´s disease and are 
familiar with the signs and symptoms of MAS in the pediatric and adult populations.  


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An adjudication committee charter will describe the process for the adjudication and outline 
the committee membership, responsibilities, scope of activities and communication plan 
between committee, sponsor, ARO and study sites. 
3.5 
Data safety monitoring board 
An independent DSMB will be in place during the conduct of the study. Responsibilities of 
the DSMB will include review of accumulated safety data and assessments to ensure the 
safety of participating patients and overall integrity of the study, provide recommendations 
regarding the further conduct of the study and identify any safety issues which may suggest 
risk to the patients enrolled in the study or prospective patients. A DSMB charter will outline 
the membership, responsibilities, scope of activities, meeting frequency and communication 
plan between committee, sponsor, ARO and study sites. The members of the DSMB will 
collectively have competence and experience with Still's disease (in children and adults), 
MAS, conduct of randomized clinical studies, interpretation of clinical study data and also 
have previous DSMB experience. 
4 
Introduction 
4.1 
Background 
In 1897, the English physician Sir George Frederic Still described a form of polyarthritis in 
children with a unique constellation of symptoms that included chronic arthritis, adenopathy, 
splenomegaly and fever. Initially called Still’s disease, it is now known as SJIA. The 
diagnosis is based on its typical features and an age at onset of less than 16 years (5).   
About the same time as G. F. Still’s case description, the first adult patient exhibiting the 
same symptoms was reported. Later in 1971, E. G. Bywaters described 14 adult patients with 
the same symptoms as those seen in the pediatric Still's disease, establishing the diagnosis 
AOSD (6).  
AOSD and SJIA are rare systemic disorders and their pathogenesis is still not completely 
understood, but is believed to be of autoinflammatory nature. Laboratory and clinical 
observations suggest an inappropriate activation of the innate immune system, with 
hypersecretion of the proinflammatory cytokines IL-1 and IL-6. They share common clinical 
manifestations such as daily spiking fever, typical transient cutaneous rash, arthritis, 
lymphadenopathy, hepatosplenomegaly and serositis, and laboratory manifestations such as 
high ESR, CRP, platelet and neutrophil counts (7). The two diseases also share the increased 
risk for MAS, a severe, potentially fatal, complication (3, 4). The principal difference 
between SJIA and AOSD is the patient's age at the time of onset; childhood and 
young/middle aged adults, respectively. The two groups of patients are typically treated by 
pediatricians (SJIA) and by adult rheumatologists (AOSD) separately as if they are two 
separate diagnostic entities. 
There is a growing understanding that SJIA and AOSD are one single disease representing an 
age continuum of a single biologic disease entity (7, 8, 9, 10, 11, 12, 13, 14, 15 and 16). If 
symptoms appear during the late teens it appears arbitrary whether a diagnosis of SJIA or 


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AOSD is used. Therefore we will refer to Still’s disease as the overarching name when 
describing the disease in both the pediatric and adult population.  
Although the disease manifestations and treatment approach are similar irrespective of age of 
symptom onset of the disease, there is presently no drug approved for treatment at all ages in 
USA and Canada. To date, NSAIDs, glucocorticoids, methotrexate and IL-1/IL-6 inhibitors 
are used in the treatment of Still’s disease. In USA and Canada the long acting IL-1 inhibitor 
canakinumab and the IL-6 inhibitor tocilizumab are approved for treatment of SJIA, but no 
treatments are approved for AOSD. In Europe both anakinra and canakinumab are approved 
for treatment of Still’s disease including SJIA and AOSD.  
Existing publications indicate that IL-1 inhibitor treatment early in the disease process is 
beneficial since it is particularly efficacious in treating the systemic symptoms, which are 
prominent early during disease progression (17, 18, 19). Early treatment with an IL-1 
inhibitor may also reduce the risk for a later development of arthritis (20), and enable 
tapering of glucocorticoids to avoid the risk of dependency and the associated risks of 
osteoporosis, diabetes, serious infections and growth disturbances in children (21, 22). 
There is an unmet medical need for an IL-1 blocking agent with a short half-life which allows 
quick modification or withdrawal of treatment should untoward effects occur. This is 
particularly important since there is no diagnostic test for SJIA or AOSD which may mimic 
other severe diseases, such as infections and malignancy. Therefore it is an advantage to be 
able to quickly terminate IL-1 blocking therapy in case of infections or other clinical reasons 
for discontinuation. Anakinra, with a short half-life (approximately 6 hours), could be an 
alternative treatment to the currently approved therapies. 
In both the consensus treatment plans developed by CARRA (23, 24) and the treatment 
pathways published by ACR (25) anakinra is presented as an alternative first line treatment 
for patients with SJIA although it is not approved for the indication in the US and 
Canada.This is a reflection of how important a short-acting IL-1 blocking therapy is for the 
treatment of the disease. IL-1 and IL-6 blocking therapies are also included as treatment 
options in the published treatment recommendations for AOSD (26, 27). 
Anakinra is a recombinant IL-1 receptor antagonist (IL-1Ra) that blocks the biological 
activity of cytokine IL-1 (IL-1 and IL-1) by competitively inhibiting its binding to the IL-1 
type I receptor and thereby controlling active inflammation. Anakinra has a short half-life 
and is self-administered as a daily s.c. injection.  
Kineret® is currently approved in the US (2001), Canada (2002), and EU/EEA (2002) for the 
treatment of RA. Kineret is also approved for the most severe form of CAPS, i.e., NOMID, in 
the US (2012), and for all forms of CAPS in EU/EEA (2013). In addition, Kineret is 
approved for the treatment of SJIA in Australia (2015) and for Still’s disease, including SJIA 
and AOSD in EU (2018). 
In the currently available data there are no relevant differences in the safety profile between 
pediatric and adult patients. Neither are there any relevant differences in the safety profile of 
patients with Still’s disease compared to patients with other indications for anakinra 
treatment. However, post marketing reports describing hepatic events and events of MAS are 
over-represented in patients with Still’s disease, especially in pediatric patients. 
Hepatic events, mainly liver enzyme elevations, but also cases of non-infectious hepatitis, 
have been associated with anakinra. Hepatic events during post marketing use have mainly 


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been reported in patients with predisposing factors, e.g., history of transaminase elevations 
before start of anakinra treatment. Hepatic events are common manifestations of Still’s 
disease and hepatic events occur also in anakinra-treated patients with Still’s disease. 
Cases of MAS have been described in anakinra-treated patients with Still’s disease, both in 
publications and in spontaneous reports during post marketing use. However, patients with 
Still’s disease, both pediatric and adults, have an increased risk for spontaneous development 
of MAS. A causal relationship between anakinra and development of MAS has not been 
established. 
There is limited information about the PK of anakinra in SJIA patients, and no information 
about the PK of anakinra in AOSD patients. The PK of anakinra is however well 
characterized in healthy volunteers and RA patients. The bioavailability is high (95%), tmax 
is about 6 hours and anakinra serum concentrations decline with a half-life of 4-6 hours 
following s.c. administration to RA patients. The exposure increases in approximate 
proportion to dose, accumulation is modest following once daily administration and 
approximately 80% of anakinra is eliminated by the kidney. In JIA patients trough anakinra 
concentrations were lower in the age group 3-6 years compared to older children and in 22 
SJIA patients clearance was higher in children with a lower body-weight (28).   
For a detailed description of anakinra characteristics, contraindications, warnings and 
precautions, adverse reactions and pharmaceutical properties, refer to the product 
information/monograph and the IB.    
4.2 
Study rationale 
There is evidence that IL-1 plays an important role in the systemic features of Still’s disease 
and that inhibition of IL-1 can be an effective treatment strategy for this condition (29, 30, 
31).  
The aim of this phase 3 study is to demonstrate the efficacy and to evaluate the safety, PK 
and immunogenicity of anakinra in patients with newly diagnosed Still’s disease, including 
SJIA and AOSD.  
4.3 
Potential benefits and risks 
IL-1 inhibition appears to be of particular importance when systemic symptoms of Still’s 
disease are predominant. Published data demonstrate that anakinra induces a rapid resolution 
of systemic features, such as fever, rash and acute phase reactants elevations (19, 32). 
Another important benefit of anakinra treatment compared to registered biologic treatments is 
the short half-life which enables flexible dosing including fast wash-out.. 
It seems that most beneficial effects of anakinra are obtained if treatment with anakinra is 
started early after disease onset, before significant arthritis has developed (19). Partial 
response to anakinra has also been reported in some patients with well-established disease at 
treatment onset (32).  
The efficacy of anakinra in adult patients with Still's disease has been evaluated in a meta-
analysis conducted by Hong et al. (33). Anakinra was shown to be effective in remitting the 
manifestations of AOSD, in reducing the doses of glucocorticoid, and was also well tolerated.  


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The safety profile of anakinra is well established with the known common risks associated 
predominantly with ISRs as well as known less common but more severe risks, such as 
development of neutropenia and serious infections. The safety profile has been similar across 
indications, age groups and dose levels, with the exception of ISRs that were more frequent 
when doses of >100 mg s.c. were administered to patients with RA. ISRs are typically 
reported within the first 4 weeks of therapy with a median duration in RA studies of 14 to 28 
days and resolve during continued anakinra treatment. In long-term studies, there are no 
indications of an increasing AE frequency over time. In addition, there is more than 15 years 
of post-marketing use during which the safety profile has remained stable. From the 
information available, there are no indications of any relevant differences in the safety profile 
of anakinra in patients with Still's disease compared to patients with other indications for 
anakinra treatment. However, hepatic events during postmarketing use have been more 
commonly reported in predisposed patients, including patients with Still's disease, than for 
patients treated for RA and CAPS. A maximum tolerated dose has not been established for 
anakinra. 
In this study one third of the study population will be randomized to placebo. All patients 
included in the study will be carefully monitored and patients that do not respond to IMP can 
at any time withdraw from study and receive standard of care treatment, thus minimizing the 
time patients are exposed to ineffective treatment (placebo or non-response to active 
treatment).  
The potential risks associated with anakinra administration will be closely monitored by the 
sponsor as part of the safety evaluations being performed in the study. To further monitor the 
safety there will be an independent DSMB. 
The overall assessment is that the benefit of using anakinra in Still’s disease outweighs the 
known risks associated with it.  
 
 


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5 
Study objectives and endpoints 
5.1 
Primary objective and endpoint 
Primary 
objective 
The primary objective of this study is to demonstrate efficacy of anakinra versus 
placebo in Still’s disease as assessed by ACR30 response including absence of 
fever. 
Primary 
endpoint 
- 
The primary endpoint is ACR30 response at Week 2 with absence of fever 
attributable to the disease during the 7 days preceding Week 2. 
Definition of ACR30 response: An improvement of ≥ 30% from baseline in at least 3 of 
any 6 variables listed below. Also, no more than 1 of the 6 variables may worsen by 
> 30% from baseline. 
1. Physician global assessment of disease activity (VAS) 
2. Patient/parent global assessment of overall well-being (VAS) 
3. Number of joints with active arthritis 
4. Number of joints with limitation of motion 
5. Assessment of physical function (CHAQ/SHAQ) 
6. CRP (mg/L) 
Definition of fever: Body temperature ≥ 38.0 °C (100.4 °F) attributable to the disease 
5.2 
Secondary endpoints supporting primary objective 
Secondary 
endpoints 
supporting 
primary 
objective 
- 
ACR30 response at Week 1 with absence of fever attributable to the 
disease during 24 hours preceding Week 1. 
- 
ACR50, ACR70 and ACR90 response at Week 1 and Week 2 with 
absence of fever attributable to the disease during 24 hours before 
Week 1 and 7 days preceding Week 2.  
- 
Response in the individual components of ACR at Week 1 and 
Week 2. Response is defined as an improvement of ≥ 30%, 50%, 
70% and 90% from baseline.  
o Physician global assessment of disease activity (VAS) 
o Patient/parent global assessment of overall well-being (VAS) 
o Number of joints with active arthritis 
o Number of joints with limitation of motion 
o Assessment of physical function (CHAQ/SHAQ)  
o CRP (mg/L) 
- 
Absence of fever during the 7 days preceding Week 2. 


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5.3 
Key secondary objective and endpoints 
Objective 
To demonstrate early onset of efficacy of anakinra versus placebo in Still’s 
disease. 
Endpoints 
- 
Absence of fever during the 24 hours preceding Week 1. 
 
- 
Change from baseline in physician global assessment of disease 
activity (VAS) at Week 1. 
 
- 
Change from baseline in patient/parent global assessment of overall 
well-being (VAS) at Week 1. 
 
- 
Change from baseline in CRP at Week 1. 
5.4 
Secondary objectives and endpoints  
 
Secondary efficacy objectives and endpoints 
Objective 
To evaluate sustained efficacy of anakinra versus placebo in patients that 
reached at least ACR30 response at Week 2.  
Endpoint 
- 
Sustained ACR response at Week 4, Week 8 and Week 12 
compared to ACR response at Week 2. 
 
 
Objective 
To evaluate efficacy of anakinra versus placebo during 12 weeks 
treatment. 
Endpoints 
- 
ACR30, ACR50, ACR70 or ACR90 response with absence of 
fever 24 hours before Week 1 or during the 7 days preceding the 
visit at Week 2, Week 4, Week 8 and Week 12.  
 
- 
Absence of rash 24 hours before Week 1 or during the 7 days 
preceding Week 2, Week 4, Week 8 and Week 12. 
 
- 
Change from baseline in CRP, Hb, platelet count and ferritin at 
Week 1, Week 2, Week 4, Week 8 and Week 12. 
 
- 
Change from baseline in patient/parent global assessment of 
disease related pain (VAS) at Week 1, Week 2, Week 4, Week 8 
and Week 12. 
 
- 
Inactive disease at Week 12. 
 
- 
Change from baseline in JADAS27 at Week 2 and Week 12.   
 
 


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Objective 
To evaluate time to study drug discontinuation in anakinra versus 
placebo.  
Endpoint 
- 
Time to study drug discontinuation for any reason. 
 
- 
Time to study drug discontinuation due to lack of efficacy or 
progressive disease.  
 
 
Objective 
To evaluate glucocorticoid tapering in anakinra and placebo treated 
patients. 
Endpoints 
- 
Number of patients who have initiated tapering of glucocorticoids 
at Week 12. 
 
- 
Number of patients with decreased dose of glucocorticoids by at 
least 50% at Week 12 compared to baseline. 
 
- 
Percentage decrease of glucocorticoid dose at Week 12 compared 
to baseline. 
 
 
Objective 
To evaluate the efficacy of anakinra in the 2 separate dose groups. 
Endpoint 
- 
Efficacy endpoints as described above. 
 
Safety objective and endpoint 
Objective 
To evaluate the safety of anakinra.  
Endpoint 
AEs (including MAS), vital signs and laboratory safety assessments. 
 
Pharmacokinetic objective and endpoint 
Objective 
To evaluate the PK of anakinra. 
Endpoint 
- 
Anakinra trough plasma concentrations and repeated-dose PK 
parameters at Week 12. 
 
Immunogenicity objectives and endpoints 
Objective 
To evaluate occurrence of ADAs, NAbs and cross-reactivity.  
Endpoint 
- 
Occurrence of ADAs, NAbs, and cross-reactivity and titer levels of 
ADA and NAbs at baseline, Week 1, Week 2, Week 4, Week 8 and 
Week 12. 


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Objective 
To evaluate ADAs in relation to safety. 
Endpoint 
- 
Occurrence and titer levels of ADAs in relation to AEs at Week 1, 
Week 2, Week 4, Week 8 and Week 12. 
 
 
Objective 
To evaluate ADAs, and NAbs in relation to efficacy.  
Endpoint 
- 
Occurrence and titer levels of ADA, including NAb in relation to 
ACR response and CRP at Week 1, Week 2, Week 4, Week 8 and 
Week 12.  
 
Productivity objective and endpoint 
Objective 
To evaluate absenteeism from school or work. 
Endpoint 
- 
Number of days off school or work due to Still’s disease.  
5.5 
Exploratory objectives and endpoints 
Objective 
To explore PK/PD relationship between IL-1Ra/anakinra serum concentrations 
and selected efficacy and safety parameters.  
Endpoint 
- 
Population PK/PD parameter estimates and associated covariates describing 
intra- and inter-individual variability in respective parameter estimate. 
 
 
Objective 
To explore the PK properties of anakinra using population analysis. 
Endpoint 
- 
Population PK parameter estimates and associated covariates describing intra-
and inter-individual variability in respective parameter estimate.  
 
 
Objective 
To explore the effect of anakinra on the exploratory inflammatory biomarkers (IL-6, 
IL-18, calprotectin and neopterin) in the treatment of patients with Still´s disease. 
Endpoint 
- 
Change from baseline in exploratory inflammatory biomarkers at Week 1, 
Week 2 and Week 12. 
 
 
Objective 
To collect a blood sample for future analysis for genetic factors potentially 
contributing to the patient's response to anakinra, safety and tolerability. Will be 
reported separately.  


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6 
Investigational plan 
6.1 
Overall study design and plan 
Figure  1 
Study design 
 
 
 
The study consists of a 12-week, randomized, double-blind, placebo controlled period with 
two dose levels of anakinra and a 4-week safety follow-up after last dose of IMP. The 
primary endpoint will be evaluated at Week 2. Sustained efficacy and time to study drug 
discontinuation will be evaluated during the full study period.  
A screening visit is optional and may be done to identify patients that could be suitable for 
the study. See Figure  1. During the study 6 visits and 2 telephone contacts are scheduled i.e., 
Day 1 (baseline visit), Day 4Tel, Week 1, Week 2, Week 4, Week 8, Week 12 and Week 16Tel 
(End of Study).  
Patients will be randomly assigned to study drug, after they meet all of the inclusion criteria 
and none of the exclusion criteria. Patients will receive treatment for 12 weeks, either 
anakinra or placebo. Patients will be randomized to anakinra in a dose of either 2 or 4 
mg/kg/day, with a maximum dose of 100 or 200 mg once daily, respectively. Patients will be 
randomized to placebo with corresponding volumes for each of the two anakinra dose levels.  
To be able to evaluate the primary objective of the study it is important that patients remain 
in the study until the Week 2 visit whenever possible. However, patients can discontinue 
study drug at any time during the study e.g. due to lack of efficacy or progressive disease. 
Patients fulfilling the escape criteria are a subcategory of patients that discontinue study drug 
due to progressive disease (see Table 1). 


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Table 1 Escape criteria  
 symptomatic serositis, or  
 flare i.e., a worsening of >30% from baseline in at least 3 of any 6 components part of 
ACR.  
 
 
 
If the investigator judges that a patient must discontinue study drug before the Week 12 visit, 
a Study Drug Discontinuation visit should be performed before standard of care treatment is 
initiated, if possible. If the study drug is discontinued on a scheduled visit, the Study Drug 
Discontinuation visit should be performed instead of the scheduled visit unless the study drug 
is discontinued at the Week 12 visit. For a patient that discontinues study drug before the 
Week 2 visit, the Week 2 visit should still be performed according to the original schedule of 
assessments, see 6.3.3. However, if the Study Drug Discontinuation visit is performed within 
3 days prior to the Week 2 visit, the scheduled Week 2 visit should be omitted. A final 
follow-up call will be conducted 4 weeks after the last IMP administration according to the 
assessments described for the Week 16Tel visit (see 6.5.1.8).  
All patients included in the study will be carefully monitored by the investigator and if there 
is a need patients can withdraw from the study at any time, see 6.3.3. 
If a patient is on glucocorticoid treatment the dose can be tapered starting earliest at the Week 
2 visit. The patient must have reached at least ACR50 response with no fever in the preceding 
7 days at the visit initiating tapering. 
If a patient develops MAS, the patient will terminate the study treatment and will be treated 
according to standard of care. If the MAS event occurs before the Week 2 visit it is preferred, 
if possible, that the patient returns to conduct the Week 2 visit according to the schedule of 
assessments. For all patients that are diagnosed with MAS, irrespective of timepoint in the 
study, a follow-up call should be conducted 4 weeks after the last IMP administration 
according to the assessments described for the Week 16Tel visit (see 6.5.1.8) before the 
patient is withdrawn from the study. MAS is defined as an event of special interest in this 
study and must be reported as a serious adverse event. 
PK sampling will be conducted in all patients at all study visits. In addition, repeated PK 
sampling (4-5 time points) will be conducted at Week 12 at a selected number of sites in 
approximately 30 patients (see 6.5.6.1.1). All patients at these pre-selected sites will be asked 
to participate in the repeated PK sampling until the target number of patients have completed 
the repeated PK sampling. If a patient declines to participate in the repeated PK sampling, 
he/she will still be eligible to participate in the main study. When the overall number of 81 
patients has been reached in the study the enrollment will be stopped regardless of whether 
the target number of repeated PK patients has been reached. 
6.2 
Discussion of study design 
A randomized placebo controlled double-blind study is the optimal way to document safety 
and efficacy of an investigational product. In this study the number of patients receiving 


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placebo has been kept to a minimum, which means that only one third of the patients will be 
randomized to placebo and two thirds will be randomized to active treatment in two dose 
levels.  
The main comparison will be between anakinra (combined dose groups) and placebo at 
week 2. In order to be able to evaluate the primary endpoint at week 2, patients that 
discontinue study drug before week 2 will be encouraged to do a Study Drug Discontinuation 
visit as well as the Week 2 visit (if the Study Drug Discontinuation visit is performed within 
3 days prior to the Week 2 visit, the scheduled Week 2 visit should be omitted). Patients who 
discontinue study drug will receive standard of care. Options for standard of care will be 
determined at the discretion of the investigator in dialogue with the patient/caregiver. As 
patients may already have been administered anakinra in the study this should be taken into 
consideration when switching to standard of care. 
Since IL-1 inhibition has a rapid onset of effect, supported by the published data showing that 
approximately 90% of patients became afebrile after three days of anakinra treatment and the 
fact that ACR response rates were similar at day 15 and day 29 in the study with the IL-1 
inhibitor canakinumab, it is appropriate to evaluate the primary endpoint after two weeks 
treatment with anakinra (19, 20, 34). Sustained efficacy of anakinra treatment will be 
evaluated during the 12 week period for patients who are responders at week 2. In addition, 
time to study drug discontinuation will be an endpoint for evaluation of efficacy in the study 
as well as the possibility to taper glucocorticoid treatment. 
Trough and repeated PK assessments will be included in this study in order to characterize 
the pharmacokinetics of anakinra in this patient population.  
 
