Clinical trial NCT03002974
Conditions: Acute Gouty Arthritis
Keywords: Gout Interleukin 1 receptor antagonist IL-1 receptor antagonist
Sponsor: Swedish Orphan Biovitrum
Start date: 2016-12-01; Completion date: 2019-08-01
Enrollment: 165 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate how anakinra relieves pain for patients with acute gout that cannot take non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine. The patients will be divided in different treatment groups to compare anakinra to the available drug triamcinolone.

Detailed description:
Patients will be randomized to treatment at their first gout flare in the study. The first treatment period will be followed by an extension period during which the patients will receive the same treatment for any subsequent flares within 52 weeks of randomization of last patient in the study. The extension period for the individual patient in the study will be maximum two years (104 weeks). Each new flare treated will initiate a new series of study visits and assessments according to specified schedule of events. Only if a patient experience a new flare after Day 15 of the latest flare they can start a new treatment period. The comparison of primary interest is between anakinra (100 mg and 200 mg combined) and 40 mg triamcinolone, and as a secondary objective the 2 different doses of anakinra will be evaluated as well as assessment for subsequent flares.

Arms: arm 1: 1 subcutaneous injection of Anakinra 100 mg once daily for 5 days, 1 subcutaneous injection of Placebo to Anakinra 100 mg once daily for 5 days and 1 single intramuscular injection of Placebo to Triamcinolone Acetonide 40 mg arm 2: 2 subcutaneous injections of Anakinra 100 mg (2 syringes) once daily for 5 days and 1 single intramuscular injection of Placebo to Triamcinolone Acetonide 40 mg arm 3: 2 subcutaneous injections of Placebo to Anakinra 100 mg once daily for 5 days and 1 single intramuscular injection of Triamcinolone Acetonide 40 mg
Interventions: intervention 1: Anakinra 100 mg intervention 2: Triamcinolone Acetonide 40 mg intervention 3: Placebo to Anakinra 100 mg intervention 4: Placebo to Triamcinolone Acetonide 40 mg
Intervention descriptions: intervention 1: 100 mg/0.67 mL solution in single-use prefilled syringes for subcutaneous injection intervention 2: 1 mL intramuscular injection of a 40 mg/mL injectable suspension intervention 3: sterile solution for injection (0.67 mL) in a single-use prefilled syringe identical to the anakinra syringe intervention 4: 1 mL intramuscular injectable suspension with identical appearance as the Triamcinolone Acetonide suspension

Protocol documents:
Prot_000.pdf: 
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Kineret®(anakinra) 
Clinical Study No: Sobi.anakin-401 
Version 6.0, Amendment 4, 24 Jan 2018 
 
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Study Protocol 
 
 
Protocol number: 
Sobi.ANAKIN-401 
NCT number:  
03002974 
Study title: 
A randomized, double-blind, active-control, multicenter, efficacy and 
safety study of 2 dose levels of subcutaneous anakinra compared to 
intramuscular triamcinolone in the treatment of acute gouty arthritis, 
followed by an extension period of up to 2 years. The anaGO study. 
 
Version: 
Version 6.0, Amended protocol including amendment 4 
Date: 
24 January 2018 
 
 
 


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 A randomized, double-blind, active-control, multicenter, efficacy and safety 
study of 2 dose levels of subcutaneous anakinra compared to intramuscular 
triamcinolone in the treatment of acute gouty arthritis, followed by an 
extension period of up to 2 years 
The anaGO study 
Amended Protocol of the Study Sobi.ANAKIN-401 
IND No: 003611 
Type of Study: Therapeutic exploratory Phase 2 
 
Original protocol date: 9 September 2016 
Amendment no 1: 13 December 2016 
Amendment no 2: 5 May 2017 
Amendment no 3: 8 September 2017 
Amendment no 4: 24 January 2018 
Sponsor’s Medical Director 
Sven Ohlman, MD, PhD 
Swedish Orphan Biovitrum AB (publ)  
112 76 Stockholm, Sweden 
Telephone No: +46 8 697 28 37 
E-mail: sven.ohlman@sobi.com  
Principal Coordinating Investigator 
Kenneth G. Saag, MD, MSc                                              
Professor of Medicine                                                       
University of Alabama in Birmingham                             
2000 6th Ave S FL 3 Birmingham, AL 35233, USA        
Telephone No: +1 205-249-7746                                      
E-mail: ksaag@uab.edu 
Sponsor’s Study Manager 
Sponsor’s Statistician 
Kristine Bäck, BSc 
Clinical Program Leader 
E-mail: kristine.back@sobi.com 
Lisa Osterling Koskinen, MSc 
Product Statistician 
E-mail: lisa.osterlingkoskinen@sobi.com 
Signature
Date
 
 
 
 
 
 
 
 
 
 


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Investigator statement 
 
I have read the protocol entitled “A randomized, double-blind, active-control, multicenter, 
efficacy and safety study of 2 dose levels of subcutaneous anakinra compared to intramuscular 
triamcinolone in the treatment of acute gouty arthritis followed by an extension period of up to 2 
years” and the accompanying current investigator’s brochure and summary of product 
characteristics. I agree to conduct the clinical investigation in compliance with the Protocol, 
Version 6.0, 24 January 2018, the International Council for Harmonisation (ICH) harmonised 
guideline E6(R2): Guideline for Good Clinical Practice, applicable regulatory/government 
regulations, and in accordance with the latest revision of the Ethical Principles for Medical 
Research Involving Human Subjects (the Declaration of Helsinki). I will not implement any 
changes to study procedures or conduct without prior approval from the sponsor and, when 
applicable, the Institutional Review Board and Regulatory Authority. 
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 
1 
Synopsis ....................................................................................................................... 9 
2 
Abbreviations and definition of terms ......................................................................... 19 
3 
Ethics.......................................................................................................................... 22 
3.1 
Independent ethics committee ................................................................................ 22 
3.2 
Ethical conduct of the study ................................................................................... 22 
3.3 
Patient information and consent .............................................................................. 22 
4 
Study administrative structure ..................................................................................... 22 
4.1 
Sponsor .................................................................................................................. 22 
4.2 
Contract research organization ............................................................................... 23 
4.3 
Central Laboratories ............................................................................................... 23 
5 
Background ................................................................................................................ 23 
5.1.1 
Gouty arthritis.................................................................................................... 23 
5.1.2 
Current therapy for gouty arthritis flare and medical need .................................. 24 
5.1.3 
Rationale for IL-1 blocking therapy ................................................................... 24 
5.1.4 
Anakinra ............................................................................................................ 25 
5.1.4.1 Reports on clinical benefit in gouty arthritis flares ......................................... 25 
5.1.4.2 Safety ............................................................................................................ 25 
5.2 
Study rationale ....................................................................................................... 26 
5.3 
Potential risks and benefits ..................................................................................... 26 
6 
Study objectives and endpoints ................................................................................... 28 
6.1 
Primary objective ................................................................................................... 28 
6.1.1 
Primary endpoint ............................................................................................... 28 
6.1.2 
Secondary endpoints supporting primary objective ............................................ 28 
6.2 
Secondary objectives .............................................................................................. 28 
6.2.1 
Secondary endpoints .......................................................................................... 29 
6.3 
Exploratory objectives ............................................................................................ 29 
6.3.1 
Exploratory endpoints ........................................................................................ 30 
7 
Investigational plan ..................................................................................................... 30 
7.1 
Overall study design and plan ................................................................................. 30 
7.2 
Discussion of study design ..................................................................................... 32 
7.2.1 
Study population ................................................................................................ 32 
7.2.2 
Efficacy evaluation ............................................................................................ 33 
7.2.2.1 Definition of primary endpoint ...................................................................... 33 
7.2.2.2 Definitions of secondary efficacy endpoints .................................................. 33 
7.2.3 
Comparator ........................................................................................................ 34 


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7.2.4 
Dose and treatment duration .............................................................................. 34 
7.2.4.1 Dosage regimen ............................................................................................ 34 
7.2.4.2 Dose levels .................................................................................................... 34 
7.2.4.3 Treatment duration ........................................................................................ 35 
7.3 
Selection of study population ................................................................................. 35 
7.3.1 
Inclusion criteria ................................................................................................ 35 
7.3.2 
Exclusion criteria ............................................................................................... 36 
7.3.3 
Withdrawal of patients from treatment or study ................................................. 38 
7.3.3.1 Withdrawal from study treatment .................................................................. 38 
7.3.3.2 Withdrawal from study .................................................................................. 38 
7.3.4 
Replacement of withdrawn patients ................................................................... 38 
7.3.5 
Screen failures ................................................................................................... 39 
7.3.6 
Patients with data collection failure for primary endpoint ................................... 39 
7.4 
Treatments ............................................................................................................. 39 
7.4.1 
Treatments administered .................................................................................... 39 
7.4.2 
Identity of investigational medicinal products .................................................... 39 
7.4.3 
Storage of IMP .................................................................................................. 40 
7.4.4 
Method of assigning patients to a treatment group ............................................. 40 
7.4.5 
Selection of doses .............................................................................................. 41 
7.4.6 
Selection and timing of doses for each patient .................................................... 41 
7.4.6.1 Home storage and transportation ................................................................... 41 
7.4.6.2 Preparation and dosage .................................................................................. 41 
7.4.6.3 Administration .............................................................................................. 42 
7.4.7 
Blinding ............................................................................................................. 42 
7.4.8 
Prior and concomitant therapy ........................................................................... 43 
7.4.9 
Treatment compliance ........................................................................................ 44 
7.4.10 
Overdose management ....................................................................................... 44 
7.5 
Efficacy and safety assessments ............................................................................. 44 
7.5.1 
Study schedule ................................................................................................... 44 
7.5.1.1 Schedule of events ........................................................................................ 44 
7.5.1.2 Pre-screening (optional) ................................................................................ 44 
7.5.1.3 Baseline, Visit 1 ............................................................................................ 44 
7.5.1.4 Follow up by telephone at 24 and 48 hours (reminder calls) .......................... 45 
7.5.1.5 72-hour, Visit 2 ............................................................................................. 45 
7.5.1.6 Day 8, Visit 3 ................................................................................................ 46 
7.5.1.7 Day 15, Visit 4 .............................................................................................. 46 
7.5.1.8 Day 28, Visit E .............................................................................................. 46 


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7.5.1.9 Week 12, Visit 5 ........................................................................................... 46 
7.5.1.10 Follow up by telephone every 12 weeks (retention calls) ............................... 47 
7.5.1.11 End of study call ........................................................................................... 47 
7.5.2 
Medical and surgical history .............................................................................. 47 
7.5.3 
Medical examination of current flare ................................................................. 47 
7.5.4 
Demography ...................................................................................................... 48 
7.5.5 
Efficacy assessments ......................................................................................... 48 
7.5.5.1 Patient-assessed pain intensity, VAS scale .................................................... 48 
7.5.5.2 Patient assessed pain intensity, Likert scale ................................................... 48 
7.5.5.3 Global response to treatment, Likert scale ..................................................... 48 
7.5.5.4 Use of rescue medication............................................................................... 49 
7.5.5.5 Clinical signs of the most affected joint  (index joint tenderness, swelling and 
erythema) ...................................................................................................... 49 
7.5.5.6 Inflammatory biomarkers .............................................................................. 49 
7.5.6 
Safety assessments ............................................................................................. 50 
7.5.6.1 Adverse events .............................................................................................. 50 
7.5.6.2 Laboratory safety assessments ....................................................................... 55 
7.5.6.3 Vital signs and physical examination ............................................................. 56 
7.5.6.4 Electrocardiograms ....................................................................................... 57 
7.5.6.5 Anti-drug antibodies ...................................................................................... 57 
7.5.7 
Anakinra serum concentrations .......................................................................... 57 
7.5.7.1 Sampling procedure ...................................................................................... 57 
7.5.7.2 Bioanalytical method..................................................................................... 58 
7.5.8 
Exploratory assessments .................................................................................... 58 
7.5.8.1 Health related quality of life and health care resource utilization ................... 58 
7.5.8.2 Exploratory inflammatory biomarkers ........................................................... 59 
7.5.8.3 Exploratory pharmacogenetic assessment ...................................................... 59 
8 
Quality control and quality assurance .......................................................................... 60 
9 
Statistical plan ............................................................................................................ 60 
9.1 
Determination of sample size ................................................................................. 60 
9.2 
Definition of study populations .............................................................................. 60 
9.3 
Overall statistical and analytical plan ...................................................................... 61 
9.3.1 
General statistical issues .................................................................................... 61 
9.3.2 
Demographics and baseline characteristics ......................................................... 61 
9.3.3 
Analysis related to primary objective ................................................................. 61 
9.3.3.1 Primary endpoint ........................................................................................... 61 
9.3.3.2 Secondary endpoints supporting the primary objective .................................. 62 


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9.3.4 
Analysis related to secondary objectives ............................................................ 63 
9.3.4.1 Pain intensity for anakinra dose groups, 100 and 200 mg ............................... 63 
9.3.4.2 Response ....................................................................................................... 63 
9.3.4.3 Onset of effect ............................................................................................... 63 
9.3.4.4 Resolution of pain ......................................................................................... 64 
9.3.4.5 Rescue medication ........................................................................................ 64 
9.3.4.6 Physician’s assessment of global response to treatment ................................. 64 
9.3.4.7 Physician’s assessment of clinical signs ........................................................ 64 
9.3.4.8 Patient´s assessment of global response to treatment ..................................... 65 
9.3.4.9 Inflammatory biomarkers .............................................................................. 65 
9.3.4.10 Subsequent flares .......................................................................................... 66 
9.3.4.11 Anti-drug antibodies ...................................................................................... 66 
9.3.4.12 Serum concentration of IL-1Ra/anakinra ....................................................... 67 
9.3.5 
Analysis related to exploratory objectives .......................................................... 67 
9.3.5.1 SF-36 ............................................................................................................ 67 
9.3.5.2 EQ-5D-5L ..................................................................................................... 67 
9.3.5.3 WPAI:SHP .................................................................................................... 67 
9.3.5.4 Health care resource utilization ..................................................................... 67 
9.3.5.5 Exploratory inflammatory biomarkers ........................................................... 68 
9.3.6 
Analysis of safety and tolerability data ............................................................... 68 
9.3.6.1 Adverse events .............................................................................................. 68 
9.3.6.2 Clinical laboratory results .............................................................................. 68 
9.3.7 
Interim analysis ................................................................................................. 68 
9.3.8 
Multiple comparison/multiplicity ....................................................................... 68 
9.3.9 
Exploratory subgroup analyses .......................................................................... 69 
9.3.10 
Handling of missing data ................................................................................... 69 
10 
Data collection, handling and record keeping .............................................................. 69 
10.1 
Data standards ........................................................................................................ 69 
10.2 
Case report form ..................................................................................................... 69 
10.3 
Source data ............................................................................................................. 70 
10.4 
Database closure .................................................................................................... 70 
10.5 
Record retention ..................................................................................................... 71 
11 
End of study ............................................................................................................... 71 
12 
Sponsor’s discontinuation criteria ............................................................................... 71 
13 
Dissemination and publication of results ..................................................................... 71 
14 
References .................................................................................................................. 72 
15 
Appendices ................................................................................................................. 77 


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1 
Synopsis 
STUDY IDENTIFIERS 
 
Title of study:  
A randomized, double-blind, active-control, multicenter, efficacy and 
safety study of 2 dose levels of subcutaneous anakinra compared to 
intramuscular triamcinolone in the treatment of acute gouty arthritis, 
followed by an extension period of up to 2 years 
Clinical study number: 
 
Investigators:  
Sobi.anakin-401 
 
Kenneth G. Saag, MD, MSc, Principal Coordinating Investigator   
University of Alabama                                     
2000 6th Ave S FL 3 Birmingham, AL 35233, USA 
Approximately 35 additional investigators 
 
Study center(s): 
 
 
Approximately 35 centers in US  
Type of study: 
Therapeutic Exploratory Phase 2  
 
 
STUDY OBJECTIVES 
 
Primary objective:  
To evaluate the efficacy of anakinra compared to triamcinolone acetonide 
with respect to patient-assessed pain intensity in the treatment of a gouty 
arthritis flare (based on patients’ first flare treated in the study). 
 
Secondary objective(s): 
To evaluate the primary and the secondary endpoints supporting primary 
objective for the 2 different anakinra dose groups (100 and 200 mg) 
compared to triamcinolone (40 mg) in the treatment of the first gouty 
arthritis flare.  
To evaluate the time to onset of effect, time to response, time to pain 
resolution, time to rescue medication, physician’s assessment of global 
response and clinical signs, patient´s assessment of global response, 
inflammatory biomarkers and safety of anakinra compared to 
triamcinolone in the treatment of the first gouty arthritis flare both for the 
combined anakinra group (100 and 200 mg) and the 2 different anakinra 
dose groups.  
To evaluate the primary and secondary endpoints and safety of the 
combined anakinra group (100 and 200 mg), the 2 different anakinra dose 
groups and triamcinolone in the treatment of subsequent flares. 
Subsequent flares are flares occurring after the first flare in the study and   
within 52 weeks of randomization of the last randomized patient in the 
study. However the extension will be a maximum of two years (104 
weeks) for the individual patient in the study. 
Exploratory objective(s): 
To explore the effect of anakinra on health related quality of life (HRQL) 
and health care resource utilization in the treatment of gouty arthritis. 


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To explore the effect of anakinra on exploratory inflammatory biomarkers 
in serum in the treatment of gouty arthritis flares. 
To analyze for genetic factors potentially contributing to the patient's 
response to anakinra, safety and tolerability. 
 
 
STUDY ENDPOINTS 
 
Primary endpoint: 
Change in patient-assessed pain intensity from baseline to 24-72 hours 
(average of the assessments performed at 24, 48 and 72 hours).  
Patient will score their pain intensity in the joint most affected at baseline 
(i.e., the index joint) on a 0-100 mm visual analogue scale (VAS), ranging 
from no pain (0) to unbearable pain (100).  
 
Secondary endpoint(s) 
supporting primary 
objective  
Change from baseline in patient-assessed pain intensity in the index joint 
as measured by VAS and a 5-point Likert scale at 6, 12, 18, 24, 36, 48, 72 
hours and Days 5, 6, 7 and 8. 
 
Secondary endpoint(s): 
The following endpoints will be assessed for the first flare and subsequent 
flares. All comparisons versus baseline (pre-dose measurement at Visit 1) 
will be made against the baseline of the first and subsequent flares, 
respectively.   
 
Time to onset of effect (20% change from baseline pain intensity 
on VAS). 
 
Time to response (50% change from baseline pain intensity on 
VAS). 
 
Response (50% change from baseline on VAS) at 24, 48 and 72 
hours, Day 8 and Day 15 (Yes/No). 
 
Resolution of pain (defined as <10 mm on VAS) at 72 hours, Day 
8 and Day 15 (Yes/No). 
 
Time to resolution of pain (defined as <10 mm on VAS). 
 
Time to intake of rescue medication from first IMP 
administration. 
 
Type and number of occasions of intake of rescue medication 
from first IMP administration to Day 8. 
 
Physician’s assessment of global response to treatment (5-point 
Likert scale) at 72 hours, Day 8 and Day 15. 
 
Physician’s assessment of clinical signs (index joint tenderness, 
swelling and erythema) at 72 hours, Day 8 and Day 15. 
 
Patient´s assessment of global response to treatment (5-point 
Likert scale) at 72 hours, Day 8 and Day 15. 
 
Change from baseline in the inflammatory biomarkers CRP and 
SAA at 72 hours, Day 8 and Day 15. 
 
Safety variables (AEs, vital signs, laboratory safety assessments). 


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 
Serum concentration of IL-1Ra/anakinra at baseline, 72 hours 
(just before IMP administration) and at Day 8, Day 15, Day 28 
and Week 12 (the assessment at Day 28 and Week 12 will only be 
performed if no subsequent flare has occurred at the specific 
timepoint). 
 
Occurrence of ADA against anakinra at Visit 1 (before IMP 
administration) and at Day 8, Day 15, Day 28 and Week 12 (the 
assessment at Day 28 and Week 12 will only be performed if no 
subsequent flare has occurred at the specific timepoint).  
 
Additional assessment for the subsequent flares:  
 
Change in patient-assessed pain intensity from baseline to 24-72 
hours (average of the assessments performed at 24, 48 and 72 
hours). 
 
Change from baseline in patient-assessed pain intensity in the 
index joint as measured by VAS score and 5-point Likert scale at 
6, 12, 18, 24, 36, 48, 72 hours and Days 5, 6, 7 and 8.  
 
Exploratory endpoint(s): 
 
Change from baseline in health related quality of life (Short Form 
(36) Health Survey (SF-36®)) at Day 8 and Day 15.  
 
Work productivity and activity impairment due to a gouty arthritis 
flare (WPAI:SHP) and health care resource utilization: number of 
days of unscheduled outpatient visits during the last week 
recorded at Day 8 and Day 15 with hospitalization and number.  
 
Change from baseline in exploratory inflammatory biomarkers in 
serum at 72 hours, Day 15 and Week 12. 
 
Change from baseline in health related quality of life (EQ-5D-5L) 
at Day 8 and Day 15. 
 
 
 
STUDY DESIGN AND 
METHODS 
 
Study design: 
This is a randomized, double-blind, active-control, multicenter study to 
investigate the efficacy and safety of 2 doses of anakinra in the treatment 
of a gouty arthritis flare followed by an extension period to investigate the 
safety and efficacy of anakinra when treating subsequent flares.  
 
The study consists of three periods: an optional pre-screening period, a 
double-blind treatment period and an extension period.  
The treatment period of the first flare is double-blind, and the patients will 
be randomized to treatment with 100 mg anakinra, 200 mg anakinra or 40 
mg triamcinolone acetonide in a 1:1:1 ratio. Anakinra is administered as 
once daily s.c. doses for 5 days and the reference product (Triamcinolone 
acetonide 40 mg) as one i.m. injection. The treatment period will be 
followed by an extension period during which the patients will receive the 


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same treatment for any subsequent flares after Day 15 of the latest flare, 
see figure below.  Each new flare treated with IMP will initiate a new 
serie of study visits and assessments according to the schedule of events. 
The extension period will continue for all patients until 52 weeks after 
randomization of the last randomized patient in the study. However an 
individual patient’s treatment will not start later than two years (104 
weeks) after randomization. Thus the study will not exceed 104+12 weeks 
for any patient. 
 
 
 
When all patients have conducted the Day 15 visit of the first flare (Visit 
4), the database will be locked and a primary analysis will be conducted. 
A second database lock will be conducted when all patients have 
completed the study.   
The treatment period for each flare will consist of  4 to 6 visits to the 
study center. The visits are the screening/baseline visit (Visit 1/Day 1), the 
72-hour visit (Visit 2/Day 4), the one-week visit (Visit 3/Day 8), the two-
week visit (Visit 4/Day 15), the four-week visit (Visit E/Day 28) and the 
3-month visit (Visit 5/Week 12). If a subsequent flare has been treated 
with IMP beforeDay 28 and/or Week 12 visit, the Day 28 and/or  Week 12 
visit will be cancelled. 
A follow-up by phone will be performed at 24 and 48 hours post first IMP 
administration to remind the patients to complete the assessments and 
recordings in the eDiary. A follow-up by phone will also be performed 
every 12 weeks following Visit 5 of the latest flare. 
The patient’s participation in the study will be completed by an End-of-
study follow-up by phone at the end of the extension period or at the 
Week 12 visit of the last flare treated with IMP in the study, whichever 
occurs latest.  
 