Rationale for selection of doses 
The selection of doses is based on published studies, clinical practice and treatment 
guidelines. 
Anakinra is recommended for treatment of SJIA in the Consensus Treatment Plans for New-
Onset SJIA by the CARRA (23). Based on clinical experience, CARRA recommends a 
starting dose of 2 mg/kg/day (max 100 mg) and a maximum dose of 4 mg/kg/day (max 200 
mg). 
The proposed doses of 2 and 4 mg/kg/day are also supported by previous published 
experiences and the maximum dose of 4 mg/kg/day was used in a number of the supporting 
publications (19, 20, 32, 35). In a few cases, 4 mg/kg/day has been used as the starting dose 
(37).  
In a published study by Vastert et al 2014, anakinra was used as first-line therapy in patients 
with new-onset SJIA (19). Patients fulfilled the ILAR criteria for SJIA. Anakinra 2 
mg/kg/day was used as a starting dose, with a maximum dosage of 100 mg/day, in all 20 
included patients. The 2 mg/kg/day dose was maintained in 18 of the patients and increased 
to 4 mg/kg/day in 2 patients. Treatment was stopped if patients met at least adapted ACR 
Pedi 90 improvement (i.e., 90% improvement of ACR with absence of fever) after 3 months 
treatment. The authors concluded that an excellent response was observed in nearly all 
patients within 3 months, and that more than 80% of the patients achieved persistent disease 
remission, either on or off medication, during a mean follow-up of 2 years and 8 months. 


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Population PK parameter estimates of anakinra based on an analysis of sparse sampling 
concentration data from children and adolescents was published by Urien et al 2013 (28). The 
study included data from 87 patients of which 22 were SJIA patients with a median age of 7.6 
years (range 2.26 to 16.8 years) and a median body weight of 21 kg (range 10 to 83 kg). 
From a PK point of view, higher dose levels are needed in small children due to higher 
clearance in children with lower body weight (see Table 2). As an example, based on this 
population PK analysis, a patient with a body weight of 20 kg is predicted to require a dose of 
4 mg/kg/day to achieve similar anakinra exposure (AUC0-24h, ss and Cmin, ss) as a dose of 
2mg/kg/day in a 50 kg patient.  
Table 2 Predicted exposure of anakinra in three hypothetical patients 
 
 
Anakinra 2 mg/kg/day (max 100 mg) 
Anakinra 4 mg/kg/day (max 200 mg) 
BW 
AUC0-24h,ss1 
(ngh/mL) 
Cmin,ss1  
(ng/mL) 
AUC0-24h,ss1 
(ngh/mL)  
Cmin,ss1  
(ng/mL)  
20 kg 
11561 
95 
23121 
191 
50 kg  
18776 
236 
37552 
472 
100 kg 
13556 
212 
27111 
424 
1 Predicted steady-state exposure based on the following published population PK parameters for anakinra (28): 
  ka = 0.38 (h-1); CL/F = 0.847 x (BW/70)0.47 (L/h); V/F = 2.581 x (BW/70)0.76 (L) 
 
There are no guidelines available for the treatment of AOSD. The efficacy of anakinra in the 
treatment of AOSD has been reported in retrospective case series and in one prospective, 
randomized, open-label trial (36). In a meta-analysis evaluating the evidence for efficacy of 
anakinra in AOSD, all included published studies reported the use of a dosage regimen of 
100 mg/day. The overall remission rate with anakinra estimated in the eight studies included 
in the meta-analysis was more than 80% (33). The efficacy of higher doses of anakinra in 
AOSD patients has not previously been evaluated in a systematic manner. Thus, in the 
current study, including also the higher dose level 4 mg/kg with a maximum dose of 200 mg 
anakinra, we will evaluate if higher dose levels would give further benefit for AOSD patients. 
 
Rationale for primary endpoint 
ACR30 is an established measurement of efficacy in arthritis studies (38, 39, 40, 41). The 
addition of “absence of fever attributable to the disease in the preceding 7 days” makes the 
primary endpoint more appropriate to capture improvements in the clinical features of Still’s 
disease (42). ACR30 with the addition of fever is recommended by CARRA for treatment 
outcome research in SJIA and has been used in pivotal regulatory studies with canakinumab 
and tocilizumab in SJIA. ACR30 is not age specific and is therefore also well suited to study 
treatment outcome in the adult population.  
6.3 
Selection of study population 
A total of 81 patients will be randomized, 54 patients to anakinra and 27 patients to placebo 
treatment. At least a third of the randomized patients should have had a disease onset before 
the age of 16, and at least a third of the randomized patients in the study should have had a 
disease onset at the age of 16 or above.  


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Inclusion criteria 
A patient must fulfill all of the following criteria in order to be included in the study: 
1. Signed informed consent. 
2. Male and female patients with a body weight ≥ 10 kg. 
3. Diagnosis of Still’s disease:  
a. If < 16 years of age at disease onset, according to adapted ILAR criteria i.e., 
CARRA-criteria for SJIA. See Appendix 1.  
b. If ≥16 years of age at disease onset, according to Yamaguchi criteria. 
See Appendix 1. 
4. If currently on glucocorticoid treatment, a stable dose for at least 1 week prior to 
randomization. Maximum dose allowed is 1 mg/kg/day, up to a maximum of 
60 mg/day.  
5. If currently on methotrexate treatment, a stable dose for at least 8 weeks prior to 
randomization. Maximum dose allowed is 20 mg/m2/week. If prior treatment with 
methotrexate, discontinuation is required to be at least 4 weeks prior to 
randomization. 
6. Active disease confirmed by the following three signs and symptoms: 
a. Active arthritis in ≥1 joint 
b. CRP >30 mg/L 
c. At least one fever episode attributable to the disease within one week before 
randomization.  
(Definition of fever: body temperature ≥38.0°C) 
7. Female patients of childbearing potential must use an effective method of 
contraception during the study (abstinence being a possible option) as well as present 
a negative pregnancy test prior to randomization. 
8. Negative interferon-gamma release assay or PPD test within 2 months prior to 
randomization. If not available, a test should be performed at day of randomization 
(see 6.5.5.6.1).  
 
Exclusion criteria 
The presence of any of the following will exclude a patient from inclusion in the study: 
1. Diagnosis of Still’s disease more than 6 months prior to randomization.  
2. Previous randomization into this study  
3. Participation in another concurrent clinical interventional study within 30 days of 
randomization. 
4. Treatment with an investigational drug within 5 half-lives prior to randomization. 
5. Previous or current treatment with anakinra, canakinumab or any other IL-1 inhibitor.  
6. Use of the following therapies prior to randomization:  
 Narcotic analgesics within 24 hours prior to randomization  
 Dapsone or etanercept within 3 weeks prior to randomization  
 Intraarticular, intramuscular or intravenous administration of glucocorticoids 
or intravenous Ig within 4 weeks prior to randomization 
 Intravenous Ig with proven Still’s disease modifying effect, leflunomide, 
infliximab, or adalimumab within 8 weeks prior to randomization 


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 Thalidomide, cyclosporine, mycophenolate mofetil, 6-mercaptopurine, 
azathioprine, cyclophosphamide, chlorambucil, or any other 
immunosuppressant within 12 weeks prior to randomization 
 Tocilizumab within 12 weeks prior to randomization or any other 
immunomodulatory medication within 4 half-lives prior to randomization 
 Rituximab within 26 weeks prior to randomization 
7. Live vaccines within 1 month prior to randomization. 
8. Known presence or suspicion of active, chronic or recurrent bacterial, fungal or viral 
infections, including tuberculosis, HIV infection or hepatitis B or C infection. 
9. Clinical evidence of liver disease or liver injury as indicated by presence of abnormal 
liver tests 
 AST or ALT >5 x ULN, or  
 AST or ALT >3 x ULN accompanied by elevated bilirubin >2 x ULN. 
10. Presence of severe renal function impairment CKD stages 4 and 5 (estimated 
creatinine clearance < 30 mL/min/1.73m2). 
11. Presence of neutropenia (ANC < 1.5 x 109/L). 
12. Presence or suspicion of MAS at baseline. (See Appendix 2 for guidance).  
13. A diagnosis of MAS within 2 months prior to randomization.  
14. History of malignancy within 5 years. Exceptions are basal cell skin cancer, 
carcinoma-in-situ of the cervix or low-risk prostate cancer after curative therapy. 
15. Known hypersensitivity to E coli-derived proteins, or any components of Kineret 
(anakinra). 
16. Pregnant or lactating women.  
17. Foreseeable inability to cooperate with given instructions or study procedures. 
18. Presence of any medical or psychological condition or laboratory result that in the 
opinion of the investigator can interfere with the patient’s ability to comply with the 
protocol requirements or makes the patient not appropriate for inclusion to the study 
and treatment with IMP. 
 
Study drug discontinuation and withdrawal of patients from the 
study 
A patient can discontinue study drug and withdraw from the study at any time. If a patient 
discontinues study drug, a Study Drug Discontinuation visit should be performed before 
standard of care treatment is initiated, when possible. If the study drug is discontinued on a 
scheduled visit, the Study Drug Discontinuation visit should be performed instead of the 
scheduled visit unless the study drug is discontinued at the Week 12 visit.   
For patients that discontinue study drug before the Week 2 visit, a Week 2 visit should still be 
performed according to the original schedule of assessments unless consent is withdrawn. 
However, if the Study Drug Discontinuation visit is performed within 3 days prior to the 
Week 2 visit, the scheduled Week 2 visit should be omitted. 
For patients who discontinue study drug and are unable to visit the clinic before initiation of 
standard of care treatment appropriate assessments should be performed to substantiate the 
reason for study drug discontinuation, e.g. local lab results. 
A final follow-up call will be conducted 4 weeks after the last IMP administration according 
to the assessments described for the Week 16Tel visit.  


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If a patient discontinues study drug because of an AE, the reason should always be stated as 
‘adverse event’ irrespective of whether the study drug discontinuation was decided by the 
investigator or due to patient’s withdrawal of consent. 
Patients who fail to return to the clinic or cannot be reached by telephone for follow-up 
assessments will be contacted by the study site personnel (2 documented phone calls 
followed by 1 registered letter) in an attempt to have them comply with the protocol and to 
document the reason for withdrawal.   
Irrespective of when a patient is withdrawn a follow-up call should be conducted 4 weeks 
after the last IMP dose, according to Week 16Tel (see 6.5.1.8).   
 
Replacement of withdrawn patients 
A randomized patient that is withdrawn will not be replaced.   
 
Screening failures 
Screening failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized into the study. A minimal set of screening failure 
information is required which includes demographics, reason for screen failure, failed 
eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screening failure) may 
be rescreened. Rescreened participants should be assigned the same enrolment number as for 
the initial screening. 
6.4 
Treatments 
 
Treatments administered  
Patients will receive treatment for 12 weeks, either anakinra or placebo depending on the 
randomization schedule, see Table 3. The anakinra doses that will be evaluated are 2 
mg/kg/day (max 100 mg/day) and 4 mg/kg/day (max 200 mg/day). The dose will be adjusted 
according to actual body weight (rounded to the nearest kg) and will remain the same 
throughout the study. See dosing instructions in Appendix 3. 
The placebo will be given in a corresponding volume of the anakinra dose. These means that: 
 Patients randomized to 2 mg/kg/day (max 100 mg/day) and patients with a body 
weight < 29 kg and randomized to 4 mg/kg/day (max 200 mg/day) or placebo will 
only require one injection per day.  
 Patients randomized to 4 mg/kg/day (max 200 mg/day), or placebo, with a body 
weight ≥ 29 kg will require two injections per day.  
 
 
 
 
 


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Table 3 Investigational medicinal products  
Investigational 
product 
Daily dose 
Dosage form 
Route 
Dosage regimen 
anakinra 
2 mg/kg (max 100 mg) 
Solution for injection in 
pre-filled syringe 
Subcutaneous 
Once daily 
corresponding 
volume of 
placebo 
Solution volume 
equivalent to 2 mg/kg  
(max 100 mg [0.67 
mL]) 
Solution for injection in 
pre-filled syringe 
Subcutaneous 
Once daily 
anakinra 
4 mg/kg (max 200 mg) 
Solution for injection in 
pre-filled syringe 
Subcutaneous 
Once daily 
corresponding 
volume of 
placebo 
Solution volume 
equivalent to 4 mg/kg  
(max 200 mg 
[1.33 mL]) 
Solution for injection in 
pre-filled syringe  
Subcutaneous 
Once daily 
 
Identity of investigational medicinal products 
The investigational product anakinra is delivered as a sterile solution for injection, pre-filled 
in a single-use graduated syringe with the strength 100 mg. The total volume of injection is 
0.67 mL and the concentration of anakinra in the solution is 150 mg/mL. The pre-filled 
graduated syringe has a pre-attached 29 Gauge thin wall half inch needle, a butyl rubber 
plunger and a latex free rigid needle shield.  
The placebo is also delivered as a sterile solution for injection, in an identical single-use pre-
filled graduated syringe. The placebo consists of the active product vehicle (0.67 mL) but 
without the active ingredient, anakinra. 
The anakinra drug substance is manufactured by Boehringer Ingelheim (Vienna, Austria) and 
Pfizer Health AB (Strängnäs, Sweden) and drug product and placebo are manufactured by 
Patheon Italia SpA (Monza, Italy).  
The IMP is packaged and labeled by Rechon Life Science AB (Limhamn, Sweden). Each kit 
consists of 7 syringes. 
Labeling of IMP complies with national regulatory requirements. 
 
Storage, preparation and administration of IMP 
The IMP (anakinra or placebo pre-filled graduated syringes) must be stored at refrigerated 
conditions at 2-8 °C (36°-46°F) in a secure area at the study center. The investigational 
product should be kept in its original carton and away from light both at the clinic and when 
stored by the patient. The IMP should not be frozen or shaken. The IMP will be transported 
by the patients to their homes in provided cooler bags.  
Possible deficiencies related to the handling, quality or identity of the IMP should be reported 
both to the study monitor and also directly to complaints@sobi.com. Possible deficiencies 
related to site distribution or storage of investigational products should be reported in 
accordance with instructions provided in the pharmacy manual.  


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6.4.3.1 
Preparation and administration of IMP  
The IMP is intended to be injected by the patient or the caregiver. Each IMP syringe contains 
0.67 mL equivalent to 100 mg anakinra or placebo. Depending on the patient weight and 
randomized dose, the full content of a syringe or part of the content of a syringe will be 
injected to match the prescribed dose.  
The prefilled graduated syringe(s) should be taken out from cold storage and be placed in 
room temperature 30 minutes before injection.  
The IMP should be administered at the same time each day, preferably in the morning, by a 
s.c. injection into fat tissue in one of the following areas: 
 outer area of the upper arms 
 abdomen (except the 2-inch area around the belly button) 
 front of the middle thighs 
 upper outer areas of the buttocks 
The IMP administration will be supervised by the investigator or investigational site staff at 
the Day 1 visit and the exact time point for the administration will be recorded. At all other 
occasions when the IMP is self-administered the patient will record the exact time point of 
the administration in the diary.  
The graduated syringes are for single use and must be discarded after use.  
See detailed instructions regarding preparation and administration of IMP in the pharmacy 
manual. 
 
Method of assigning patients to a treatment group 
A total of 81 patients will be randomized, 54 patients are planned to be randomized to 
anakinra treatment and 27 patients are planned to be randomized to placebo. The different 
treatment groups are; 
 placebo (corresponding volume of anakinra 2 mg/kg/day [max 100 mg/day]), or 
 placebo (corresponding volume of anakinra 4 mg/kg/day [max 200 mg/day]), or 
 anakinra 2 mg/kg/day (max 100 mg/day) or  
 anakinra 4 mg/kg/day (max 200 mg/day)  
The ratio between the treatment groups is 1:1:2:2, i.e. the ratio placebo:ankinra is 1:2.  
The randomization numbers will be generated in blocks. Each block will include the four 
treatment groups per the ratio described above. The block size will not be revealed before 
breaking of the blind.  
The randomization will be stratified by age at onset of disease (< 16 years, ≥ 16 years) and 
glucocorticoid use at inclusion (yes, no) with a requirement to randomize at least a third of 
the patients with an age at onset of disease < 16 years and a third of the patients with an age 
at onset ≥ 16 years. Medidata Balance Randomization and Trial Supply System will be used 
for IRS and Biostatistics at DCRI will be responsible for generating the randomization 
scheme, which will link sequential patient randomization numbers to treatment codes.  


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Blinding and unblinding 
6.4.5.1 
Blinded treatment assignment   
The treatment assignment will be blinded (placebo and active treatment) for the patients, the 
investigators and any personnel involved with the study conduct or evaluation at the 
investigational sites, ARO and sponsor. In order to avoid the need to give all patients two 
injections daily the placebo will be given in a corresponding volume of the anakinra dose 
(see 6.4.4).  
Unblinding, i.e., breaking the code for an individual patient during the study, is restricted to 
emergency situations and should only be used under circumstances where knowledge of the 
treatment is necessary for the proper handling of the patient. The decision to break the code 
must be made by the investigator. The study monitor and sponsor must as soon as possible be 
informed about the code break. 
Unblinding should be documented according to instructions in the Medidata Balance 
Randomization and Trial Supply System. 
6.4.5.2 
Blinded independent joint assessor 
To minimize bias from observed efficacy or laboratory changes a blinded independent and 
trained assessor will perform the joint examination. To improve consistency between 
evaluations, it is strongly recommended that the assessments are conducted by the same 
assessor at a site.  
 
Prior and concomitant therapy 
Intraarticular, intramuscular and intravenous administration of glucocorticoids are prohibited 
within 4 weeks prior to randomization and during the study. Other administration of 
glucocorticoid treatment is allowed as concomitant medication during the study if the patient 
has had a stable dose for at least 1 week prior to randomization. Maximum dose allowed is 
1 mg/kg/day (max 60 mg/day). If the patient is on glucocorticoid treatment, the dose can be 
tapered starting earliest at the Week 2 visit. The patient must have reached at least ACR50 
response with no fever in the preceding 7 days at the visit initiating tapering. A suggested 
glucocorticoid tapering schedule is provided in Appendix 4. All other glucocorticoid 
treatment is prohibited during the study except topical and inhaled.  
Methotrexate is allowed as concomitant medication during the study if the patient has had a 
stable dose for at least 8 weeks prior to randomization. The dose should remain stable 
throughout the study as long as it is well tolerated. If prior treatment with methotrexate, 
discontinuation is required to be at least 4 weeks prior to randomization.  
Initiation of continuous NSAID treatment is prohibited during the study. However on demand 
treatment is allowed. 
Narcotic analgesics are not allowed 24 hours prior any study visit. 
Use of the following treatments are not allowed concomitantly with the IMP (wash-out 
periods before randomization are stated in the exclusion criteria see 6.3.2):  
 Intraarticular, intramuscular or intravenous administration of glucocorticoids 
 Intravenous immunoglobulins 


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 Canakinumab or any other IL-1 inhibitor 
 Tocilizumab, rituximab or any other immunomodulatory medication 
 Etanercept, adalimumab, infliximab, or any other TNF inhibitor (investigational or 
marketed)  
 Dapsone or mycophenolate mofetil,Leflunomide, thalidomide or cyclosporine, 6-
Mercaptopurine, azathioprine, cyclophosphamide, chlorambucil, or any other 
immunosuppressant 
 Use of any other investigational drug 
Live vaccines is not allowed within 1 month prior to randomization and until after 1 month 
following the last study dose. Inactivated vaccines may be permitted according to the 
investigator’s discretion. The investigator should instruct the patient to notify the study site 
about any new medications he/she takes after the start of the study drug. All medications and 
significant non-drug therapies administered after the patient starts treatment with study drug 
until Week 16Tel must be listed on the concomitant medication CRF page.  
Following the 12 week double blind treatment, the patient will be treated at the discretion of 
the investigator according to standard of care.  
 
Treatment compliance 
IMP accountability records will be kept. The pharmacy and the investigator must maintain 
accurate records demonstrating date and amount of IMP(s) received, to whom and by whom 
administered or dispensed (patient-by-patient accounting), and accounts of returned IMP(s) 
and any IMP accidentally or deliberately destroyed. At the end of the study, any remaining 
IMP(s) will be returned to identified drug depot for destruction, or destroyed locally. In either 
case, a certificate of destruction must be issued. 
 
Overdose management 
For this study, any dose of IMP greater than dose prescribed will be considered an overdose. 
No dose-limiting toxicities have been observed during clinical studies and a maximum 
tolerated dose for anakinra has not been established. No specific treatment is indicated for 
IMP overdose. If an overdose of IMP is administered, the actual dose taken will be recorded 
in the CRF, and any untoward medical occurrence associated with an overdose will be 
recorded the same way as any adverse event (see 6.5.5.1). 
6.5 
Efficacy, safety, pharmacokinetic, and exploratory assessments 
 
Study schedule 
See the schedule of assessments in Appendix 5 
6.5.1.1 
Screening visit (optional)  
The screening may be done at a separate visit before the baseline visit to identify patients that 
could be suitable for the study and/or to ensure that required lab results are available before 
randomization (see 6.5.5.6.1). Applicable ICFs must be obtained prior to any screening 


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activities (see 2.3). Once the ICF has been signed, the patient will be assigned an enrolment 
number. 
Any SAE that occur after the informed consent has been signed must be reported (see 
6.5.5.1.4). 
6.5.1.2 
Baseline visit, Day 1 
If a screening visit has not been performed applicable ICFs must be obtained prior to any 
study related activities. Once the ICF has been signed, the patient will be assigned an 
enrolment number. 
Any SAE that occur after the informed consent has been signed must be reported.  
All inclusion and exclusion criteria should be reviewed (see 6.3) to assess patient’s eligibility. 
The laboratory tests that are needed for evaluation of inclusion and exclusion criteria should 
be performed before randomization (see 6.5.5.6.1). If it is expected that any of the lab results 
are not available within reasonable time a screening visit should be performed the day before 
(the eligibility laboratory results are valid for 36 hours). See 6.5.1.1. However, a patient can 
be randomized before results from a interferon-gamma release assay or a PPD test has been 
confirmed. If the results from this test is positive, that is not due to vaccination (PPD), the 
patient must be withdrawn from the study (see 6.3.3).  
Data will be collected on medical history (see 6.5.2), demographics (see 6.5.3) and prior and 
concomitant medication (see 6.4.6). Vital signs (see 6.5.5.2) and physical examination (see 
6.5.5.3) will be performed. 
If the patient has been found eligible, the patient will be randomized . 
As part of ACR the physician global assessment of disease activity, patient or parent global 
assessment of overall well-being, the patient or parent assessment of physical function, 
assessment of number of joints with active arthritis and number of joints with limited range 
of motion will be assessed (see 6.5.4.1). Global assessment of the patient disease related pain 
(see 6.5.4.2), and a 12-lead ECG (see 6.5.5.4) will be assessed.  
Prior to the first IMP administration, blood samples will be collected for central laboratory 
assessments (see 6.5.5.6.2) immunogenicity assessments (see 6.5.5.5 ), IL-1Ra/anakinra 
serum concentration assessments (see 6.5.6) and exploratory inflammatory biomarkers (see 
6.5.7). For patients consenting to pharmacogenetic assessment an additional blood sample 
will be collected at a suitable visit after randomization (see 6.5.7.2). 
Finally, the first dose of IMP is to be administered and the time point of administration will 
be recorded. The patient or patient’s caregiver will be instructed how to administer the IMP 
dose on a daily basis and how to complete the diary (see 9.2) and IMP covering the period 
until next visit will be dispensed.  
Adverse events, will be recorded from the time of the first IMP administration (see 6.5.5.1). 
6.5.1.3 
Day 4Tel telephone follow-up 
A telephone contact will be performed at Day 4 for retention reasons, to follow-up on 
compliance of study procedures and to answer any additional questions from patients or 
parents/caregivers. Data will be collected on adverse events. If not possible to reach patient 
or parent/caregiver this should be documented in the CRF.  