All patients will be followed throughout the study, irrespective of 
treatment withdrawal or use of rescue medication. 
At each baseline visit (first and subsequent flares), the joint that is most 
affected i.e., most painful will be defined as the index joint. 


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Rescue medication: Patients who have difficulty in tolerating their pain 
are allowed to take rescue medication after the 24-hour post-dose pain 
assessment but not within 6 hours before the 48- and 72-hour post-dose 
pain assessments. Permitted rescue medication includes topical ice/cold 
packs, paracetamol and/or codeine or short-acting tramadol.  
Patients still having insufficient relief with the rescue medication listed 
above after the 72-hour post-dose pain assessment are allowed to take oral 
prednisone or prednisolone at a starting dose up to 0.5 mg/kg per day for a 
maximum of 5 days.  
 
Number of patients 
planned: 
A maximum of 169 patients can be randomized in this study.  
Initially159 patients will be randomized, 53 to triamcinolone and 106 to 
anakinra (53 to 100 mg and 53 to 200 mg). For each randomized patient 
that have not contributed with any value for analysis of the primary 
endpoint (e.g. no value collected for patient-assessed pain intensity from 
baseline to 72 hours), one extra patient can be randomized in the study. A 
maximum of 10 extra patients can randomized under this protocol.  
 
Diagnosis and main 
criteria for inclusion: 
Main inclusion criteria: 
1. Signed informed consent to participate in this study. 
2. Male and female patients, aged ≥18 years. 
3. Patient meeting the American College of Rheumatology 
(ACR)/European League Against Rheumatism (EULAR) 
2015 gout classification criteria. 
4. History of ≥1 self-reported flares of gouty arthritis within 12 
months prior to randomization. 
5. Patient-reported current ongoing flare of gouty arthritis 
characterized by baseline pain intensity in the index joint of 
≥50 mm on a 0-100 mm VAS.  
6. Currently tender (≥1 on a 0-4-point Likert scale) and swollen 
(≥1 on a 0-4-point Likert scale) index joint. 
7. Onset of current ongoing flare within 4 days prior to 
randomization. 
8. The patient meets at least one of the following criteria for 
both treatment options NSAIDs and colchicine  
a. At least one episode of being intolerant, or 
unresponsive to the treatment, see Appendices 4-6. 
b. The investigator judges that the patient is either 
contraindicated or not appropriate for the treatment. 
Inappropriateness may be due to anticipated changes 
in patient status such as worsening of comorbidities 
or use of concomitant medication, see Appendices 4-
6. 


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9. Criterion omitted  
10. If on urate-lowering therapy, a stable dose and regimen for at 
least 2 weeks prior to randomization and expectance to 
remain on a stable dose and regimen for ≥ 2 weeks after 
administration of the first dose of study treatment. 
11. Women of childbearing potential willing to use adequate 
contraception 
12. If applicable, willingness and capability to make s.c. 
injections at home.  
13. Patient is willing and able to use an electronic device for e.g. 
recording of pain.  
Inclusion criteria for IMP treatment of subsequent flare(s): 
14. Patient-reported, current flare of gouty arthritis characterized 
by pain intensity in the index joint of ≥30 mm on a 0–100 mm 
VAS.  
15. Tender (≥1 on a 0-4-point Likert scale) and swollen (≥1 on a 
0-4-point Likert scale) index joint. 
16. Women of childbearing potential willing to use adequate 
contraception 
 
Main exclusion criteria: 
1. 
Use of specified pain relief medications or biologics 
(including glucocorticoids, narcotics, 
paracetamol/acetaminophen, NSAIDs, colchicine, IL-
blockers and tumor necrosis factor [TNF] inhibitors) within 
specified periods (see Appendix 1) prior to randomization. 
2. 
Contra-indication to triamcinolone acetonide.  
3. 
Polyarticular gouty arthritis involving more than 4 joints. 
4. 
Rheumatoid arthritis, evidence/suspicion of infectious/septic 
arthritis, or other acute inflammatory arthritis. 
5. 
History of malignancy within the past 5 years. Exceptions are 
basal cell skin cancer, carcinoma-in-situ of the cervix or low-
risk prostate cancer after curative therapy. 
6. 
Known hypersensitivity to Escherichia coli-derived proteins, 
Kineret® (anakinra), Kenalog® (triamcinolone acetonide) or 
any components of the products. 
7. 
Participation in another concurrent investigational study 
within 30 days of randomization or intake of an 
investigational drug within five times the half-life of that 
investigational drug has passed. 
8. 
Previous inclusion in this study. 
9. 
Known presence or suspicion of active or recurrent bacterial, 
fungal or viral infections at the time of randomization, 
including tuberculosis, or HIV infection or hepatitis B or C 
infection.


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10. Presence of severe renal function impairment chronic kidney 
disease (CKD) stages 4 and 5 (estimated creatinine clearance 
30 mL/min/1.73m2). 
11. Presence of neutropenia (ANC < 1.5 x 109/L). 
12. Uncontrolled clinically significant hematologic, pulmonary, 
endocrine, metabolic, gastrointestinal, CNS or hepatic 
disease as judged by the investigator. 
13. History of myocardial infarction, unstable angina, 
cerebrovascular events, or coronary artery bypass grafting,  
New York Heart Association (NYHA) class III or IV heart 
failure within the previous 3 months prior to randomization. 
14. ECG with clinically relevant finding making the patient not 
appropriate for inclusion in the study, as judged by the 
investigator. 
15. Patients with a documented history of alcohol or substance 
abuse within 12 months prior to randomization (consumption 
of > 21 units of alcohol/week is considered alcohol abuse) 
16. Patients who have undergone major surgery within 2 weeks, 
or have an unhealed operation wound/s. 
17. Presence of any medical or psychological condition or 
laboratory result that in the opinion of the investigator might 
create risk to the patients (or interfere with the subject´s 
ability to comply with the protocol requirements, or to 
complete the study).  
18. Earlier or current treatment with anakinra  
19. Pregnant and lactating women  
20. History of >12 flares overall in the 6 months prior to 
randomization. 
 
Exclusion criteria for IMP re-treatment of subsequent flare(s): 
21. IMP treatment of latest flare initiated within the last 14 days. 
22. Known presence or suspicion of active or recurrent bacterial, 
fungal or viral infections, including tuberculosis, or HIV 
infection or hepatitis B or C infection. 
23. Presence of severe renal function impairment CKD stages 4 
and 5 (estimated creatinine clearance 30 mL/min/1.73m2). 
24. Presence of neutropenia (ANC < 1.5 x 109/L). 
25. History of myocardial infarction, unstable angina, 
cerebrovascular events, or coronary artery bypass grafting, 
NYHA class III or IV heart failure within the previous 3 
months prior to Visit 1. 
26. ECG with clinically relevant finding making the patient not 
appropriate for IMP treatment, as judged by the investigator. 
27. Patients who have undergone major surgery within 2 weeks 
prior to Visit 1, or have an unhealed operation wound/s. 
28. Pregnant or lactating women


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29. Presence of any condition or laboratory result  that in the 
opinion of the investigator makes the patient not appropriate  
for treatment with IMP. 
 
Visit schedule and 
assessments: 
The schedule of events is presented in Appendix 2.  
Pre-screening (optional): Eligibility based on the inclusion and exclusion 
criteria. 
Visit 1 (Screening and baseline): Obtain signed informed consent, 
eligibility based on the inclusion and exclusion criteria, medical and 
surgical history, prior and concomitant medication, demographics, 
medical examination of current flare (including identification of index 
joint), local screening laboratory safety assessments, physical 
examination, vital signs and ECG, and patient’s assessment of pain 
intensity. The patient´s assessment of health related quality of life (SF-
36®, EQ-5D-5L®), the physician´s assessment of clinical signs will be 
performed.  Blood will be collected for central laboratory safety 
assessments, immunogenicity, inflammatory biomarker and 
IL1ra/anakinra serum concentration assessments. Randomization, IMP 
administration patient/caregiver IMP injection training and  patient diary 
training.  
Follow-up by phone at 24 and 48 hours (reminder calls): A follow-up 
telephone call will be made to remind the patient to record pain intensity, 
IMP-administration and any use of rescue medication in the eDiary.  
Visit 2 (72 hours): Patient´s assessment of pain intensity, the patient´s and 
physician´s global assessment of response to treatment, the physician´s 
assessment of clinical signs, blood sampling for central laboratory safety, 
inflammatory biomarkers and IL1ra/anakinra serum concentration 
assessments, vital signs, AEs and concomitant and rescue medication. 
IMP administration. 
Visit 3 (Day 8): Blood sampling for central laboratory safety. Patient’s 
assessment of pain intensity, patient´s and physician’s global assessment 
of response, physician´s assessment of clinical signs, the patient´s 
assessment of health related quality of life and health care resource 
utilization, assessments, immunogenicity assessments, inflammatory 
biomarkers and anakinra serum concentration assessments, vital signs, 
AEs and concomitant and rescue medication. 
Visit 4 (Day 15): Patient´s assessment of pain intensity, the patient´s and 
physician’s global assessment of response, the physician´s assessment of 
clinical signs, the patient´s assessment of health related quality of life and 
health care resource utilization. 
Blood sampling for central laboratory safety assessments, immunogenicity 
assessments, inflammatory biomarkers and IL1ra/anakinra serum 
concentration assessments, physical examination and vital signs, AEs and 
concomitant and rescue medication. 


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Visit E (Day 28):  Visit E will only be performed if no subsequent flare 
has occurred.  Data will be collected on concomitant medication and 
adverse events. Blood will be collected for immunogenicity assessments 
and IL-1Ra/anakinra serum concentration assessments.   
Visit 5 (Week 12): Visit 5 will only be performed if no subsequent flare 
has occurred. SAEs and outcomes of previously recorded AEs will be 
recorded and blood will be collected for immunogenicity assessments, 
inflammatory biomarkers and IL-1Ra/anakinra serum concentration 
assessments.  
Follow up by telephone at every 12 weeks after Visit 5 of the latest flare 
(retention calls): A follow-up telephone call  will be made to record 
outcomes of previously reported AEs and to encourage patient to remain 
in the study.  
Subsequent flare(s):  
Visits 1 to 5 (six visits; baseline, 72 hours, Day 8, Day 15, Day 28 and 
Week 12 after first IMP dose for subsequent flare): Assessments as 
described for Visits 1 to 5 above with the exception of informed consent, 
demographics (excluding weight) and randomization. Type of AEs to be 
collected will depend on time since last administration of IMP.  
Follow-up by phone at 24 and 48 hours  after first IMP dose for 
subsequent flare and at every 12 weeks after Visit 5 : Assessments as 
described for the first flare. 
End of study:  
End-of-study follow-up by phone will be performed either;  
1. 52 weeks after randomization of the last patient in the study 
or 
2. 104 weeks after randomization of the individual patient 
whichever occurs first. 
If the IMP treatment started week 40 or later in case 1), or week 92 in case 
2), the Week 12 visit will replace the End-of-study follow-up by phone.  
Outcomes of previously reported AEs will then be recorded. 
 
Test product; dose and 
mode of administration: 
Arm A: anakinra, 100 mg, s.c. injection, once daily for 5 days. 
Arm B: anakinra, 200 mg, s.c. injection, once daily for 5 days. 
Arm C: matching anakinra placebo, s.c. injection, once daily for 5 days. 
During the extension period the patients will continue to receive the same 
treatment for subsequent flares occurring after Day 15 of the last flare.  
 
Reference product; dose 
and mode of 
administration: 
Arms A and B: Matching Triamcinolone placebo, single i.m. injection. 
Arm C: Triamcinolone, 40 mg single i.m. injection. 
 


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Duration of treatment(s): 
For each flare, IMP will be administered for 5 days. 
 
 
Randomization: 
Patients will be randomized to treatment with anakinra 100 mg, anakinra 
200 mg or triamcinolone 40 mg in a 1:1:1 ratio. The randomization will be 
stratified by ULT use (yes/no) and BMI (30.0 or 30.0 kg/m2) at 
inclusion. 
For subsequent flares in the extension period, patients will continue to 
receive treatment with anakinra 100 mg, anakinra 200 mg or 
triamcinolone 40 mg in a 1:1:1 ratio.  
The randomized groups will be as follows: 
Arm A: anakinra 100 mg  
Arm B: anakinra 200 mg 
Arm C: triamcinolone 40 mg 
 
 
Statistical methods: 
At least 159 patients will be randomized, 53 to triamcinolone and 106 to 
anakinra (53 to 100 mg and 53 to 200 mg). 
The sample size calculation is based on the change in pain intensity on a 
visual analog scale (VAS) 0-100 mm from baseline to the average over 
24-72 hours. A sample size of 106 randomized patients receiving anakinra 
and 53 randomized patients receiving triamcinolone is required to ensure a 
power of 80% to reject the null hypothesis of no difference between 
anakinra and triamcinolone assuming a true difference of 12 mm on VAS 
mean change and a standard deviation of 25 mm when using a two-sided 
test with a significance level of 5%. 
The comparison of primary interest is between anakinra (100 mg and 200 
mg combined) and triamcinolone. The primary endpoint will be estimated 
using a mixed model repeated measures analysis with the measurements 
on the individual time points as responses (baseline, 6, 12, 18, 24, 48 and 
72 hours), and with treatment (anakinra 100 mg, anakinra 200 mg and 
triamcinolone), ULT use (yes/no), BMI (<30.0 and ≥30.0 kg/m2), visit 
and treatment-visit-interaction as fixed effects and center as random 
effect. An unstructured covariance matrix will be used to account for 
within-subject correlation. The estimated mean change from baseline to 
24-72 hours for each treatment group (anakinra and triamcinolone), the 
estimated difference between the groups and the associated 95 % 
confidence interval and p-value based on this model will be presented. 
Further, each of the two doses of anakinra, 100 mg and 200 mg, will be 
compared to triamcinolone using the same model as for the primary 
comparison.  
The secondary time-to-event endpoints will be analyzed using a stratified 
log-rank test, with ULT use (yes/no) and BMI (30.0 or 30.0 kg/m2) as 
stratification factors. 
The secondary continuous endpoints will be analyzed using an analysis of 
covariance including factors for treatment, ULT use (yes/no) and BMI 
(30.0 or 30.0 kg/m2) and baseline value as covariate. 


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2 
Abbreviations and definition of terms 
ACR 
ADA 
AE 
American College of Rheumatology 
Anti-drug antibodies 
Adverse event 
Anakinra  
Recombinant interleukin 1 receptor antagonist 
ANC  
Absolute neutrophil count 
BMI 
Body mass index 
CAPS 
Cryopyrin-associated periodic syndrome 
CDASH 
Clinical data acquisition standards harmonization 
CDISC 
Clinical data interchange standards consortium 
The secondary binary endpoints will be analyzed using a logistic 
regression model with treatment, ULT use (yes/no) and BMI (30.0 or 
30.0 kg/m2) as explanatory variables. Safety tabulations of adverse event 
data and laboratory data will be performed.  
Continuous variables will be summarized using the number of patients, 
the mean, the standard deviation, the median, the minimum value, and the 
maximum value. Categorical variables will be summarized using 
frequency counts and percentages. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CKD 
CLIA 
Chronic kidney disease 
Clinical laboratory improvement amendments 
CRO 
Contract research organization 
CRP  
C-reactive protein  
ECG  
Electrocardiogram  
eCRF  
EEA 
Electronic case report form  
European economic area 
ED 
Emergency department  
eGFR 
Estimated glomerular filtration rate 
EQ-5D-5L® 
EULAR 
EuroQol 5 dimensions 5 levels 
European League Against Rheumatism 
GCP 
GLP 
HRQL 
Good clinical practice 
Good laboratory practice 
Health related quality of life 
IB 
Investigator brochure 
ICF 
Informed consent form 
ICH 
IEC 
International conference on harmonisation 
Independent Ethics Committee 
IL 
Interleukin 
IL-1Ra 
Endogenous Interleukin 1 receptor antagonist  
i.m. 
Intramuscular 
IMP 
Investigational medicinal product 
IRB  
Institutional review board  
ISR 
Injection-site reaction 
ITT 
Intention-to-treat 
IWRS 
Interactive web response system 
MAR 
Missing at random 
MCS 
Mental component summary 
MedDRA 
Medical dictionary for regulatory activities 
MNAR 
Missing not at random 
MPO 
Myeloperoxidase 


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MSD-ECL 
Meso Scale Discovery Electrochemiluminescence 
MSU 
NAb 
NOMID 
Monosodium urate 
Neutralizing antibodies 
Neonatal onset multisystem inflammatory disease 
NSAID 
Non steroidal anti-inflammatory drugs  
NYHA 
OMERACT 
New York Heart Association 
Outcome measures in rheumatology 
PCS 
Physical component summary  
PK 
Pharmacokinetic 
PP 
Per-protocol 
QoL 
Quality of life  
RA 
Rheumatoid arthritis 
SAA 
Serum amyloid A 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
s.c. 
Subcutaneous 
SDTM 
Study data tabulation model 
SF-36 
SJIA  
Short Form (36) Health Survey (acute v. 2) 
Systemic juvenile idiopathic arthritis 
Sobi 
SOP 
SUSAR 
Swedish Orphan Biovitrum AB (publ) 
Standard operating procedure 
Suspected unexpected serious adverse reaction 
TIA 
Transient ischemic attack  
TNF 
ULT  
Tumour necrosis factor 
Urate lowering therapy  
VAS 
WHODRUG 
WPAI:SHP 
Visual analogue scale 
World health organisation drug dictionary 
Work productivity and activity impairment:specific health 
problems  
 
 
 


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3 
Ethics 
3.1 
Independent ethics committee 
It is the responsibility of the investigator to obtain independent ethics committee (IEC)/ 
institutional review board (IRB) approval of the study protocol, possible amendments and the 
written patient information and informed consent form (ICF). The investigator should file all 
correspondence with the IRB. Copies of IRB correspondence and approvals should be forwarded 
to the contract research organization (CRO). 
3.2 
Ethical conduct of the study 
This study will be conducted in compliance with this protocol, the International council of 
harmonisation (ICH) Guideline for good clinical practice (GCP) (1), applicable regulatory 
requirements, and in accordance with the latest revision of the ethical principles for medical 
research involving human subjects (the declaration of Helsinki) (2). 
3.3 
Patient information and consent 
It is the responsibility of the investigator to give each patient prior to any study-related activities, 
full and adequate verbal and written information regarding the objective and procedures of the 
study and the possible risks involved. The patients must be informed about their right to 
withdraw from the study at any time. The written patient information and/or consent form must 
not be changed without prior discussion with Swedish Orphan Biovitrum AB (publ) (Sobi). 
Before any revisions are implemented, the revised written patient information and/or consent 
form must be approved by the IRB/IEC. 
It is the responsibility of the investigator to obtain signed informed consent from all patients 
prior to any study related activities. The patients should receive a copy of the written information 
and signed ICF. 
Once the ICF has been signed, the patient will be assigned an enrollment number.  
4 
Study administrative structure 
4.1 
Sponsor 
The sponsor of the study is Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden.  
 


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4.2 
Contract research organization  
The conduct of the study is fully outsourced to Pharmaceutical Research Associates, Inc., 
Raleigh, North Carolina, USA (PRA). Site evaluation, monitoring, development of master 
written patient information and ICF, data management, investigational product management, 
safety reporting and vendor management are some of the related activities and responsibilities 
that are transferred to PRA.  
PRA has assigned Almac, for investigational medicinal product (IMP) depot and IMP logistics, 
ERT, Philadelphia, Pennsylvania, USA to provide and manage electronic diaries and Perceptive, 
a division of Parexel International Corp, Waltham, Massachusetts, USA for handling of the 
interactive web response system (IWRS).  
Statistical analysis and development of the clinical study report will remain the responsibility of 
Sobi.  
4.3 
Central Laboratories 
Central laboratories will be used for all study specific laboratory assessments. All central 
laboratories are compliant with good laboratory practice (GLP). 
The analysis of anti-drug antibodies (ADA), including validation of the bridging method to be 
used, and the analysis of endogenous interleukin 1 receptor antagonist (IL-1Ra)/anakinra 
concentrations, including validation of the Meso Scale Discovery electrochemiluminescence  
(MSD-ECL)based method to be used for the purpose will be performed by York Bioanalytical 
Solutions Limited, Cedar House, Northminster Business Park, Upper Poppleton, York, United 
Kingdom.  
The analysis of neutralizing ADA (NAb) including development and validation of the cell-based 
method to be used will be performed by Euro Diagnostica, Malmö, Sweden. 
PRA has assigned the central laboratory sample shipments, intermediate depot storage and 
analysis of laboratory safety variables, C-reactive protein (CRP) and serum amyloid A (SAA), to 
Eurofins Central Laboratory, Lancaster, Pennsylvania, USA which has accreditation for the 
purpose. 
Analysis of inflammatory biomarkers will be performed by Eurofins Global Central Laboratory, 
Breda, the Netherlands under clinical laboratory improvement amendments (CLIA) accreditation 
(IL-6, IL-8, calprotectin, neopterin and myeloperoxidase). 
5 
Background 
5.1.1 
Gouty arthritis 
Gouty arthritis is a chronic, progressive inflammatory arthritis characterized by the deposition of 
monosodium urate (MSU) crystals primarily in and around joints, as a result of persistent 
hyperuricemia. Development of gouty arthritis is typically observed in patients with serum urate 


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concentrations above the level at which MSU crystals form at physiological pH and temperature 
(6.8 mg/dL, 0.41 mmol/L) (12).  It is one of the most common inflammatory arthritis in adults 
(22). 
The long-term goal in the treatment of gouty arthritis is to reduce serum uric acid concentrations 
(12), and urate-lowering therapy (ULT) has been shown to be effective in preventing gouty 
arthritis flares (18). However, many patients fail to achieve adequate uric acid control and some 
patients experience flares of gouty arthritis at normal serum uric acid levels. 
A gouty arthritis flare is an acute and severely painful condition caused by the inflammatory 
response triggered by the MSU crystals. The flares are characterized by rapid onset and build-up 
of severe pain, warmth, swelling, decreased range of motion, and redness of the involved joints. 
Early during the disease, flares tend to last from a few hours up to a week. Later during the 
course of the disease, the flares tend to last longer. The frequency of flares also often increases 
over time in patients who are inadequately treated (9). 
5.1.2 
Current therapy for gouty arthritis flare and medical need  
A gouty arthritis flare causes extreme pain and significant disability, and the goal of acute 
pharmacologic therapy is to provide a prompt, effective and safe pain relief. There are several 
anti-inflammatory pharmacological options approved for the treatment of acute gouty arthritis, 
including non steroidal anti-inflammatory drugs (NSAIDs), colchicine, and glucocorticoids. 
Recently, both the European League Against Rheumatism (EULAR) and the American College 
of Rheumatology (ACR) published guidelines and recommendations for the management of gout 
(12, 17). However, in daily practice, many patients continue to experience poor clinical outcome 
of therapy. Conventional therapy is not always suitable or effective, and many patients with 
gouty arthritis have underlying comorbidities, including hypertension, chronic kidney disease, 
coronary artery disease, hyperlipidemia, chronic hepatitis, osteoporosis, gastroesophageal 
disease and diabetes (11). There is, thus, a need for effective treatment for patients who have 
either contraindications to, or are not appropriate for, are intolerant of, or have disease that is 
refractory to existing therapies. 
5.1.3 
Rationale for IL-1 blocking therapy 
The central pathogenic cause of gout is MSU crystal deposition. MSU crystals induce secretion 
of interleukin-1β (IL-1β) via activation of the NALP3 inflammasome (14). IL-1β is a pivotal 
cytokine that mediates inflammation and joint damage. Several lines of evidence suggest that the 
initiation of inflammation in gouty arthritis is similar to that occurring in hereditary 
autoinflammatory syndromes such as e.g. cryopyrin-associated periodic syndromes (CAPS), for 
which IL-1 blockade is highly effective (31). Therefore, IL-1 blockade may be an appropriate 
therapeutic intervention for gouty arthritis flares. This is supported by clinical data for 
canakinumab (20, 5) and by published case studies, retrospective reviews and case reports on 
anakinra in gouty arthritis (19, 7, 10, 16, 21). 


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5.1.4 
Anakinra 
Anakinra is a recombinant IL-1 receptor antagonist 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 controls active inflammation. Anakinra has a short half-life (4-6 hours) and is 
administered as a subcutaneous (s.c.) injection daily at home.  
Anakinra is currently approved in the US (2001), Canada (2002), and EU/EEA (2002) for the 
treatment of rheumatoid arthritis (RA). Anakinra is also approved for the most severe form of 
CAPS, i.e. neonatal onset multisystem inflammatory disease (NOMID), in the US (2012), and 
for all forms of CAPS in EU/EEA (2013). In addition, anakinra is approved for the treatment of 
systemic juvenile idiopathic arthritis (SJIA) in Australia (2015). 
For a detailed description of anakinra characteristics, contraindications, warnings and 
precautions, adverse reactions and pharmaceutical properties, refer to the product 
information/monograph and the investigator brochure (IB).    
5.1.4.1 
Reports on clinical benefit in gouty arthritis flares 
Published clinical case series have evaluated the clinical efficacy of anakinra in gouty arthritis in 
various clinical situations (19, 7, 10, 16, 21). Different dose regimens have been used, but most 
patients have been treated with once-daily s.c. injections of 100 mg for 3 to 5 days. The 
characteristics of the treated patients have varied, including different clinical manifestations of 
gouty arthritis, intolerance to, or inadequate response to conventional therapies, such as NSAIDs, 
colchicine, or glucocorticoids.  
The published case series have provided supportive evidence for the efficacy of IL-1 inhibition 
with anakinra in the treatment of gouty arthritis flares. No new or unexpected adverse events 
have occurred and the safety profile is consistent between these reports and the known safety 
profile for anakinra in other indications. 
5.1.4.2 
Safety  
The safety profile of anakinra is well established. Since its approval in the US 2001 for the 
treatment of RA, it is calculated that, up to 01 May 2016, the total post-marketing exposure is 84 
408 patient-years.   
In placebo-controlled studies in RA patients, the most frequently reported adverse reactions were 
injection-site reactions (ISRs), which were mild to moderate in most patients. From studies in 
RA there are indications that ISRs are more frequent when daily doses of >100 mg s.c. are 
administered. In RA studies, the vast majority of ISRs occurred within the first 4 weeks of 
therapy. Less than 20% of the ISRs occurred during the first 5 days, also when daily doses of 
>100 mg were administered.  
The incidence of serious adverse events (SAEs) at the recommended dose in RA (100 mg/day) 
was comparable with placebo. The incidence of serious infections was higher in anakinra-treated 
patients with RA compared to patients receiving placebo (2 % vs. < 1 %). In clinical studies and 
during post-marketing use, rare cases of opportunistic infections have been observed including 
fungal, mycobacterial, bacterial, and viral pathogens. In clinical studies of RA, neutropenia 
(absolute neutrophil count (ANC) <1 x 109/L) occurred in 0.4 % of patients receiving anakinra. 


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Repeated short-term administration of anakinra has not been previously studied. This type of 
administration could possibly result in an increased risk for development of ADA, which may 
result in an increased risk for allergic/anaphylactic reactions, ISRs or reduced efficacy. The 
occurrence of ADA against anakinra has been evaluated in clinical studies in RA, and no 
correlation between ADA development and AEs has been observed.  
In an open-label study in NOMID (the most severe form of CAPS), patients were treated with 
anakinra up to 5 years. The safety profile was similar to the safety profile observed in studies of 
patients with RA, with the exception of the ISR frequency which was comparable to the ISR 
frequency of placebo-treated patients in RA studies.  
In previous clinical studies of sepsis, more than 1000 patients received anakinra i.v. at doses up 
to 2 mg/kg/hour over a 72-hour treatment period. The safety profile in these studies was similar 
to that seen in other indications (33, 34, 35). The maximum tolerated dose of anakinra has not 
been established in humans. 
The safety profile of anakinra is similar across indications and dose levels studied. In long-term 
studies, there are no indications of increasing AE rates over time. The safety profile is also 
comparable between adults below 65 years of age and elderly. 
 
5.2 
Study rationale 
The main aim of this study is to evaluate the efficacy and safety of anakinra in patients for whom 
NSAIDs and colchicine are either contraindicated or not appropriate, not tolerated or do not 
provide an adequate response, and to select the appropriate  dose in order to reduce the pain and 
inflammation of a gouty arthritis flare. The study will also evaluate the safety and 
immunogenicity of anakinra when treating subsequent flares during a 1-2 years study extension.   
 
5.3 
Potential risks and benefits 
Published case series have provided supportive evidence for the efficacy of IL-1 inhibition with 
anakinra in the treatment of gouty arthritis flares (19, 7, 10, 16, 21). No new or unexpected 
adverse events have occurred, and the safety profile is consistent between the reports and the 
known safety profile of anakinra. 
The use of anakinra for the treatment of gouty arthritis flares is supported by the described 
central pathogenic role of IL-1 in acute gouty arthritis (14) as well as by clinical data for the 
IL-1β inhibitor canakinumab (20, 5). 
The safety profile of anakinra is well established and has been similar across indications and 
dose levels (see 5.1.4.2), with the exception of ISRs that were more frequent when doses of 
>100mg s.c. were administered to patients with RA. However, less than 20% of ISRs occurred 
during the first 5 days of anakinra treatment. From the limited information available, there are no 


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indications of any relevant differences in the safety profile of anakinra in patients with gouty 
arthritis compared to patients with other indications for anakinra treatment.  
There is limited experience of the intermittent, short-term treatment with anakinra that is planned 
for patients with repeated flares of gouty arthritis in this study. This type of administration may 
result in an increased development of ADA, which could possibly result in an increased risk for 
allergic/anaphylactic reactions, injection-site reactions or reduced efficacy.  
The proposed indication for anakinra treatment of acute gouty arthritis includes patients that are 
refractory to, or do not tolerate standard therapy, i.e., patients eligible for anakinra treatment are 
expected to have several comorbidities. Patients with coronary artery disease (29, 25), type 1 
diabetes (28), type 2 diabetes (27), and hepatic failure (45) have all been studied in separate 
studies with anakinra. There are no indications from these studies that the studied populations 
have a different safety profile than other patient groups treated with anakinra. In addition, 
patients with stroke have been treated with anakinra bolus doses up to 500 mg i.v. followed by 
up to 10 mg/kg/hour i.v. for 24 hours (36) with a similar safety profile and no dose-limiting 
toxicities (30, 26). Since anakinra elimination is dependent on renal function, a study with 
administration of single 100 mg s.c. doses in patients with various degrees of renal failure has 
been performed. The results show that both systemic exposure and plasma clearance were 
significantly correlated with the degree of renal impairment but there were no relevant 
differences in the safety profile of anakinra between subjects with normal renal function and 
those with different degrees of renal impairment (47). 
The potential risks associated with anakinra administration (including development of ADA) will 
be closely monitored as part of the safety evaluations being performed in the study. 
The suggested class effect of IL-1 blocking therapy, the well-established safety profile of 
anakinra, and its short half-life makes anakinra a candidate for treatment of patients with gouty 
arthritis flares. Based on the information available, the proposed treatment with anakinra is not 
expected to present any major additional risks for the patient population.  
In this study, all patients will receive active treatment (100 mg anakinra, 200 mg anakinra or 40 
mg triamcinolone) and are expected to get pain relief when treated for their gouty arthritis flares. 
Patients are also allowed to add on treatment with rescue medication. To be included in the 
study, the  patients cannot have taken pain medication during the last 1 to 24 hours (dependent 
on the half-life of the medicines). It is therefore important that the patients are included as soon 
as possible after the onset of the flare to minimize the patient’s time without pain relief 
treatment.  
The benefits for the patients to participate in the study are the possibility to access an 
investigational drug potentially more effective than conventional treatment and to get a thorough 
medical follow-up of each flare occurring during one year. To strive for normalized serum urate 
levels the patient will be allowed to continue or initiate ULT treatment during the course of the 
study (40). 


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6 
Study objectives and endpoints   
6.1 
Primary objective  
To evaluate the efficacy of anakinra compared to triamcinolone acetonide 40 mg intramuscular 
(i.m) injection, hereafter referred to as triamcinolone, with respect to patient-assessed pain 
intensity in the treatment of a gouty arthritis flare (based on patients’ first flare treated in the 
study). 
6.1.1 
Primary endpoint 
Change in patient-assessed pain intensity from baseline to 24-72 hours (average of the 
assessments performed at 24, 48 and 72 hours).  
Patients will score their pain intensity in the joint most affected at baseline (i.e., the index joint) 
on a 0-100 mm visual analogue scale (VAS), ranging from no pain (0) to unbearable pain (100). 
6.1.2 
Secondary endpoints supporting primary objective 
Change from baseline in patient-assessed pain intensity in the index joint as measured by VAS 
and a 5-point Likert scale at 6, 12, 18, 24, 36, 48, 72 hours and Days 5, 6, 7 and 8.  
6.2 
Secondary objectives  
To evaluate the primary endpoint and the secondary endpoints supporting primary objective for 
the 2 different anakinra dose groups compared to triamcinolone in the treatment of the first gouty 
arthritis flare.  
To evaluate the time to onset of effect, time to response, time to pain resolution, time to rescue 
medication, physician’s assessment of global response and clinical signs, patient´s assessment of 
global response, inflammatory biomarkers and safety of anakinra compared to triamcinolone in 
the treatment of the first gouty arthritis flare both for the combined anakinra group (100 and 200 
mg) and the 2 different anakinra dose groups.  
To evaluate the primary and secondary endpoints and safety of the combined anakinra group 
(100 and 200 mg), the 2 different anakinra dose groups and triamcinolone in the treatment of 
subsequent flares. Subsequent flares are flares occurring after the first flare in the study and 
within 52 weeks of randomization of the last randomized patient in the study.However the 
extension will be a maximum of two years (104 weeks) after randomization for the individual 
patient in the study. 


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6.2.1 
Secondary endpoints 
The following endpoints will be assessed for the first flare and subsequent flares. All 
comparisons versus baseline (pre-dose measurement at Visit 1) will be made against the baseline 
of the first and subsequent flares, respectively.   
 Time to onset of effect (defined as 20% change from baseline pain intensity on VAS). 
 Time to response (defined as 50% change from baseline pain intensity on VAS). 
 Response (defined as 50% change from baseline pain intensity on VAS) at 24, 48 and 
72 hours, Day 8 and Day 15 (Yes/No). 
 Resolution of pain (defined as <10 mm on VAS) at 72 hours, Day 8 and Day 15 
(Yes/No). 
 Time to resolution of pain (defined as <10 mm on VAS). 
 Time to intake of rescue medication from first IMP administration. 
 Type and number of occasions of intake of rescue medication from first IMP 
administration to Day 8. 
 Physician’s assessment of global response to treatment (5-point Likert scale) at 72 hours 
Day 8 and Day 15. 
 Physician’s assessment of clinical signs at 72 hours, Day 8 and Day 15 in index joint 
tenderness, swelling and erythema. 
 Patient´s assessment of global response to treatment (5-point Likert scale) at 72 hours, 
Day 8 and Day 15. 
 Change from baseline in the inflammatory biomarkers CRP and SAA at 72 hours, Day 8 
and Day 15. 
 Safety variables (AEs, vital signs, laboratory safety assessments). 
 Serum concentration of IL-1Ra/anakinra at baseline, 72 hours (just before IMP 
administration) and at Day 8, Day 15, Day 28 and Week 12 (the assessment at Week 12 
will only be performed if no subsequent flare has occurred). 
 Occurrence of ADA against anakinra at Visit 1 (before IMP administration) and at Day 8, 
Day 15, Day 28 and Week 12 (the assessment at Day 28 and Week 12 will only be 
performed if no subsequent flare has occurred).  
 
Additional assessment for the subsequent flares:  
 Change in patient-assessed pain intensity from baseline to 24-72 hours (average of the 
assessments performed at 24, 48 and 72 hours). 
 Change from baseline in patient-assessed pain intensity in the index joint as measured by 
VAS score and 5-point Likert scale at 6, 12, 18, 24, 36, 48, 72 hours and Days 5, 6, 7 and 
8. 
6.3 
Exploratory objectives  
To evaluate the effect of anakinra compared to triamcinolone on health related quality of life 
(HRQL) and health care resource utilization in the treatment of gouty arthritis flares. 


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To evaluate the effect of anakinra compared to triamcinolone on exploratory inflammatory 
biomarkers in serum in the treatment of gouty arthritis flares. The results will be reported 
separately.  
To analyze for genetic factors potentially 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. The results will be reported 
separately.  
6.3.1 
Exploratory endpoints 
The following exploratory endpoints will be assessed for both the first and subsequent gouty 
arthritis flares. All comparisons versus baseline (pre-dose measurement at Visit 1) will be made 
against the baseline of the first and subsequent flares, respectively.   
 Change from baseline in health related quality of life (Short Form (36) Health Survey, 
acute version 2 (SF-36®)) at Day 8 and Day 15.  
 Work productivity and activity impairment due to a gouty arthritis flare (WPAI:SHP 
v.2.0) and health care resource utilization: number of days with hospitalization and 
number of unscheduled outpatient visits during the last week recorded at Day 8 and Day 
15.  
 Change from baseline in exploratory inflammatory biomarkers in serum at 72 hours, Day 
15 and Week 12. 
 Change from baseline in health related quality of life (EQ-5D-5L) at Day 8 and Day 15. 
 
7 
Investigational plan 
7.1 
Overall study design and plan 
This is a randomized, double-blind, active-control, multicenter study to investigate the efficacy 
and safety of 2 doses of anakinra in the treatment of a gouty arthritis flare followed by an 
extension period to investigate the safety and efficacy of anakinra when treating subsequent 
flares.  
The study consists of three periods: an optional pre-screening period, a double-blind treatment 
period and an extension period.  
The treatment period of the first flare is double-blind, and the patients will be randomized to 
treatment with 100 mg anakinra, 200 mg anakinra or 40 mg triamcinolone in a 1:1:1 ratio. 
Anakinra will be administered as once daily s.c. injections for 5 days (Days 1 to 5) and 
triamcinolone as one i.m. injection (Day 1). The treatment period will be followed by an 
extension period. During this period the patients will receive the same treatment for subsequent 
flares occurring after Day 15 of the latest flare. The extension period will continue for all 
patients until 52 weeks after randomization of the last randomized patient in the study. However 


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the study treatment of an individual patient’s flare will not start later than 2 years (104 weeks) 
after randomization of that patient. Thus the study will not exceed 104 + 12 weeks for any 
patient. Figure 1. 
Figure 1 Study flow chart 
When all patients have conducted the Day 15 visit of the first flare (Visit 4), the database will be 
locked and the primary analysis will be conducted. A second database lock will be conducted 
when all patients have completed the extension period.  
The assessment period for each flare will consist of 4 to 6 visits to the study center. The visits are 
the screening/baseline visit (Visit 1/Day 1), the 72-hour visit (Visit 2/Day 4), the one-week visit  
(Visit 3/Day 8), the two-week visit (Visit 4/Day 15), the four week visit (Visit E/Day 28)  and 
the 3-month visit (Visit 5/Week 12). If a subsequent flare has been treated before the Day 28 
visit, the Day 28 and Week 12 visits will be cancelled. If a subsequent flare has been treated 
before the Week 12 visits that visit will be cancelled. 
An end-of-study follow-up will be performed either; 
1. 52 weeks after randomization of the last patient in the study  
or 
2. 104 weeks after randomization of the individual patient 
whichever occurs first. 
If the IMP treatment started week 40 or later in case 1), or week 92 weeks in case 2), the Week 
12 visit will replace the End-of-study follow-up by phone.  
All patients will have their follow-up visits/phone calls, irrespective of treatment withdrawal or 
use of rescue medication. 
A follow-up by phone will be performed at 24 and 48 hours post first IMP administration to 
remind the patient to complete the assessments and recordings in the eDiary. A follow-up by 
phone will also be performed every 12 weeks following Visit 5 of the latest flare.   


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Subsequent flares occurring before the Day 15 visit of the latest flare (Visit 4) will be treated 
with permitted rescue medication i.e., no IMP will be administered. 
7.2 
Discussion of study design 
7.2.1 
Study population 
This study is designed to evaluate the efficacy and safety of anakinra in the treatment of gouty 
arthritis flares in patients for whom NSAIDs and colchicine are either contraindicated or not 
appropriate due to anticipated changes in patient status, not tolerated or do not provide an 
adequate response. Both in- and out-patients can be included in the study.  
The appropriateness for treatment with NSAIDs and colchicine will depend on several factors, 
for example:  
 Presence, severity and number of controlled and/or uncontrolled co-morbidities  
 Number and type of concomitant medications  
 Age of the patient 
 Previous experience of therapy i.e., individual efficacy and safety outcomes 
Due to the complexity of the numerous combinations of above-mentioned factors, the suitability 
for treatment will be assessed at the discretion of the investigator. To increase consistency, the 
investigators’ assessment will be supported by checklists (see Appendices 4-6). 
To ensure a reliable diagnosis of gouty arthritis, patients to be included in the study must meet 
the ACR/EULAR 2015 gout classification criteria (15).  
At least one self-reported flare of gouty arthritis during the previous 12 months is required for 
inclusion in the study to ensure that the patients have an active gouty arthritis.   
To ensure that a significant number of subsequent flares are treated in the study, the extension 
period will continue for all patients until 52 weeks after randomization of the last randomized 
patient in the study or a maximum of 104 weeks after randomization of the individual patient in 
the study.  
The first flare of gouty arthritis to be treated in the study will be characterized by a baseline pain 
intensity in the index joint of ≥50 mm on a 0 to 100 mm VAS. This VAS cut-off ensures 
restriction of the study population to patients with moderate to severe pain.  
For subsequent flares to be treated with IMP, a cut-off level of ≥30 mm on a 0 to 100 mm VAS 
will be used. This cut-off is based on a proposed definition for a flare based on self-reported 
items in patients previously diagnosed as having gouty arthritis (32). Patient-reported flare, joint 
pain at rest (>3 (0-10 scale)), warm joints, and swollen joints were the most strongly associated 
with presence of a gouty arthritis flare. The rationale behind including and, thus, giving IMP 
treatment to patients with lower VAS scores at subsequent flares compared to the initial flare 
(≥50 mm on a 0 to 100 mm VAS), is that the aim of the extension phase is primarily to study 
safety and immunogenicity, not efficacy. If gouty arthritis flares of mild pain intensity (30-50 
mm on the VAS scale) were to be treated outside the study i.e. with a mix of acute gout 
therapies, the safety assessment of the IMP treatments would be confounded.  


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The required time from flare onset to treatment initiation (≤4 days) was selected to minimize the 
likelihood that a treatment effect coincide with the natural resolution of the flare (usually within 
7 to 10 days). 
7.2.2 
Efficacy evaluation 
7.2.2.1 
Definition of primary endpoint 
The primary endpoint is the change in patient-assessed pain intensity from baseline to 24-72 
hours (average of the assessments performed at 24, 48 and 72 hours). Patients will score their 
pain intensity in the joint most affected at baseline (i.e. the index joint) on a 0 to 100 mm VAS. 
The maximum severity of pain during a gouty arthritis flare is usually reached within 12 to 24 
hours and complete resolution usually occurs within 7 to 10 days in patients with moderate to 
severe gouty arthritis (17). Therefore, an average of the assessments performed at 24, 48 and 72 
hours over a critical period of 24 to 72 hours is proposed. The likelihood of spontaneous 
recovery is also lower during the early phase of a flare.  
The proposed primary endpoint is in line with the FDA Guidance for Industry, Analgesic 
Indications: Developing Drug and Biological Products (24): 
• 
“Efficacy endpoints in an analgesic trial should reflect direct rating of pain intensity by 
the patient… We recommend the use of a well-defined and reliable patient-reported 
outcome  measure of the patient’s pain intensity” (IV.A.3 page 10) 
• 
“…visual or numerical rating of pain intensity, or a categorical rating with several 
categories. It may be a single rating at a given point in time, or an average or other 
summary or several ratings over a period of time.” (IV.B.11.a page 25) 
Patient-reported outcome is also endorsed by the Outcome Measures in Rheumatology 
(OMERACT) gout special interest group (8), and has been used as primary endpoint when the 
effect on the pain of a gouty arthritis flare has been studied with conventional, US-approved 
therapy such as etoricoxib and colchicine, as well as with investigational therapy such as 
canakinumab and rilonacept.    
The comparison of primary interest is between anakinra (100 mg and 200 mg combined) and 40 
mg triamcinolone. As a secondary objective, the 2 different doses of anakinra will be compared 
to 40 mg triamcinolone in respect to the primary endpoint, i.e. change in pain intensity from 
baseline to 24-72 hours.  
7.2.2.2 
Definitions of secondary efficacy endpoints  
Response (50% change from baseline on VAS) 
According to the FDA Guidance mentioned above, a responder analysis, in which the outcome 
for each patient is summarized as a success or a failure based on a single cut-off point can be 
used (24).  
In this study, response is defined as a VAS pain relief of 50% or greater from baseline. In the 
ACR guidelines, an adequate response is defined as ≥50 % improvement in pain score at ≥24 


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hours (12). This definition has also been used in previous acute gouty arthritis studies with 
colchicine and canakinumab (43, 5). 
Onset of effect (20% change from baseline on VAS) 
Two studies in patients admitted to emergency departments with heterogeneous causes of pain 
have indicated that a difference of 13 mm on a VAS represents, on average, the minimum 
change in acute pain that is clinically significant (3, 4). In the canakinumab gouty arthritis 
studies, the patients had mean VAS score of approximately 70 mm at baseline. 13 mm/70 mm is 
less than a 20% change from baseline (5). This would justify a cut-off of 20% change from 
baseline on VAS as clinically meaningful. In the ACR guidelines an adequate response was 
defined as ≥20 % improvement in pain score within 24 hours (12). 
Resolution of pain in patient-assessed pain intensity (VAS<10)  
In this study, resolution of pain is defined as <10 mm in pain intensity on the VAS scale.   
To fully assess time to onset of effect, time to response and time to resolution of pain, the 
patients will record their pain assessment daily up until Day 15. 
7.2.3 
Comparator 
According to the FDA Guidance for Industry, Analgesic Indications: Developing Drug and 
Biological Products“ trials intended to support a finding of efficacy for an analgesic should be 
designed as superiority trials. The comparator can be a lower dose of the investigational drug, a 
placebo or an active comparator” (24). 
A gouty arthritis flare is an acute and severely painful condition, and using placebo as a  
comparator is not considered ethical (8).  
A single i.m. dose of 40 mg triamcinolone has been selected as comparator in this study since 
good pain reduction has been shown when compared to canakinumab (5, 20). Furthermore, one 
injection of a systemic glucocorticoid eliminates the need for a glucocorticoid tapering regimen. 
7.2.4 
Dose and treatment duration 
7.2.4.1 
Dosage regimen 
The pharmacokinetic (PK) profile of anakinra in adult RA patients supports once-daily s.c. 
administration also to patients with a gouty arthritis flare. With once daily administration, steady 
state serum concentrations of anakinra will almost be reached already after the first dose. As 
reflected in the approved label for anakinra, sufficient anakinra exposure has been maintained 
during a once-daily dosage interval. 
7.2.4.2 
Dose levels 
In published case series of anakinra (see Section 10.2.1), different dose levels have been used. 
The majority of patients have been treated with once-daily s.c. injections of 100 mg anakinra 
with generally positive outcome. In the case series where patients were treated with 100 mg for 3 
days, patient-assessed improvement of pain varied between 50 and 100 % (19).  