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6.5.1.4 
Week 1 visit 
The visit should be scheduled as close as possible to 24 hours after last IMP dose.  
Assessments conducted at the visits are the ACR variables, physical examination including 
complete joint exam, vital signs, concomitant medication and global assessment of the patient 
disease related pain. If any fever or rash attributable to the disease has occurred during the 
last 24 hours, this will be recorded. Data from the patient diary will support the evaluation.  
Blood will be collected for central laboratory assessments, immunogenicity assessments, 
IL-1Ra/anakinra serum concentration assessments and exploratory inflammatory biomarkers. 
Adverse events as well as number of days of absenteeism from school or work since the 
baseline visit (also recorded for guardians where appropriate) will be recorded. The patient 
diary will be reviewed to confirm that instructions are followed and IMP covering the period 
until next visit will be dispensed. After all assessments have been performed, the daily IMP 
administration can occur.  
6.5.1.5 
Week 2 visit 
The visit should be scheduled as close as possible to 24 hours after last IMP dose.   
Assessments conducted at the visit are the ACR variables, physical examination including a 
complete joint count, vital signs, concomitant medication, and global assessment of the 
patient disease related pain. If any fever or rash attributable to the disease has occurred 
during the 7 days preceding the Week 2 visit, this will be recorded. Data from the patient 
diary will support the evaluation.  
Blood samples will be collected for central laboratory assessments, immunogenicity 
assessments, IL-1Ra/anakinra serum concentration assessments and exploratory 
inflammatory biomarkers. Adverse events as well as number of days of absenteeism from 
school or work since previous visit (also recorded for guardians where appropriate) will be 
recorded. The patient diary will be reviewed to confirm that instructions are followed and 
IMP covering the period until next visit will be dispensed. After all assessments have been 
performed, the daily IMP administration can occur. 
If the patient is on glucocorticoid treatment the possibility to start tapering can be 
commenced earliest at the Week 2 visit. The patient should have reached at least ACR50 
response with no fever in the preceding 7 days at the visit initiating tapering. See Appendix 4 
for suggested glucocorticoid tapering instructions. 
6.5.1.6 
Week 4 and Week 8 visits 
The visits will be scheduled as close as possible to 24 hours after last IMP dose.  
Assessments conducted at the visits are the ACR variables, physical examination including 
complete joint exam, global assessment of the patient disease related pain, vital signs, and 
concomitant medication. If any fever or rash attributable to the disease has occurred during 
the 7 days preceding the visit, this will be recorded. Data from the patient diary will support 
the evaluation.  
Blood samples will be collected for central laboratory assessments, immunogenicity 
assessments and IL-1Ra/anakinra serum concentration assessments. Adverse events as well 
as number of days of absenteeism from school or work since previous visit (also recorded for 
guardians where appropriate) will be recorded. The patient diary will be reviewed to confirm 


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that instructions are followed and IMP covering the period until next visit will be dispensed. 
After all assessments have been performed at the visit the daily IMP administration can 
occur. 
If the patient is on glucocorticoid treatment consider the possibility to taper if the patient has 
reached at least ACR50 response with no fever in the preceding 7 days. See Appendix 4 for 
suggested glucocorticoid tapering instructions.  
6.5.1.7 
Week 12 visit 
The visit will be scheduled as close as possible to 24 hours after last IMP dose.  
Assessments conducted at the visit are the ACR variables, physical examination including 
complete joint exam, global assessment of the patient disease related pain, vital signs, and 
concomitant medication. If any fever or rash attributable to the disease has occurred during 
the 7 days preceding the Week 12 visit, this will be recorded. Data from the patient diary will 
support the evaluation.  
Blood samples will be collected for central laboratory assessments, immunogenicity 
assessments, IL-1Ra/anakinra serum concentration assessments and exploratory 
inflammatory biomarkers. Inactive disease (see 6.5.4.5) will be evaluated. Adverse events as 
well as number of days of absenteeism from school or work since previous visit (also 
recorded for guardians where appropriate) will be recorded. The patient’s diary will be 
reviewed. Finally all IMP should be collected from the patient and accounted for. 
For patients enrolled in the repeated-dose PK sampling, this visit should be scheduled on the 
same day as the last dose of IMP administration is planned. For details regarding the blood 
sampling procedure and IMP administration see 6.5.6.1.  
6.5.1.8 
Week 16Tel telephone follow-up 
A follow-up telephone call will be made at Week 16Tel (End of study). Data will be collected 
on concomitant medications and adverse events.  
6.5.1.9 
Study Drug Discontinuation visit 
The visit is performed if the investigator judges that a patient must discontinue study drug 
before the Week 12 visit. A Study Drug Discontinuation visit should be performed before 
standard of care treatment is initiated, when possible. If the study drug is discontinued on a 
scheduled visit, the assessments for the Study Drug Discontinuation visit should be 
performed instead of the assessments of the scheduled visit, unless the study drug is 
discontinued at the Week 12 visit. 
Assessments conducted at the visit are the ACR variables, physical examination including 
complete joint exam, global assessment of the patient disease related pain, vital signs, and 
concomitant medication. If any fever or rash attributable to the disease has occurred during 
the 7 days preceding the Study Drug Discontinuation visit, this will be recorded. If this visit 
is performed before the Week 1 visit, fever and rash attributable to the disease during the 24-
hours preceding the Study Drug Discontinuation visit will be recorded. Data from the patient 
diary will support the evaluation.  
Blood samples will be collected for central laboratory assessments, immunogenicity 
assessments, IL-1Ra/anakinra serum concentration assessments and exploratory 


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inflammatory biomarkers. Inactive disease (see 6.5.4.5) will be evaluated. Adverse events, 
number of days of absenteeism from school or work since previous visit (for guardians where 
appropriate) as well as morning stiffness will be recorded.  The reason for study drug 
discontinuation is recorded in the CRF. “Escape criteria” can be evaluated in the CRF. 
Finally, all IMP should be returned and accounted for.  
Patients that discontinue study drug before the Week 2 visit should still return for a Week 2 
visit according to original schedule of assessments. If the Study Drug Discontinuation visit is 
performed within 3 days prior to the Week 2 visit, the scheduled Week 2 visit should be 
omitted. 
A final follow-up call will be conducted 4 weeks after the last IMP administration according 
to the assessments described for the Week 16Tel. 
 
Medical history 
The details of the patient’s relevant medical history as judged by the investigator will be 
recorded in the CRF at visit Day 1 (baseline).  
 
Demographics 
The patient´s date of birth, gender, race and ethnicity will be recorded in the CRF at the first 
visit, either the optional screening visit or Day 1 (baseline). 
 
Efficacy assessments 
6.5.4.1 
ACR with absence of fever 
The ACR30 criteria will be used to determine efficacy defined as improvement from baseline 
of at least 30% in at least 3 of response variables 1 to 6, with no more than one variable 1 to 6 
worsening by more than 30% and no intermittent fever attributable to the disease during the 
preceding 7 days.  
 
 
The variables listed below are included in ACR: 
1. Physician global assessment of disease activity (on a 0-100 mm VAS) 
2. Patient/parent global assessment of overall well-being (on a 0-100 mm VAS) 
3. Number of joints with active arthritis 
4. Number of joints with limitation of motion 
5. Assessment of physical function (CHAQ/SHAQ) 
6. CRP (mg/L) 
Definition of fever: Body temperature ≥38.0 °C (100.4 °F) attributable to the disease. 
 
Physician global assessment of disease activity 
The physician will rate the patient’s current condition on a 0-100 mm VAS, ranging from no 
disease activity (0 mm) to very severe disease activity (100 mm). Scores on the 100-mm 
linear scale will be measured to the nearest millimeter from the left. To enhance objectivity, 
the physician must not be aware of the patient or parent global assessment of patient’s overall 


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well-being, when performing his own assessment on that patient. The assessment should be 
completed by the treating physician and is conducted at the following visits: Day1, Week 1, 
Week 2, Week 4, Week 8, Week 12 and, if applicable, the Study Drug Discontinuation visit. 
See Appendix 7.  
 
Patient/parent global assessment of overall well-being 
For patients ≥18 years the global assessment of overall well-being will be assessed on a VAS 
scale ranging from 0–100 mm, from very well (0 mm) to very poor (100 mm). Scores on the 
100-mm linear scale will be measured to the nearest millimeter from the left. For patients 
< 18 years of age at randomization this VAS will be assessed by the CHAQ health status 
index which will be completed by parent or guardian. To ensure consistency, the form should 
be completed throughout the study by the same parent or guardian who completed the 
baseline global assessment.  
The assessment is conducted at the following visits: Day 1, Week 1, Week 2, Week 4, 
Week 8, Week 12 and, if applicable, the Study Drug Discontinuation visit. See Appendix 8 
and Appendix 9. 
 
Number of joints with active arthritis 
The number of joints with active arthritis will be assessed using the ACR definition. The 
ACR definition of active arthritis is any joint with swelling, or in the absence of swelling, 
limitation of motion accompanied by either pain on motion or tenderness not due to 
deformity.  
A blinded independent trained assessor will conduct the joint evaluation at the following 
visits: Day 1, Week 1, Week 2 Week 4, Week 8, Week 12 and, if applicable, the Study Drug 
Discontinuation visit. 
 
Number of joints with limitation of motion 
The number of joints with limitation of motion will be assessed using the ACR definition. A 
blinded independent trained assessor will conduct the joint evaluation at the following visits: 
Day 1, Week 1, Week 2, Week 4, Week 8, Week 12, and, if applicable, the Study Drug 
Discontinuation visit. 
 
Assessment of physical function  
6.5.4.1.5.1 
Childhood Health Assessment Questionnaire  
The CHAQ© is validated to assess physical ability and functional status for children (43, 44). 
Hence, CHAQ will be administered throughout the study for patients that are <18 years of 
age at the time of randomization and will be completed by the parent or guardian as a proxy 
for the child. To ensure consistency, the CHAQ should be completed throughout the study by 
the same parent or guardian who completed the baseline CHAQ assessment, if possible.  
The CHAQ has three indices: disability, discomfort and health status. The disability index 
assesses the physical function in 8 domains: dressing and grooming, arising, eating, walking, 
reaching, personal hygiene, gripping and activities. The score range is 0-3, 0 = without any 
difficulty; 1 = with some difficulty; 2 = with much difficulty; 3 = unable to do. The highest 
scoring item in each domain determines the score for that domain. The mean score for the 8 


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domains is the disability index (range 0-3). The discomfort and health status index will be 
presented separately, see section 6.5.4.2 and 6.5.4.1.2. 
The assessment is conducted at the following visits: Day 1, Week 1, Week 2, Week 4, 
Week 8, Week 12 and, if applicable, the Study Drug Discontinuation visit. See Appendix 9.  
6.5.4.1.5.2 
Stanford Health Assessment Questionnaire 
The SHAQ© is a PRO instrument designed to represent a model of patient-oriented outcome 
assessment for patients ≥18 years (45, 46). The SHAQ assesses the patient’s level of 
functional ability and includes questions of fine movements of the upper extremity, 
locomotor activities of the lower extremity and activities that involve both upper and lower 
extremities. There are 20 questions in eight categories of functioning which represent a 
comprehensive set of functional activities – dressing, rising, eating, walking, hygiene, reach, 
grip and usual activities. The stem of each item asks over the past week “are you able to…” 
perform a particular task. The patient’s response are made on a scale from zero (no disability) 
to three (completely disabled). The score for each category is the single response within the 
category with the highest score (greatest difficulty). The score for the disability index is the 
mean of the eight category scores. 
The assessment is conducted at the following visits: Day 1, Week 1, Week 2, Week 4, 
Week 8, Week 12 and, if applicable, the Study Drug Discontinuation visit. See Appendix 9.  
 
C-reactive protein 
CRP will be determined in serum in order to identify the presence and severity of 
inflammation, and to monitor response to treatment. The assessment is conducted at the 
following visits: Day 1, Week 1, Week 2, Week 4, Week 8, Week 12 and, if applicable, the 
Study Drug Discontinuation visit. 
 
Fever 
For endpoint evaluation in this study the definition of fever is ≥38.0°C (100.4 °F) and should 
be attributable to the disease as judged by the investigator.  
Fever will be measured orally, under the tongue and using the same thermometer (provided 
for the study) throughout the study. The measurement and time point will be recorded in the 
patient’s diary. Fever will be measured during the treatment period whenever there is a fever 
episode. In addition the patient will get a question daily in the diary asking if he/she 
experienced any fever episode that day.  
6.5.4.2 
Global assessment of the patient disease related pain 
For patients ≥18 years the global assessment of disease related pain will be assessed on a 
VAS scale ranging from 0 – 100 mm, from no pain (0 mm) to very severe pain (100 mm). 
Scores on the 100-mm linear scale will be measured to the nearest millimeter from the left. 
For patients < 18 years of age at randomization this VAS will be assessed by the CHAQ 
discomfort index which will be completed by the parent or guardian as a proxy. To ensure 
consistency, the VAS should be completed throughout the study by the same parent or 
guardian who completed the baseline global assessment.  


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The assessment is conducted at the following visits: Day 1, Week 1, Week 2, Week 4, 
Week 8,Week 12 and, if applicable, the Study Drug Discontinuation visit. See Appendix 9 
and Appendix 10. 
6.5.4.3 
JADAS27  
JADAS is a tool that will be assessed for scoring actual disease activity (47, 48, 49). The 
JADAS27 includes 4 measures: physician global assessment of disease activity, patient or 
parent global assessment of overall well-being, 27 active joint count, and CRP. The JADAS 
variables are part of the ACR response criteria with the joint evaluation performed to count 
the number of joints with active disease. The JADAS27 includes the following 27 joints: 
cervical spine, elbows, wrists, metacarpophalangeal joints (from first to third), proximal 
interphalangeal joints, hips, knees, and ankles.  
JADAS27 is calculated as the sum of its four components, physician global assessment of 
disease activity converted to cm from the VAS (0=no activity, 10=maximum activity); patient 
global assessment of well-being converted to cm from the VAS (0=very well, 10=very poor); 
active joint count (0-27); and CRP. Prior to calculation CRP is truncated to a 0 – 10 scale 
according to the following formula: (CRP (mg/l) −10)/10. Before calculation, CRP values 
<10 mg/l are converted to 10 and CRP values >110 mg/l are converted to 110. The JADAS27 
tool yields a global score of 0–57.  
The JADAS27 components are collected and evaluated at the Day 1, Week 2,Week 12 and, if 
applicable, at the Study Drug Discontinuation visit. See Appendix 11. 
6.5.4.4 
Rash  
A typical sign of Still’s disease is the characteristic evanescent salmon-colored rash. Rash is 
an endpoint and will be evaluated throughout the study.  
Any occurrence of rash will be recorded on a daily basis by the patient in the diary. If present 
and attributable to the disease, rash will also be recorded as part of the physical examination 
performed at every visit. In addition, at Week 12 and, if applicable, at the Study Drug 
Discontinuation visit the presence or absence of rash will be recorded to assess “inactive 
disease”.  
6.5.4.5 
Inactive disease 
In the absence of a biologic marker for active or inactive disease, clinical signs and 
symptoms become necessary to determine the state of the disease. Inactive disease is a 
composite of the following parameters: no joints with active arthritis, no fever, no rash, no 
serositis, no splenomegaly, no generalized lymphadenopathy attributable to Still’s disease, 
CRP level within normal limits, physician’s global assessment of disease activity score below 
10 mm on a 100 mm VAS and a documented morning stiffness ≤15 minutes (50).  
The inactive disease assessment is conducted at Week 12 and at the Study Drug 
Discontinuation visit. 
6.5.4.6 
Absenteeism from school or work 
The number of days a patient is away from formal education, or work, due to Still’s disease 
since last visit will be recorded in the CRF at all visits after baseline including a possible 


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Study Drug Discontinuation visit. The same is valid for the patient caregiver when the patient 
requires their attendance.  
 
Safety assessments 
6.5.5.1 
Adverse events 
 
Definitions 
Adverse event 
An AE is any untoward medical occurrence in a patient or trial patient administered a 
pharmaceutical product; the event does not necessarily have a causal relationship with the 
treatment or usage. 
Adverse events include the following: 
 Abnormal test findings, as specified below. 
 Clinically significant signs and symptoms. 
 Changes in physical examination findings. 
 Progression/worsening of underlying disease. 
In addition, signs and symptoms resulting from the following should also be handled 
according to the same principles as Adverse Events: 
 Overdose. 
 Withdrawal of treatment. 
 Interactions. 
 Abuse. 
 Misuse. 
Abnormal test findings 
An abnormal test finding, e.g. abnormal laboratory analysis results, vital signs or ECG, 
should be recorded as an Adverse Event in any of the following situations: 
 The test is associated with accompanying symptoms. Note, that the symptom, not the 
test result, should be recorded as an AE. 
 The test result leads to a medical/surgical intervention including withdrawal of IMP 
or discontinuation from the study. Repeat/confirmatory testing is not considered a 
medical intervention. 
 The investigator considers the test result to be clinically significant. 
Preexisting conditions  
A preexisting condition (i.e., a disorder present before the adverse event reporting period 
started and noted on the pretreatment medical history/physical examination form) should not 


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be reported as an adverse event unless the condition worsens or episodes increase in 
frequency during the adverse event reporting period.  
Worsening of Still’s disease  
A worsening of the disease under study should not be reported as an adverse event unless it 
leads to hospitalization or fulfills any other seriousness criterion. 
Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event. For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event and the resulting appendectomy entered in the comments section of the 
CRF. 
Serious adverse event (SAE) 
An adverse event that meets one or more of the following criteria/outcomes is classified as 
serious: 
 Results in death. 
 Is life-threatening (i.e., at immediate risk of death). 
 Requires in-patient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect (i.e., in an offspring to the study patient). 
Other medically important adverse events that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or the patient may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency 
or abuse. 
SAEs also include any other event that the investigator or sponsor judges to meet SAE 
reporting criteria. Any suspected transmission of an infectious agent via IMP shall also be 
considered an SAE. 
Medical events of special interest for safety surveillance 
MAS is defined as an event of special interest in this study, for rationale see 4.1. The 
diagnosis of MAS will be made by the investigator based on the patients overall clinical signs 
and symptoms, including laboratory changes over time. The 2016 Classification Criteria for 
Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis for 
patients < 16 years of age may be used to guide this assessment for all patients in the study. 
See Appendix 2. If a MAS diagnosis is made at any point after patient signed informed 


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consent, the event must be reported as a serious adverse event and the patient will be 
withdrawn from the study and will be treated according to standard of care, see 6.3.3.  
Hospitalization 
Hospitalization or prolongation of hospitalization, includes transfers within a hospital (e.g., 
from the psychiatric unit to the intensive care unit) and also includes admissions less than 24 
hours. The following situations are not considered hospitalizations (although other SAE 
criteria may still apply): 
 Outpatient procedures / ambulatory care. 
 Emergency department visits. 
Hospitalization in the absence of an adverse event occurring during the study should not be 
considered an SAE. This includes 
 Hospitalization due to a pre-existing condition not associated with a worsening of the 
pre-existing condition. 
 Protocol specified admission. 
 Elective admission, e.g., due to cosmetic surgery. 
 Pre-planned admission for a condition specified at baseline for the patient. 
 Admission or prolongation for administrative reasons, such as technical, practical, or 
social reasons. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is a serious adverse event which is not consistent with the Investigator’s Brochure 
and that the investigator and or Sobi identifies as related to IMP.  
 
Adverse event reporting period 
SAEs should be recorded within the CRF, from the time the patient has signed the informed 
consent until 4 weeks past the last dose of IMP. See Figure 2. Non-serious AEs will be 
recorded within the CRF from the first administration of IMP until 4 weeks past the last dose 
of IMP. Furthermore any SAE, if a causal relationship between the event and the IMP(s) is 
suspected, which occurs after last study visit/telephone follow-up, should be reported (see 
6.5.5.1.4). 
Refer to section 6.5.5.1.6 for information how unresolved adverse events and SAEs should be 
followed up.  
 


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Figure 2 
Adverse event report period 
 
 
 
Eliciting and recording adverse event information 
The investigator is to record all directly observed adverse events, and all adverse events 
spontaneously reported by the patient, in the CRF using concise medical terminology. In 
addition, each patient will be questioned about adverse events at each clinic visit and follow 
up telephone contact following initiation of treatment as described in schedule of assessments 
(see Appendix 5). At the first study visit the question asked will be “Since you started 
treatment have you had any health problems?”. At subsequent visits/telephone calls the 
question asked will be: “Since last asked, have you had any health problems?”. 
When possible and appropriate, a diagnosis rather than individual signs and symptoms shall 
be recorded. The investigator is responsible for obtaining sufficient information to determine 
seriousness, causality and outcome of each adverse event. 
Severity assessment 
The investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum intensity of the adverse event. For the purpose of consistency, these intensity 
grades are defined as follows:  
MILD 
Does not interfere with patient's usual function 
MODERATE  
Interferes to some extent with patient's usual function 
SEVERE 
 
Interferes significantly with patient's usual function 
 
Note the distinction between the gravity (seriousness) and the intensity (severity) of an 
adverse event. Severe is a measure of intensity; thus, a severe reaction is not necessarily a 
serious reaction. For example, a headache may be severe in intensity, but would not be 
classified as serious unless it met one of the criteria for serious events listed above. 
Causality assessment 
For each adverse event, the investigator must make a causality assessment to determine if 
there is a reasonable possibility that the IMP(s) caused the adverse event. The adverse event 
is assessed as related or not related to the IMP(s). 
Adverse Event reporting
Serious Adverse Event reporting
Informed 
consent 
signed  
First dose  
of IMP 
Day 1 
Related SAE reporting
Last dose  
of IMP 
Week 12 
4 weeks past last dose of IMP 
Week 16Tel 
Last study visit/Tel f-up 


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Serious adverse event reporting 
Both serious and non-serious adverse events are to be reported on the adverse event page of 
the CRF as specified in the CRF instructions. 
If an SAE occurs, it must be recorded in the CRF within 24 hours of awareness of the event 
by the investigator. 
All new information obtained, relevant to an SAE report, should be reported within the same 
timeframe as the initial information. 
The investigator shall provide sufficient information to enable a complete medical assessment 
of the reported event. Best efforts shall be made by the investigator to provide additional 
information related to any SAE as requested. 
If the CRF is not functioning, the SAE can be reported by faxing/emailing a completed paper 
SAE report form or by direct telephone communication with DCRI Safety Surveillance at the 
numbers provided below. The event must be updated electronically in the CRF by the clinical 
site once CRF function resumes. 
Fax information to DCRI Safety Surveillance: 
Toll Free Fax: 1-866-668-7138 
Toll Free Phone: 1-866-668-7799 
Email: dcrisafetysurveillance@dm.duke.edu 
Any SAE, if a causal relationship between the event and the IMP(s) is suspected, which 
occurs after the last study visit/telephone follow-up, should be reported to Sobi by e-mail to 
drugsafety@sobi.com or fax to + 46 8 697 32 30 and according to local regulations as 
applicable. 
Sobi will report SUSARs to the relevant competent health authorities in all concerned 
countries according to local regulations. DCRI will notify Duke IRB, central IRBs and 
investigators. Investigators will then report SUSARs to their local IRB/REB as per individual 
IRB/REB guidelines.  
 
Exposure during pregnancy and breastfeeding 
Pregnancy occurring during a clinical investigation, although not considered a serious 
adverse event, must be reported within the same timelines as a serious adverse event. All 
events of exposure to the IMP during pregnancy (female patient or male patient’s partner) or 
breastfeeding shall be recorded within 24 hours of awareness by any study personnel, 
whether the exposure is associated with an adverse event or not. This includes all situations 
where a female is or has been found to be pregnant after being exposed to IMP; directly, 
indirectly or via her partner (paternal exposure). 
The pregnancy will be reported on the appropriate pregnancy form. The investigator is 
responsible for monitoring the outcome of the pregnancy and to inform DCRI (or, if the study 
has been completed, inform Sobi by e-mail to drugsafety@sobi.com or fax to + 46 8 697 32 
30) of relevant information and any information requested related to the outcome of the 
pregnancy.  


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Any adverse events and SAEs observed during and in relation to pregnancy, delivery or 
breastfeeding should be recorded in the CRF and as applicable be reported to DCRI as 
described previously in this section. 
 
Follow-up of unresolved adverse events 
All adverse events should be followed until they are resolved or the investigator assesses 
them as chronic or stable, or the patient’s participation in the study ends, i.e., until the last 
follow-up visit or at the follow-up by telephone Week 16Tel, as applicable. How to report 
changes in an ongoing adverse event during a patient's participation in the study is described 
in the CRF instructions.  
In addition, all serious and non-serious adverse events assessed by the investigator as related 
to the IMP should continue to be followed until they resolve or until the investigator assesses 
them as “chronic” or “stable”, even after the patient's participation in the study is over, but 
without further recordings into the CRF.  
6.5.5.2 
Vital signs  
Vital signs (blood pressure, heart rate and body weight) will be assessed at the Day 1 visit 
before the first IMP administration and at all visits until the Week 12. It will also be assessed 
if the Study Drug Discontinuation visit is performed. Height will only be measured at the 
Day 1 visit. Blood pressure and heart rate will be measured in sitting position after the patient 
has rested comfortably for at least 5 minutes.  
New clinically significant abnormal vital signs values should be reported as adverse events 
(see 6.5.5.1.1 for details).  
6.5.5.3 
Physical examination  
A general physical examination will be assessed at Day 1 and at all visits until the Week 12 
visit. It will also be assessed if the Study drug Discontinuation visit is performed. The 
assessment will be recorded as “normal” or “abnormal”. Abnormalities should be specified.  
At the Week 12 visit and at the Study Drug Discontinuation visit, if applicable, the presence 
or absence of specific physical examination findings which are associated with Still’s disease 
such as rash, serositis, splenomegaly and generalized lymphadenopathy will be recorded to 
assess “inactive disease” (see 6.5.4.5). 
Any persisting abnormalities should be stated each time the examination is performed. If any 
abnormalities are reported at baseline they should be recorded as medical history. New 
abnormalities reported after first dose of IMP should be recorded as AEs (see 6.5.5.1.1 for 
details).  
The presence or absence of signs of joint inflammation will not be reported as AEs (see 
6.5.5.1.1 Preexisting conditions/Worsening of Still’s disease) but will be captured in joint 
assessment as part of ACR.  
Any occurrence of rash will be recorded on a daily basis by the patient in the diary and as 
part of the physical examination assessment performed at the visits (see 6.5.4.4). If not 
judged to be attributable to the disease it should be recorded as an AE.   


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6.5.5.4 
Electrocardiogram 
A baseline 12-lead ECG will be recorded before the first IMP administration, at the Day 1 
visit. The 12-lead ECG recordings will be measured in supine position after the patient has 
rested comfortably for at least 5 minutes.  
The ECGs will be reviewed and documented in the CRF. If a patient shows an abnormal 
ECG, additional safety recordings may be made and the abnormality followed to resolution if 
required. If any clinically significant abnormalities are found at baseline they should be 
recorded as medical history. However, if findings are judged serious it should be reported as 
a SAE (see 6.5.5.1.1 for details). 
6.5.5.5 
Anti-drug antibodies 
Blood samples for determination of ADA will be collected before the first IMP 
administration at the Day 1 visit and at all visits until the Week 12. It will also be collected if 
the Study Drug Discontinuation visit is performed. Once dosing with IMP has started, the 
ADA samples should preferably be taken 24 hours after a previous dose of anakinra or as 
close to the next IMP administration as possible in order to improve detection of ADA. 
The sampling handling procedures, including the time of each blood collection, the time of 
placement of sera into frozen storage (at the end of the sample workup) and the date of 
transfer or shipment of the samples to the responsible analyst will be documented in detail in 
the laboratory manual. The procedures and materials used, e.g., collection and storage tubes, 
will be described in the laboratory manual. 
If the blood volume required for the planned lab assessments at any visit exceeds the 
maximum allowed blood volume collection the assessments for the study should be 
prioritized according to the specification in the laboratory manual. 
Serum samples to determine ADA will be analyzed by York Bioanalytical Solutions Limited 
using validated methods. This includes a bridging format immunoassay for screening of 
samples using a statistically defined cut-point for determination of a positive result and a 
confirmatory assay with a statistically pre-defined confirmatory cut-point. Confirmed 
positive samples will be further analyzed for antibody titers and for potential cross-reactivity 
with IL-1Ra produced by a human cell line to achieve an endogenous-like glycosylation 
pattern to mimic natural human IL-1Ra.  
Confirmed ADA positive samples will also be further analyzed for the presence of NAb at 
Euro Diagnostica with a validated method using an IL-1 responsive reporter gene cell line. 
Inhibition of the antagonistic effect of IL-1Ra on IL-1 mediated cell activation in the 
presence of an ADA positive serum sample will indicate the presence of NAbs in the sample. 
6.5.5.6 
Laboratory assessments 
Clinically significant abnormal laboratory values should be reported as adverse events, 
except at baseline when they should be recorded as part of the medical history. 
The laboratory lab manual will define which labs to prioritize to ensure that the maximum 
allowed blood volume is never exceeded in pediatric patients according to NIH guidelines or 
any local guidelines (54, 55). Blood sampling for the care of the patients should always have 
the priority over blood samples collected specifically for this study. For patients with a body 


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weight <15 kg, central laboratory hematology and coagulation samples should not be 
repeated at Week 1 visit, if not clinically indicated, in order to preserve blood volume. 
All laboratory assessments should be performed also for patients <15 kg body weight at the 
Study Drug Discontinuation visit. If the Week 2 visit is peformed after the Study Drug 
Discontinuation visit, central lab should also be collected at the Week 2 visit, if not exceeding 
the maximum allowed blood volume collection according to limitations in relation to the 
body-weight of the patient. 
In case any of the safety central lab assessments cannot be analysed from the Week 12 visit 
the patient should be asked to return for an unscheduled visit to ensure that results are 
available for all lab assessments..  
 
Local laboratory assessments 
Laboratory tests needed for evaluation of inclusion and exclusion criteria can be performed at 
the local laboratory before randomization. See Table 4. However, a patient can be 
randomized before results from an interferon-gamma release assay or a PPD test has been 
confirmed. If the results from this test is positive, that is not due to vaccination (PPD), the 
patient must be withdrawn from the study. If available, and if there are no concerns regarding 
blood volume for sampling, it is preferable to use the interferon-gamma release assay. Local 
laboratory results are valid for 36 hours before randomization, provided that the patient does 
not show signs and/or symptoms of new ailments or increasing signs and/or symptoms that 
makes the patient non-eligible for the study in the opinion of the investigator. The local 
laboratory results are valid for inclusion regardless of central laboratory results, however any 
clinically significant findings in central laboratory results should be followed up. 
To guide the investigator for decision making to determine start of glucocorticoid tapering 
and to evaluate if the patient is fulfilling the escape criterion, a local lab CRP assessment can 
be done, if not possible to await central lab results.  
Table 4 Test conducted at local laboratory to confirm patient eligibility  
Clinical chemistry 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Total bilirubin (if >upper limit of normal also 
conjugated and non-conjugated bilirubin) 
Alkaline phosphatase (ALP) 
Triglycerides 
Creatinine 
Ferritin 
C-reactive protein (CRP) 
Hematology 
White blood cells 
Differential blood count  
Thrombocytes (platelet count) 
 
Coagulation 
Fibrinogen 
 
Urine analysis 
Human chorionic gonadotropin (hCG) test (for 
women of childbearing potential)   
 
Interferon-gamma release assay or PPD test* 
 
*Only required if no interferon-gamma release assay or PPD test is present within 2 months prior 
randomization. Interferon-gamma release assay can be analysed by central lab. 
 


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Central laboratory, clinical chemistry hematology and coagulation 
Blood and urine samples for determination of hematology, coagulation and clinical chemistry 
variables will be collected at all visits and will be performed by the central safety laboratory 
using routine methods. The date and time of collection will be recorded on the appropriate 
CRF. See Table 5.  
The sampling handling procedures, including the time of each blood/urine collection, the 
time of placement of sera/plasma into frozen storage (at the end of the sample workup) and 
the date of transfer or shipment of the samples to the responsible analyst, will be described in 
detail in the laboratory manual. Additionally, the procedures and materials used, e.g., 
collection and storage tubes, will be described in the laboratory manual.  
 
 
 


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Table 5 Laboratory assessments  
Clinical chemistry 
C-reactive protein (CRP) 
Ferritin 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Total bilirubin (if >upper limit of normal also 
conjugated and non-conjugated bilirubin) 
Alkaline phosphatase (ALP） 
Gamma-Glutamyl Transferase ( GT) 
Albumin 
Cholesterol (total, LDL and HDL) 
Triglycerides 
Blood Urea nitrogen 
Creatinine 
Sodium (Na) 
Potassium (K) 
Calcium (Ca) 
Phosphorous (P) 
Magnesium (Mg) 
Glucose 
Lactate dehydrogenase (LDH) 
 
Hematology 
Hemoglobin 
Hematocrit 
White blood cells 
Differential blood count 
Thrombocytes (platelet count)  
 
Coagulation 
Fibrinogen 
D-dimer 
Prothrombin 
 
 
 
Pharmacokinetic assessments 
A pre-selected number of sites will be involved to evaluate the repeated-dose PK of anakinra. 
The specific sites will include patients into the PK assessments until the required number of 
patients has been reached.  
In addition to the patients enrolled at the PK sites, serum concentrations of IL-1Ra/anakinra 
will be determined at every study visit for all patients randomized into the study.  
For all PK assessment, the exact date and time of blood sampling as well as the date and time 
of the IMP administrations before the PK sampling should be recorded in the CRF. 
6.5.6.1 
Sampling procedure 
If the blood volume required for the planned lab assessments at any visit exceeds the 
maximum allowed blood volume collection according to limitations in relation to the body-
weight of the patient the assessments for the study should be prioritized according to the 
specification in the laboratory manual. 
 
Repeated-dose pharmacokinetics (pre-selected PK sites)  
The repeated-dose PK of anakinra will be evaluated at 2 mg/kg/day (max 100 mg/day) and 4 
mg/kg/day (max 200 mg/day). The planned target per dose level is 5 patients with disease 
onset <6 years, 5 patients with disease onset ≥6 to <16 years and 5 patients with a disease 
onset ≥16 years.  


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At the Week 12 visit, the IMP dose will be administered at the site and blood samples will be 
collected before the IMP administration and at 2, 4, 6 and 8 hours after IMP administration. 
The visit will be scheduled so that the IMP dose will be administered 24 hours (acceptance 
range 22-30 hours) after previous IMP dose the day before. 
If exceeding maximum allowed blood volume for any patient, the samples at 4 and 6 hours 
may be replaced by a sample at 5 hours.  
 See Appendix 6 for a detailed description of the PK sampling procedure. 
 
Anakinra serum concentrations (all sites) 
Blood samples for determination of IL-1Ra/anakinra serum concentrations will be collected 
from all patients before IMP administration at all visits. 
6.5.6.2 
Bioanalytical method 
Serum samples to determine the combination of endogenous IL-1Ra concentrations and 
anakinra (IL-1Ra/anakinra) will be analyzed by York Bioanalytical Solutions Limited using 
an immunoassay validated following the FDA Guidance for Industry on Bioanalytical 
Method Validation (May 2001), the EMA Guideline on bioanalytical method validation 
(2012) and Viswanathan CT et al Workshop/Conference Report AAPS Journal. 
2007;9(1):E30-E42 in which IL-1Ra/anakinra is captured between a solid phase bound 
monoclonal antibody and polyclonal antibodies to anakinra. 
6.5.6.3 
Pharmacokinetic evaluation  
 
Non-compartmental analysis 
The serum anakinra concentration data from full PK sampling will be analyzed by non-
compartmental analysis (NCA) using Phoenix WinNonlin. The following PK variables will 
be derived where applicable: 
Cmax 
Observed maximum serum concentration of anakinra 
tmax 
Time to reach Cmax following dose injection 
AUClast 
Area under the serum concentration-time curve from time zero to the last 
quantifiable concentration (Clast), calculated by the linear up-log down 
trapezoidal method 
AUC0-24h 
Area under the serum concentration-time curve during a dosage interval 
 
 
Vd/F 
Apparent volume of distribution following subcutaneous administration 
t½ 
Apparent terminal half-life, calculated by 0.693/z  
CL/F 
Apparent total clearance of drug from serum after subcutaneous administration 
 
 
The individual serum concentration data, and the actual time for anakinra administration and 
blood sampling will be used throughout the analyzes. 


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Samples with serum concentrations below the lower limit of quantitation (LLOQ) at early 
time-points will be treated as zero. Serum concentrations below the LLOQ appearing in the 
terminal samples will be omitted from the analysis. 
 
Exploratory population PK analysis  
All anakinra serum concentration data will be included in the population PK analysis. The 
objective is to explore the PK and the impact of covariates (e.g. body weight, age and dose 
level) on the PK of anakinra. The outcome may facilitate simulations of PK within the patient 
population(s).The population PK analysis may be reported separately.   
 
Exploratory population PK/PD analysis  
All anakinra serum concentration data will be included in the population PK/PD analysis. 
The objective of this analysis is to explore the relationship between anakinra exposure and 
selected efficacy endpoints e.g. CRP and safety endpoints. The outcome may facilitate 
simulations of concentration-effect relationships within the patient population(s). The 
population PK/PD analysis may be reported separately.   
 
Exploratory laboratory assessments 
If the blood volume required for the planned lab assessments at any visit exceeds the 
maximum allowed blood volume collection the assessments for the study should be 
prioritized according to the specification in the laboratory manual. 
6.5.7.1 
Exploratory inflammatory biomarkers  
Several biomarkers of inflammation have been described to be indicative of the severity of 
rheumatic disease including JIA, SJIA, AOSD and RA and with potential value in the 
evaluation of response to treatment. Blood samples for determination of the exploratory 
inflammatory biomarkers IL-6, IL-18, calprotectin and neopterin will be collected before the 
first IMP administration at Day 1 and thereafter at following visits: Week 1, Week 2, 
Week 12 and, if applicable, at the Study Drug Discontinuation visit. The date and time of 
collection will be recorded in the CRF. 
The sampling handling procedures, including the time of each blood collection, the time of 
placement of sera/plasma into frozen storage (at the end of the sample workup) and the date 
of transfer or shipment of the samples to the responsible analyst, will be described in detail in 
the laboratory manual. The procedures and materials used, e.g., collection and storage tubes, 
will be described in the central manual. 
6.5.7.2 
Exploratory pharmacogenetic assessment  
For patients consenting to pharmacogenetic assessment an additional blood sample will be 
collected at a suitable time point after randomization. This sample may be stored for up to 10 
years and analyzed for genetic factors contributing to the patient's response to anakinra, 
safety and tolerability. Such genetic factors may include genes within the target pathway, or 
other genes believed to be related to the response to anakinra. Some genes currently 
insufficiently characterized or unknown may be understood to be important at the time of 
analysis. The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to anakinra.  


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The sample handling procedures, including the time of each blood sample collection, the time 
of placement into frozen storage (at the end of the sample workup) and the date of transfer or 
shipment of the samples will be documented in detail in the laboratory manual. The 
procedures and materials used, e.g., collection and storage tubes, as described in the 
laboratory manual.  
7 
Quality control and quality assurance 
This study will be conducted in compliance with this protocol, study specific procedures, 
ARO SOPs, Sobi SOPs (for unblinding of suspected unexpected serious adverse reaction 
[SUSARs], statistical analysis and study reporting), the ICH GCP guideline, and applicable 
regulatory requirements. 
Sobi will systematically review the study quality management to identify, evaluate and 
control risks to study critical processes and data which would affect subject safety and 
reliability of study data. 
Sobi will establish a systematic, prioritized, risk-based approach to monitoring and has 
chosen a combination of on-site and centralized monitoring. 
Monitoring visits to the study site will be performed periodically during the study, to help 
ensure compliance with the protocol, study specific procedures and applicable regulatory 
requirements. Source documents will be reviewed for verification of agreement with data in 
CRFs. All patient ICFs will be reviewed. The investigator or institution guarantees access to 
source documents by Sobi, its representatives, and appropriate regulatory agencies. 
The study site may be subject to a quality assurance audit by Sobi or its representatives, as 
well as inspection by appropriate regulatory agencies. 
It is important that the investigator(s) and the(ir) relevant personnel are available during the 
monitoring visits and possible audits and that sufficient time is devoted to these processes. 
8 
Statistical plan 
8.1 
Determination of sample size 
Assuming that the ACR30 response rate is 65 % in patients receiving anakinra and 25 % in 
placebo patients, 81 evaluable patients (54 anakinra and 27 placebo) are required to ensure 
90 % power in demonstrating that anakinra improves clinical features of Still’s disease using 
a two-sided test at a 5 % significance level. These assumptions are based on the canakinumab 
and tocilizumab phase III clinical studies in SJIA where 65-85 % of active patients and 10-25 
% of placebo patients responded at two weeks, as well as the Nordstrom study in AOSD 
where 50 % of anakinra treated patients were in remission after 4 weeks of treatment.  
While the study is powered to demonstrate efficacy in the overall population, it will also be 
possible to estimate the treatment effect with reasonable precision in the sub-groups 
(< 16 years, ≥ 16 years of age at disease onset). With at least 30 patients in one of the sub-
populations, the lower 95 % confidence limit for the odds ratio will exceed 1.0 when the 


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ACR30 (+ absence of fever) response rate is 65 % in patients receiving anakinra and 25 % in 
the placebo patients. 
8.2 
Definition of study populations 
The following analysis sets/populations will be used for the statistical analyses: 
ITT population: This population is the primary analysis population and will comprise all 
randomized patients, grouped according to randomization. 
PP population: This population will comprise ITT patients that do not have any major 
protocol violations potentially influencing efficacy variables up to the Week 2 visit. Patients 
will be grouped according to treatment actually received and the correct stratification 
information.  
Safety population: This population will comprise all patients who received at least one kit of 
investigational product and patients will be grouped according to the actual treatment 
received. Patients randomized to placebo that incorrectly received one kit of anakinra or more 
will be included in the corresponding anakinra group. Patients randomized to anakinra who 
incorrectly received only placebo kits will be included in the placebo group.    
PK population: This population will comprise patients who received anakinra without any 
major protocol deviations with respect to administration of investigational product. All 
patients with at least one PK measurement will be included in the population to present 
anakinra plasma concentrations. Patients in the repeated dose PK population should not have 
any major protocol deviations with respect to the repeated dose PK measurements.  
The ITT is the primary analysis population for the primary and secondary efficacy endpoints. 
The PP population will be used as a sensitivity analysis for the primary endpoint, the 
endpoints supporting the primary objective and the key secondary endpoints. The Safety 
population will be used for the safety analyses. The PK population will be used for evaluating 
the PK of anakinra.  
8.3 
Overall statistical and analytical plan 
All details of the statistical analyses will be described in a separate study specific SAP which 
will be finalized before the clinical database is locked and the treatment code is unblinded. 
Statistical analysis will be performed using SAS software Version 9.4 or later (SAS Institute, 
Inc, Cary, North Carolina, United States). 
 