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In the 2 anakinra dose-response studies in patients with RA (30, 75, 150 mg (44) and 0.04, 0.1, 
0.4, 1, 2 mg/kg (46)), the change from baseline in patient-reported pain intensity (a component of 
the primary efficacy endpoint) tended to increase with increasing doses, and the largest 
differences versus placebo were achieved at daily s.c. doses of 150 mg and 2 mg/kg, 
respectively.  
Based on the results of the RA studies and the case series in acute gouty arthritis, 100 mg was 
selected as the lowest daily dose to be tested in this study. 
The gouty arthritis population proposed to be indicated for treatment with anakinra is assumed to 
have a higher mean body weight than the RA patients. For reference, the mean (SD) body weight 
was 98 (18) kg in the canakinumab clinical studies in patients with acute gouty arthritis (N=368) 
(6), as compared to 77 (19) kg in the anakinra clinical study safety pool in RA patients 
(N=3330). As the anakinra clearance increases with increasing body weight, once-daily s.c. 
doses of both 100 and 200 mg will be evaluated in this study.  
The safety profile of anakinra is well established and has been similar across indications and 
dose levels during long-term treatment (see section 5.1.4.2). Thus, a once-daily s.c. 
administration of 200 mg anakinra is not expected to result in an increased incidence of adverse 
events compared with 100 mg, the only exception being ISRs that, in studies of RA, were more 
frequent with s.c. doses above 100 mg.  
The dose range chosen for this study may not allow discrimination based on statistically 
significant differences. The study will allow descriptive comparisons of efficacy and safety at 2 
relevant dose levels. 
7.2.4.3 
Treatment duration 
The treatment duration of 5 days is chosen to cover the most severe part of the flare and to 
minimize IMP exposure. 
7.3 
Selection of study population 
7.3.1 
Inclusion criteria 
A patient must fulfill the following criteria in order to be included in the study: 
1. Signed informed consent to participate in this study. 
2. Male and female patients, aged ≥18 years 
3. Patient meeting the ACR/EULAR 2015 gout classification criteria (Appendix 7 (15)).  
4. History of ≥1 self-reported flares of gouty arthritis within 12 months prior to 
randomization. 
5. Patient-reported, current ongoing flare of gouty arthritis characterized by baseline pain 
intensity in the index joint of ≥50 mm on a 0-100 mm VAS.  
6. Currently tender (≥1 on a 0-4-point Likert scale) and swollen (≥1 on a 0-4-point Likert 
scale) index joint. 


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7. Onset of currently ongoing flare within 4 days prior to randomization. 
8. The patient meets at least one of the following criteria for both treatment options 
NSAIDs and colchicine  
a. At least one episode of being intolerant, or unresponsive to the treatment, see 
Appendices 4-6. 
b. The investigator judges that the patient is either contraindicated or not appropriate 
for the treatment. Inappropriateness may be due to anticipated changes in patient 
status such as worsening of comorbidities or use of concomitant medication, see 
Appendices 4-6. 
9. Criterion omitted  
10. If on urate-lowering therapy, a stable dose and regimen for at least 2 weeks prior to 
randomization and expectance to remain on a stable dose and regimen for ≥ 2 weeks after 
administration of the first dose of study treatment. 
11. Women of childbearing potential willing to use adequate contraception. 
12. If applicable, willingness and capability to make s.c. injections at home.  
13. Willingness and capability to use an electronic device for e.g. recording of pain.  
Inclusion criteria for IMP treatment of subsequent flare(s): 
14. Patient-reported, current flare of gouty arthritis characterized by pain intensity in the 
index joint of ≥30 mm on a 0–100 mm VAS, see section 7.2.1.  
15. Tender (≥1 on a 0-4-point Likert scale) and swollen (≥1 on a 0-4-point Likert scale) 
index joint. 
16. Women of childbearing potential willing to use adequate contraception. 
7.3.2 
Exclusion criteria 
The presence of any of the following will exclude a patient from inclusion in the study: 
1. Use of specified pain relief medications or biologics (including glucocorticoids, 
narcotics, paracetamol/acetaminophen, NSAIDs, colchicine, IL-blockers and tumor 
necrosis factor [TNF] inhibitors) within specified periods (see Appendix 1) prior to 
randomization. 
2. Contraindication to triamcinolone.  
3. Polyarticular gouty arthritis involving more than 4 joints. 
4. Rheumatoid arthritis, evidence/suspicion of infectious/septic arthritis, or other acute 
inflammatory arthritis. 
5. History of malignancy within the past 5 years. Exceptions are basal cell skin cancer,  
carcinoma-in-situ of the cervix or low-risk prostate cancer after curative therapy. 
6. Known hypersensitivity to Escherichia coli-derived proteins, Kineret® (anakinra), 
Kenalog® (triamcinolone acetonide) or any components of the products. 


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7. Participation in another concurrent investigational study within 30 days of randomization 
or intake of an investigational drug within five times the half-life of that investigational 
drug has passed. 
8. Previous inclusion in this study. 
9. Known presence or suspicion of active or recurrent bacterial, fungal or viral infections, 
including tuberculosis, or HIV infection or hepatitis B or C infection. 
10. Presence of severe renal function impairment chronic kidney disease (CKD) stages 4 and 
5 (estimated creatinine clearance 30 mL/min/1.73m2). 
11. Presence of neutropenia (ANC < 1.5 x 109/L). 
12. Uncontrolled clinically significant hematologic, pulmonary, endocrine, metabolic, 
gastrointestinal, CNS or hepatic disease as judged by the investigator. 
13. History of myocardial infarction, unstable angina, cerebrovascular events, or coronary 
artery bypass grafting, New York Heart Association (NYHA) class III or IV heart failure 
within the previous 3 months prior to Visit 1. 
14. ECG with clinically relevant finding making the patient not appropriate for IMP 
treatment, as judged by the investigator. 
15. Patients with a documented history of alcohol or substance abuse within 12 months prior 
to randomization (consumption of > 21 units of alcohol/week is considered alcohol 
abuse). 
16. Patients who have undergone major surgery within 2 weeks prior to randomization, or 
have an unhealed operation wound/s. 
17. Presence of any medical or psychological condition or laboratory result that in the 
opinion of the investigator might create risk to the patients (or interfere with the patient´s 
ability to comply with the protocol requirements, or to complete the study).  
18. Earlier or current treatment with anakinra. 
19. Pregnant or lactating women.  
20. History of >12 flares overall in the 6 months prior to randomization. 
 
Exclusion criteria for IMP re-treatment of subsequent flare(s): 
21. IMP treatment of latest flare initiated within the last 14 days. 
22. Known presence or suspicion of active or recurrent bacterial, fungal or viral infections, 
including tuberculosis, or HIV infection or hepatitis B or C infection. 
23. Presence of severe renal function impairment CKD stages 4 and 5 (estimated creatinine 
clearance 30 mL/min/1.73m2). 
24. Presence of neutropenia (ANC < 1.5 x 109/L). 
25. History of myocardial infarction, unstable angina, cerebrovascular events, or coronary 
artery bypass grafting, NYHA class III or IV heart failure within the previous 3 months 
prior to Visit 1. 
26. ECG with clinically relevant finding making the patient not appropriate for IMP 
treatment, as judged by the investigator. 
27. Patients who have undergone major surgery within 2 weeks prior to Visit 1, or have an 
unhealed operation wound/s. 
28. Pregnant or lactating women. 


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29. Presence of any condition or laboratory result  that in the opinion of the investigator 
makes the patient not appropriate  for treatment with IMP. 
 
7.3.3 
Withdrawal of patients from treatment or study 
7.3.3.1 
Withdrawal from study treatment 
A patient should be withdrawn from the study treatment if, in the opinion of the investigator, it is 
medically necessary, or if it is the wish of the patient.  
When a patient is withdrawn from treatment, the date of the last IMP administration and the date 
and reason for treatment withdrawal should be clearly described in the relevant sections of the 
electronic case report form (eCRF). If a patient is removed from treatment because of an adverse 
event (AE), the reason for treatment withdrawal should always be stated as ‘adverse event’ 
irrespective of whether this was the investigator’s or the patient’s decision. 
If a patient has been withdrawn from study treatment of one flare but fulfils the eligibility criteria 
for a subsequent flare, study treatment can be re-initiated. However, this is not applicable if the 
withdrawal from study treatment was due to a safety concern related to the IMP treatment, as 
judged by the investigator, see below (7.3.3.2). 
All patients will continue to participate in the study and should be followed and assessed 
according to the protocol until the End of study follow-up call even if study treatment is 
discontinued unless consent is withdrawn or the patient is lost to follow-up.  
7.3.3.2 
Withdrawal from study 
A patient can withdraw from the study at any time but should be encouraged to complete all 
study assessment up to Visit E, Day 28, following the last treated flare. If this is not possible an 
attempt should be made to examine the patient and collect relevant samples and make all 
relevant assessments according to the next scheduled visit.  
 
The eCRF should be completed as far as possible .If a patient has been withdrawn from study 
treatment due to safety concerns as judged by the investigator to be related to IMP treatment the 
patient should be withdrawn from the study after Visit E. 
If a patient’s treatment allocation is unblinded at the request of the investigator, IMP treatment 
should be stopped and the patient should be withdrawn from the study after Visit E. 
7.3.4 
Replacement of withdrawn patients 
Patients withdrawn from the study will not be replaced.  


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7.3.5 
Screen failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized into the study. A minimal set of screen failure information is required 
which includes demography, reason/s for screen failure, eligibility criteria, and any SAE. 
Patients who do not meet the criteria for participation in this study (screen failure) may be 
rescreened for a later flare. Rescreened patients should keep the same study specific patient ID as 
for the initial screening. 
7.3.6 
Patients with data collection failure for primary endpoint 
Patients with data collection failure for primary endpoint are defined as patients who are 
randomized in the clinical study but have no values collected for patient-assessed pain intensity 
from baseline to 72 hours for the first flare. These patients will however continue in the study 
and be included in the ITT and safety populations. 
For each primary endpoint collection failures, one extra patient can be randomized in the study.  
Maximum 10 extra patients can be randomized under this protocol. 
7.4 
Treatments 
7.4.1 
Treatments administered  
The patients will receive IMPs according to the randomization schedule, Table 1. 
Table 1 
Investigational medicinal products 
Arm 
Investigational 
product 
Dosage form 
Route 
Daily 
dose 
Dosage regimen 
A 
Anakinra 
Solution 
s.c. injection 
100 mg 
Once daily for 5 days 
Anakinra placebo 
Solution 
s.c. injection 
- 
Once daily for 5 days 
Triamcinolone placebo 
Solution 
i.m. injection 
- 
Single injection 
B 
Anakinra 
Solution 
s.c. injection 
100 mg 
Once daily for 5 days 
Anakinra 
Solution 
s.c. injection 
100 mg 
Once daily for 5 days 
Triamcinolone placebo 
Solution 
i.m. injection 
- 
Single injection 
C 
Anakinra placebo 
Solution 
s.c. injection 
- 
Once daily for 5 days 
Anakinra placebo 
Solution 
s.c. injection 
- 
Once daily for 5 days 
Triamcinolone  
Solution 
i.m. injection 
40 mg 
Single injection 
7.4.2 
Identity of investigational medicinal products 
The investigational product anakinra is delivered as a sterile solution for injection, prefilled in a 
single-use syringe with the strength 100 mg. The total volume of injection is 0.67 mL and the 


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concentration of anakinra in the solution is 150 mg/mL. The prefilled syringe has a pre-attached 
29 Gauge thin wall half inch needle, a rubber plunger and a latex free rigid needle shield.  
The matching placebo for anakinra is delivered as a sterile solution for injection in a single-use 
prefilled syringe identical to the anakinra 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) or by 
Pfizer (Strängnäs, Sweden) and drug product and matching placebo for anakinra are 
manufactured by Patheon Italia SpA (Monza, Italy).  
The registered triamcinolone (Kenalog®) will be used as reference product and a matching 
placebo triamcinolone will be prepared for this study. The triamcinolone acetonide placebo is 
manufactured by Apotek Produktion & Laboratorier AB (Umeå, Sweden). 
The reference product, triamcinolone acetonide (Kenalog®), is delivered in vials containing a 40 
mg/mL solution, 1 mL for i.m. injection.  
The matching placebo for triamcinolone acetonide injectable suspension is manufactured as an 
emulsion to have the same appearance as the reference product. The triamcinolone acetonide 
placebo will be prepared by diluting commercially available lipid emulsion with physiological 
saline to obtain a white emulsion with appropriate tonicity for i.m. injection. The obtained 
emulsion is identical in appearance as the comparator suspension. The triamcinolone acetonide 
placebo is delivered in a vial and stopper identical to the triamcinolone acetonide vial and 
stopper. However, the colour of the caps on the Kenalog vials and the corresponding placebo 
vials might not be identical during the whole study duration (see section 7.4.6.2 regarding the 
role of the unblinded pharmacist/nurse).  
Labeling will comply with national regulatory requirements. 
Possible deficiencies related to the quality or identity of the investigational products should be 
reported both to the CRO study monitor and also directly to complaints@sobi.com. 
7.4.3 
Storage of IMP  
The IMP (anakinra or placebo prefilled 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. The IMP should not be frozen or shaken. 
Possible deficiencies related to site distribution or storage of IMP should be reported in 
accordance with instructions provided in the IMP handling manual.  
For more details, see also 7.4.6. 
7.4.4 
Method of assigning patients to a treatment group 
The patients will be randomized to treatment with 100 mg anakinra, 200 mg anakinra or 40 mg 
triamcinolone in a 1:1:1 ratio.  
The randomized groups will be as follows: 


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Arm A: anakinra 100 mg,  
Arm B: anakinra 200 mg 
Arm C: triamcinolone 40 mg  
An IWRS will be used for the randomization. Biostatistics at Perceptive will generate the 
randomization scheme for the IWRS, which will link sequential patient randomization numbers 
to treatment codes.  
The randomization will be stratified by ULT use (yes/no) and BMI (30.0 or 30.0 kg/m2) at 
inclusion. 
The randomization numbers will be generated in blocks. Within each block, equal numbers of 
patients will be allocated to each treatment group. The block size will not be revealed before 
breaking of the blind.  
A separate IWRS manual will be provided to the investigators. 
7.4.5 
Selection of doses 
Refer to Section 7.2.4.1, 7.2.4.2 and 7.2.4.3 for the rationale for the selected dosage regimen, 
dose levels and treatment duration. The rationale for the choice of reference product is presented 
in Section 7.2.3. 
7.4.6 
Selection and timing of doses for each patient 
7.4.6.1 
Home storage and transportation 
The Day 1 IMP injections will be administered at the hospital/clinic. Patients who are then 
discharged from the hospital or clinic, will get IMP for the next two days (Day 2 and 3) to be 
injected at home. The patients will return to the hospital/clinical Day 4 and the fourth dose of 
IMPs will be administered at site. When the patients return home they will get the IMP for the 
next day (Day 5) to be injected at home. The IMP will be transported by the patients to their 
homes in provided cold packs. The IMPs should be kept refrigerated at home in its original 
cartons and protected from light. The IMPs should not be frozen or shakened during storage. 
7.4.6.2 
Preparation and dosage 
Anakinra and matching placebo 
At each day of IMP administration period (Days 1 to 5), the anakinra and/or  matching placebo 
will be given as two (2) s.c. injections of 0.67 mL solution in single-use prefilled syringes for s.c. 
injection.  
30 minutes before injection, the prefilled syringes should be taken out from cold storage to 
equilibrate the injection solution with room temperature. 
Triamcinolone and matching placebo  


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At Visit 1 of each flare, the triamcinolone or matching placebo will be given as one (1) i.m. 1 
mL injection withdrawn with a syringe from a vial containing a 40 mg/mL solution. The vial 
should be shaken before use to ensure a uniform suspension. Prior to withdrawal, the suspension 
should be inspected for clumping or granular appearance (agglomeration). An agglomerated 
product results from exposure to freezing temperatures and should not be used.  
In addition to the above instructions, a separate study drug handling manual will be provided. 
The manual will include working instructions for unblinded pharmacist/nurse responsible for 
removal of the triamcinolone/placebo vial caps if the caps differ in colour. The unblinded 
pharmacist/nurse must not be involved in the conduct of the study. The study monitor will 
inform the Investigator/Study Coordinator if an unblinded procedure is needed. 
7.4.6.3 
Administration  
The IMP administration will be initiated on the day of randomization (Visit 1) and the 
administrations scheduled for the first day of each flare will be supervised or given by the 
investigator (or delegated study staff) at the out-patient clinic, emergency department (ED) or 
hospital. If the patient is treated by an out-patient clinic or is discharged from ED/hospital before 
the end of 5-day IMP administration period, the daily s.c. injections at 24, 48 hours and Day 5 
will be administered at home by the patient themselves or a caregiver.  
At the 72-hour visit (Day 4, Visit 2), the IMP administration will be supervised or given by the 
investigator. 
Instructions on appropriate use should be given by the investigator to the patient or caregiver. 
Patients or caregivers should not be allowed to administer any IMP until the patient or caregiver 
has demonstrated a thorough understanding of procedures and an ability to inject the IMP 
correctly. A patient leaflet with detailed instructions on the handling, injection and disposal of 
IMP will be handed out.  
Anakinra and matching placebo 
The IMP should be administered using subcutaneous injections into fat tissue. 
The used syringes should be disposed of and the patients will receive disposal boxes for at home 
use. 
Triamcinolone and matching placebo  
For systemic therapy, injection should be made deeply into the gluteal muscle. For adults, a 
minimum needle length of 1½ inches is recommended. In obese patients, a longer needle may be 
required.  
Throughout each treatment period, the actual number of IMP administrations and timepoint of 
each administration will be recorded in the eCRF or the patient diary. 
7.4.7 
Blinding 
The first part of the study, i.e. treatment and follow-up of the patients’ first flare, is double-blind. 
Treatment assignment will be blinded for the patients, the investigators and any personnel 
involved with the study conduct or evaluation at the investigational sites, CRO and sponsor.  


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Until all patients have completed the Day 15 visit of the first flare (Visit 4), the randomization 
scheme will only be disclosed to selected CRO personnel to ensure correct packaging of the IMP 
and correct set-up of the IWRS. The disclosure of the randomization scheme and any individual 
patient’s treatment assignment will be protected by standard operating procedures (SOPs) of the 
CRO. 
When all patients have completed the Day 15 visit of the first flare, collected data up to this date 
will be analysed by the Sponsor. Blinding will be maintained for patients, investigators, site 
staff, CRO and applicable vendors throughout the extension phase to prevent any bias in data 
handling. The Sponsor will take no part in the operational conduct of the study during the 
extension phase. Details of this process will be outlined in the “Process guideline data integrity  
document”  
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 IWRS manual.  
7.4.8 
Prior and concomitant therapy  
For a list of medication restricted or prohibited (including timeframe) before randomization, see 
Appendix 1. Other therapy considered necessary for the patient’s welfare may be given at the 
discretion of the investigator. 
All therapy taken within specified timelines (see below) prior to and up to 30 days after first IMP 
administration of each treated flare will be recorded in the eCRF:  
 3 months: treatment with amiodarone, digitoxin, leflunomide, and amphotericin 
 1 month: all other prescription drugs         
 1 week: herbal products, vitamins, minerals, and over-the-counter medications 
No other medicinal product under investigation may be used during the study.  
Live vaccines should not be given concurrently with anakinra.   
Patients are allowed to take urate lowering therapy (ULT) during the study. To be eligible for 
study participation, the patients should be on a stable dose and regimen for ≥ 2 weeks prior to 
randomization and expected to remain on a stable dose and regimen for ≥ 2 weeks after study 
start. During the study, initiation or change of dose and regimen of ULT treatment are allowed 
after the pain assessment at Day 15 of each flare. The treatment should follow ACR guidelines 
for ULT (13).   
Concomitant pain medication will be restricted and only rescue medication will be allowed, see 
7.5.5.4. 


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7.4.9 
Treatment compliance 
The date and time of the IMP administrations on Day 1 (Visit 1) and Day 4 (Visit 2) will be 
recorded in the eCRF. The date and time of the IMP administrations on Days 2, 3 and 5 will be 
recorded in the patient diary. 
7.4.10 
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 trials. No specific treatment is 
indicated for IMP overdose. If an overdose of IMP is administered, the actual dose taken should 
be recorded in the eCRF, and any untoward medical occurrence associated with an overdose 
should be recorded the same way as any adverse event (see section 7.5.6.1). 
7.5 
Efficacy and safety assessments 
7.5.1 
Study schedule 
7.5.1.1 
Schedule of events 
See appendix 2. 
7.5.1.2 
Pre-screening (optional) 
Pre-screening is optional and may be done to identify patients that fulfil the study eligibility 
criteria with the exception of having a current flare of gouty arthritis.  
When a pre-screened patient reports a flare of gouty arthritis, the procedures for the baseline visit 
(Visit 1) will be followed. 
7.5.1.3 
Baseline, Visit 1  
A signed informed consent form must be obtained from the patient prior to any study-related 
activities. Once the ICF has been signed, the patient will be assigned an enrollment number.  
Any SAE that occur after informed consent has been signed must be reported (see Section 
7.5.6.1.4). 
Data will be collected on medical and surgical history (see Section 7.5.2), prior and concomitant 
medication (see Section 7.4.8) and demographics (see Section 7.5.4). 
Medical examination of current flare (see 7.5.3), local screening laboratory safety assessments 
(see Section 7.5.6.2), vital signs and physical examination (see Section 7.5.6.3) and a 12-lead 
ECG (see Section 7.5.6.4) will be performed. 
The joint that is most affected, i.e. most painful, will be defined as the index joint and the patient 
will assess the pain intensity in the index joint on a VAS and Likert scale. These pain 
assessments will be done as close as possible to randomization and will serve as baseline values.  


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Once all inclusion and exclusion criteria have been reviewed and recorded (see Section 7.3) and 
the patient has been found eligible, the patient will be randomized and assigned a randomization 
number. 
Prior to the first IMP administration, blood will be collected for central laboratory safety 
assessments (see 7.5.6.2), CRP and SAA(see 7.5.5.6), immunogenicity assessments (see 7.5.6.5), 
exploratory inflammatory biomarkers (see 7.5.8), exploratory pharmacogenetic markers (see 
7.5.8.3) and IL-1Ra/anakinra serum concentration assessments (see 7.5.7). The patient 
assessment of health related quality of life (SF-36® and EQ-5D-5L), the physician´s assessment 
of clinical signs will be performed (see 7.5.5).  
Once all predose assessments have been completed, the IMP (i.m. and s.c. injections) will be 
supervised or administered by the investigator. If the patient or a caregiver is to administer 
subsequent s.c. injections at home, detailed instructions will be given before discharge (not 
applicable if patient is hospitalized) (see 7.4.6.3) and IMP for Days 2 and 3 will be provided to 
the patient.  
The patient will be given detailed instructions on how to use the patient diary to record pain 
intensity (VAS and Likert scale), IMP administration and intake of rescue medication. The 
patient will also be instructed on the use of permitted rescue medication.  
Adverse events, both serious and non-serious, will be recorded from the time point of the first 
IMP administration (see 7.5.6.1).  
For subsequent flares, Visit 1 will not include the informed consent procedure, randomization 
and recording of demographic data (except body weight).  
7.5.1.4 
Follow up by telephone at 24 and 48 hours (reminder calls) 
Follow up telephone calls to remind the patient to complete the pain intensity assessements and 
to record the IMP-adminstration and intake of any rescue medication will be made at 24±2 hours 
and at 48±2 hours after the first IMP administration.  
7.5.1.5 
72-hour, Visit 2  
Visit 2 will occur 72±4 hours after the first IMP administration of each flare (Day 4).  
Vital signs will be recorded and data will be collected on concomitant medication including 
rescue medication. Adverse events will be recorded. 
The compliance with the instructions for how to use the patient diary will be reviewed. 
Prior to the IMP administration, blood will be collected for central laboratory safety assessments, 
CRP and SAA, exploratory inflammatory biomarkers and IL-1Ra/anakinra serum concentration 
assessments. The patient´s assessment of pain intensity, the patient´s global assessment of 
response to treatment, the physician´s global assessment of response to treatment, the physician´s 
assessment of clinical signs will be performed 
Once all predose assessments have been completed, the IMP (s.c. injections) will be supervised 
or administered by the investigator.  


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If the patients is to take the remaining s.c. injection at home, IMP for Day 5 will be provided to 
the patient.  
7.5.1.6 
Day 8, Visit 3 
Visit 3 will occur 1 week after the first IMP administration of each flare (Day 8±1 day ). 
The patient´s assessment of pain intensity, the patient´s global assessment of response to 
treatment, physician´s global assessment of response to treatment, the physician´s assessment of 
clinical signs will be performed. 
The patient´s assessment of health related quality of life (SF-36® and EQ-5D-5L), will be 
performed and the health care resource utilization including WPAI:SHP will be recorded. 
Vital signs will be recorded and data will be collected on concomitant medication including 
rescue medication. Adverse events will be recorded. 
The compliance with the instructions for how to use the patient diary will be reviewed. 
Blood will be collected for central laboratory safety assessments, CRP and SAA, 
immunogenicity assessments, and IL-1Ra/anakinra serum concentration assessments.  
7.5.1.7 
Day 15, Visit 4 
 
Visit 4 will occur 2 weeks after the first IMP administration of each flare (Day 15±1 day). 
The patient´s assessment of pain intensity, the patient´s global assessment of response to 
treatment, physician´s global assessment of response to treatment, the physician´s assessment of 
clinical signs will be performed. 
The patient´s assessment of health related quality of life (SF-36® and EQ-5D-5L), will be 
performed and the health care resource utilization including WPAI:SHP will be recorded. 
Blood will be collected for central laboratory safety assessments, CRP and SAA, 
immunogenicity assessments, exploratory inflammatory biomarkers and IL-1Ra/anakinra serum 
concentration assessments.  
Vital signs, physical examination  and concomitant medication including rescue medication will 
be recorded. Adverse events will be recorded. 
The compliance with the instructions for how to use the patient diary will be reviewed. 
7.5.1.8 
Day 28, Visit E  
Visit E will only be performed at Day 28±2 days if no subsequent flare has occurred.  
Adverse events and concomitant medication will be recorded. Blood will be collected for, 
immunogenicity assessments and IL-1Ra/anakinra serum concentration assessments. 
7.5.1.9 
Week 12, Visit 5 
Visit 5 will only be performed at Week 12±5 days if no subsequent flare has occurred.  


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SAEs and outcomes of previously recorded AEs will be recorded and blood will be collected for 
CRP and SAA, immunogenicity assessments, exploratory inflammatory biomarkers and IL-
1Ra/anakinra serum concentration assessments.  
7.5.1.10 
Follow up by telephone every 12 weeks (retention calls) 
A follow-up telephone call to record outcomes of previously reported AEs and encourage patient 
to remain in the study will be done  every 12 weeks  ± 5 days after Visit 5 of last flare. These 
calls will be performed until study end. 
7.5.1.11 
End of study call  
An end-of-study phone call will be performed either; 
1. 52 weeks after randomization of the last patient in the study  
or 
2. 104 weeks after randomization of the individual patient 
whichever occurs first. 
If the IMP treatment started week 40 or later in case 1), or week 92 weeks in case 2), the Week 
12 visit will replace the End-of-study follow-up by phone.  
Outcomes of previously reported AEs will be recorded. 
7.5.2 
Medical and surgical history 
The patient’s medical and surgical history will be recorded in the eCRF at Visit 1 at first flare 
and will be updated at Visit 1 of subsequent flares.  
The patient´s gouty arthritis, the disease duration, the number of gouty arthritis flares during  the 
past 12 months, presence of tophi and presence of gout-related joint damage will be recorded at 
the first flare. 
Detailed information on the presence of the following selected comorbidities will be collected: 
CKD, current or previous symptoms of heart failure, diabetes,  hypertension, obesity, coronary 
artery disease, hypercholesterolemia, osteoporosis and presence of severe infections. For 
definitions, see Appendix 3.  
Intolerance, unresponsiveness, contraindication or other inappropriateness for treatment with 
NSAIDs and colchicine will be recorded. 
The source of information may be medical records, referral letters, interviews and/or clinical 
assessments.  
7.5.3 
Medical examination of current flare 
Time of pain onset, the number and distribution of joints involved and index joint will be 
determined and recorded in the eCRF at Visit 1 of each flare.  


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The medical examination of subsequent flares will be recorded even if the patient is not eligible 
for IMP treatment of the current flare. 
7.5.4 
Demography 
The patient’s date of birth, gender, race, ethnicity, body weight, body length and waist 
circumference will be recorded in the eCRF at Visit 1 of the first flare. The body weight 
recording will be repeated at Visit 1 of subsequent flares. 
7.5.5 
Efficacy assessments 
7.5.5.1 
Patient-assessed pain intensity, VAS scale   
The patients will score their current pain intensity in the joint most affected (i.e., the index joint) 
on a continuous 0-100 mm visual analogue scale (VAS), ranging from no pain (0) to unbearable 
pain (100).  
For each flare, the pain intensity will be assessed in the index joint and recorded in the patient 
diary prior to the first IMP administration. Subsequent pain assessment will be recorded in the 
patient diary at 6, 12, 18, 24, 36, 48, 72 hours and Day 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. At 
24, 48, 72 hours and Day 5, the assessments will take place just before IMP administration. If the 
time point for assessment occurs during sleep, pain intensity will be recorded just before and 
after sleep, and the assessment closest to the scheduled timepoint will be used in the analysis. 
7.5.5.2 
Patient assessed pain intensity, Likert scale  
In addition to the VAS scale, the patients will score their current pain intensity in the index joint 
on a 5-point Likert scale (0-4 point scale: “none”, “mild”, “moderate”, “severe”, “extreme”).  
For each flare, the pain intensity will be assessed in the index joint and recorded in the patient 
diary prior to the first IMP administration. Subsequent pain assessment will be recorded in the 
patient diary at 6, 12, 18, 24, 36, 48, 72 hours and Day 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. At 
24, 48, 72 hours and Day 5 the assessments will take place before IMP administration. If the 
time point for assessment occurs during sleep, pain intensity will be recorded just before and 
after sleep. 
7.5.5.3 
Global response to treatment, Likert scale 
Both the patient and the investigator will assess the global response to treatment on a 5-point 
Likert scale (0-4 point scale: 0=excellent, 1=very good, 2=good, 3=fair, 4=poor response to 
treatment ). 
For each flare, the global response to treatment will be assessed in the eCRF at 72 hours, Day 8 
and Day 15. 


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7.5.5.4 
Use of rescue medication  
Patients who have difficulty in tolerating their pain are allowed to take rescue medication as 
needed after the 24-hour post-dose pain assessment but not within 6 hours before the 48- and 72-
hour post-dose pain assessments.  
Rescue medication can be used at the discretion of the investigator and should be prescribed 
according to the product label; contraindications, interactions and precautions. 
Permitted rescue medication includes paracetamol/acetaminophen (up to 1000 mg 4 times daily) 
and/or codeine  (up to 50 mg 4 times daily) or short acting tramadol (up to 100 mg 4 times 
daily). 
Topical ice/cold packs may also be used as rescue therapy.   
However, patients will be permitted to continue thrombosis prophylaxis with low dose acetyl 
salicylic acid  (≤ 325 mg/day).  
At the discretion of the investigator, patients still having insufficient relief with above drugs after 
the 72-hour post-dose pain assessment are allowed to take oral prednisone, prednisolone or 
equivalent at a dose up to 0.5 mg/kg per day for a maximum of 5 days.  
Subsequent flares occurring before Day 15 of the latest flare will be treated with permitted 
rescue medication. 
The name, dose, date and time of all rescue medication taken at site will be recorded in the eCRF 
at Visit 1 to 4 of each flare. Rescue medication taken at home between Visit 1 and 4 of each flare 
will be recorded in the patient diary. 
7.5.5.5 
Clinical signs of the most affected joint  (index joint tenderness, swelling and 
erythema)  
The investigator will assess the tenderness (on the basis of palpation or passive motion) of the 
index joint on a 4-point Likert scale (0=no pain, 1=mild/patient states there is pain when 
touched, 2=moderate/patient states there is pain and winces, 3=severe/patient states there is pain, 
winces and withdraws).  
The investigator will assess the swelling of the index joint on a 4-point Likert scale (0=no 
swelling, 1=mild swelling, 2=moderate swelling, 3=severe swelling or bulging beyond joint 
margins). 
The investigator will assess erythema of the index joint as either “present” or “absent”. 
For each flare, assessments of joint tenderness, swelling and erythema will be performed and 
recorded in the eCRF at baseline, 72 hours, Day 8 and Day 15.  
7.5.5.6 
Inflammatory biomarkers 
Blood samples will be collected for assessment of CRP and SAA at baseline, 72 hours, Day 8, 
Day 15 and Week 12 of each flare. The date and time of blood collection will be recorded in the 
eCRF. 


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7.5.6 
Safety assessments 
7.5.6.1 
Adverse events 
 
Definitions 
Adverse event 
An adverse event is any untoward medical occurrence in a patient or trial subject 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 adverse event. 
 The test result leads to a medical/surgical intervention including withdrawal of IMP(s) 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 be reported 
as an adverse event unless the condition worsens or episodes increase in frequency during the 
adverse event reporting period.  


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Gouty arthritis flare 
A flare of gouty arthritis 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 eCRF. 
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 patient or 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. 
Serious also includes any other event that the investigator or company judges to be serious. Any 
suspected transmission of an infectious agent via IMP shall also be considered serious. 
Hospitalization 
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 or prolongation of 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. 


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 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. 
 
Adverse event reporting period 
The period for recording all adverse events, including SAEs, on the eCRF begins upon receiving 
the first dose of IMP and ends at visit E, 28 days  after the first dose of IMP.  SAEs will also be 
collected from signing of the ICF until the Week 12 visit (Visit 5). Furthermore, any SAE should 
be reported irrespective of the time of occurrence if a causal relationship between the event and 
the IMP(s) is suspected, Figure 2.  
If the patient is treated with IMP for a subsequent flare, the adverse event (including SAE) 
reporting period starts again when the first dose is administered. 
Refer to section 7.5.6.1.4 for information how unresolved adverse events and SAEs should be 
followed up.  
Figure 2 
AE reporting 
 


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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 eCRF using concise medical terminology. In 
addition, each patient will be questioned about adverse events at each clinic visit and follow up 
during the AE-reporting period (see Figure 2). At visit 2 of each flare the question asked will be 
“Since you started treatment of this flare have you had any health problems”. At subsequent 
visits 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). 
 
Serious adverse event reporting 
Both serious and non-serious adverse events are to be reported on the adverse event page of the 
eCRF as specified in the eCRF instructions. 
If an SAE occurs, Drug Safety at PRA is to be notified by entering required information about 
the SAE into the appropriate module of the eCRF using the designated Serious Adverse Event 
Form within 24 hours of awareness of the event by the investigator. 
The form for collection of SAE information is not the same as the general adverse event eCRF 
page. Where the same data are collected, the forms must be completed in a consistent manner. 
For example, the same adverse event term should be used on both forms. 
All new information obtained, relevant to an SAE report, should be forwarded to Drug Safety at 
PRA within the same timeframe as the initial information. 


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The investigator shall provide Drug Safety at PRA with sufficient information to enable a 
complete medical assessment of the reported event. Best efforts shall be made by the investigator 
to provide Drug Safety at PRA with additional information related to any SAE as requested. 
If the eCRF is not functioning, the SAE can be reported by faxing/emailing a completed paper 
SAE report form or by direct telephone communication with Drug Safety at PRA at the numbers 
provided below. The event must be updated electronically in the eCRF by the clinical site once 
eCRF function resumes. 
Fax information to Drug Safety at PRA. For the attention of: 
PRA Drug Safety associate 
Toll Free Fax: 1.888.772.6619 
Toll Free Phone: 1.800.772.2215 
Email: SAOSafety@prahs.com 
 
Exposure during pregnancy 
All events of exposure to the IMP during pregnancy (female patient or male patient’s partner) 
shall be reported to Drug Safety at PRA Health sciences (see section above 7.5.6.1.4) 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). 
In all reported situations of exposure during pregnancy, PRA Health sciences will provide the 
investigator with a Pregnancy Report Form which shall be completed and returned by the 
investigator. The investigator is responsible for monitoring the outcome of the pregnancy and to 
inform PRA (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.  
Any adverse events and SAEs observed during and in relation to pregnancy or delivery should be 
recorded in the eCRF and as applicable be reported to PRA Health sciences 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 follow-up by telephone, as applicable. How to report changes in an ongoing adverse event 
during a patient's participation in the study is described in the eCRF 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.  


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7.5.6.2 
Laboratory safety assessments 
Clinically significant abnormal laboratory values should be reported as adverse events (see 
7.5.6.1.1 for details).  
Blood and urine samples for determination of hematology, biochemistry and coagulation 
variables will be collected before the first IMP administration, at 72 hours (before IMP 
administration), Day 8 and Day 15 of each flare, see Table 2. The date and time of blood and 
urine collection will be recorded in the eCRF.  
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. The procedures and materials used, e.g. collection and storage tubes, will be 
described in the laboratory manual.  
Laboratory safety assessments performed to assess a patient´s eligibility for study inclusion will 
be conducted by the local laboratories according to each clinic´s standard procedures. All other 
laboratory safety analyses will be performed by the central safety laboratory using routine 
methods. The sampling handling procedures for laboratory tests run at the local laboratory will 
be described in the laboratory manual. 


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Table 2 
The laboratory safety variables 
Biochemistry 
Aspartate aminotransferase (AST)* 
Alanine aminotransferase (ALT)* 
Total bilirubin* (if >upper limit of normal also 
conjugated and non-conjugated bilirubin) 
Alkaline phosphatase (ALP） 
Prothrombin Time/International Normalized Ratio (PT-
INR)* 
Albumin* 
Cholesterol (total, LDL and HDL) 
Triglycerides 
Creatinine* 
Sodium (Na)* 
Potassium (K)* 
Ferritin 
Erythrocyte sedimentation rate* 
Uric acid 
Glucose* 
HbA1c 
Troponin T 
C-reactive protein (CRP) 
Serum amyloid A (SAA) 
Calcium 
Magnesium  
Hematology  
Hemoglobin* 
Hematocrit 
White blood cells* 
Differential blood count* 
Thrombocytes* 
 
Bacteriology  
Tuberculosis§ 
 
Urine analysis 
Albumin 
U-erythrocytes 
Human chorionic gonadotropin (hCG) test (for women 
of child-bearing age)*   
*At Visit 1 of each flare, these laboratory safety variables will also be assessed at the local laboratory to assess a 
patient´s eligibility before inclusion. Baseline safety laboratory tests can be taken up to 72 hours before 
randomization, provided that the patient does not show signs and/or symptoms of new ailments or increasing signs 
and/or symptoms of known concomitant diseases. 
§To be taken at Visit 1 or 2 (if Visit 1 occurs on a Friday or Saturday) of first flare to have result available before 
treatment of subsequent flares. 
7.5.6.3 
Vital signs and physical examination  
Vital signs (blood pressure, heart rate and body temperature) will be recorded in the eCRF before 
the first IMP administration, at 72 hours (before IMP administration), Day 8 and Day 15 of each 
flare. 
Blood pressure and heart rate will be measured in sitting position after the patient has rested 
comfortably for at least 5 minutes. 
Body temperature will be measured using a tympanic thermometer according to each clinic´s 
standard procedures. 
Clinically significant abnormal vital signs values should be reported as adverse events (see 
7.5.6.1.1 for details).   


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A general physical examination will be assessed and recorded as “normal” or “abnormal” at Day 
1 and Day 15. Abnormalities should be specified. Any persisting abnormalities should be stated 
each time the examination is performed. New abnormalities should be recorded as adverse 
events. 
7.5.6.4 
Electrocardiograms 
A baseline 12-lead ECG will be recorded before the first IMP administration of each flare. The 
12-lead ECG recordings will be measured in supine position after the patient has rested 
comfortably for at least 5 minutes. 
All recorded ECGs will be reviewed by the investigator and the review will be documented in 
the eCRF. If a patient shows an abnormal ECG, additional safety recordings may be made and 
the abnormality followed to resolution if required. If any 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 7.5.6.1 for details). 
7.5.6.5 
Anti-drug antibodies  
Blood samples for determination of ADA will be collected before the first IMP administration, at 
Day 8, Day 15, Day 28 and Week 12 of each flare (at Day 28 and/or Week 12 only if no 
subsequent flare has occurred at an earlier time point). The date and time of blood collection will 
be recorded in the eCRF. 
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 analytical site 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. 
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 an antibody positive result and a 
confirmatory assay with a statistically pre-defined confirmatory cut-point. Confirmed positive 
samples will be further analysed for antibody titers and for potential cross-reactivity with IL-1Ra 
that has been 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 analysed for the presence of neutralizing 
antibodies (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 NAb in the sample.  
7.5.7 
Anakinra serum concentrations 
7.5.7.1 
Sampling procedure 
Blood samples for determination of endogenous IL-1Ra/anakinra serum concentrations will be 
collected before the first IMP administration, pre-dose at 72 hours (as close to 24 hours after 


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previous  IMP administration as possible), Day 8, Day 15, Day 28 and Week 12 of each flare (at 
Day 28 and/or Week 12 only if no subsequent flare has occurred at an earlier time point). The 
date and time of blood collection will be recorded in the eCRF. 
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 bioanalytical laboratory 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. 
7.5.7.2 
Bioanalytical method 
The current available bioanalytical method will not differentiate between endogenous IL-1Ra 
and anakinra concentrations in serum. Serum samples to determine the combined level of 
endogenous IL-1Ra concentrations/anakinra concentrations will be analyzed by York 
Bioanalytical Solutions Limited using a validated MSD-ECL method in which endogenous IL-
1Ra/anakinra are captured between a solid phase bound monoclonal antibody and polyclonal 
antibodies to anakinra.  
7.5.8 
Exploratory assessments 
7.5.8.1 
Health related quality of life and health care resource utilization 
Health related quality of life will be assessed by the patients using the Short Form (36) Health 
Survey (SF-36® , acute v. 2) and the EuroQol 5 dimension 5 levels (EQ-5D-5L) at baseline and 
at Day 8 and 15 at first  and subsequent flares.  
SF-36® measures the impact of disease on overall quality of life. It consists of eight individual 
domains that can be grouped into two domains; a physical component summary (PCS), 
composed of physical functioning, role-physical, bodily pain and general health, and a mental 
component summary (MCS) composed of vitality, social functioning, role-emotional and mental 
health (37). Scores range from 0 to 100, where 0 represents the worst possible health and 100 is 
perfect health (38). SF-36® has been validated for use in patients with gouty arthritis (39, 40). In 
this study the acute (one-week) recall version of SF-36®  version 2 will be used (41). It was 
created by changing the recall period for six of the eight scales (Role-Physical, Bodily Pain, 
Vitality, Social Functioning, Role-Emotional and Mental Health) from “the past four weeks” to 
“the past week”. The other two scales, Physical Functioning and General Health, do not have a 
recall period and the items and instructions for these scales are accordingly identical in the acute 
and standard forms.  
 
The EQ-5D-5L, a self-report questionnaire, is a descriptive system of health-related quality of 
life states consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) each of which can take one of five responses. The responses record five 
levels of severity (no problems/slight problems/moderate problems/severe problems/extreme 
problems) within a particular EQ-5D dimension. 
 