General statistical issues 
The comparison of primary interest is between anakinra (2 mg/kg and 4 mg/kg combined) 
and placebo. The two dose groups of anakinra will be evaluated descriptively. 
All statistical tests will be two-sided and performed using a 5 % significance level if not 
stated otherwise. Results will be presented as the estimated value for each treatment group, 
anakinra (2 mg/kg and 4 mg/kg combined) and placebo, the estimated difference between 
groups, the associated two-sided 95 % confidence interval and p-value. The estimated value 
for each dose group of anakinra and the associated two-sided 95 % confidence interval will 


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also be presented. For continuous secondary endpoints, if assumption of normal distribution 
seems to be violated for a specific endpoint, corresponding non-parametric methods will be 
used to check the robustness of the results. 
Continuous variables will be summarized using the number of patients, the mean, the 
standard deviation, the median, the minimum and the maximum value. Categorical variables 
will be summarized using frequency counts and percentages. 
The laboratory data evaluation will be based on the results from the central laboratory. 
 
Demographics and baseline characteristics 
Demographic data and baseline characteristics will be presented using descriptive statistics.  
 
Analysis related to primary objective 
The primary endpoint is ACR30 response at Week 2 with absence of fever attributable to the 
disease during the 7 days preceding Week 2.  
In order to evaluate the ACR30 response, the relative change from baseline to Week 2 will be 
calculated for the following variables: 
1. 
Physician global assessment of disease activity (VAS) 
2. 
Patient/parent global assessment of overall well-being (VAS) 
3. 
Number of joints with active arthritis 
4. 
Number of joints with limitation of motion 
5. 
Assessment of physical function CHAQ/SHAQ 
6. 
CRP (mg/L) results from central laboratory 
If the change from baseline in at least 3 out of these 6 variables is an improvement of ≥ 30 % 
and no more than 1 of the 6 variables has a worsening of > 30 %, and absence of fever during 
the 7 days preceding Week 2 the patient will be deemed a responder. Patients who have 
discontinued study drug prior to Week 2 will be treated as non-responders in the analysis. 
The null and alternative hypotheses with respect to the primary efficacy endpoint are defined 
as: 
H0: OR = 1  
HA: OR ≠ 1  
ACR30 response will be analyzed using a logistic regression model with treatment, age at 
onset of disease (< 16 years, ≥ 16 years) and glucocorticoid use (yes, no) as explanatory 
variables. The estimated probability of ACR30 response in each treatment group and 95 % 
confidence interval will be presented. The estimated odds ratio of anakinra (combined dose 
groups) to placebo, the corresponding 95 % confidence interval and the p-value from the 
model will be presented. 


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Analysis related to secondary endpoints supporting the primary 
objective 
To further support the primary endpoint, the following secondary endpoints will be analyzed: 
- 
ACR30 response at Week 1 with absence of fever during 24 hours preceding Week 1.  
- 
ACR50, ACR70 and ACR90 response at Week 1 and Week 2 with absence of fever 
attributable to the disease during 24 hours before Week 1 and 7 days preceding Week 
2. 
- 
Response in the individual components of ACR at Week 1 and Week 2. Response is 
defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline.  
o Physician global assessment of disease activity (VAS) 
o Patient/parent global assessment of overall well-being (VAS) 
o Number of joints with active arthritis 
o Number of joints with limitation of motion 
o Assessment of physical function (CHAQ/SHAQ)  
o CRP (mg/L) 
- 
Absence of fever during the 7 days preceding Week 2. 
ACR30, ACR50, ACR70 and ACR90, with absence of fever in the preceding 24 hours at 
Week 1 and ACR50, ACR70 and ACR90, with absence of fever in the preceding 7 days, at 
Week 2 will be analyzed using logistic regression models with treatment, age at onset of 
disease (< 16 years, ≥ 16 years) and glucocorticoid use (yes, no) as explanatory variables. 
Patients who have discontinued study drug will be treated as non-responders in the analyses.  
The response in the individual components of ACR at Week 1 and Week 2 will be analyzed 
using logistic regression models with treatment, age at onset of disease (< 16 years, ≥ 16 
years) and glucocorticoid use (yes, no) as explanatory variables. Patients who have 
discontinued study drug prior to Week 1 will be treated as non-responders in the analyses of 
the individual components of ACR at Week 1 and patients who have discontinued study drug 
prior to Week 2 will be treated as non-responders in the analyses of the individual 
components of ACR at Week 2.  
The absence of fever at Week 2 will be analyzed using a logistic regression model with 
treatment, age at onset of disease (< 16 years, ≥ 16 years) and glucocorticoid use (yes, no) as 
explanatory variables. Patients who have discontinued study drug prior to Week 2 will be 
treated as having a presence of fever in the analysis. 
The response in the individual components of ACR at Week 1 and Week 2 will also be 
presented descriptively by using the number of responders/non responders/non responders 
due study drug discontinuation. In this presentation non responders who have remained on 
study drug in the study to the week of interest will be further classified into two categories: 
no response defined as < 30% improvement to < 30% worsening and worsening of response 
defined as at least 30% worsening from baseline. 
 
Analysis related to key secondary objective  
To evaluate the key secondary objective, the following endpoints will be analyzed: 
 Absence of fever during the 24 hours preceding Week 1. 


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 Change from baseline in physician global assessment of disease activity (VAS) at 
Week 1.  
 Change from baseline in patient/parent global assessment of overall well-being (VAS) 
at Week 1. 
 Change from baseline in CRP at Week 1. 
The absence of fever at Week 1 will be analyzed using a logistic regression model with 
treatment, age at onset of disease (< 16 years, ≥ 16 years) and glucocorticoid use (yes, no) as 
explanatory variables. Patients who discontinued study drug prior to Week 1 will be treated 
as having a presence of fever in the analysis. The estimated probability of absence of fever in 
each treatment group, the estimated odds ratio of anakinra to placebo, the corresponding 95 
% confidence interval and the p-value from the model will be presented. 
The three continuous endpoints; change in CRP, change in physician’s global assessment of 
disease activity and change in patient/parent global assessment of overall well-being, will be 
analyzed using a mixed model repeated measurement with the measurements on the 
individual timepoints (i.e. Baseline and Week 1 or if the Week 1 visit is not performed due to 
Study drug discontinuation before Week 1 the Study drug Discontinuation visit will be used) 
as responses and with treatment, age at onset of disease (< 16 years, ≥ 16 years) and 
glucocorticoid use (yes, no), visit and treatment-visit interaction as fixed effects. For the 
comparison between anakinra (combined dose groups) and placebo for each endpoint, the 
estimated difference, the associated 95 % confidence interval and the p-value from the model 
will be presented. 
 
Analysis related to secondary objectives  
8.3.6.1 
Sustained efficacy in ACR- responders 
To evaluate sustained efficacy in patients that initially responded to treatment at Week 2, the 
ACR responses at Week 4, Week 8 and Week 12 will be compared to the response at Week 
2. For patients that met the ACR30, ACR50, ACR70 or ACR90 response criteria, with 
absence of fever in the preceding 7 days at Week 2, the number and percentage that still meet 
the corresponding ACR response criteria at Week 4, Week 8 and Week 12 will be presented.  
In addition, sustained efficacy will be presented in relationship to glucocorticoid tapering.  
8.3.6.2 
Efficacy of anakinra during 12 weeks treatment  
The number and percentage of patients with ACR30, ACR50, ACR70 or ACR90 response 
with absence of fever (during 24 hours before Week 1 or 7 days preceding Week 2, Week 4, 
Week 8 and Week 12) at Week 1, Week 2, Week 4, Week 8 and Week 12 will be presented. 
Each ACR (+ absence of fever) response will also be tabulated and presented graphically in a 
stacked bar plot, reflecting the proportions of patients in each treatment group that: 
 Remain in the study on study drug at the applicable timepoint and are ACR (+ 
absence of fever) responders. 
 Remain in the study on study drug at the applicable timepoint and are non-
responders. 
 Discontinued study drug before the applicable timepoint and did fulfill the 
escape criteria. 


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 Discontinued study drug before the applicable timepoint due to progressive 
disease (except those that did fulfill the escape criteria). 
 Discontinued study drug before the applicable timepoint due to lack of 
efficacy. 
 Discontinued study before the applicable timepoint due to other reasons than 
lack of efficacy and progressive disease.  
The number and percentage of patients with absence of rash (during 24 hours before Week 1 
or 7 days preceding Week 2, Week 4, Week 8 and Week 12) at Week 1, Week 2, Week 4, 
Week 8 and Week 12 will be presented. 
The absolute values and the changes from baseline in CRP, Hb, platelet count and ferritin at 
Week 1, Week 2, Week 4, Week 8 and Week 12 will be presented by descriptive statistics. 
The absolute values and the changes from baseline in patient/parent global assessment of 
disease related pain (VAS) at Week 1, Week 2, Week 4, Week 8 and Week 12 will be 
presented by descriptive statistics. 
8.3.6.3 
Time to study drug discontinuation  
The time to study drug discontinuation will be analyzed using a stratified log-rank test, with 
age at onset of disease (< 16 years, ≥ 16 years) and glucocorticoid use (yes, no) as 
stratification factors. Based on this model, the estimated hazard ratio of anakinra (combined 
dose groups) versus placebo and the 95% confidence interval will be presented.  
The time to study drug discontinuation due to lack of efficacy or progressive disease will be 
analyzed using a stratified log-rank test, with age at onset of disease (< 16 years, ≥ 16 years) 
and glucocorticoid use (yes, no) as stratification factors. Study drug discontinuation for other 
reasons than lack of efficacy or progressive disease will be censored at the time of study drug 
discontinuation in the analysis. Based on this model, the estimated hazard ratio of anakinra 
(combined dose groups) versus placebo and the 95% confidence interval will be presented.  
Kaplan Meier curves will be generated for anakinra (combined dose groups), anakinra 
2 mg/kg, anakinra 4 mg/kg and placebo.  
8.3.6.4 
Glucocorticoid tapering 
The number and percentage of patients who have initiated tapering of glucocorticoids at 
Week 12 will be presented. 
The number and percentage of patients that have been able to decrease the glucocorticoid 
dose with at least 50 % from baseline to Week 12 will be presented.  
For patients that initiated tapering the percentage decrease of glucocorticoid dose at Week 12 
compared to baseline will be presented by descriptive statistics. 
 
Analysis of safety and tolerability data 
8.3.7.1 
Adverse events 
All adverse events will be coded using MedDRA.The number and percentage of patients with 
at least one adverse event recorded at each level of summarization will be summarized in 


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frequency tables by treatment, system organ class, preferred term, relation to investigational 
product and maximum severity. Percentages will be based on the number of patients in the 
safety population for the specific treatment group. 
The number and percentage of patients with at least one SAE, including death, at least one 
non-SAE, and adverse events leading to investigational product discontinuation will also be 
tabulated by system organ class and preferred term.  
The number and percentage of patients with MAS will be tabulated.  
8.3.7.2 
Clinical laboratory results  
Clinical laboratory safety data will be presented over time by descriptive statistics. In 
addition, the number of patients with abnormal laboratory values will be presented using shift 
tables.  
8.3.7.3 
Vital signs 
Weight, blood pressure and heart rate will be presented over time by descriptive statistics. 
8.3.7.4 
Physical examination 
The number and percentage of patients with presence of physical examination findings will 
be presented over time. 
8.3.7.5 
Anti-drug antibodies  
The number and percentage of patients with ADA and NAb and cross-reactivity at baseline, 
Week 1, Week 2, Week 4, Week 8 and Week 12 will be presented. ADA titers at baseline, 
Week 2, Week 4, Week 8 and Week 12 will be summarized by descriptive statistics. 
Occurrence and titer levels of ADA in relation to AEs will be presented.  
Occurrence and titer levels of ADA, including Nab in relation to ACR response and CRP will 
be presented. 
 
Analysis of pharmacokinetics 
The PK variables will be presented by descriptive statistics by dose and age group. 
 
Analysis related to productivity objective 
The number of days off school or work due to Still’s disease during the study will be 
presented for each visit by descriptive statistics. 
 
Analysis related to exploratory objectives  
8.3.10.1 
Inactive disease  
The number and percentage of patients with inactive disease at Week 12 will be presented. 


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8.3.10.2 
JADAS27  
The change from baseline in JADAS27 at Week 2, and Week 12 will be presented by 
descriptive statistics. 
8.3.10.3 
Population PK/PD analysis  
See section 6.5.6.3. 
8.3.10.4 
Population PK analysis  
See section 6.5.6.3. 
8.3.10.5 
Inflammatory biomarkers 
The change from baseline in IL-6, IL-18, calprotectin and neopterin at Week 1, Week 2 and 
Week 12 will be presented by descriptive statistics.  
 
Interim analysis 
No interim analysis of efficacy data is planned. An independent DSMB will review safety 
data on an ongoing basis (details will be specified in a separate DSMB charter). 
 
Multiple comparison/multiplicity 
A multiple testing procedure, combining fixed sequence testing and Hochberg procedure, will 
be used to ensure an overall significance level of 0.05. 
A fixed sequential testing will apply for the primary and the key secondary endpoints, i.e., the 
key secondary endpoints will only be tested if the null hypothesis related to the primary 
endpoint is rejected. The Hochberg procedure will then be applied for the three key 
secondary endpoints.  
 
Exploratory subgroup analyses 
Supportive analyses of the primary endpoint in each subgroup defined by the stratification 
variables age at onset of disease (< 16 years, ≥ 16 years of) and glucocorticoid use at 
inclusion (yes, no) , as well as body weight (≤50 kg, > 50 kg), sex and race will be performed 
in order to examine the consistency of the treatment effect. For each subgroup, the estimated 
probability of ACR30 (+ absence of fever) response in each treatment group, the estimated 
odds ratio of anakinra to placebo, and the corresponding 95 % confidence interval will be 
presented. 
Exploratory subgroup analyses of the key secondary endpoints will also be performed for 
subgroups, including those defined by the stratification variables age at onset of disease 
(< 16 years, ≥ 16 years) and glucocorticoid use at inclusion (yes, no), as well as body weight 
(≤50 kg, > 50 kg), sex and race.  
Further subgroup analyses may be defined in the statistical analysis plan.  
No formal hypothesis tests will be performed. 


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8.4 
Data standards 
Collection of data should be performed in the CDASH format, according to the CDISC. The 
standards should be used to the extent possible and/or required for the specific study/project. 
The minimum requirement of the CDISC standard is to collect all core variables specified as 
‘Required’ in the SDTM format.  
 
Handling of missing data 
For the primary endpoint ACR30 the following imputation will be used:  
 Patients that discontinue study drug prior to Week 2 will be set to non-responders. 
 For patients with missing information in any of the ACR30 components, that specific 
component will be set to no change. For patients with missing information on fever, 
the patients will be treated as having a presence of fever.  
For the key secondary endpoints the following imputation will be used: 
 Patients who have missing information on fever during 24 hours preceding Week 1 
will be treated as having a presence of fever in the analysis. 
 For the continuous key secondary endpoints repeated measures models will be used to 
handle missing data.  
For the other secondary endpoints no imputation will be performed, i.e., all presentations will 
be based on observed cases. 
 
Sensitivity analyses 
The primary efficacy endpoint and the key secondary endpoints will be analysed using the PP 
population as described in Section 8.3.4 and 8.3.5. 
For patients who discontinue study drug before Week 2, a Study Drug Discontinuation visit 
should be performed before standard of care treatment is initiated and a Week 2 visit should 
preferably also be performed (if the Study Drug Discontinuation visit is performed within 3 
days prior to the Week 2 visit, the scheduled Week 2 visit should be omitted). As a sensitivity 
analysis, for both the primary analysis of ACR30 (+ absence of fever) at Week 2 and the 
supportive analysis of ACR30 (+ absence of fever) at Week 1 a comparison of treatment 
groups including patients who have discontinued study drug will be performed using the 
ACR assessment closest to Week 2 or Week 1 respectively. However, study drug 
discontinuation due to progressive disease will be treated as non-responders. 
A tipping point analysis will also be performed for the primary efficacy endpoint. For 
patients where no plausible assumption can be made depending on the reason for the missing 
outcome (e.g. patients that discontinue study drug due to lack of efficacy and progressive 
disease), the number of responders that can potentially be observed among patients with a 
missing ACR30 outcome at Week 2 in the anakinra group versus the placebo group will be 
presented in a basic tipping point display. Pairs of number of responders in the anakinra and 
placebo group that lead to statistical significance will be marked and pairs that lead to non-
significance will not be marked. The tipping point boundary is the staircase region between 
marked and unmarked rectangles (51). This analysis will be repeated allowing the 
assumptions to vary for all patients with a missing ACR30 outcome at Week 2, except those 


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patients who have discontinued study drug and fulfilled the escape criteria who will still be 
treated as non-responders.   
9 
Data collection, handling and record keeping 
9.1 
Case report form 
A CRF is required and should be completed for each included patient. In this study electronic 
CRF will be used. The completed original CRFs are the sole property of Sobi and should not 
be made available in any form to third parties, except for authorized representatives of 
appropriate Regulatory Authorities, without written permission from Sobi. 
It is the responsibility of the investigator to ensure completion and to review and approve all 
CRFs. CRFs must be signed electronically by the investigator. These signatures serve to 
attest that the information contained on these CRFs is correct. At all times, the investigator 
has final responsibility for the accuracy and authenticity of all clinical and laboratory data 
entered on the CRFs.  
9.2 
Patient diary  
A patient diary will be used by the patient during the treatment period to record any 
occurrence of rash, time point of any fever episode together with the actual body temperature 
and timepoint of all IMP administrations. The patient or patient caregiver will be instructed 
on how to complete the diary at their first visit. The diary will be reviewed at each visit for 
completeness.  
9.3 
Source data 
Patient source documents are the physician’s patient records maintained at the study site. In 
most cases, the source documents will be the hospital’s or the physician’s chart. In those 
cases, the information collected on the CRFs must match those charts. In some cases, a 
portion of the source documents for a given patient may be the CRF or patient diary.  
In this study, the following could be recorded as source data directly in the CRFs: 
 Number of joints with active arthritis 
 Number of joints of limitation of motion 
 Joint count for JADAS27 
 Morning stiffness 
 Absenteeism from school or work 
In this study, the following are recorded as source data directly in a patient diary: 
 Fever 
 Rash 
 IMP administration  


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9.4 
Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to study subjects. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.  
When a deviation from the protocol is identified, the investigator or designee must ensure 
that DCRI is notified. DCRI will follow up with the investigator, as applicable, to assess the 
deviation and the possible impact to the safety and/or efficacy of the subject to determine 
subject continuation in the study. 
The investigator and DCRI must contact Sobi immediately if a deviation is discovered that 
significantly affects or has the potential to significantly affect human subject protection or the 
reliability of study results. 
The investigator will also assure that deviations are reported and documented in accordance 
with IRB/REB requirements. Any applicable regulatory requirements will be the 
responsibility of Sobi.  
 
9.5 
Database closure 
Prior to database closure, all tasks or criteria defined in the data management plan must be 
completed and documented. The study database must be locked before breaking of the blind 
and before generation of any results. The database lock will be approved by relevant study 
personnel and all edit accesses will be removed. The study database can only be unlocked in 
case critical errors, affecting the main conclusions of the study, are discovered. Medical 
coding will be performed by DCRI and approved by Sobi before database lock. AEs, 
diagnoses from Medical History and procedures will be classified according to MedDRA. 
Previous and Concomitant Medications will be coded using the latest version of the World 
Health Organisation Drug Dictionary (WHODRUG).  
A reconciliation of the clinical and safety database will be performed prior to database lock.  
9.6 
Record retention 
The investigator should maintain a record of the location(s) of investigator’s essential 
documents as defined in the ICH GCP Guideline [1] including source documents and should 
have control of and continuous access to all essential documents and records generated by the 
investigator/institution before, during, and after the study.  
All documents and data relating to the study will be kept securely by the investigator in a 
secure file and/or electronically. The storage system used during the study and for archiving 
(irrespective of the type of media used) should provide for document identification, version 


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history, search and retrieval. The data will be available for evaluation and/or audits from 
Health Authorities, Sobi or Sobi’s representatives. 
When a copy is used to replace an original document (e.g. source documents, CRF), the copy 
should fulfill the requirements for certified copy as defined in ICH GCP Guideline 1.  
 
The records should be retained by the investigator according to local regulations or as 
specified in the Clinical Trial Agreement. 
If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator or another 
institution. Archiving on behalf of the investigator can also be delegated to Sobi.   
 
 


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10 
End of study 
The end of this study is defined as the date of last patient’s last visit. 
11 
Sponsor’s discontinuation criteria 
Sobi reserves the right to discontinue the study prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. 
After such a decision, the investigator must contact all participating patients within 30 days. 
All study materials must be collected at sites and all the CRFs completed to the greatest 
extent possible. 
12 
Dissemination and publication of results 
Sobi will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with applicable laws and regulations, e.g., 
www.clinicaltrials.gov. 
The results of this study will be published within 1 year after the product has received 
marketing approval. If drug development is discontinued before approval, the results will be 
published within 1 year after such discontinuation. 
Sobi is committed to publishing study results in a complete, accurate, balanced, transparent 
and timely manner. Sobi follows the principles of the International Committee of Medical 
Journal Editors (ICMJE) recommendations for the conduct, reporting, editing, and 
publication of scholarly work in medical journals including criteria for authorship (57). 
The data from this study will be considered for reporting at a scientific meeting or for 
publication in a scientific journal. The sponsor will be responsible for these activities and will 
work with the investigators to determine how the publication is written, the number and order 
of authors, the journal or scientific meeting to which it will be submitted, and other related 
issues. The results of the study, or any part thereof, shall not be published without the prior 
written consent and approval of Sobi, such consent and approval not to be unreasonably 
withheld. 
 
 


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13 
References 
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ICH Harmonised Guideline: Integrated addendum to ICH E6 (R1), Guideline for 
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guidelines.html 
 
 
2 
World Medical Association Declaration of Helsinki; Ethical Principles for Medical 
Research Involving Human Patients. Adopted by the 18th WMA General Assembly, 
Helsinki, Finland, June 1964, latest amendment at the 64th WMA General Assembly, 
Fortaleza, Brazil, October 2013 Available from: 
 
https://www.wma.net/publications/wma-doh-1964-2014/  
 
3 
Ravelli A et al. 2016 Classification Criteria for Macrophage Activation Syndrome 
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4 
Lenert A et al. Macrophage activation syndrome complicating adult onset Still’s 
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5 
Gurion R et al. Systemic arthritis in children: A review of clinical presentation and 
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6 
Bywaters EG. Still's disease in the adult. Ann Rheum Dis 1971;30:121–133 
 
7 
Jamilloux Y et al. Pathogenesis of adult-onset Still’s disease: new insights from the 
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8 
Nirmala N et al. Gene-expression analysis of adult-onset Still’s disease and systemic 
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9 
Uppal SS et al. Adult onset Still’s disease in northern India: comparison with juvenile 
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10 
Luthi F et al. “Adolescent-onset Still’s disease”: characteristics and outcome in 
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11 
Pay S et al. A multicenter study of patients with adult-onset Still’s disease compared 
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12 
Cabane J et al. Comparison of long term evolution of adult onset and juvenile onset 
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13 
Gerfaud-Valentin M et al. Adult-onset Still's disease. Autoimmun Rev, 2014A;13(7): 
708-722 
 
14 
Mellins ED et al. Pathogenesis of systemic juvenile idiopathic arthritis: some answers, 
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15 
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17 
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Vastert SJ et al. Effectiveness of first-line treatment with recombinant interleukin-1 
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20 
Nigrovic P et al. Anakinra as first-line disease-modifying therapy in systemic juvenile 
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21 
Beukelman T et al. Rates of hospitalized bacterial infection associated with juvenile 
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22  
Gerfaud-Valentin M et al. Adult-onset still disease: Manifestations, treatment, 
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23 
DeWitt EM et al, Consensus treatment plans for new-onset systemic juvenile 
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24 
Kimura Y et al. Adding canakinumab to the Childhood Arthritis and Rheumatology 
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Comment on the article by DeWitt et al. Arthritis Care Res (Hoboken). 
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26 
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Research Clinical Rheumatology 2012;26: 477–487 
 
27  
Jamilloux Y et al. Treatment of adult-onset Still’s disease: a review. Therapeutics and 
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28  
Urien et al. Anakinra pharmacokinetics in children and adolescents with systemic-
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and Toxicology 2013;14:40 
 
29 
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30  
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31 
Raffeiner B et al. Adult-onset Still’s disease with myocarditis successfully treated 
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32 
Quartier P et al. A multicentre, randomised, double-blind, placebo-controlled trial 
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33 
Hong D et al. Interleukin 1 inhibition with anakinra in adult-onset Still disease: a 
meta-analysis of its efficacy and safety. Drug Des Devel Ther. 2014;8:2345-2357 
 
34  
Ruperto N et al. Two randomized trials of canakinumab in systemic juvenile 
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35  
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onset still's disease. An open, randomized, multicenter study. J Rheumatol. 
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38  
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39  
Ruperto N et al. Performance of the preliminary definition of improvement in juvenile 
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40 
Felson D et al. The American College of Rheumatology, Preliminary core set of 
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41 
Felson D et al. The American College of Rheumatology, Preliminary definition of 
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42  
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43  
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44 
Klepper S. Measures of Pediatric Function: The Child Heath Assessment 
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(POSNA) Pediatric Musculoskeletal Functional Health Questionnaire. Arthritis 
Rheum. 2003:49:5–14 
 
45 
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Bruce B et al. The Health Assessment Questionnaire (HAQ). Clin Exp Rheumatol 
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Sawhney S et al. Outcome Measures in Pediatric Rheumatology. Indian Journal 
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Consolaro A et al. Development and Validation of a Composite Disease Activity 
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49  
Nordal E et al. Juvenile Arthritis Disease Activity Score (JADAS) based on CRP; 
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Wallace CA et al. American College of Rheumatology Provisional Criteria for 
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52 
Petty RE et al. International League of Associations for Rheumatology Classification 
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53 
Yamaguchi M et al. Preliminary criteria for classification of adult Still's disease. J 
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54 
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55 
NIH Clinical Center Pediatric Guidelines C.Ramanathan MD, Nathan’s Hematology 
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56  
Ravelli A et al. Preliminary diagnostic guidelines for macrophage activation 
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updated 
 
 
 


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Diagnose criteria 
 
Onset of the disease <16 years of age  
 
Adapted ILAR criteria (52)  
 Arthritis in one or more joints with, or preceded by 
 daily fever for at least 2 weeks, that at some point is documented to be quotidian for at 
least 3 days, and 
Accompanied by one or more of the following: 
1. Evanescent (non-fixed) erythematous rash 
2. Generalized lymph node enlargement 
3. Hepatomegaly and/or splenomegaly 
4. Serositis 
Exclusions: 
a. Psoriasis or a history of psoriasis in the patient or first degree relative 
b. Arthritis in an HLA-B27 positive male beginning after the 6th birthday  
c. Ankylosing spondylitis, enthesitis related arthritis, sacroilitis with inflammatory bowel 
disease, Reiter’s syndrome, or acute anterior uveitis, or a history of one of these disorders 
in a first degree relative 
d. The presence of IgM rheumatoid factor on at least 2 occasions at least 3 months apart  
 
 


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Onset of the disease ≥16 years of age 
 
Yamaguchi criteria (53) 
Classification of AOSD requires 5 or more criteria including 2 or more major criteria.$ 
Any disease listed under “exclusions” should be excluded.  
Major criteria: 
1. Fever of 39˚C or higher, lasting 1 week or longer 
2. Arthralgia lasting 2 weeks or longer 
3. Typical rash* 
4. Leukocytosis (10,000/mm3 or greater) including 80% more of granulocytes 
Minor criteria: 
1. Sore throat 
2. Lymphadenopathy and/or splenomegalya 
3. Liver dysfunctionb 
4. Negative RF and negative ANAc 
Exclusions:  
I. Infections (especially, sepsis and infectious mononucleosis). 
II. Malignancies (especially, malignant lymphoma) 
III. Rheumatic diseases (especially, polyarteritis nodosa and rheumatoid vasculitis with 
extraarticular features) 
* Macular or maculopapular nonpruritic salmon-pink eruption usually appearing during fever. 
a Lymphadenopathy is defined as recent development of significant lymph node swelling, and splenomegaly is 
confirmed on palpation or by an echogram. 
b Liver dysfunction is defined as an abnormally elevated level of transaminases and/or lactate dehydrogenase, 
which is attributed to liver damage associated with this disease but not with drug allergy/toxicity or other 
causes. For the differentiation, it is recommended to see if liver function returns to normal upon discontinuation 
of hepatotoxic drug or not, before applying this criterion. 
c RF in serum must be negative by routine test for the detection of IgM RF, and serum ANA must be negative 
by routine immunofluorescence test. 
$ All criteria are applicable only in absence of other clinical explanations. 
 
 


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Guidance for MAS diagnosis 
Characteristic clinical features of macrophage activation syndrome (MAS) are high non-
remitting fever, hepatosplenomegaly, generalized lymphadenopathy, central nervous system 
dysfunction, and hemorrhagic manifestations. Typical laboratory abnormalities include 
pancytopenia, increased levels of ferritin, liver enzymes, lactate dehydrogenase, triglycerides, 
D-dimers, and soluble CD25 (sCD25), and decreased fibrinogen level. A typical 
histopathologic feature of MAS is the accumulation of well-differentiated macrophages 
exhibiting hemophagocytic activity in bone marrow biopsy specimen or aspirates (3, 56). 
In patients <16 years old with systemic juvenile idiopathic arthritis the following laboratory 
classification criteria have been proposed (3), which can be used as a guidance, but the 
diagnosis of MAS will be made by the investigator based on the patients overall clinical signs 
and symptoms, including laboratory changes over time. 
 
2016 Classification of macrophage activation syndrome in systemic juvenile idiopathic 
arthritis (3) 
A febrile patient with known or suspected systemic juvenile idiopathic arthritis is classified 
as having macrophage activation syndrome if the following criteria is met: 
 Ferritin >684 ng/ml 
 and any 2 of the following: 
 Platelet count ≤181 x 109/liter 
 Aspartate aminotransferase >48 units/liter 
 Triglycerides >156 mg/dl 
 Fibrinogen ≤360 mg/dl 
Laboratory abnormalities should not be otherwise explained by the patient’s condition, such 
as, for example, concomitant immune-mediated thrombocytopenia, infectious hepatitis, 
visceral leishmaniasis, or familial hyperlipidemia. 
 
 
 
 


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Dosing instructions 
 
Dose 2 mg/kg/day (max 100 mg/day) 
Body weight (kg) 
IMP  
dose administered (mg) 
Range of dose received (mg/kg) 
10-12 
20 
1.7-2.0 
13-17 
30 
1.8-2.3 
18-22 
40 
1.8-2.2 
23-27 
50 
1.9-2.2 
28-32 
60 
1.9-2.1 
33-37 
70 
1.9-2.1 
38-42 
80 
1.9-2.1 
43-47 
90 
1.9-2.1 
≥48 
100 
≤2.1 
 
 
Dose 4 mg/kg/day (max 200 mg/day) 
Body weight (kg) 
IMP  
dose administered (mg) 
Range of dose received (mg/kg) 
10-11 
40 
3.6-4.0 
12-13 
50 
3.8-4.2 
14-16 
60 
3.8-4.3 
17-18 
70 
3.9-4.1 
19-21 
80 
3.8-4.2 
22-23 
90 
3.9-4.1 
24-28 
100 
3.6-4.2 
29-31 
120 
3.9-4.1 
32-33 
130 
3.9-4.1 
34-36 
140 
3.9-4.1 
37-38 
150 
3.9-4.1 
39-41 
160 
3.9-4.1 
42-43 
170 
4.0 
44-46 
180 
3.9-4.1 
47-48 
190 
4.0 
≥49 
200 
≤4.1 
 
 


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Guidance for glucocorticoid tapering 
 
Tapering of the glucocorticoid dose is suggested at an interval of every second week. The 
table below describes an example of tapering steps if the start dose is = 1 mg/kg.  
The tapering can be commenced earliest at the Week 2 visit and if the patient has reached at 
least ACR50 response with no fever in the preceding 7 days.  
 
 
Body weight 
 
 
10-20 kg 
20-30 kg 
30-40 kg 
40-50 kg 
50-60 kg 
≥60 kg 
Weight-
based dose 
Stable dose at 
baseline 
10 mg 
20 mg 
30 mg 
40 mg 
50 mg 
60 mg 
1 mg/kg 
(max 60mg) 
Dose prescribed at 
first tapering step 
(earliest at Week 2) 
7.5 mg 
15 mg 
22.5 mg 
30 mg 
37.5 mg 
45 mg 
0.75 mg/kg 
Dose prescribed at 
second tapering step  
(2 weeks after 
tapering commences) 
5 mg 
10 mg 
15 mg 
20 mg 
25 mg 
30 mg 
0.5 mg/kg 
Dose prescribed at 
third tapering step 
(4 weeks after 
tapering commences) 
2.5 mg 
5 mg 
7.5 mg 
10 mg 
12.5 mg 
15 mg 
0.25 mg/kg 
Dose prescribed at 
fourth tapering step 
(6 weeks after 
tapering commences) 
1 mg 
2.5 mg 
2.5 mg  
5 mg 
5 mg 
7,5 mg 
0,12 mg/kg 
Dose prescribed at 
fifth tapering step 
(8 weeks after 
tapering commences) 
off 
off 
off 
off 
off 
off 
off 


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Schedule of assessments 
Assessments - page 1(2) 
Screening 
visit 
(optional) 
Visit 1 
Tel f-up 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Tel f-up 
Study Drug 
Discontinua-
tion visit 
Day 1 
Day 4Tel 
(+/-2 days) 
Week 1 
(+2 days) 
Week 2 
(+2 days) 
Week 4 
(+/-2 days) 
Week 8 
(+/-2 days) 
Week 12 
(+/-2 days) 
Week 16Tel 
(+5 days) 
 
 
 
 
Day 8 
Day 15 
Day 29 
Day 57 
Day 85 
Day 113 
 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Medical history & Demographics 
 
X 
 
 
 
 
 
 
 
 
Vital signs 
Blood pressure  
 
X 
 
X 
X 
X 
X 
X 
 
X 
Heart rate 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Body weight 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
 
X 
X 
X 
X 
X5 
 
X5 
ECG 
 
X 
 
 
 
 
 
 
 
 
Prior and/or concomitant 
medication 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood Collection  
Laboratory assessments (incl. CRP) 
 
X 
 
X3 
X7 
X 
X 
X 
 
X6 
Immunogenicity assessments 
 
X 
 
X 
X 
X 
X 
X 
 
X 
IL-1Ra/anakinra serum 
concentration 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Inflammatory biomarkers  
(IL-6, IL-18, calprotectin, neopterin)
 
X 
 
X 
X 
 
 
X 
 
X 
Exploratory pharmacogenetics 
markers
 
X4 
 
 
1 Assessment performed by blinded, trained and independent joint assessor.  
2 A diary will be used for daily recordings of fever episodes, patient´s assessment of rash and time point of IMP administrations. 
3 For patients with a body weight <15 kg hematology and coagulation samples should not be repeated at visit Week 1, if not clinically indicated, in order to preserve blood volume.  
4 Any time after randomization. 
5 For evaluating inactive disease, the following signs will specifically be recorded: rash, serositis, splenomegaly, hepatomegaly and generalized lymphadenopathy. 
6 All laboratory assessments should be performed also for patients <15 kg body weight .  
7 If the Week 2 visit is peformed after the Study Drug Discontinuation visit, central lab should also be collected at the Week 2 visit, if not exceeding the maximum allowed blood volume collection according to limitations in 
relation to the body-weight of the patient. 
 


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Assessments - page 2(2) 
Screening 
visit 
(optional) 
Visit 1 
Tel f-up 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Tel f-up 
Study Drug 
Discontinua-
tion visit 
Day 1 
Day 4Tel 
(±2 days) 
Week 1 
(+2 days) 
Week 2 
(+2 days) 
Week 4 
(+/-2 days) 
Week 8 
(+/-2 days) 
Week 12 
(+/-2 days) 
Week 16Tel 
(+ 5 days) 
 
 
 
 
Day 8 
Day 15 
Day 29 
Day 57 
Day 85 
Day 113 
 
Efficacy Assessments 
Physician global assessment of 
disease activity (VAS)
 
X 
 
X 
X 
X 
X 
X 
 
X 
Patient/parent global assessment of 
overall well-being (VAS)
 
X 
 
X 
X 
X 
X 
X 
 
X 
Number of joints with active 
arthritis1
 
X 
 
X 
X 
X 
X 
X 
 
X 
Number of joints with limitation of 
motion1
 
X 
 
X 
X 
X 
X 
X 
 
X 
Physical function (CHAQ or 
SHAQ)
 
X 
 
X 
X 
X 
X 
X 
 
X 
Global assessment of the patient 
disease related pain (VAS)
 
X 
 
X 
X 
X 
X 
X 
 
X 
Morning stiffness 
 
 
 
 
 
 
 
X 
 
X 
Completion of diary2 
 
X 
 
 
Recording of absenteeism from 
school or work 
 
 
 
X 
X 
X 
X 
X 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP administration (at site) 
 
X 
 
 
 
 
 
 
 
 
IMP dispensing 
 
X 
 
X 
X 
X 
X 
 
 
 
1 Assessment performed by blinded, trained and independent joint assessor.  
2 A diary will be used for daily recordings of fever episodes, patient´s assessment of rash and time point of IMP administrations. 
3 For patients with a body weight <15 kg hematology and coagulation samples should not be repeated at visit Week 1, if not clinically indicated, in order to preserve blood volume.  
4 Any time after randomization. 
5 For evaluating inactive disease, the following signs will specifically be recorded: rash, serositis, splenomegaly, hepatomegaly and generalized lymphadenopathy. 
6 All laboratory assessments should be performed also for patients <15 kg body weight.  
7 If the Week 2 visit is peformed after the Study Drug Discontinuation visit, central lab should also be collected at the Week 2 visit, if not exceeding the maximum allowed blood volume collection according to limitations in 
relation to the body-weight of the patient. 


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Schedule of repeated PK assessments Week 12 
 
The assessments described below are additional assessments for patient enrolled to the repeated-
dose PK sampling. All patients that do the repeated-dose PK assessments are also assessed 
according to schedule of assessments in Appendix 5.  
 
 
Visit 1 
Tel f-up 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Tel f-up 
Day 1 
Day 4Tel 
(+/-2 days) 
Week 1 
(+2 days) 
Week 2  
(+2 days) 
Week 4 
(+/- 2 days) 
Week 8 
(+/- 2 days) 
Week 12 
(+/- 2 days) 
Week 16Tel  
(+/- 2 days) 
 
 
 
Day 8 
Day 15 
Day 29 
Day 57 
Day 85 
Day 113 
Blood collection - repeated-dose pharmacokinetics 
Pre-dose 
 
 
 
 
 
 
X 
 
2h after dose 
 
 
 
 
 
 
X 
 
4h after dose 
 
 
 
 
 
 
X1 
 
6h after dose 
 
 
 
 
 
 
X1 
 
8h after dose 
 
 
 
 
 
 
X 
 
IMP administration 
(at site) 
 
 
 
 
 
 
a, X 
 
1If exceeding maximum allowed blood volume for any patient, the samples at 4 and 6 hours may be replaced by a sample at 5 hours 
a No administration of IMP at home before the visit  
 
 


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Physician global assessment of disease activity 
 
The physician will rate the patient’s current condition on a 0-100 mm VAS, ranging from no 
disease activity (0 mm) to very severe disease activity (100 mm). 
The below question will be answered by the investigator.  
“Considering all the ways that Still’s disease affects your patient, how would you rate his or her 
condition today?” 
Please place a single mark on the line below. 
 
Very well   0  
 
 
 
 
 
 
          100    Very poor 
 
Note: The VAS above is not presented in accurate length 
 
The result of the investigator’s assessment of the patient’s disease activity should be withheld 
from the patient to minimize influencing his/her own assessment.  
 
 
 


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Patient/parent global assessment of overall well-being 
 
The patient or parent global assessment of overall well-being will be assessed on a 0-100 mm 
VAS, from very well (0 mm) to very poor (100 mm).  
For patients <18 years of age at randomization, this question will be collected as a part of the 
CHAQ (see Appendix 9).  
For patients ≥18 years of age at randomization, this question will be collected as a part of the 
SHAQ (see Appendix 9).   
 
 


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Physical function (CHAQ/SHAQ) 
Parent proxy reporting CHAQ for children <18 years old:
 


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 Global assessment of the patient disease related pain 
 
The patient’s global assessment of disease related pain will be assessed on a 0-100 mm VAS, 
from no pain (0 mm) to very severe pain (100 mm). 
For patients <18 years of age at randomization, this question will be collected as a part of the 
CHAQ (see Appendix 9).  
For patients ≥18 years of age at randomization, this question will be collected as a part of the 
SHAQ (see Appendix 9). 
 
 
 
 


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 Joint count JADAS27 
 
The JADAS included the following 4 measures: physician global assessment of disease activity, 
patient/parent global assessment of well-being, active joint count and CRP.  
 
Joint count 
The JADAS27 includes the following joints: cervical spine, elbows, wrists, metacarpophalangeal 
joints (from first to third), proximal interphalangeal joints, hips, knees, and ankles (48). 
 
 
Joint count 
Left 
Right 
Elbow 
 
 
Wrist 
 
 
MCP 
1 
 
 
 
2 
 
 
 
3 
 
 
PIP 
1 
 
 
 
2 
 
 
3 
 
 
4 
 
 
 
5 
 
 
Knee 
 
 
Hips 
 
 
Ankles 
 
 
Cervical spine 
 
NA 
 
 
 
Total 
 
 
 
 
 


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 Additional Protocol Signatures 
 
Sponsor’s Clinical Program Leader  
Anna Olsson, MSc 
Clinical Program Leader 
E-mail: anna.olsson@sobi.com 
 
 
 
  
 
Sponsor’s Statistician 
Agneta Lissmats, BSc  
Study statistician 
E-mail: agneta.lissmats@sobi.com 
 

SAP_000.pdf: 
 
 
Statistical Analysis Plan 
 
Protocol number: 
Sobi.ANAKIN-301 
NCT number:  
03265132 
Study title: 
A randomized, double-blind, placebo-controlled, multicenter, phase 3 
efficacy and safety study of 2 dose levels of subcutaneous anakinra 
(Kineret®) in patients with Still’s disease (SJIA and AOSD) 
Version: 
Final 1.0 
Date: 
24 July 2019 
 
 
 
 
 
 


Sobi.ANAKIN-301 
 
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Table of contents 
1 
Abbreviations and definition of terms ................................................................................ 5 
2 
Introduction ....................................................................................................................... 6 
3 
Study objectives and endpoints .......................................................................................... 7 
3.1 
Primary objective .......................................................................................................... 7 
3.2 
Secondary objectives .................................................................................................... 7 
3.3 
Study endpoints ............................................................................................................ 8 
3.3.1 Primary efficacy endpoint ...................................................................................... 8 
3.3.2 Secondary endpoints supporting the primary objective ........................................... 8 
3.3.3 Key secondary efficacy endpoints .......................................................................... 9 
3.3.4 Other secondary efficacy endpoints ........................................................................ 9 
3.3.5 Safety endpoints ................................................................................................... 10 
3.3.6 Pharmacokinetic endpoints ................................................................................... 10 
3.3.7 Immunogenicity endpoints ................................................................................... 10 
3.3.8 Productivity endpoints ......................................................................................... 10 
3.3.9 Exploratory endpoints .......................................................................................... 10 
4 
Study methods ................................................................................................................. 11 
4.1 
Overall study design and plan ..................................................................................... 11 
4.2 
Selection of study population ...................................................................................... 12 
4.3 
Method of treatment assignment and randomization .................................................... 12 
5 
Sequence of planned analysis .......................................................................................... 13 
5.1 
Interim analyses .......................................................................................................... 13 
5.2 
Analyses and reporting ............................................................................................... 13 
6 
Sample size determination ............................................................................................... 13 
7 
Analysis sets .................................................................................................................... 14 
7.1 
The mITT set .............................................................................................................. 14 
7.2 
Safety set .................................................................................................................... 14 
7.3 
Pharmacokinetic (PK) set ............................................................................................ 14 
7.4 
Protocol deviations ..................................................................................................... 15 
8 
General issues for statistical analysis ............................................................................... 15 
8.1 
Time windows ............................................................................................................ 16 
8.2 
Handling of missing data and outliers ......................................................................... 16 
8.2.1 Imputation for efficacy endpoints ......................................................................... 16 
8.2.2 Imputation of Adverse Event start dates ............................................................... 17 
8.2.3 Imputation of prior/concomitant medication start/stop date .................................. 17 