Health care resource utilization due to acute gouty arthritis will be collected for the period 
between Day 1 and Day 15. Number of days with hospitalization and number of unscheduled 


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outpatient visits during the last week will be recorded at Day 8 and Day 15. In addition, the 
Work Productivity and Activity Impairment Questionnaire V2.0 (WPAI:SHP) will be completed 
by the patient at the same timepoints. The WPAI is a patient-reported quantitative assessment of 
the amount of absenteeism, presenteeism and daily activity impairment attributable to general 
health (WPAI:GH) or a specific health problem (WPAI:SHP). The 6 questions in the WPAI:SHP 
questionnaire for gout are; employment status (yes/no), work hours missed due to gout, work 
hours missed  due to any other reason, hours of actual working, productivity while were working 
(0-10 scale; gout had no effect on my work/gout completely prevented me from working) and a 
global measure of activity impairment (1-10, gout had no effect on my daily activities/gout 
completely prevented me from doing my daily activities) (42). WPAI:SHP has a recall period 
defined as “past 7 days not including today”. 
7.5.8.2 
Exploratory inflammatory biomarkers 
Blood samples for determination of the exploratory inflammatory biomarkers IL-6, IL-8, 
calprotectin, neopterin and myeloperoxidase (MPO) will be collected before the first IMP 
administration, at 72 hours (before IMP administration), Day 15 and Week 12 of each flare. The 
date and time of blood collection will be recorded in the eCRF.  
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 also 
be described in the laboratory manual. 
Samples collected for IL-8, calprotectin and neopterin will be analyzed by Eurofins Global 
Central Laboratory, Bergschot 71, 4817 PA Breda, the Netherlands. Full details of the methods 
used will be described in a separate bioanalytical report(s). Blood samples collected for later 
analysis of IL-6, MPO and possibly other exploratory biomarkers will be stored at the Eurofins 
laboratory in case of a need to further evaluate proinflammatory responses/lack of response to 
treatment.   
 
7.5.8.3 
Exploratory pharmacogenetic assessment  
A pharmacogenetics sample will be collected at Day 1 of the first flare from all patients 
randomized in the study. 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.  
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 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 examined 


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prior to any analytical measurements as part of the analytical method validation, to rule out any 
possible interference with the analyte.  
8 
Quality control and quality assurance 
This study will be conducted in compliance with this protocol, study specific procedures, CRO 
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. 
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 eCRFs. All patient 
informed consent forms 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. 
9 
Statistical plan 
9.1 
Determination of sample size 
Up to totally 169 patients can be randomized in the study. Initially 159 patients will be 
randomized, 53 to triamcinolone and 106 to anakinra (53 to 100 mg and 53 to 200 mg). As 
described in protocol section 7.3.6, up to a maximum of 10 extra patients can be randomized.  
The sample size calculation is based on the change in pain intensity on a VAS 0-100 mm from 
baseline to the average over 24-72 hours. A sample size of 106 randomized patients receiving 
anakinra and 53 randomized patients receiving triamcinolone is required to ensure a power of 
80% to reject the null hypothesis of no difference between anakinra and triamcinolone assuming 
a true difference of 12 mm on VAS mean change and a standard deviation of 25 mm when using 
a two-sided test with a significance level of 5%. 
9.2 
Definition of study populations 
The following analysis sets/populations will be used for the statistical analyses: 
Intention-to-treat (ITT) population: This population is the primary analysis population and will 
comprise all randomized patients, grouped according to randomized treatment. 
Per-protocol (PP) population: This population will comprise all ITT patients who have no major 
protocol violations potentially affecting efficacy. Patients will be grouped according to treatment 


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actually received and the actual stratification information. Patient assignment to the PP 
population will be performed prior to breaking the blind.  
Safety population: This population will comprise all patients who received at least one dose of 
investigational product. Patients will be grouped according to actual treatment during the first 
gouty arthritis flare. 
The ITT is the primary analysis population for the primary and secondary efficacy endpoints. 
Presentations of efficacy endpoints for subsequent flares will also be based on the ITT 
population. The PP population will be used for sensitivity analyses of efficacy endpoints for the 
first flare. The safety population will be used for analyses of safety endpoints for the whole study 
period.   
9.3 
Overall statistical and analytical plan 
All details of the statistical analyses of primary and secondary variables will be described in a 
separate study specific statistical analysis plan (SAP) which will be finalized before the clinical 
database is locked for the study period containing the first gouty arthritis flare and the treatment 
code unblinded.  
Statistical analysis will be performed using SAS software Version 9.4 or later (SAS Institute, 
Inc, Cary, North Carolina, United States). 
9.3.1 
General statistical issues 
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 mean value for each treatment group, the 
estimated difference between groups, the associated 95% two-sided confidence interval and p-
value. 
9.3.2 
Demographics and baseline characteristics 
Demographic data and baseline characteristics including physical examination and medical 
examination of current flare will be presented using summary statistics. Continuous variables 
will be summarized using the number of patients, the mean, the standard deviation, the median, 
the minimum value, and the maximum value. Categorical variables will be summarized using 
frequency counts and percentages. 
9.3.3 
Analysis related to primary objective  
9.3.3.1 
Primary endpoint 
The primary endpoint is the change in patient-assessed pain intensity from baseline to 24-72 
hours (average of the assessments performed at 24, 48 and 72 hours) for the patients’ first flare.  
The comparison of primary interest is between anakinra (100 mg and 200 mg combined) and 
triamcinolone, and the null and alternative hypotheses with regard to this are defined as: 


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H0: μ anakinra = μ triamcinolone  
HA: μ anakinra ≠ μ triamcinolone  
The primary endpoint will be estimated using a mixed model repeated measures analysis with 
the measurements on the individual time points as responses (baseline, 6, 12, 18, 24, 48 and 72 
hours), and with treatment (anakinra 100 mg, anakinra 200 mg and triamcinolone), ULT use 
(yes/no), BMI (<30.0 and ≥30.0 kg/m2), visit and treatment-visit-interaction as fixed effects and 
center as random effect. An unstructured covariance matrix will be used to account for within-
subject correlation.. The estimated mean change from baseline to 24-72 hours for each treatment 
group (anakinra and triamcinolone), the estimated difference between the groups and the 
associated 95 % confidence interval and p-value based on this model will be presented. 
The assumptions of normality and homogeneity of variance will be assessed by inspection of 
normal probability plots and residual plots.  
The primary efficacy analysis mixed model repeated measures approach assumes that the 
underlying missing data mechanism is missing at random (MAR). Since the MAR assumption 
may not hold, a tipping point analysis will be used for performing sensitivity analysis under the 
missing not at random (MNAR) assumption. For data that is missing, a shift parameter (with a 
range of values) will be added to imputed values. This will assess the value of the shift 
parameters, for anakinra and triamcinolone, which would overturn the conclusions of the 
primary analysis. The tipping point analysis will assume that the missing outcomes on anakinra 
and triamcinolone will vary independently including scenarios where the dropouts on anakinra 
have worse outcomes than triamcinolone. 
The full details of the sensitivity analyses to assess the robustness of the primary analysis will be 
pre-specified in the SAP. 
 
9.3.3.2 
Secondary endpoints supporting the primary objective 
To further evaluate the effect of anakinra, the change from baseline in pain intensity at 6, 12, 18, 
24, 36, 48, 72 hours and at Days 5, 6, 7 and 8 for the first flare will be evaluated using the 
following two patient-assessed scales: 
• 
Patient-assessed pain intensity in the index joint on a VAS scale 
• 
Patient-assessed pain intensity in the index joint on a 5-point Likert scale 
The VAS pain intensity will be evaluated using a similar mixed model repeated measures 
analysis as for the primary endpoint. For each time point, the estimated change from baseline for 
each treatment group (anakinra and triamcinolone), the estimated difference between the groups 
and the associated 95 % confidence interval and p-value based on this model will be presented. 
The Likert pain intensity will be evaluated using a mixed model repeated measures analysis with 
the measurements on the individual time points as responses, and with treatment (anakinra 100 
mg, anakinra 200 mg and triamcinolone), ULT use (yes/no), BMI (<30.0 and ≥30.0 kg/m2), visit 
and treatment-visit-interaction as fixed effects. For each time point, the estimated mean change 
from baseline for each treatment group (anakinra and triamcinolone), the estimated difference 


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between the groups and the associated 95 % confidence interval and p-value based on this model 
will be presented. 
9.3.4 
Analysis related to secondary objectives  
9.3.4.1 
Pain intensity for anakinra dose groups, 100 and 200 mg 
The primary endpoint, change in patient-assessed pain intensity as measured by VAS from 
baseline to 24-72 hour for the first flare, will be evaluated for the two different anakinra doses 
(100 mg and 200 mg) in comparison to triamcinolone.  
The effect of the two different anakinra doses will be evaluated using the same mixed model 
repeated measures model analysis as for the primary endpoint. The estimated mean change from 
baseline to 24-72 hours for each of the two anakinra doses (100 mg and 200 mg) and 
triamcinolone, the estimated differences anakinra 100 mg – triamcinolone and anakinra 200 mg 
– triamcinolone and the associated 95% confidence intervals and p-values from the model will 
be presented. 
The estimated mean change from baseline for the secondary endpoints supporting the primary 
endpoint for each of the two anakinra doses (100 mg and 200 mg) and triamcinolone, the 
estimated differences anakinra 100 mg – triamcinolone and anakinra 200 mg – triamcinolone and 
the associated 95% confidence intervals and p-values from the model will also be presented. 
 
9.3.4.2 
Response 
Response is defined as at least 50% change from baseline pain intensity on VAS, and the time to 
response for the first flare will be analyzed using a stratified log-rank test, with ULT use (yes/no) 
and BMI (<30.0 or ≥30.0 kg/m2) as stratification factors. Based on this model, the estimated 
hazard ratio (anakinra vs. triamcinolone), 95% confidence interval and p-value will be presented. 
Further, the hazard ratios for the comparisons of the two different anakinra treatment groups 
versus triamcinolone will also be estimated, with corresponding 95% confidence intervals and p-
values. 
In addition, the number and proportion of responders in the different treatment groups at 24, 48 
and 72 hours, Day 8 and Day 15 will be presented. 
The change in pain intensity will also be visualized by graphically presenting the percent of 
patients who improved in each category of percent improvement on the VAS scale at 72 hours. 
 
9.3.4.3 
Onset of effect 
Onset of effect is defined as at least 20% change from baseline pain intensity on VAS, and the 
time to onset of effect for the first flare will be analyzed using a stratified log-rank test, with 
ULT use (yes/no) and BMI (<30.0 or ≥30.0 kg/m2) as stratification factors. Based on this model, 
the estimated hazard ratio (anakinra vs. triamcinolone), 95% confidence interval and p-value will 
be presented. Further, the hazard ratios for the comparisons of the two different anakinra 


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treatment groups versus triamcinolone will also be estimated, with corresponding 95% 
confidence intervals and p-values. 
In addition, the number and proportion of patients with onset of effect in the different treatment 
groups at 6, 12, 24, 48 and 72 hours will be presented. 
9.3.4.4 
Resolution of pain 
Resolution of pain is defined as <10 mm in patient-assessed pain intensity on VAS, and the time 
to resolution for the first flare will be analyzed using a stratified log-rank test, with ULT use 
(yes/no) and BMI (<30.0 or ≥30.0 kg/m2) as stratification factors. Based on this model, the 
estimated hazard ratio (anakinra vs. triamcinolone), 95% confidence interval and p-value will be 
presented. Further, the hazard ratios for the comparisons of the two different anakinra treatment 
groups versus triamcinolone will also be estimated, with corresponding 95% confidence intervals 
and p-values. 
In addition, the number and proportion of patients with resolution of pain in the different 
treatment groups at 72 hours, Day 8 and Day 15 will be presented. 
9.3.4.5 
Rescue medication 
Time to first intake of rescue medication during the first flare will be analyzed using a stratified 
log-rank test, with ULT use (yes/no) and BMI (<30.0 or ≥30.0 kg/m2) as stratification factors. 
Based on this model, the estimated hazard ratio (anakinra vs. triamcinolone), 95% confidence 
interval and p-value will be presented. Further, the hazard ratios for the comparisons of the two 
different anakinra treatment groups versus triamcinolone will also be estimated, with 
corresponding 95% confidence intervals and p-values. 
In addition, the proportion of patients who took rescue medication from the first IMP 
administration at Visit 1 up to and including Day 8 and Day 15 in the different treatment groups 
will be presented. The type and number of occasions of intake of rescue medication will also be 
presented by descriptive statistics. 
9.3.4.6 
Physician’s assessment of global response to treatment 
Physician’s assessment of global response to treatment at 72 hours, Day 8 and Day 15 for the 
first flare will be evaluated using an analysis of variance model including factors for treatment 
(anakinra 100 mg, anakinra 200 mg and triamcinolone), ULT use (yes/no) and BMI (<30.0 or 
≥30.0 kg/m2). The estimated mean global response to treatment for each treatment group 
(anakinra and triamcinolone), the estimated difference between the groups and the associated 
95% confidence interval and p-value from the model will be presented. 
Further, the difference of the two different anakinra treatment groups versus triamcinolone will 
also be estimated, with corresponding 95% confidence intervals and p-values. 
9.3.4.7 
Physician’s assessment of clinical signs 
The investigator will assess the tenderness, swelling and presence of erythema in the index joint.  
Physician’s assessment of tenderness at 72 hours, Day 8 and Day 15 for the first flare will be 
evaluated using an analysis of covariance model including factors for treatment (anakinra 100 


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mg, anakinra 200 mg and triamcinolone), ULT use (yes/no) and BMI (<30.0 or ≥30.0 kg/m2), 
and baseline tenderness as covariate. The estimated mean tenderness for each treatment group 
(anakinra and triamcinolone), the estimated difference between the groups and the associated 
95% confidence interval and p-value from the model will be presented. Further, the estimated 
mean tenderness for each of the two anakinra doses (100 mg and 200 mg), the difference of the 
two different anakinra treatment groups versus triamcinolone will also be estimated, with 
corresponding 95% confidence intervals and p-values. 
Physician’s assessment of swelling at 72 hours, Day 8 and Day 15 for the first flare will be 
evaluated using an analysis of covariance model including factors for treatment (anakinra 100 
mg, anakinra 200 mg and triamcinolone), ULT use (yes/no) and BMI (<30.0 or ≥30.0 kg/m2), 
and baseline swelling as covariate. The estimated mean swelling for each treatment group 
(anakinra and triamcinolone), the estimated difference between the groups and the associated 
95% confidence interval and p-value from the model will be presented. Further, the estimated 
mean swelling for each of the two anakinra doses (100 mg and 200 mg), the difference of the 
two different anakinra treatment groups versus triamcinolone will also be estimated, with 
corresponding 95% confidence intervals and p-values. 
The presence of erythema at 72 hours, Day 8 and Day 15 for the first flare will be analyzed using 
a logistic regression model with treatment, ULT use (yes/no) and BMI (<30.0 or ≥30.0 kg/m2) as 
explanatory variables. The estimated risk of erythema in each treatment group, the estimated 
odds ratio of anakinra to triamcinolone, the corresponding 95% confidence interval and the p-
value from the model will be presented. Further, the odds ratios for the comparisons of the two 
different anakinra treatment groups versus triamcinolone will also be estimated, with 
corresponding 95% confidence intervals and p-values. 
9.3.4.8 
Patient´s assessment of global response to treatment 
Patient’s assessment of global response to treatment at 72 hours, Day 8 and Day 15 for the first 
flare will be evaluated using an analysis of variance including factors for treatment (anakinra 100 
mg, anakinra 200 mg and triamcinolone), ULT use (yes/no) and BMI (<30.0 and ≥30.0 kg/m2). 
The estimated mean global response to treatment for each treatment group (anakinra and 
triamcinolone), the estimated difference between the groups and the associated 95% confidence 
interval and p-value from the model will be presented. Further, the estimated mean global 
response for each of the two anakinra doses (100 mg and 200 mg), the difference of the two 
different anakinra treatment groups versus triamcinolone will also be estimated, with 
corresponding 95% confidence intervals and p-values. 
9.3.4.9 
Inflammatory biomarkers 
The change from baseline in CRP at 72 hours, Day 8 and Day 15 will be evaluated using an 
analysis of covariance model including factors for treatment, ULT use (yes/no) and BMI (<30.0 
or ≥30.0 kg/m2), and baseline CRP as covariate. The estimated mean change in CRP for each 
treatment group (anakinra and triamcinolone), the estimated difference between the groups and 
the associated 95% confidence interval and p-value from the model will be presented. Further, 
the estimated mean change in CRP for each of the two anakinra doses (100 mg and 200 mg), the 
estimated differences anakinra 100 mg – triamcinolone and anakinra 200 mg – triamcinolone and 
the associated 95% confidence intervals and p-values from the model will be presented. 


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The change from baseline in SAA at 72 hours, Day 8 and Day 15 will be evaluated using an 
analysis of covariance model including factors for treatment, ULT use (yes/no) and BMI (<30.0 
or ≥30.0 kg/m2), and baseline SAA as covariate. The estimated mean change in SAA for each 
treatment group (anakinra and triamcinolone), the estimated difference between the groups and 
the associated 95% confidence interval and p-value from the model will be presented. Further, 
the estimated mean change in SAA for each of the two anakinra doses (100 mg and 200 mg), the 
estimated differences anakinra 100 mg – triamcinolone and anakinra 200 mg – triamcinolone and 
the associated 95% confidence intervals and p-values from the model will be presented. 
The evaluation of CRP and SAA at Week 12 will be presented by descriptive statistics. 
9.3.4.10 
Subsequent flares 
The evaluation of efficacy at subsequent flares will be presented by the combined anakinra 
group, the 2 different anakinra doses (100 mg and 200 mg) and triamcinolone, and by flare, i.e. 
patient’s 2nd flare, 3rd flare etc.  
Patient-assessed pain intensity on VAS and Likert will be summarized by descriptive statistics 
for each time point, i.e. baseline, 6, 12, 18, 24, 36, 48, 72 hours and Days 5, 6, 7 and 8 as well as 
the change from baseline at these time points. 
The number and proportion of responders in the treatment groups at 24, 48 and 72 hours, Day 8 
and Day 15 will be summarized by descriptive statistics. 
The number and proportion of patients with onset of effect in the different treatment groups at 6, 
12, 24, 48 and 72 hours will be summarized by descriptive statistics. 
The number and proportion of patients with resolution of pain in the treatment groups at 72 
hours, Day 8 and Day 15, respectively, will be summarized by descriptive statistics. 
The number and proportion of patients that took rescue medication from the first IMP 
administration at Visit 1 up to and including the Day 8 visit in the treatment groups will be 
summarized by descriptive statistics. The type and amount of rescue medication will also be 
presented.  
Physician’s assessment of global response to treatment, physician’s assessment of clinical signs 
and patient’s assessment of global response to treatment at 72 hours, Day 8 and 15, respectively, 
will be summarized by descriptive statistics. 
The change from baseline in CRP and SAA at 72 hours, Day 8 and Day 15, respectively, will be 
summarized by descriptive statistics. 
9.3.4.11 
Anti-drug antibodies  
The number and proportion of patients with ADA and NAb at baseline, Day 8, Day 15, Day 28 
and Week 12 will be summarized by descriptive statistics. ADA titers at baseline, Day 8, Day 
15, Day 28 and Week 12 will be summarized by descriptive statistics. For baseline, Day 8 and 
Day 15, pain intensity on VAS will be presented by ADA presence and by NAb presence. The 
presentations will be repeated for each subsequent flare. 
AEs and SAEs will be presented by ADA presence for the whole study period. AEs and SAEs 
will be classified as occurring during ADA presence when the starting date for the AE is within 


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the time period after the latest negative assessment until next negative assessment with a positive 
assessment of ADA in between. 
9.3.4.12 
Serum concentration of IL-1Ra/anakinra 
The serum concentration of endogenous IL-1Ra/anakinra at baseline, 72 hours, Day 8, Day 15, 
Day 28 and Week 12 for the first flare and subsequent flare will be presented by descriptive 
statistics.  
9.3.5 
Analysis related to exploratory objectives 
9.3.5.1 
SF-36 
Based on the SF-36 questionnaire, the patient’s score for each of the individual eight domains as 
well as the PCS and the MCS will be calculated.  
The change from baseline in SF-36 physical functioning domain score at Day 8 for the first flare 
will be evaluated using an analysis of covariance model including factors for treatment, ULT use 
(yes/no) and BMI (<30.0 or ≥30.0 kg/m2), and baseline SF-36 physical functioning score as 
covariate. The estimated mean change in SF-36 physical functioning domain score for each 
treatment group (anakinra and triamcinolone), the estimated difference between the groups and 
the associated 95% confidence interval and p-value from the model will be presented. 
The change from baseline in the patient’s score for the other 7 domains as well as the PCS and 
the MCS will be presented by descriptive statistics.  
For subsequent flares the 8 domains from SF-36 as well as the PCS and the MCS will be 
presented by descriptive statistics. 
9.3.5.2 
EQ-5D-5L 
The change from baseline in the five domains in EQ-5D, the EQ-5D Index and the EQ-5D-VAS 
at baseline, Day 8 and Day 15 for each flare will be presented by descriptive statistics. 
9.3.5.3 
WPAI:SHP 
Based on the WPAI:SHP the following scores will be calculated for Day 8 and Day 15; percent 
work time missed due to gout, percent impairment while working due to gout, percent overall 
work impairment due to gout and percent activity impairment due to gout. 
The WPAI:SHP scores at Day 8 and Day 15 for the first flare and subsequent flares will be 
presented by descriptive statistics. 
9.3.5.4 
Health care resource utilization  
The number of days with hospitalization and the number of un-scheduled outpatient visits from 
Day 1 to Day 15 for the first flare and subsequent flares will be presented by descriptive 
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9.3.5.5 
Exploratory inflammatory biomarkers 
The change from baseline in exploratory inflammatory biomarkers in serum (primarily IL-8, 
calprotectin and neopterin) at 72 hours, Day 15 and Week 12 (in case of no subsequent flare 
prior to the Week 12 time point) for the first flare and subsequent flares will be presented by 
descriptive statistics. The same presentations will be made if samples are analyzed for IL-6 and 
MPO.   
9.3.6 
Analysis of safety and tolerability data 
Safety tabulations will be performed with respect to adverse event data, clinical laboratory 
results and vital sign data. Continuous variables will be summarized using the number of 
patients, the mean, the standard deviation, the median, the minimum value, and the maximum 
value. Categorical variables will be summarized using frequency counts and percentages. No 
statistical hypothesis tests will be performed. 
All data will be displayed in individual patient data listings. 
9.3.6.1 
Adverse events 
All adverse events will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA).  
The number and percent of patients with at least one adverse event recorded at each level of 
summarization will be summarized in 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 percent 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. Separate presentations will be made for the double-
blind period (first flare) and the extension period. 
9.3.6.2 
Clinical laboratory results  
Clinical laboratory safety data will be presented using summary statistics. In addition, the 
number of patients with abnormal laboratory values will be presented using shift tables. The 
presentations will be based on the results from the central laboratory safety data.  
9.3.7 
Interim analysis  
No interim analysis of efficacy data is planned. The main efficacy analyses will be performed 
when all patients have completed the Day 15 visit of the first flare (Visit 4). 
9.3.8 
Multiple comparison/multiplicity 
No adjustment for multiplicity will been performed. 