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8.2.4 Imputation of date of disease diagnosis ................................................................ 17 
8.3 
Multicenter studies ...................................................................................................... 18 
8.4 
Multiple comparisons and multiplicity ........................................................................ 18 
8.5 
Derived and computed variables ................................................................................. 18 
8.5.1 ACR response ...................................................................................................... 18 
8.5.2 Absence of fever .................................................................................................. 18 
8.5.3 JADAS27 ............................................................................................................. 19 
8.5.4 Inactive disease .................................................................................................... 19 
8.5.5 Primary disease characteristics ............................................................................. 19 
8.5.6 Treatment exposure .............................................................................................. 19 
8.5.7 Non-compartmental pharmacokinetic analysis ..................................................... 20 
9 
Patient disposition ........................................................................................................... 21 
10 
Demographics and baseline characteristics ...................................................................... 21 
10.1 Demographics ............................................................................................................. 21 
10.2 ECG ........................................................................................................................... 21 
10.3 Primary Still’s disease characteristics .......................................................................... 21 
10.4 Medical history ........................................................................................................... 21 
11 
Prior and concomitant medication ................................................................................... 21 
12 
Efficacy analyses ............................................................................................................. 22 
12.1 Primary efficacy endpoint ........................................................................................... 22 
12.1.1 Sensitivity analyses of the primary endpoint......................................................... 22 
12.2 Secondary endpoints supporting the primary objective ................................................ 23 
12.3 Key secondary efficacy endpoints ............................................................................... 23 
12.4 Other secondary efficacy endpoints ............................................................................. 24 
12.4.1 Sustained efficacy in ACR-responders ................................................................. 24 
12.4.2 Efficacy of anakinra during 12 weeks treatment ................................................... 24 
12.4.3 Inactive disease .................................................................................................... 24 
12.4.4 Time to study drug discontinuation ...................................................................... 24 
12.4.5 Glucocorticoid tapering ........................................................................................ 25 
12.5 Subgroup Analyses ..................................................................................................... 25 
13 
Safety analyses ................................................................................................................ 25 
13.1 Treatment exposure..................................................................................................... 25 
13.2 Adverse events ............................................................................................................ 25 
13.2.1 Serious adverse events ......................................................................................... 26 
13.2.2 Adverse events leading to withdrawal .................................................................. 26 
13.2.3 Deaths .................................................................................................................. 26 


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13.3 Laboratory data ........................................................................................................... 26 
13.4 Vital signs ................................................................................................................... 26 
13.5 Physical examination .................................................................................................. 26 
14 
Pharmacokinetic analyses ................................................................................................ 27 
15 
Immunogenicity analyses ................................................................................................ 27 
16 
Productivity analyses ....................................................................................................... 27 
17 
Exploratory endpoints ..................................................................................................... 27 
17.1.1 Population PK/PD analysis .................................................................................. 27 
17.1.2 Inflammatory biomarkers ..................................................................................... 27 
18 
References ....................................................................................................................... 28 
 
 


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1 
Abbreviations and definition of terms 
ACR 
American College of Rheumatology 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AOSD 
Adult-onset Still’s disease 
ATC 
Anatomical therapeutic chemical 
AUClast 
Area under the serum concentration-time curve from time zero to 
the last quantifiable concentration (Clast), calculated by the linear 
up-log down trapezoidal method 
AUC0-24h,ss 
Area under the serum concentration-time curve during a dosage 
interval 
CARRA 
The Childhood Arthritis and Rheumatology Research Alliance 
CHAQ 
Childhood health assessment questionnaire 
CL/F 
Apparent total clearance of drug from serum after subcutaneous 
administration 
CM 
Concomitant medication 
Cmax 
Observed maximum serum concentration of anakinra 
CRP 
C-reactive protein 
CSR 
Clinical study report 
DCRI 
Duke Clinical Research Institute 
ECG 
Electrocardiogram 
Hb 
Hemoglobin 
ICH 
International council of harmonization of technical requirements 
for registration of pharmaceuticals for human use 
ILAR 
International League of Associations for Rheumatology 
IL-1Ra 
Interleukin 1 receptor antagonist 
IL-6 
Interleukin 6 
IL-18 
Interleukin 18 
IMP 
Investigational medicinal product 
IRS 
Interactive response system 
mITT 
Modified intention-to-treat 


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JADAS 
Juvenile arthritis disease activity score 
LLOQ 
Lower limit of quantitation 
MAS 
Macrophage activation syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralizing antibodies 
NCA 
Non-compartmental analysis 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SHAQ 
Stanford Health Assessment Questionnaire 
SJIA 
Systemic juvenile idiopathic arthritis 
Sobi 
Swedish Orphan Biovitrum 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment-emergent AE 
t½ 
Apparent terminal half-life, calculated by 0.693/z  
tmax 
Time to reach Cmax following dose injection 
VAS 
Visual analogue scale 
Vd/F 
Apparent volume of distribution following subcutaneous 
administration 
WHO 
World Health Organization 
 
2 
Introduction 
This SAP describes the planned analysis and reporting for the Sobi anaSTILLs study 
(Sobi.ANAKIN-301), a randomized, double-blind, placebo-controlled, multicenter, phase 3 
efficacy and safety study of 2 dose levels of subcutaneous anakinra (Kineret®) in patients with 
Still’s disease (SJIA and AOSD).  
The purpose of this SAP is to outline the planned analyses to be completed to support the CSR 
for protocol Sobi.ANAKIN-301. The planned analyses identified in this SAP will be included in 


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potential regulatory submissions and/or future manuscripts. Also, exploratory analyses not 
necessarily identified in this SAP may be performed to support the clinical development 
program. Any post-hoc, or unplanned, analyses not identified in this SAP will be clearly 
identified in the CSR. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and ICH: Guidance on statistical principles in clinical trials (ICHE9). All 
work planned and reported for this SAP will follow internationally accepted guidelines, 
published by the American Statistical Association and the Royal Statistical Society, for statistical 
practice.  
3 
Study objectives and endpoints 
3.1 
Primary objective 
The primary objective of this study is: 
 To demonstrate efficacy of anakinra versus placebo in Still’s disease as assessed by 
ACR30 response including absence of fever. 
3.2 
Secondary objectives 
The key secondary objective is: 
 To demonstrate early onset of efficacy of anakinra versus placebo in Still’s disease. 
The secondary efficacy objectives are: 
 To evaluate sustained efficacy of anakinra versus placebo in patients that reached at least 
ACR30 response at Week 2. 
 To evaluate efficacy of anakinra versus placebo during 12 weeks treatment. 
 To evaluate time to study drug discontinuation in anakinra versus placebo. 
 To evaluate glucocorticoid tapering in anakinra and placebo treated patients. 
 To evaluate the efficacy of anakinra in the 2 separate dose groups. 
The safety objective is: 
 To evaluate the safety of anakinra. 
The pharmacokinetic objective is: 
 To evaluate the PK of anakinra. 
The immunogenicity objectives are: 
 To evaluate occurrence of ADAs, NAbs and cross-reactivity. 
 To evaluate ADAs in relation to safety. 
 To evaluate ADAs, and NAbs in relation to efficacy. 


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The productivity objective is: 
 To evaluate absenteeism from school or work. 
The exploratory objectives are: 
 To explore PK/PD relationship between IL-1Ra/anakinra serum concentrations and 
selected efficacy and safety parameters. 
 To explore the PK properties of anakinra using population analysis. 
 To explore the effect of anakinra on the exploratory inflammatory biomarkers (IL-6, IL-
18, calprotectin and neopterin) in the treatment of patients with Still´s disease. 
 To collect a blood sample for future analysis for genetic factors potentially contributing 
to the patient's response to anakinra, safety and tolerability. Will be reported separately. 
3.3 
Study endpoints 
3.3.1 
Primary efficacy endpoint  
The primary efficacy endpoint is: 
 ACR30 response at Week 2 with absence of fever attributable to the disease during the 7 
days preceding Week 2. 
Definition of ACR30 response: An improvement of ≥ 30% from baseline in at least 3 of 
any 6 variables listed below. Also, no more than 1 of the 6 variables may worsen by 
> 30% from baseline. 
1. Physician global assessment of disease activity (VAS) 
2. Patient/parent global assessment of overall well-being (VAS) 
3. Number of joints with active arthritis 
4. Number of joints with limitation of motion 
5. Assessment of physical function (CHAQ/SHAQ)  
6. CRP (mg/L) 
Definition of fever: Body temperature ≥ 38.0 °C (100.4 °F) attributable to the disease 
3.3.2 
Secondary endpoints supporting the primary objective 
The secondary endpoints supporting the primary objective are: 
 ACR30 response at Week 1 with absence of fever attributable to the disease during 24 
hours preceding Week 1. 
 ACR50, ACR70 and ACR90 response at Week 1 and Week 2 with absence of fever 
attributable to the disease during 24 hours before Week 1 and 7 days preceding Week 2. 
 Response in the individual components of ACR at Week 1 and Week 2. Response is 
defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline.  
o Physician global assessment of disease activity (VAS) 


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o Patient/parent global assessment of overall well-being (VAS) 
o Number of joints with active arthritis 
o Number of joints with limitation of motion 
o Assessment of physical function (CHAQ/SHAQ)  
o CRP (mg/L) 
 Absence of fever during the 7 days preceding Week 2. 
3.3.3 
Key secondary efficacy endpoints 
The key secondary efficacy endpoints are: 
 Absence of fever during the 24 hours preceding Week 1. 
 Change from baseline in physician global assessment of disease activity (VAS) at Week 
1. 
 Change from baseline in patient/parent global assessment of overall well-being (VAS) at 
Week 1. 
 Change from baseline in CRP at Week 1. 
3.3.4 
Other secondary efficacy endpoints 
Other secondary efficacy endpoints are: 
 Sustained ACR response at Week 4, Week 8 and Week 12 compared to ACR response at 
Week 2. 
 ACR30, ACR50, ACR70 or ACR90 response with absence of fever 24 hours before 
Week 1 or during the 7 days preceding the visit at Week 2, Week 4, Week 8 and Week 
12. 
 Absence of rash 24 hours before Week 1 or during the 7 days preceding Week 2, Week 4, 
Week 8 and Week 12. 
 Change from baseline in CRP, Hb, platelet count and ferritin at Week 1, Week 2, Week 
4, Week 8 and Week 12. 
 Change from baseline in patient/parent global assessment of disease related pain (VAS) 
at Week 1, Week 2, Week 4, Week 8 and Week 12. 
 Inactive disease at Week 12. 
 Change from baseline in JADAS27 at Week 2 and Week 12.   
 Time to study drug discontinuation for any reason. 
 Time to study drug discontinuation due to lack of efficacy or progressive disease. 
 Number of patients who have initiated tapering of glucocorticoids at Week 12. 
 Number of patients with decreased dose of glucocorticoids by at least 50% at Week 12 
compared to baseline. 
 Percentage decrease of glucocorticoid dose at Week 12 compared to baseline. 
 Efficacy endpoints as described above, of anakinra in the 2 separate dose groups. 


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3.3.5 
Safety endpoints 
The study has the following safety endpoints: 
 AEs (including MAS), vital signs and laboratory safety assessments. 
3.3.6 
Pharmacokinetic endpoints 
The study has the following PK endpoints: 
 Anakinra trough plasma concentrations and repeated-dose PK parameters at Week 12. 
3.3.7 
Immunogenicity endpoints 
The study has the following immunogenicity endpoints: 
 Occurrence of ADAs, NAbs, and cross-reactivity and titer levels of ADA and NAbs at 
baseline, Week 1, Week 2, Week 4, Week 8 and Week 12. 
 Occurrence and titer levels of ADAs in relation to AEs at Week 1, Week 2, Week 4, 
Week 8 and Week 12. 
 Occurrence and titer levels of ADA, including NAb in relation to ACR response and CRP 
at Week 1, Week 2, Week 4, Week 8 and Week 12. 
3.3.8 
Productivity endpoints 
The study has the following productivity endpoints: 
 Number of days off school or work due to Still’s disease.  
3.3.9 
Exploratory endpoints 
The study has the following exploratory endpoints: 
 Population PK/PD parameter estimates and associated covariates describing intra- and 
inter-individual variability in respective parameter estimate. 
 Population PK parameter estimates and associated covariates describing intra-and inter-
individual variability in respective parameter estimate. 
 Change from baseline in exploratory inflammatory biomarkers at Week 1, Week 2 and 
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4 
Study methods  
4.1 
Overall study design and plan 
The study consists of a 12-week, randomized, double-blind, placebo controlled period with two 
dose levels of anakinra and a 4-week safety follow-up after last dose of IMP. The primary 
endpoint will be evaluated at Week 2. Sustained efficacy and time to study drug discontinuation 
will be evaluated during the full study period.  
A screening visit is optional and may be done to identify patients that could be suitable for the 
study. See Figure 1. 
Figure  1 
Study design 
 
 
Abbreviations: D, day, Tel; telephone contact; W, Week. 
During the study 6 visits and 2 telephone contacts are scheduled i.e., Day 1 (baseline visit), Day 
4Tel, Week 1, Week 2, Week 4, Week 8, Week 12 and Week 16Tel (End of Study).  
Patients will be randomly assigned to study drug, after they meet all of the inclusion criteria and 
none of the exclusion criteria. Patients will receive treatment for 12 weeks, either anakinra or 
placebo. Patients will be randomized to anakinra in a dose of either 2 or 4 mg/kg/day, with a 
maximum dose of 100 or 200 mg once daily, respectively. Patients will be randomized to 
placebo with corresponding volumes for each of the two anakinra dose levels. 
To be able to evaluate the primary objective of the study it is important that patients remain in 
the study until the Week 2 visit whenever possible. However, patients can discontinue study drug 
at any time during the study e.g. due to lack of efficacy or progressive disease. Patients fulfilling 
the escape criteria are a subcategory of patients that discontinue study drug due to progressive 
disease. The escape criteria are symptomatic serositis or flare i.e., a worsening of >30 % from 
baseline in at least 3 of any 6 components part of ACR. 


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If the investigator judges that a patient must discontinue study drug before the Week 12 visit, a 
Study Drug Discontinuation visit should be performed before standard of care treatment is 
initiated, if possible. If the study drug is discontinued on a scheduled visit, the Study Drug 
Discontinuation visit should be performed instead of the scheduled visit unless the study drug is 
discontinued at the Week 12 visit. For a patient that discontinues study drug before the Week 2 
visit, the Week 2 visit should still be performed according to the original schedule of 
assessments. However, if the Study Drug Discontinuation visit is performed within 3 days prior 
to the Week 2 visit, the scheduled Week 2 visit should be omitted. A final follow-up call will be 
conducted 4 weeks after the last IMP administration according to the assessments described for 
the Week 16Tel visit in the protocol.  
All patients included in the study will be carefully monitored by the investigator and if there is a 
need, patients can withdraw from the study at any time. 
If a patient is on glucocorticoid treatment the dose can be tapered starting earliest at the Week 2 
visit. The patient must have reached at least ACR50 response with no fever in the preceding 7 
days at the visit initiating tapering. 
If a patient develops MAS, the patient will terminate the study drug and will be treated according 
to standard of care. If the MAS event occurs before the Week 2 visit it is preferred, if possible, 
that the patient returns to conduct the Week 2 visit according to the schedule of assessments. For 
all patients that are diagnosed with MAS, irrespective of timepoint in the study, a follow-up call 
should be conducted 4 weeks after the last IMP administration according to the assessments 
described for the Week 16Tel visit before the patient is withdrawn from the study. MAS is 
defined as an event of special interest in this study and must be reported as an SAE. 
Once all patients have conducted the Week 16Tel (End of Study) visit or their last visit in case of 
early discontinuation, data cleaning activities will be completed and the database will be locked 
before the final analysis will be conducted. 
4.2 
Selection of study population 
A total of 81 patients was originally planned to be randomized, but fewer patients are expected 
since recruitment will be stopped earlier. At least 12 patients are expected to be randomized, 
with a 2:1 allocation (anakinra:placebo).  
For inclusion into the study, a patient should have active Still’s disease, diagnosed not more than 
6 months prior to randomization. Diagnosis of Still’s disease:  
a) If < 16 years of age at disease onset, according to adapted ILAR criteria i.e., CARRA-
criteria for SJIA.  
b) If ≥16 years of age at disease onset, according to Yamaguchi criteria. 
4.3 
Method of treatment assignment and randomization 
The different treatment groups are; 


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 placebo (corresponding volume of anakinra 2 mg/kg/day [max 100 mg/day]), or 
 placebo (corresponding volume of anakinra 4 mg/kg/day [max 200 mg/day]), or 
 anakinra 2 mg/kg/day (max 100 mg/day) or  
 anakinra 4 mg/kg/day (max 200 mg/day)  
The ratio between the treatment groups is 1:1:2:2, i.e. the ratio placebo:anakinra is 1:2.  
The randomization numbers are generated in blocks. Each block includes the four treatment 
groups per the ratio described above. The block size will not be revealed before breaking of the 
blind.  
The randomization is stratified by age at onset of disease (< 16 years, ≥ 16 years) and 
glucocorticoid use at inclusion (yes, no). The original plan was to randomize 81 patients with the 
requirement to randomize at least a third of the patients with an age at onset of disease < 16 years 
and a third of the patients with an age at onset ≥ 16 years, however this is no longer a requisite 
due to early stopping of the study. Medidata balance randomization and trial supply system is 
used for IRS and Biostatistics at DCRI is responsible for generating the randomization scheme, 
which will link sequential patient randomization numbers to treatment codes.   
5 
Sequence of planned analysis 
5.1 
Interim analyses 
There is no planned interim analysis for this study. 
5.2 
Analyses and reporting 
All final analyses identified in the SAP will be performed after the last patient has completed the 
study. The SAP will be finalized, locked and signed prior to database lock and subsequently the 
breaking of blind.  
Any post-hoc analyses included in the CSR, which were not identified in this SAP, will be 
clearly identified as such in the relevant section of the CSR. 
6 
Sample size determination 
Assuming the ACR30 response rate with absence of fever at Week 2 is 65 % in patients 
receiving anakinra and 25 % in placebo patients, 81 evaluable patients (54 anakinra and 27 
placebo) would be required to ensure 90 % power in demonstrating that anakinra improves 
clinical features of Still’s disease using a two-sided test at a 5 % significance level. These 
assumptions are based on the canakinumab and tocilizumab phase 3 clinical studies in SJIA 
where 65 to 85 % of active patients and 10 to 25 % of placebo patients responded at two weeks, 


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as well as the Nordstrom study in AOSD where 50 % of anakinra treated patients were in 
remission after 4 weeks of treatment (Nordstrom et al 2012).  
Since recruitment will be stopped before the planned number of evaluable patients have been 
included, it is anticipated that at least 12 patients will be randomized and included in the 
analyses.  
7 
Analysis sets  
The analysis sets to be used in the statistical analyses are presented in Section 7.1 (mITT set), 
Section 7.2 (Safety set), and Section 7.3 (PK set).  
7.1 
The mITT set 
The mITT set is the primary analysis population and will comprise all randomized patients, 
except those who failed to satisfy major disease-specific entry criteria, or who received no IMP 
(see also section 7.4). The patients will be grouped according to randomization. The mITT is the 
primary analysis population for the primary and secondary efficacy endpoints. 
7.2 
Safety set 
The Safety set will comprise all patients who received at least one dose of IMP. Patients will be 
grouped according to the actual treatment received. Patients randomized to placebo that 
incorrectly received one dose of anakinra or more will be included in the corresponding anakinra 
group. Patients randomized to anakinra who incorrectly received only placebo will be included 
in the placebo group.    
The Safety set will be used for the safety analyses. 
7.3 
Pharmacokinetic (PK) set 
The PK set will comprise patients who received anakinra without any major protocol deviations 
as judged by the Clinical Pharmacology Scientist before DBL with respect to administration of 
IMP. All patients with at least one PK measurement will be included in the analysis set for the 
analysis of anakinra plasma concentrations. Patients with repeated dose PK should not have any 
major protocol deviations with respect to the repeated dose PK measurements.  
The PK set will be used for evaluating the PK of anakinra. 


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7.4 
Protocol deviations 
Protocol deviations related to study inclusion or exclusion criteria, conduct of the study, patient 
management or patient assessment will be reviewed prior to DBL and described in the CSR as 
appropriate.  
 
Major protocol deviations that will lead to exclusion from the mITT analysis set are the 
following: 
 Patient failed to satisfy major disease-specific entry criteria in accordance with the 
adapted ILAR or Yamaguchi criteria, as detailed in the CSP. 
 Patient did not get any dose of IMP. 
8 
General issues for statistical analysis 
The comparison of interest is between anakinra (2 mg/kg and 4 mg/kg combined) and placebo. 
Due to the small number of patients in the individual dose groups of anakinra, summary tables 
(except for the drug exposure summary) will not provide results by individual dose groups. 
Likewise, the randomization was stratified by age at onset of disease (< 16 years, ≥ 16 years) and 
glucocorticoid use (yes, no), but due to the very small number of patients for levels of the 
stratification factors within each treatment group, descriptive statistics and statistical analyses 
will generally not be performed by stratification factors. For primary and key secondary efficacy 
endpoints, dose-level information and stratification allocation will be included in a patient 
listing. 
All statistical tests will be two-sided and performed using a 5 % significance level, if not stated 
otherwise. Results will be presented as the estimated value for each treatment group, anakinra 
and placebo, the estimated difference between groups, the associated 95 % two-sided confidence 
interval and p-value. P-values from statistical analyses will be presented to three decimal places 
with values below 0.001 displayed as <0.001 and 95 % confidence intervals will be presented to 
one more decimal place than the raw data. 
Continuous data will be summarized using descriptive statistics: n, mean, SD, median, minimum 
and maximum, unless otherwise indicated.  Minimum and maximum will be presented to the 
same number of decimal places as the raw data and mean, SD, and median will be presented to 
one more decimal place than the raw data.   
Categorical data will be summarized using counts and percentages.  Percentages will be 
suppressed when the count is zero, however the category will still be displayed. The denominator 
for all percentages will be the number of patients within the treatment group for the population 
of interest, unless otherwise indicated.  Percentages will be presented to one decimal place. 
Statistical analyses will be performed using SAS software Version 9.4 (SAS Institute Inc, Cary, 
North Carolina, United States).  


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8.1 
Time windows 
For the purpose of the statistical analysis and if not otherwise specified, all the variables 
(primary, secondary and exploratory variables) will be assigned to the visit/assessment timepoint 
in which they were collected depending on the following analysis time windows in Table 1.  
Table 1 Time windows 
Visit 
Week 
Study Day 
Study Day window  
1 
Baseline 
1 
<1 
2 
1 
8 
2-11 
3 
2 
15 
12-22 
4 
4 
29 
23-43 
5 
8 
57 
44-71 
6 
12 
85 
>72 
 
Unscheduled visit data will be considered when assigning assessments to the analysis visit. If more 
than one assessment of the variable (scheduled or unscheduled) falls in the same time window but 
on different days, the closest to the scheduled visit day will be taken, or the earlier, in the event 
the values are equidistant from the nominal visit date. If several measurements are collected during 
the selected day, the average (for numeric values)/worst (for categorical values) of the 
measurements will be taken.  
 
In summaries of extreme values as opposed to visit-based summaries, all post baseline values 
collected are used including those collected at unscheduled visits regardless if the value is closest 
to the scheduled visit date or not. For summaries at a patient level, all values should be included, 
regardless of whether they appear in a corresponding visit-based summary, when deriving a patient 
level statistic such as a maximum. 
 
Listings will display all values contributing to a time point for a patient. 
8.2 
Handling of missing data and outliers 
8.2.1 
Imputation for efficacy endpoints 
For all endpoints related to the primary objective the following imputation will be used:  
 Patients that discontinue study drug prior to Week 2 will be set to non-responders. 
 For patients with missing information in any of the ACR30 components, that specific 
component will be set to no change. For patients with missing information on fever, the 
patients will be treated as having a presence of fever.  
For the key secondary endpoints the following imputation will be used: 


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 Patients who have missing information on fever during 24 hours preceding Week 1 will 
be treated as having a presence of fever in the analysis. 
 For the other secondary endpoints no imputation will be performed, i.e., all presentations 
will be based on observed data. 
8.2.2 
Imputation of Adverse Event start dates 
To assess if AEs are treatment emergent, missing onset dates will be imputed according to the 
following rules:  
 If day is missing and month and year of AE onset is the same as the month and year of first 
dose of study treatment, then the onset date of the AE will be assumed to be the same as 
the date of first dose of study treatment.  
 If day and month is missing and year of AE onset is the same as year of first dose, then the 
date of onset will be assumed to be the same as the first dose of study treatment. 
 Otherwise, if day is missing, then use YYYY-MM-01, and if day and month are missing, 
then use YYYY-JAN-01. 
 Completely missing onset dates will not be imputed. AEs with a completely missing onset 
date will be considered treatment-emergent. 
8.2.3 
Imputation of prior/concomitant medication start/stop date 
To assess if medications are prior or concomitant, missing onset dates will be imputed according 
to the following rules:  
 If day is missing and month and year are both available, use 01 of the month or the date 
of first dose of study treatment whichever is later. 
 If only the year is available, use 01 Jan of the year or the date of first dose whichever is 
later. 
 Completely missing onset dates will not be imputed. 
Likewise, to assess if a medication is prior, missing stop dates will be imputed according to 
 If the day is missing: Assume the last day of the month. 
 If the month is missing: Assume 31 Dec of the year. 
 Completely missing stop dates will not be imputed 
8.2.4 
Imputation of date of disease diagnosis 
Missing dates for the diagnosis of Still’s disease will be imputed according to the following 
rules: 
 If day is missing, the day will be imputed as the 15th, i.e. YYYY-MM-15, in the 
calculation.  


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 If the month is missing, it will be imputed as June, i.e. YYYY-06-15 
 Completely missing date will not be imputed 
8.3 
Multicenter studies 
No effects of centers will be evaluated in this study due to the small numbers at individual sites.  
8.4 
Multiple comparisons and multiplicity 
A fixed sequential testing will be used in the sense that the key secondary efficacy endpoints will 
only be tested if the null hypothesis related to the primary efficacy endpoint is rejected. No 
further adjustments will be applied. Testing of all secondary efficacy endpoints will be 
exploratory.  
8.5 
Derived and computed variables 
8.5.1 
ACR response 
For efficacy endpoints, ACR30 with absence of fever attributable to the disease, is defined as an 
improvement of ≥ 30% from baseline in at least 3 of any 6 variables listed below. Also, no more 
than 1 of the 6 variables may worsen by > 30% from baseline. 
1. Physician global assessment of disease activity (VAS) 
2. Patient/parent global assessment of overall well-being (VAS) 
3. Number of joints with active arthritis 
4. Number of joints with limitation of motion 
5. Assessment of physical function (CHAQ/SHAQ) 
6. CRP (mg/L) 
Correspondingly, ACR50, ACR70 and ACR90 with absence of fever attributable to the disease, 
is defined for ≥ 50%, 70% and 90% response, respectively. Likewise, in these analyses, no more 
than 1 of the 6 variables may worsen by > 30% from baseline. 
Sustained ACR30 response include patients that achieved at least ACR30 response at Week 2, 
and further had at least ACR30 response at Week 4, Week 8 or Week 12, respectively. 
8.5.2 
Absence of fever 
Separate eCRF forms will specifically query whether fever was absent or present in the 24 hours 
preceding Week 1 or absent/present in the 7 days preceding Week 2.  
Absence of fever at subsequent weeks (Week 4, 8 and 12) will be derived based on information 
recorded in the fever diary during the 7 days preceding each visit. The number of patients with 


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no missing data on fever will constitute the denominator for the percentage of patients with 
absence of fever during each week. 
8.5.3 
JADAS27 
The JADAS27 includes 4 measures: physician global assessment of disease activity, patient or 
parent global assessment of overall well-being, 27 active joint count, and CRP. The JADAS27 
includes the following 27 joints: cervical spine, elbows, wrists, metacarpophalangeal joints (from 
first to third), proximal interphalangeal joints, hips, knees, and ankles. 
JADAS27 is calculated as the sum of its four components, physician global assessment of 
disease activity converted to cm from the VAS (0=no activity, 10=maximum activity); patient 
global assessment of well-being converted to cm from the VAS (0=very well, 10=very poor); 
active joint count (0-27); and CRP. Prior to calculation CRP is truncated to a 0 – 10 scale 
according to the following formula: (CRP (mg/l) −10)/10. Before calculation, CRP values 
<10 mg/l are converted to 10 and CRP values >110 mg/l are converted to 110. The JADAS27 
tool yields a global score of 0–57. 
8.5.4 
Inactive disease 
At the Week 12 visit and at the Study Drug Discontinuation visit, if applicable, the presence or 
absence of specific physical examination findings which are associated with Still’s disease will 
be recorded to assess “inactive disease”. Inactive disease is a composite of the following 
parameters: no joints with active arthritis, no fever, no rash, no serositis, no splenomegaly, no 
generalized lymphadenopathy attributable to Still’s disease, CRP level within normal limits, 
physician’s global assessment of disease activity score below 10 mm on a 100 mm VAS and a 
documented morning stiffness ≤15 minutes. The assessment of inactive disease is based on 
observed data for all parameters, with no imputation in case of missing information. 
8.5.5 
Primary disease characteristics 
Age at Still’s disease diagnosis will be calculated based on date of birth and the date of Still’s 
disease diagnosis as recorded on the Demography eCRF form. 
Disease duration will be derived based on the Day 1 visit date and the date of Still’s disease 
diagnosis, as recorded on the Demography eCRF form. 
8.5.6 
Treatment exposure 
The anakinra doses that will be evaluated are 2 mg/kg/day (max 100 mg/day) and 4 mg/kg/day 
(max 200 mg/day). The dose will be adjusted at baseline according to actual body weight 
(rounded to the nearest kg) and will remain the same throughout the study. The IMP 
administration will be supervised by the investigator or investigational site staff at the Day 1 visit 
and the exact time point for the administration will be recorded. At all other occasions when the 


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IMP is self-administered the patient will record the exact time point of the administration in the 
diary.  
For each patient, the daily dose will be calculated as the total exposure (amount IMP (mg) given 
for the entire study) divided by the number of days on treatment.  
The total treatment duration will be calculated as (date of last IMP - date of first IMP) +1. 
8.5.7 
Non-compartmental pharmacokinetic analysis 
The serum anakinra concentration data from full PK sampling will be analyzed by NCA using 
SAS version 9.4. The following PK variables will be derived where applicable: 
Cmax 
Observed maximum serum concentration of anakinra 
tmax 
Time to reach Cmax following dose injection 
AUClast 
Area under the serum concentration-time curve from time zero to the last 
quantifiable concentration (Clast), calculated by the linear up-log down 
trapezoidal method 
AUC0-24h,ss 
Area under the serum concentration-time curve during a dosage interval 
Vd/F 
Apparent volume of distribution following subcutaneous administration 
z 
Terminal slope 
t½ 
Apparent terminal half-life, calculated by 0.693/z  
CL/F 
Apparent total clearance of drug from serum after subcutaneous 
administration 
The individual serum concentration data, and the actual time for anakinra administration and blood 
sampling will be used throughout the analyses. Samples with serum concentrations below the 
lower limit of quantitation (LLOQ) at early time-points will be treated as zero. Serum 
concentrations below the LLOQ appearing in the terminal samples will be omitted from the 
analysis. 
Cmax and tmax will be derived directly from observed serum anakinra concentration values. 
AUClast will be calculated using the linear/log trapezoidal rule.  
 
Extrapolation to 24h will be performed by adding the residual area up to 24h, (C8h, pred/λz-C24h, 
pred/ λz), where λz will be determined by linear regression of the log terminal part of the serum 
concentration versus time curve, C8h, pred will be the predicted (according to the regression line) 
concentration at the time of the last sample (8h) and C24h, pred will be the predicted (according to 
the regression line) concentration at 24h. CL/F will be calculated as Dose/AUC0-24h,ss and Vd/F 
will be calculated as z x CL/F.   


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9 
Patient disposition 
The number and percentage of patients who were enrolled, randomized, who initiated and who 
completed or discontinued treatment early (before Week 2 and anytime), and who completed or 
discontinued the study early (before Week 2 and anytime), together with the reasons for 
discontinuations, will be presented by treatment group.  
 
The number of patients in the mITT set and in the safety set will be presented. 
10 
Demographics and baseline characteristics 
10.1 
Demographics 
Baseline characteristics and demographic data, including age, sex, race, and ethnicity will be 
presented by descriptive statistics for the mITT set and for the Safety set. 
10.2 
ECG 
A baseline 12-lead ECG will be recorded before the first IMP administration, at the Day 1 visit. 
The number and percentage of patients with abnormal ECG findings will be presented. Any 
clinically significant abnormalities are also recorded as medical history, and if judged serious, as 
a SAE. 
10.3 
Primary Still’s disease characteristics 
Still’s disease characteristics including age at diagnosis, age at symptom onset and disease 
duration, will be summarized for the mITT and Safety analysis sets. 
10.4 
Medical history 
All medical history data will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA), version 21.1. 
General medical history at baseline will be presented by SOC and PT for the mITT and Safety 
analysis sets.  
11 
Prior and concomitant medication 
All prior and concomitant medication will be coded using the WHO Drug dictionary.   
The preferred term grouped by ATC level 4 will be used for presentation and sorted in 
descending order of frequency in total (both treatment groups together) at the top in the table. 


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Prior medication, concomitant medication at randomization and onset of new concomitant 
medication after randomization during the study will be summarized separately for both the 
mITT set and the Safety set. 
12 
Efficacy analyses 
12.1 
Primary efficacy endpoint 
The primary endpoint, ACR30 response at Week 2 with absence of fever attributable to the 
disease during the 7 days preceding Week 2, will be analyzed using the mITT analysis set and 
will use no missing data imputation other than that described in 8.2.1. Patients who have 
discontinued study drug prior to Week 2 will be treated as non-responders in the analysis. 
 
The null and alternative hypotheses with respect to the primary efficacy endpoint are defined as: 
H0: Panakinra = Pplacebo  
HA: Panakinra ≠ Pplacebo  
where P is the proportion of patients with ACR30 response as defined for the primary endpoint. 
Fisher’s exact test will be used to test the hypothesis at the two-sided significance level of 
α=0.05. The proportion of patients with ACR30 response in each treatment group and the 
difference in response rates between anakinra and placebo with the corresponding 95 % exact 
(Santner-Snell) confidence interval (Santner et al 1980) will be presented. 
A patient listing of ACR response and the response for individual components by visit, with 
information on dose of anakinra, age at onset of disease and glucocorticoid use at inclusion, will 
be provided. 
12.1.1 
Sensitivity analyses of the primary endpoint 
As a sensitivity analysis for both the primary analysis of ACR30 (+ absence of fever) at Week 2 
and the supportive analysis of ACR30 (+ absence of fever) at Week 1 a comparison of treatment 
groups including the actual response data for patients who have discontinued study drug will be 
performed using the ACR assessment closest to Week 2 or Week 1 respectively. However, 
patients with study drug discontinuation due to progressive disease will still be treated as non-
responders as in the main analysis. The same exact methods as for the primary analysis will be 
used. 
If the analysis of the primary efficacy endpoint results in a statistically significant outcome a 
tipping point analysis will be performed. The number of responders that can potentially be 
observed among patients with a missing ACR30 outcome at Week 2 (e.g. when non-response is 
assigned in the primary analysis due to discontinuation of study drug) in the anakinra group 
versus the placebo group will be presented in a basic tipping point display. Pairs of number of 
responders in the anakinra and placebo group that lead to statistical significance will be marked 


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and pairs that lead to non-significance will not be marked. The tipping point boundary is the 
staircase region between marked and unmarked rectangles (Yan et al 2009). 
12.2 
Secondary endpoints supporting the primary objective 
For ACR30, ACR50, ACR70 and ACR90, with absence of fever in the preceding 24 hours at 
Week 1 and ACR50, ACR70 and ACR90, with absence of fever in the preceding 7 days, at 
Week 2, the proportion of patients with a response in each treatment group, along with 95 % 
exact confidence intervals and exact tests of the difference in response between treatment 
groups, will be presented. The same exact methods as for the primary endpoint will be used. 
Patients who have discontinued study drug prior to the relevant week of the analysis (Week 1 or 
Week 2) will be treated as non-responders in the analyses.  
The response in the individual components of ACR30, ACR50, ACR70 and ACR90, 
respectively, at Week 1 and Week 2 will be analyzed in the same way as the primary endpoint 
using exact statistical methods. The proportion of patients with a response in each group, and 
exact confidence intervals of the difference will be presented. Patients who have discontinued 
study drug prior to Week 1 will be treated as non-responders in the analyses of the individual 
components of ACR at Week 1 and patients who have discontinued study drug prior to Week 2 
will be treated as non-responders in the analyses of the individual components of ACR at Week 
2.  
The numbers of patients with response/no response in the individual components of ACR at 
Week 1 and Week 2 will also be presented in bar charts. 
The absence of fever at Week 2 will be analyzed in the same way as the primary endpoint using 
exact statistical methods. Patients who have discontinued study drug prior to Week 2 will be 
treated as having a presence of fever in the analysis. 
12.3 
Key secondary efficacy endpoints 
The absence of fever at Week 1 will be analyzed in the same way as the primary endpoint using 
exact statistical methods. 
For each of the three continuous endpoints; change at Week 1 in CRP, in physician’s global 
assessment of disease activity and in patient/parent global assessment of overall well-being, 
descriptive statistics for each treatment group will be calculated. For the comparison between 
anakinra and placebo, exact rank tests based on Wilcoxon scores will be used. The exact 95% 
confidence intervals based on the Wilcoxon rank statistic for the Hodges-Lehmann estimate of 
the treatment difference, will be calculated. 


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12.4 
Other secondary efficacy endpoints 
12.4.1 
Sustained efficacy in ACR-responders 
To evaluate sustained efficacy in patients that initially responded to treatment at Week 2 
(ACR30, ACR50, ACR70 or ACR90 response criteria), the ACR responses at Week 4, Week 8 
and Week 12 will be compared to the response at Week 2. The individual response profiles will 
be displayed in a Swimmer plot with bars representing the time on study drug and markers for 
the ACR response achieved at each visit. The purpose is to show onset of ACR response and 
how it evolves over time in relation to time to treatment discontinuation. 
12.4.2 
Efficacy of anakinra during 12 weeks treatment 
The number and percentage of patients with ACR30, ACR50, ACR70 or ACR90 response with 
absence of fever (during 24 hours before Week 1 or 7 days preceding Week 2, Week 4, Week 8 
and Week 12) at Week 1, Week 2, Week 4, Week 8 and Week 12 will be presented in Swimmer 
plots (ACR response in relation to time on study drug) as mentioned in section 12.4.1. 
The number and percentage of patients with absence of fever and absence of rash (during 24 
hours before Week 1 or 7 days preceding Week 2, Week 4, Week 8 and Week 12) at Week 1, 
Week 2, Week 4, Week 8 and Week 12 will be tabulated. 
Individual absolute values and percentage change from baseline values over time at Week 1, 
Week 2, Week 4, Week 8 and Week 12 for CRP, physician’s global assessment of disease 
activity and change in patient/parent global assessment of overall well-being, will be plotted. 
The number and percentage of patients with inactive disease at Week 12 will be presented. 
Individual absolute values and percentage change from baseline values of JADAS27 at Week 2 
and Week 12 will be plotted. 
12.4.3 
Inactive disease 
The number of patients with inactive disease at Week 12 will be presented. 
12.4.4 
Time to study drug discontinuation 
Kaplan Meier curves will be generated for the anakinra and placebo groups of time to study drug 
discontinuation due to any cause. Patients completing the study without being prematurely 
discontinued will be censored at Week 12.  
Study drug discontinuation due to lack of efficacy or progressive disease will be illustrated in the 
Swimmer plots specified in section 12.4.1. 


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12.4.5 
Glucocorticoid tapering 
The number and percentage of patients who have initiated tapering of glucocorticoids at 
Week 12 will be presented.  
For patients that initiated tapering the percentage decrease of glucocorticoid dose at Week 2, 
Week 4, Week 6, Week 8 and Week 12 compared to baseline will be presented with descriptive 
statistics. The number of patients that have been able to decrease the glucocorticoid dose with at 
least 50 % from baseline to Week 12 will be presented.  
12.5 
Subgroup Analyses 
Due to the small sample size, no subgroup analyses will be performed.  
13 
Safety analyses 
13.1 
Treatment exposure 
Exposure to study drug (prescribed daily dose, actual daily dose received and duration of 
treatment) will be summarized by dose group (2 and 4 mg/kg/day) with descriptive statistics. 
13.2 
Adverse events 
All AEs will be coded using MedDRA version 21.1.  
A TEAE is defined as an AE with a start date/time after the first administration of IMP and 
within 28 days after stopping therapy.  
The number and percentage of patients with at least one TEAE, at least one severe TEAE, at 
least one serious TEAE, including death, at least one non-serious TEAE, any related TEAE, any 
fatal TEAE, any TEAE leading to study drug withdrawn and any TEAE leading to study 
withdrawal will be summarized. 
The number and percentage of patients with at least one TEAE will be summarized in frequency 
tables by treatment, system organ class and preferred term. Separate tables will present TEAEs 
classified by relationship to investigational product and TEAEs classified by maximum severity. 
These tables will be presented by PT in descending order of frequency in the anakinra group. 
Percentages will be based on the number of patients in the safety analysis set for the specific 
treatment group. 
The number of patients with MAS will be reported. 


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13.2.1 
Serious adverse events 
The number and percentage of patients with at least one serious TEAE will be tabulated by SOC 
and PT. SAEs will also be listed. The listing will include information on treatment group, age, 
sex, race, start/stop date of event, SOC/PT, causality, severity, action taken, and outcome.   
13.2.2 
Adverse events leading to withdrawal 
The number and percentage of patients with TEAEs leading to study withdrawal will be 
presented by SOC and PT. 
13.2.3 
Deaths 
Details of any deaths will be listed together with SAEs as detailed in 13.2.1. 
13.3 
Laboratory data 
The laboratory data evaluation will be based on the results from the central laboratory. 
The laboratory safety data will be presented as actual values and change from baseline values 
over time by descriptive statistics. The number and percentage of patients with low, normal, or 
high laboratory values at baseline versus subsequent visits will be presented using shift tables. 
The values at post-baseline visits versus baseline for each laboratory parameter will be presented 
in shift plots. 
13.4 
Vital signs 
Vital signs (height (at baseline only), weight, blood pressure and heart rate) will be presented as 
absolute and change from baseline values over time by descriptive statistics. Individual absolute 
values for weight, blood pressure and heart rate over time will also be plotted.  
 
13.5 
Physical examination 
A general physical examination will be assessed at Day 1/Baseline and at all visits until the 
Week 12 visit, and at the Study drug discontinuation visit if performed. Abnormal findings at 
Day 1 are reported and summarized under medical history and findings during the study are 
reported as AEs.  


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14 
Pharmacokinetic analyses 
Anakinra trough concentrations will be derived from the serum concentration data, and will be 
summarized at each visit with descriptive statistics.  
Repeated-dose PK at Week 12 will be presented using individual patient concentration-time plots 
on the semi-log and linear scales. Calculated PK parameters at Week 12 will be listed. 
15 
Immunogenicity analyses 
The number and percentage of patients with ADA and NAb and cross-reactivity at baseline, 
Week 1, Week 2, Week 4, Week 8 and Week 12 will be presented. ADA titers at baseline, 
Week 2, Week 4, Week 8 and Week 12 will be summarized by descriptive statistics. 
Occurrence and titer levels of ADA in relation to AEs will be reviewed.  
Occurrence and titer levels of ADA, including Nab in relation to ACR response and CRP will be 
presented. 
16 
Productivity analyses 
The number of days off school or work due to Still’s disease since last visit will be presented by 
visit for patients and caregivers separately using descriptive statistics. 
17 
Exploratory endpoints 
17.1.1 
Population PK/PD analysis 
These analyses are not mandatory and may be performed where appropriate. The analyses will 
be reported separately. 
17.1.2 
Inflammatory biomarkers 
The absolute values and the changes from baseline in IL-6, IL-18, calprotectin and neopterin at 
Week 1, Week 2 and Week 12 will be presented by descriptive statistics. 


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18 
References 
Nordstrom D. et al. Beneficial effect of interleukin 1 inhibition with anakinra in adult-onset still's 
disease. An open, randomized, multicenter study. Journal of Rheumatology. 
2012;39(10):2008-2011. 
Santner, T. J., and Snell, M. K. (1980). Small-Sample Confidence Intervals for and in 
Contingency Tables. Journal of the American Statistical Association. 1980;75:386–394. 
Yan X et al. Missing Data Handling Methods in Medical Device Clinical Trials. Journal of 
Biopharmaceutical Statistics 2009;19(6):1085-1098.