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9.3.9 
Exploratory subgroup analyses 
In order to examine the consistency of the treatment effect, the primary analysis will be repeated 
within predefined subgroups using the ITT population. These subgroups will include the 
randomization strata, ULT usage (yes/no) and BMI (<30.0 and ≥30.0 kg/m2), as well as age (<65 
years and ≥65 years), sex, race, renal function (CKD stage 1, 2 and 3) and usage of rescue 
medication during the first flare (yes/no). For each subgroup, the estimated change in pain 
intensity in each treatment group (anakinra and triamcinolone), the estimated difference in 
change in pain intensity between treatments and the corresponding 95% confidence intervals will 
be presented. P-values will not be presented. Further, the change in pain intensity will also be 
evaluated for the two anakinra doses for each subgroup. 
Further subgroup analyses may be defined in the statistical analysis plan. 
9.3.10 
Handling of missing data 
Patients should continue in the study even if study treatment is withdrawn and every effort 
should be made to complete the assessments according to the protocol. The evaluation of patient-
assessed pain using VAS and Likert scales have repeated assessment time points and repeated 
measures models will be used to handle missing data, i.e. no imputation is needed. To evaluate 
the robustness of this model for the primary endpoint, a tipping point analysis will be used for 
performing sensitivity analysis under the MNAR assumption (see 9.3.3.1 for details).  For the 
secondary time-to-event analyses, patients who do not have an event at the time for analysis will 
be censored at the last time point with recorded information. For other secondary endpoints the 
analyses will be based on observed data. Details will be fully described in the SAP. 
10 
Data collection, handling and record keeping 
10.1 
Data standards 
Collection of data should be performed in the Clinical Data Acquisition Standards 
Harmonization (CDASH) format, according to the Clinical Data Interchange Standards 
Consortium (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 Study Data Tabulation Model (SDTM) format.  
10.2 
Case report form 
A CRF is required and should be completed for each included patient. In this study electronic 
CRFs (eCRFs) will be used.  
The completed original eCRFs 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. 


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It is the responsibility of the investigator to ensure completion and to review and approve all 
eCRFs. eCRFs must be signed electronically by the investigator. These signatures serve to attest 
that the information contained on these eCRFs is correct. At all times, the investigator has final 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered on the 
eCRFs.  
10.3 
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 eCRFs must match those charts. In some cases, a portion of the 
source documents for a given patient may be the eCRF or the patient diary.  
 
In this study, the following are recorded as source data directly in the eCRFs: the index 
joint of current flare, time of pain onset, physician’s assessment of global response to 
treatment 
 
In this study, the following are recorded as source data directly in the patient diary: IMP 
administration (date and time), rescue medication recorded by the patients between visits   
(name, dose, date and time), patient’s assessment of pain intensity (VAS), patient’s 
assessment of global response to treatment, SF-36, EQ-5D-5L, WPAI:SHP. 
10.4 
Database closure 
The database will be locked twice, first for the primary analysis when all patients have 
conducted the Day 15 visit of the first flare in the study and then after study closure.  
 
Prior to the first database closure, all tasks or criteria defined in the data management plan must 
be completed and documented. For the primary analysis, the study database will 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. After the data transfer for primary analysis has occurred, the database will be 
unlocked to continue with data entry activities. However, records pertaining to the primary 
analysis will stay locked. The database will be locked a second time following the same 
procedure after the study is considered completed. 
 
Before each of the database locks medical coding will be performed by the CRO and approved 
by Sobi. AEs, diagnoses from Medical History and procedures will be classified according to the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA). Previous and 
Concomitant Medications will be coded using the latest version of the World Health 
Organisation Drug Dictionary (WHODRUG) and a reconciliation of AEs in the clinical and 
safety database will be performed.  


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10.5 
Record retention 
To enable evaluations and/or audits from Health Authorities or Sobi, the investigator agrees to 
keep records in accordance with the essential documents defined in the ICH GCP Guidelines (1), 
including the identity of all participating patients (sufficient information to link records, e.g., 
eCRFs and hospital records), an archival copy on compact disc of the eCRFs provided by PRA 
and detailed records of IMP accountability. 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, another 
institution, or to Sobi. The investigator must obtain Sobi’s written permission before disposing of 
any records. 
11 
End of study 
The end of this study is defined as the date of the last patient’s last visit/end of study call. 
12 
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 the primary analysis, when all patients have conducted the Day 15 visit of the first flare, 
Sobi reserves the right to discontinue the study if the data would indicate that the continuation of 
the study would not be appropriate. 
After such a decision, the investigator must contact all participating patients within 30 days. The 
investigator shall return to the CRO all unused investigational product and other study materials, 
and complete all the eCRFs to the greatest extent possible. 
13 
Dissemination and publication of results  
Sobi will publicly disclose this study by posting the protocol and study results on 
www.clinicaltrials.gov according to FDA requirements for trials studying a new use of an FDA-
approved drug,.  
After completion of the study, the data 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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14 
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Fisher, CJ. et al. Recombinant Human Interleukin 1 Receptor Antagonist in the 
Treatment of Patients With Sepsis Syndrome Results From a Randomized, Double-blind, 
Placebo-Controlled Trial. JAMA; June 1994; pp 1836-1843 
 


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35 
Fisher, CJ. et al Initial evaluation of human recombinant interleukin-1 receptor antagonist 
in the treatment of sepsis syndrome: A randomized, open-label, placebo-controlled 
multicenter trial. Critical Care Medicine 1994; Vol 22(1): pp 12-21 
 
36 
Navneet Singh et al. The effect of intravenous interleukin-1 receptor antagonist on 
inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase 
II randomised controlled trial. Journal of Neuroinflammation 2014; 11:1 
 
37 
Ware JE Jr et al. The MOS 36-item short-form health survey (SF-36). I. Conceptual 
framework and item selection. Med Care. 1992;30:473–483. 
 
38 
http://www.rand.org/health/surveys_tools/mos/36-item-short-form.html  
 
39 
Singh JA et al. Gout is associated with more comorbidities, poorer health-related quality 
of life and higher healthcare utilisation in US veterans. Ann Rheum Dis. 2008;67:1310–
1316. 
 
40  
Khanna D, Ahmed M, Yontz D, Ginsburg SS, Park GS, Leonard A, Tsevat J. The 
disutility of chronic gout. Qual Life Res. 2008;17:815–822. 
 
41 
SF-36® Health Survey Update. http://www.sf-36.org/tools/sf36.shtml. 
 
42 
Reilly MC et al. The validity and reproducibility of a work productivity and activity 
impairment instrument. PharmacoEconomics 1993; 4(5):353-65 
 
43 
Terkeltaub RA et al. High versus low dosing of oral colchicine for early acute gout flare: 
Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo  
 
controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 10 
Apr;62(4):1060-8 
 
 
 


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Page 76 of 85 
Clinical study reports submitted with the original MA-BLA: 
 
44 
Study 0560 A Randomized, Double-blind, Placebo-controlled, Multicentre, Dose-ranging 
Study of the Efficacy and Safety of Recombinant-Methionyl Human Interleukin-1  
Receptor Antagonist (Anakinra) in Patients With Active Rheumatoid Arthritis. Oct 1999. 
Data on file. 
 
45 
Study 0563: An Open-label, Single-dose Study of the Safety, Pharmacokinetics, and 
Tolerability of Recombinant-methionyl Human Interleukin-1 Receptor Antagonist (r-
metHuIL-1Ra) in Patients with Hepatic Dysfunction. Dec 1999. Data on file. 
46 
Study 960180: A 24-Week Study to Evaluate the Safety and Efficacy of Anakinra 
Therapy in the Presence of Background Methotrexate in Subjects With Active 
Rheumatoid Arthritis. Nov 1999. Data on file. 
 
47 
Study 20000268: Open-label, Single-dose Study of the Pharmacokinetics of Anakinra 
(r-metHuIL-1Ra) in Subjects With Various Degrees of Renal Function. Mar 2004. Data 
on file. 
 
 


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15 
 Appendices 
Appendix 1   
List of medication restricted or prohibited before randomization 
Glucocorticoids 
 
Oral prednisolone ≥10 mg or equivalent within 24 hours of 
randomization. 
 
Chronic glucocorticoid treatment, defined as ≥5 mg/day 
prednisolone or equivalent taken for 28 days of randomization. 
 
Intra-articular glucocorticoids within 14 days of randomization. 
 
Intramuscular glucocorticoids within 21 days of randomization. 
Narcotics 
 
Opiates including tramadol within 6 hours of randomization. 
 
Opiates with sustained release formulation within 5 days of 
randomization. 
 
Chronic opiate treatment within 14 days of randomization. 
Acetaminophen/ Paracetamol/ 
 
Any acetaminophen (paracetamol) within 1 hour or >1 g within 4 
hours of randomization. 
NSAIDs and Coxibs 
 
Any ibuprofen within 4 hours or 400 mg within 8 hours of 
randomization. 
 
Any diclofenac within 8 hours or 50 mg within 24 hours of 
randomization. 
 
Any naproxen within 12 hours or 500 mg within 24 hours of 
randomization. 
 
Any other NSAID within 24 hours of randomization. 
 
Any cyclooxygenase-2 inhibitors within 24 hours of 
randomization. 
 
Any acetyl salicylic acid within 4 hours or 600 mg within 24 
hours of randomization.1 
Colchicine 
 
Colchicine 1.2 mg within 7 days of randomization. 
IL-1 or IL-6 blocker 
 
Any IL-1 or IL-6 blocker within 30 days or 5 half-lives before 
randomization, whichever is longest. 
TNF inhibitor 
 
TNF inhibitor within 30 days or 5 half-lives before randomization, 
whichever is longest. 
Combinations and others 
 
Over-the-counter analgesic acetyl salicylic acid - or 
paracetamol/acetaminophen -based combination medication, any 
tablet within 4 hours of randomization or more than 2 tablets 
within 24 hours of randomization. 
 
Other biologic drug within 30 days or 5 half-lives before 
randomization, whichever is longest. 
 
Topical ice/cold packs within 2 hours of randomization. 
1 Patients will be permitted to continue thrombosis prophylaxis with low dose acetyl salicylic acid  (≤ 325 mg/day). 


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Appendix 2 Schedule of events  
Assessment 
Optional pre-
screening  
Baseline and subsequent flare(s) 
 
End of study  
Visit 11 
FU (by 
phone)
FU (by 
phone)
Visit 2 
Visit 3 
Visit 4 
Visit E2 
Visit 52 
FU (by 
phone)2
FU (by 
phone)12
Baseline 
(Day 1) 
24±2 hrs 
(Day 2) 
48±2 hrs 
(Day 3) 
72 
hours±4 
hrs  
(Day 4) 
Day 8± 
1day  
Day 
15±1 
day  
Day 
28±2 
days  
Week 
12±5 
days 
Every 12 
weeks ±5 
days 
Week 104 ±5 
days  
or 
52 weeks ±5 
days after last 
randomized 
patient   
Informed consent 
 
x1 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
x6 
x 
 
 
 
 
 
 
 
 
 
Medical and surgical history, and demographics 
 
x1 
 
 
 
 
 
 
 
 
 
Randomization 
 
x1 
 
 
 
 
 
 
 
 
 
IMP administration at study site
x
x
Patient/care giver IMP injection training 
 
x 
 
 
 
 
 
 
 
 
 
Patient diary training 
 
x 
 
 
 
 
 
 
 
 
 
Prior and concomitant medication 
 
x 
 
 
x 
X
x 
x 
 
 
 
Recording of rescue medication11 
 
x 
 
 
x 
x 
x 
 
 
 
 
Medical examination of current flare
x
ECG  
 
x 
 
 
 
 
 
 
 
 
 
Vital sign assessments 
 
x 
 
 
x 
x 
x 
 
 
 
 
Physical examination  
 
x 
 
 
 
 
x 
 
 
 
 
Laboratory safety assessments, local 
 
x 
 
 
 
 
 
 
 
 
 
Laboratory safety assessments, central 
 
x 
 
 
x 
x 
x 
 
 
 
 
Adverse events 
 
x8 
 
 
x8 
x8 
X8 
x 
x3 
 
 
Immunogenicity assessment 
 
x 
 
 
 
x 
x 
x 
x 
 
 
Patient´s assessment of pain intensity (VAS and Likert)5
x
x
x
x
Patient´s assessment of global response to treatment 
 
 
 
 
x 
X 
x 
 
 
 
 
Physician´s assessment of global response to 
treatment 
x
X
x


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Assessment 
Optional pre-
screening  
Baseline and subsequent flare(s) 
 
End of study  
Visit 11 
FU (by 
phone) 
FU (by 
phone) 
Visit 2 
Visit 3 
Visit 4 
Visit E2 
Visit 52 
FU (by 
phone)2 
FU (by 
phone)12 
Baseline 
(Day 1) 
24±2 hrs 
(Day 2) 
48±2 hrs 
(Day 3) 
72 
hours±4 
hrs  
(Day 4) 
Day 8± 
1day  
Day 
15±1 
day  
Day 
28±2 
days  
Week 
12±5 
days 
Every 12 
weeks ±5 
days 
Week 104 ±5 
days  
or 
52 weeks ±5 
days after last 
randomized 
patient   
Physician´s assessment of clinical signs (joint 
tenderness, swelling and erythema) 
 
x 
 
 
x 
X 
x 
 
 
 
 
Health related QoL, SF-36 (acute v. 2) 
 
x 
 
 
 
X 
x 
 
 
 
 
Health related QoL, EQ-5D-5L 
 
x 
 
 
 
X
x 
 
 
 
 
Health care resource utilization incl WPAI:SHP 
 
 
 
 
 
X
x 
 
 
 
 
Inflammatory biomarkers (CRP and SAA) 
 
x 
 
 
x 
X 
x 
 
x 
 
 
IL-1Ra/anakinra serum concentration assessment 
 
x10 
 
 
x10 
X 
x 
x 
x 
 
 
Exploratory inflammatory biomarkers 
 
x 
 
 
x 
 
x 
 
x 
 
 
Exploratory pharmacogenetic markers 
 
x9 
 
 
 
 
 
 
 
 
 
Reminder calls 
 
 
x 
x 
 
 
 
 
 
 
 
Retention/end of study call/Follow up of ongoing AEs  
 
 
 
 
 
 
 
 
 
x 
x 
 
1For subsequent flares, Visit 1 will not include informed consent, demographics (excluding weight) and randomization 
2The Visit E and 5 and the follow-up by phone every 12 weeks after last flare has occurred and been treated with IMP.  
3SAEs and outcomes of previously recorded AEs will be collected. 
4Only SAEs considered related to the IMP will be collected. 
5A patient diary will be used for patient assessment of pain intensity predose and at 6, 12, 18, 24, 36, 48, 72 (Day 4) hours and Day 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. 
6Pre-screening is optional and may be done to identify patients that fulfil the study eligibility criteria with the exception of having a current flare of gouty arthritis.  
7 Baseline safety laboratory tests can be taken up to 72 hours before randomization, provided that the patient does not show signs and/or symptoms of new ailments or increasing signs and/or symptoms of known concomitant diseases. 
8 Physician’s assessments should be performed before recording of adverse events 
9 Only assessed at first flare 
10 Pre-dose 
11  Patients should record any intake of rescue medication between visits in the patients diary.  
12 A Visit 5/Week 12 visit may replace the End of study FU by phone if the IMP treatment started week 40 or later in case 1) or week 92 weeks in case 2). See section 7.5.1.11


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Appendix 3  
 
Detailed information on the presence of selected comorbidities will be collected at Visit 1 of the 
first flare.  
Disease  
Definition  
Chronic kidney disease (CKD) 
Estimated glomerular filtration rate (eGFR) 
<90 mL/min 
Current or previous symptoms of heart failure 
Stage according to the New York  Heart 
Association (NYHA) guidelines
Diabetes mellitus 
Plasma glucose >126 mg/dL after an 
overnight fast or taking antidiabetic 
medication*
Hypertension 
Blood pressure >140/90 mmHg (at repeated 
measurements) or taking antihypertensive 
treatment 
Obesity
Body mass index (BMI) ≥30 kg/m2
Cardiovascular disease 
History of angina pectoris and myocardial 
infarction
Hyperlipidemia  
Cholesterol >240 mg/dL or taking stable 
cholesterol-lowering treatments, increased 
low-density lipoprotein levels(>160 mg/dL) , 
hypertriglyceridaemia (triglycerides >150 
mg/dL), decreased high-density lipoprotein 
levels (<40 mg/dL in men or <50 mg/dL in 
women)
Cerebrovascular disease  
Previous ischemic or hemorrhagic stroke, 
previous TIA, carotid or vertebral 
stenosis/occlusion 
Osteoporosis  
Osteoporosis (T-score ≤ −2.5) 
*A subject with a consistent range between ~100 and ~126 mg/dl (~5.6 and ~7 mmol/l) (American Diabetes 
Association guidelines) is considered hyperglycemic.  
 
 
 
 
 
 


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Appendix 4  
Evidence of intolerance after treatment of gouty arthritis flares with NSAIDs and colchicine. The 
list includes examples and are not limited to the conditions listed below. 
 
NSAIDs 
Colchicine  
Examples of intolerance after 
treatment with NSAID and 
colchicine 
 Uncontrolled hypertension (w/wo 
anti-HTN medications and 
SBP≥140 mm Hg or DBP≥90 mm 
Hg)  
 Decreased renal function (eGFR 
<60mL/min/1.73m2) 
 Fluid retention (edema)  
 Hepatic toxicity with increased 
level of liver tests  
 Nausea, dyspepsia, diarrhea  
 Central nervous system effects 
(eg, headache, dizziness) 
 Vomiting, abdominal pain, 
nausea 
 Diarrhea 
 Thrombocytopenia 
 Agranulocytosis 
 Myopathy 
 Myelotoxicity 
 Peripheral neuropathy 
 Severe cutaneous eruption  
 
HTN=hypertension SBP=systolic blood pressure DBP=diastolic blood pressure 


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Appendix 5  
List of  conditions that make the patient either contraindicated or not appropriate (safety concerns) to treatment with NSAIDs or colchicine in  
treatment of gouty arthritis flares. The list includes examples and are not limited to the conditions listed below. 
 
HTN=hypertension SBP=systolic blood pressure DBP=diastolic blood pressure MI=myocardial infarction eGFR= estimated glomerular filtration rate ACE=angiotensin 
converting enzyme CKD=chronic kidney disease GERD=gastresophageal reflux disease PPI=proton pump inhibitor PUD=peptic ulcer disease GI=gastro-intestinal P-gp=P-
glycoprotein CYP=Cytochrome P-450 PK=pharmacokinetic PD=pharmacodynamics IBS=irritable bowel syndrome 
 
NSAIDs 
Colchicine  
Unsuitable for or  
contraindicated or not 
appropriate for treatment with   
 
Uncontrolled hypertension (w/wo anti-HTN medications and 
SBP≥140 mm Hg or DBP≥90 mm Hg) 1 
 
Cardiovascular disease; history of angina, ischemia, positive 
stress test or MI  
 
Heart failure  
 
Impaired renal function (eGFR <60mL/min/1.73m2)  
 
Concurrent use of thiazide diuretics and/or an ACE inhibitor or 
angiotensin receptor II antagonists, especially in CKD  
 
Current treatment with anticoagulants  
 
Gastroesophageal disease (GERD with prescribed h2 receptor  
antagonist or PPI or documented  PUD or history of upper GI 
bleed)  
 
Active or latent peptic ulcer/GI bleed (specifically in elderly 
patients)  
 
Hypersensitivity (should not be given to patients who have 
experienced asthma, urticaria, or allergic-type reactions after 
taking aspirin (acetyl salicylic acid)  or NSAIDs)  
 
Conditions with increased risk for bleedings including 
hematological disease  
 
Inflammatory bowel disease (IBS)  
 
Patients with renal or hepatic 
impairment should not be given 
colchicine in conjunction with P-gp or 
strong CYP3A4 inhibitors  
 
Potential toxicity due to PK/PD drug 
interactions especially in conjunction 
with p-gp or CYP3A4 inhibitors (e.g., 
diltiazem, verapamil, clarithromycin 
and cyclosporin), concurrent use of 
simva-, atorva-, and fluva-, and 
pravastatin  
 
Gout attack onset ≥36 hours prior to 
treatment initiation  
 
Patients on prophylactic colchicine 
treatment already and have received 
acute gout treatment regimen with 
colchicine within 14 days  
 


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Appendix 6  
Signs of unresponsiveness to NSAIDs and colchicine treatment of gouty arthritis flares. The list includes examples and are not limited to the 
conditions listed below.  
 
NSAIDs 
Colchicine  
Unresponsiveness to therapy 
Evidence of lack of efficacy for NSAIDs (one of the 
following criteria must have been met): 
 
 
losing efficacy over time;  
 
at least 1 NSAID tested but failed; 
 
inadequate/unsatisfactory pain relief 
 
Evidence of lack of efficacy for colchicine (one of the 
following criteria must have been met): 
 
 
losing efficacy over time; 
 
failed in treating acute gout pain;  
 
inadequate/unsatisfactory pain relief;  
 
incapacity to achieve/maintain adequate dose regimen 
 


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Appendix 7   
ACR/EULAR 2015 gout classification criteria (15). 
The ACR/EULAR gout classification criteria*
Categories
Score
Step 1: Entry criterion (only apply criteria below to those meeting this 
entry criterion)
At least 1 episode of swelling, pain, or 
tenderness in a peripheral joint or bursa
 
Step 2: Sufficient criterion (if met, can classify as gout without applying 
 
criteria below) 
Presence of MSU crystals in a symptomatic 
joint or bursa (i.e., in synovial fluid) or tophus 
 
Step 3: Criteria (to be used if sufficient criterion not met)
Clinical
Pattern of joint/bursa involvement during symptomatic episode(s) ever† 
Ankle or midfoot (as part of monoarticular or 
oligoarticular episode without involvement of 
the first metatarsophalangeal joint
1 
 
Involvement of the first metatarsophalangeal 
joint (as part of monoarticular or 
oligoarticular episode)
2 
Characteristics of symptomatic episode(s) ever
 
Erythema overlying affected joint (patient- reported or physician-
observed)
One characteristic
1
Can't bear touch or pressure to affected joint
Two characteristics
2
Great difficulty with walking or inability to use affected joint
Three characteristics
3
Time course of episode(s) ever 
Presence (ever) of ≥2, irrespective of anti-inflammatory treatment:
 
 
Time to maximal pain <24 hours
One typical episode
1
Resolution of symptoms in ≤14 days
Recurrent typical episodes
2
 
Complete resolution (to baseline level) between symptomatic 
 
episodes 
 
 
Clinical evidence of tophus (Figure 2)
 
Draining or chalk-like subcutaneous nodule under transparent skin, 
 
often with overlying vascularity, located in typical locations: joints, 
ears, olecranon bursae, finger pads, tendons (e.g., Achilles)
Present 
4 
Laboratory
Serum urate: Measured by uricase method. Ideally should be scored at a 
 
time when the patient was not receiving urate-lowering treatment 
 
and it was >4 weeks from the start of an episode (i.e., during 
 
intercritical period); if practicable, retest under those conditions. The 
highest value irrespective of timing should be scored.
<4 mg/dl (<0.24 mmoles/liter)  
6–<8 mg/dl (0.36–<0.48 mmoles/liter) 
8–<10 mg/dl (0.48–<0.60 mmoles/liter) 
≥10 mg/dl (≥0.60 mmoles/liter) 
-4 
2 
3 
4 
Synovial fluid analysis of a symptomatic (ever)  
joint or bursa (should be assessed by a trained observer)d
MSU negative
-2
Imaging (Figure 3)e 
 
 
 
 
Imaging evidence of urate deposition in symptomatic (ever) joint or 
 
bursa: ultrasound evidence of double-contour sign or DECT 
demonstrating urate deposition
Present (either modality) 
4 
 
Imaging evidence of gout-related joint damage: conventional 
 
radiography of the hands and/or feet demonstrates at least 1 erosion 
Present 
4 
* A web-based calculator can be accessed at: http://goutclassificationcalculator.auckland.ac.nz, and through the American College 
of Rheumatology (ACR) and European League Against Rheumatism (EULAR) web sites. 
† Symptomatic episodes are periods of symptoms that include any swelling, pain, and/or tenderness in a peripheral joint or bursa. 


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‡ If serum urate level is <4 mg/dl (<024 mmoles/liter), subtract 4 points; if serum urate level is ≥4-<6 mg/dl (≥0.242, 0.36 
mmoles/liter), score this item as 0. 
§ If polarizing microscopy of synovial fluid from a symptomatic (ever) joint or bursa by a trained examiner fails to show monosodium 
urate monohydrate (MSU) crystals, subtract 2 points. If synovial fluid was not assessed, score this item as 0. 
¶ If imaging is not available, score these items as 0. 
# Hyperechoic irregular enhancement over the surface of the hyaline cartilage that is independent of the insonation angle of the 
ultrasound beam (note: false-positive double-contour sign [artifact] may appear at the cartilage surface but should disappear with a 
change in the insonation angle of the probe) (31, 32) 
** Presence of color-coded urate at articular or periarticular sites. Images should be acquired using a dual-energy computed 
tomography (DECT) scanner, with data acquired at 80 kV and 140 kV and analyzed using gout-specific software with a 2-material 
decomposition algorithm that color-codes urate (33). A positive scan is defined as the presence of color-coded urate at articular or 
periarticular sites. Nailbed, submillimeter, skin, motion, beam hardening, and vascular artifacts should not be interpreted as DECT 
evidence of urate deposition (33). 
†† Erosion is defined as a cortical break with sclerotic margin and overhanging edge, excluding distal interphalangeal joints and gull 
wing appearance. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan 
 
 
 
Protocol number: 
Sobi.ANAKIN-401 
NCT Number: 
03002974 
Title: 
A randomized, double-blind, active-control, multicenter, efficacy and 
safety study of 2 dose levels of subcutaneous anakinra compared to 
intramuscular triamcinolone in the treatment of acute gouty arthritis, 
followed by an extension period of up to 2 years 
SAP version: 
Final 1.0 
Date: 
17 August 2018 
 
 
 
 
 
 
 
 
 
 


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Version 1.0, Final 2018/08/17 
Table of contents 
1 
List of abbreviations and definition of terms ...................................................................... 6 
2 
Introduction ....................................................................................................................... 8 
3 
Study objectives and endpoints .......................................................................................... 8 
3.1 
Primary objective .......................................................................................................... 8 
3.2 
Secondary objectives .................................................................................................... 8 
3.2.1 Exploratory objectives ........................................................................................... 9 
3.3 
Study endpoints ............................................................................................................ 9 
3.3.1 Primary efficacy endpoint and secondary endpoints supporting the primary 
objective ................................................................................................................ 9 
3.3.1.1 
Primary efficacy endpoint ........................................................................... 9 
3.3.1.2 
Secondary endpoints supporting the primary objective ................................ 9 
3.3.2 Secondary efficacy endpoints ............................................................................... 10 
3.3.3 Safety endpoints ................................................................................................... 10 
3.3.4 Serum concentrations ........................................................................................... 11 
3.3.5 Exploratory endpoints .......................................................................................... 11 
4 
Study methods ................................................................................................................. 11 
4.1 
Overall study design and plan ..................................................................................... 11 
4.2 
Selection of study population ...................................................................................... 13 
4.3 
Method of treatment assignment and randomization .................................................... 14 
5 
Changes from protocol affecting the statistical analysis ................................................... 15 
6 
Sequence of planned analysis .......................................................................................... 15 
6.1 
Main efficacy analysis ................................................................................................ 15 
6.2 
Final analysis .............................................................................................................. 16 
6.3 
Reporting .................................................................................................................... 16 
7 
Sample size determination ............................................................................................... 16 
8 
Analysis populations ....................................................................................................... 17 
8.1 
Intention-to-treat (ITT) ............................................................................................... 17 
8.2 
Per-protocol population (PP) ....................................................................................... 17 
8.3 
Safety population ........................................................................................................ 17 
9 
General considerations for statistical analysis .................................................................. 18 
9.1 
Handling of missing data and outliers ......................................................................... 18 
9.2 
Multicenter studies ...................................................................................................... 19 
9.3 
Multiple comparisons and multiplicity ........................................................................ 19 
10 
Patient disposition ........................................................................................................... 19 


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11 
Demographics and baseline characteristics ...................................................................... 20 
11.1 Demographics ............................................................................................................. 20 
11.2 Baseline characteristics ............................................................................................... 20 
11.3 Medical and surgical history ....................................................................................... 20 
12 
Prior and concomitant medication ................................................................................... 21 
13 
Study drug compliance .................................................................................................... 21 
14 
Efficacy analyses ............................................................................................................. 22 
14.1 Primary efficacy endpoint ........................................................................................... 22 
14.1.1 Subgroup analyses ............................................................................................... 23 
14.1.2 Sensitivity analysis of the primary endpoint ......................................................... 23 
14.1.2.1 
Sensitivity to subject population ............................................................... 24 
14.1.2.2 
Sensitivity to missing data handling .......................................................... 24 
14.1.2.3 
Tipping point analysis ............................................................................... 24 
14.2 Secondary endpoints supporting the primary objective ................................................ 26 
14.2.1 Patient-assessed pain intensity in the index joint on a Visual analogue scale (VAS)
 ............................................................................................................................ 26 
14.2.2 Patient-assessed pain intensity in the index joint on a 5-point Likert scale ............ 27 
14.3 Secondary efficacy endpoints ...................................................................................... 28 
14.3.1.1 
Pain intensity for anakinra dose groups, 100 and 200 mg .......................... 28 
14.3.1.2 
Onset of effect .......................................................................................... 28 
14.3.1.3 
Response .................................................................................................. 29 
14.3.1.4 
Resolution of pain ..................................................................................... 29 
14.3.1.5 
Rescue medication .................................................................................... 30 
14.3.1.6 
Physician’s assessment of global response to treatment ............................. 31 
14.3.1.7 
Physician’s assessment of clinical signs .................................................... 31 
14.3.1.8 
Patient´s assessment of global response to treatment ................................. 30 
14.3.1.9 
Inflammatory biomarkers .......................................................................... 32 
14.3.1.10 Subsequent flares ...................................................................................... 32 
15 
Serum concentrations of Interleukin 1 receptor antagonist (IL-1Ra)/anakinra .................. 34 
16 
Safety analyses ................................................................................................................ 34 
16.1 Drug exposure ............................................................................................................ 34 
16.2 Adverse events ............................................................................................................ 34 
16.2.1 Serious adverse events ......................................................................................... 35 
16.2.2 Adverse events leading to withdrawal .................................................................. 35 
16.2.3 Deaths .................................................................................................................. 36 
16.3 Laboratory data ........................................................................................................... 36 


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16.4 Vital signs ................................................................................................................... 36 
16.5 Electrocardiogram ....................................................................................................... 36 
16.6 Anti-drug antibodies ................................................................................................... 36 
16.6.1 Presence of anti-drug antibodies ........................................................................... 37 
16.6.2 Anti-drug antibodies versus safety ....................................................................... 37 
16.6.3 Anti-drug antibodies versus efficacy .................................................................... 37 
16.6.4 Anti-drug antibodies versus serum concentration of IL-1Ra/anakinra ................... 38 
17 
Exploratory endpoints ..................................................................................................... 38 
17.1 Short Form (36) Health Survey (SF-36) ...................................................................... 38 
17.2 EuroQol 5 dimensions 5 levels (EQ-5D-5L) ................................................................ 38 
17.3 Work productivity and activity impairment:specific health problems (WPAI:SHP) ..... 39 
17.4 Health care resource utilization ................................................................................... 39 
17.5 Exploratory inflammatory biomarkers ......................................................................... 39 
18 
Derived and computed variables ...................................................................................... 39 
18.1 Unpermitted rescue medication ................................................................................... 39 
18.2 Age ............................................................................................................................. 40 
18.3 Body mass index (BMI) .............................................................................................. 40 
18.4 Age at diagnosis of gouty arthritis ............................................................................... 40 
18.5 Disease duration ......................................................................................................... 40 
18.6 Start of medical and surgical history ........................................................................... 41 
18.7 eGFR category ............................................................................................................ 41 
18.8 Obesity ....................................................................................................................... 41 
18.9 Cardiovascular disease ................................................................................................ 41 
18.10 Hyperlipidemia ........................................................................................................... 41 
18.11 Cerebrovascular disease .............................................................................................. 42 
18.12 Start of prior and concomitant medication ................................................................... 42 
18.13 Glucocorticoid use ...................................................................................................... 42 
18.14 ULT use ...................................................................................................................... 42 
18.15 Study drug compliance ............................................................................................... 42 
18.16 Time windows for pain intensity assessments (Visual analogue scale – VAS-  and 
Likert) ........................................................................................................................ 43 
18.17 Pain intensity on Visual analogue scale (VAS) ............................................................ 44 
18.18 Pain intensity on Likert ............................................................................................... 44 
18.19 Onset of effect ............................................................................................................ 44 
18.20 Response .................................................................................................................... 45 
18.21 Resolution of pain ....................................................................................................... 45 


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18.22 Time to rescue medication .......................................................................................... 45 
18.23 Drug exposure ............................................................................................................ 46 
18.24 Adverse event start/stop day........................................................................................ 47 
18.25 Treatment emergent abnormal vital signs .................................................................... 48 
18.26 Immunogenicity .......................................................................................................... 48 
18.27 Short Form (36) Health Survey (SF-36) ...................................................................... 48 
18.28 EuroQol 5 dimensions 5 levels (EQ-5D-5L) ................................................................ 49 
18.29 Work productivity and activity impairment:specific health problems (WPAI:SHP) ..... 50 
18.30 Health care resource utilization ................................................................................... 51 
19 
References ....................................................................................................................... 52 
 
Table of tables 
Table 1 
eGFR categories ................................................................................... 41 
Table 2 
Time windows for pain intensity assessments (VAS and Likert) ........... 43 
Table of figures 
Figure 1 
Study design ........................................................................................ 12 
Figure 2 
SF-36 domain scores .............................. Error! Bookmark not defined. 
 
 
 


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1 
List of abbreviations and definition of terms 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical Classification 
System 
BMI 
Body mass index 
CRF 
Case report form 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
eGFR 
Estimated glomerular filtration rate 
ePRO 
Electronic PRO 
EQ-5D-5L 
EuroQol 5 dimensions 5 levels 
EULAR 
European League Against Rheumatism 
FDA 
Food and Drug Administration 
GFR 
Glomerular filtration rate 
HR 
Heart rate 
HRQL 
Health related quality of life 
ICF 
Informed consent form 
ICH 
International Council of Harmonization 
IL-1Ra 
Endogenous interleukin 1 receptor antagonist 
IL-6   
Interleukin-6 
IL-8 
Interleukin-8 
i.m. 
Intramuscular 
IMP 
Investigational medicinal product 
ITT 
Intention-to-treat 
IWRS 
Interactive web response system 
LS 
Least square 
LSM 
Least square means 
MAR 
Missing at random 
MCS 
Mental component summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measures 


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Abbreviation 
Definition 
MNAR 
Missing not at random 
MPO 
Myeloperoxidase 
NAb 
Neutralizing anti-drug antibodies 
No. 
Number 
NSAID 
Non-steroidal anti-inflammatory drugs 
PCS 
Physical component summary 
PP 
Per-protocol  
PRO 
Patient reported outcome 
PT 
Preferred term 
SAA 
Serum amyloid A 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
s.c. 
Subcutaneous 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
SF-36 
Short Form (36) Health Survey (acute, Version 2) 
Sobi 
Swedish Orphan Biovitrum 
SOC 
System organ class 
SOP 
Standard operating procedure 
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 
ULT 
Urate lowering therapy 
VAS 
Visual analogue scale 
WPAI:SHP 
Work productivity and activity impairment:specific 
health problems 
 
 
 


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2 
Introduction 
This SAP describes the planned analyses and reporting for the Sobi study Sobi.ANAKIN-401, A 
randomized, double-blind, active-control, multicenter, efficacy and safety study of 2 dose levels 
of subcutaneous anakinra compared to intramuscular triamcinolone in the treatment of acute 
gouty arthritis, followed by an extension period of up to 2 years. 
This phase II study is being completed to assess the efficacy and safety of anakinra for the 
treatment of acute gouty arthritis in patients for whom NSAIDs and colchicine are either 
contraindicated or not appropriate due to anticipated changes in patient status, not tolerated or do 
not provide an adequate response.  
The purpose of this SAP is to outline the planned analyses to be completed to support the CSR 
for the study Sobi.ANAKIN-401. The planned analyses identified in this SAP will be included in 
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 respective 
CSR. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and International Council of Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use (ICH): Guidance on Statistical Principles in 
Clinical Trials. 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 the study is to evaluate the efficacy of anakinra compared to 
triamcinolone acetonide 40 mg i.m. injection, hereafter referred to as triamcinolone, with respect 
to patient-assessed pain intensity in the treatment of a gouty arthritis flare (based on patients’ 
first flare treated in the study). 
3.2 
Secondary objectives 
The secondary objectives of the study are: 
 To evaluate the primary endpoint and the secondary endpoints supporting primary 
objective for the 2 different anakinra dose groups compared to triamcinolone in the 
treatment of the first gouty arthritis flare.  
 To evaluate the time to onset of effect, time to response, time to pain resolution, time to 
rescue medication, physician’s assessment of global response and clinical signs, patient´s 


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assessment of global response, inflammatory biomarkers, and safety of anakinra 
compared to triamcinolone in the treatment of the first gouty arthritis flare both for the 
combined anakinra group (100 and 200 mg) and the 2 different anakinra dose groups.  
 To evaluate the primary and secondary endpoints and safety of the combined anakinra 
group (100 and 200 mg), the 2 different anakinra dose groups and triamcinolone in the 
treatment of subsequent flares. Subsequent flares are flares occurring after the first flare 
in the study and within 52 weeks of randomization of the last randomized patient in the 
study. However the extension will be a maximum of 2 years (104 weeks) after 
randomization for the individual patient in the study.  
3.2.1 
Exploratory objectives  
The exploratory objectives of the study are: 
 To evaluate the effect of anakinra compared to triamcinolone on HRQL and health care 
resource utilization in the treatment of the first gouty arthritis flare. 
 To evaluate the effect of anakinra compared to triamcinolone on exploratory 
inflammatory biomarkers in serum in the treatment of gouty arthritis flares. (Statistical 
analyses of exploratory inflammatory biomarkers of more exploratory nature will not be 
described in this SAP and these results may be reported separately).  
 To analyze for genetic factors potentially 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. The statistical 
analysis of genetic factors will not be described in this SAP and these results may be 
reported separately.  
3.3 
Study endpoints 
3.3.1 
Primary efficacy endpoint and secondary endpoints supporting the 
primary objective 
3.3.1.1 
Primary efficacy endpoint 
The primary efficacy endpoint is: 
 The change in patient-assessed pain intensity from baseline to 24 to 72 hours (average of 
the assessments performed at 24, 48, and 72 hours) for the first flare.  
3.3.1.2 
Secondary endpoints supporting the primary objective 
The following secondary endpoints will be evaluated to support the primary objective: 
 Change from baseline in patient-assessed pain intensity in the index joint as measured by 
VAS at 6, 12, 18, 24, 36, 48, 72 hours, and Days 5, 6, 7, and 8 for the first flare. 


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 Change from baseline in patient-assessed pain intensity in the index joint as measured by 
a 5-point Likert scale at 6, 12, 18, 24, 36, 48, 72 hours, and Days 5, 6, 7, and 8 for the 
first flare. 
3.3.2 
Secondary efficacy endpoints 
The following secondary endpoints will be assessed for the first flare and subsequent flares. All 
comparisons versus baseline (pre-dose measurement at Visit 1) will be made against the baseline 
of the first and subsequent flares, respectively.   
 Time to onset of effect (defined as 20 % change from baseline pain intensity on VAS). 
 Time to response (defined as 50 % change from baseline pain intensity on VAS). 
 Response (defined as 50 % change from baseline pain intensity on VAS) at 24, 48 and 
72 hours, Day 8 and Day 15 (yes/no). 
 Resolution of pain (defined as <10 mm on VAS) at 72 hours, Day 8 and Day 15 
(Yes/No). 
 Time to resolution of pain (defined as <10 mm on VAS). 
 Time to intake of rescue medication from first IMP administration. 
 Type and number of occasions of intake of rescue medication taken from first IMP 
administration to Day 8. 
 Patient´s assessment of global response to treatment (5-point Likert scale) at 72 hours, 
Day 8 and Day 15. 
 Physician’s assessment of global response to treatment (5-point Likert scale) at 72 hours, 
Day 8 and Day 15. 
 Physician’s assessment of clinical signs at 72 hours, Day 8 and Day 15 in index joint 
tenderness, swelling and erythema. 
 Change from baseline in the inflammatory biomarkers CRP and SAA at 72 hours, Day 8 
and Day 15. 
Additional assessment for the subsequent flares:  
 Change in patient-assessed pain intensity in the index joint as measured by VAS score 
from baseline to 24 to 72 hours (average of the assessments performed at 24, 48 and 72 
hours). 
 Change from baseline in patient-assessed pain intensity in the index joint as measured by 
VAS score at 6, 12, 18, 24, 36, 48, 72 hours and Days 5, 6, 7 and 8. 
 Change from baseline in patient-assessed pain intensity in the index joint as measured by 
a 5-point Likert scale at 6, 12, 18, 24, 36, 48, 72 hours and Days 5, 6, 7 and 8. 
3.3.3 
Safety endpoints 
The study has the following safety endpoints: 
 Occurrence of AEs. 
 Laboratory safety assessments. 


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 Vital signs . 
 Occurrence of ADA against anakinra at Visit 1 (before IMP administration) and at Day 8, 
Day 15, Day 28 and Week 12 (the assessment at Day 28 and Week 12 will only be 
performed if no subsequent flare has occurred at that timepoint).  
3.3.4 
Serum concentrations 
The following endpoint will be assessed to evaluate anakinra serum concentrations: 
 Serum concentration of IL-1Ra/anakinra at baseline, 72 hours (just before IMP 
administration) and at Day 8, Day 15, Day 28 and Week 12 (the assessment at Day 28 
and Week 12 will only be performed if no subsequent flare has occurred at that 
timepoint). 
3.3.5 
Exploratory endpoints 
The following exploratory endpoints will be assessed for both the first and subsequent gouty 
arthritis flares. All comparisons versus baseline (pre-dose measurement at Visit 1) will be made 
against the baseline of the first and subsequent flares, respectively.   
 Change from baseline in health related quality of life (SF-36® Health Survey, acute 
Version 2) at Day 8 and Day 15.  
 Change from baseline in health related quality of life (EQ-5D-5L) at Day 8 and Day 15.  
 Work productivity and activity impairment due to a gouty arthritis flare (WPAI:SHP 
Version 2.0) and health care resource utilization: number of days with hospitalization and 
number of unscheduled outpatient visits during the last week recorded at Day 8 and Day 
15.  
 Change from baseline in the exploratory inflammatory biomarkers IL-6, IL-8, 
calprotectin, neopterin and MPO in serum at 72 hours, Day 15 and Week 12. 
4 
Study methods 
4.1 
Overall study design and plan 
The study consists of 3 periods: an optional pre-screening period, a double-blind treatment 
period and an extension period.  
The treatment period of the first flare is double-blind, and the patients will be randomized to 
treatment with 100 mg anakinra, 200 mg anakinra or 40 mg triamcinolone acetonide in a 1:1:1 
ratio. At Visit 1 of each flare, the triamcinolone or matching placebo will be given as one i.m. 
injection of 1 mL, and at each day of IMP administration period (Days 1 to 5), the anakinra 
and/or matching placebo will be given as 2 s.c. injections of 0.67 mL.  


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The double-blind period will be followed by an extension period. During this period, the patients 
will receive the same treatment for subsequent flares occurring after Day 15 of the latest flare. 
The extension period will continue for all patients until 52 weeks after randomization of the last 
randomized patient in the study. However the study treatment of an individual patient’s flare will 
not start later than 2 years (104 weeks) after randomization of that patient. Thus the study will 
not exceed 104 + 12 weeks for any patient An overview of the study design is presented in  
Figure 1. 
Figure 1 
Study design 
 
Abbreviations: FU, Follow-up; N, Number of patients. 
At each baseline visit (first and subsequent flares), the joint that is most affected, i.e. most 
painful, will be defined as the index joint. 
The assessment period for each flare will consist of 4 to 6 visits to the study center. The visits are 
the screening/baseline visit (Visit 1/Day 1), the 72-hour visit (Visit 2/Day 4), the 1-week visit 
(Visit 3/Day 8), the 2-week visit (Visit 4/Day 15), the 4-week visit (Visit E/Day 28) and the 
3 month visit (Visit 5/Week 12). If a subsequent flare has been treated before the Day 28 visit, 
the Day 28 and Week 12 visits will be cancelled. If a subsequent flare has been treated before a 
Week 12 visit, that Week 12 visit will be cancelled. Subsequent flares occurring before the 
Day 15 visit of the latest flare (Visit 4) will be treated with permitted rescue medication, i.e. no 
IMP will be administered. 
A follow-up by phone will be performed at 24 and 48 hours post first IMP administration to 
remind the patient to complete the assessments and recordings in the eDiary. A follow-up by 
phone will also be performed every 12 weeks following Visit 5 of the latest flare.   
An end-of-study follow-up will be performed either; 
1. 52 weeks after randomization of the last patient in the study  
or 


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2. 2 years (104 weeks) after randomization of the individual patient 
whichever occurs first. 
If the IMP treatment started week 40 or later in case 1), or week 92 weeks in case 2), the 
Week 12 visit will replace the End-of-study follow-up by phone.  
All patients will have their follow-up visits/phone calls, irrespective of treatment withdrawal or 
use of rescue medication. 
Subsequent flares occurring before the Day 15 visit of the latest flare (Visit 4) will be treated 
with permitted rescue medication i.e., no IMP will be administered. 
The AE reporting period for all AEs, including SAEs, begins upon receiving the first dose of 
IMP and ends at Visit E, 28 days after the first dose of IMP. SAEs will also be collected from 
signing of the ICF until the Week 12 visit (Visit 5). Furthermore, any SAE should be reported 
irrespective of the time of occurrence if a causal relationship between the event and the IMP(s) is 
suspected. If the patient is treated with IMP for a subsequent flare, the AE (including SAE) 
reporting period starts again when the first dose is administered. 
Patients who have difficulty in tolerating their pain are allowed to take rescue medication after 
the 24-hour post-dose pain assessment but not within 6 hours before the 48- and 72-hour post-
dose pain assessments. Permitted rescue medication includes topical ice/cold packs, 
paracetamol/acetaminophen (up to 1000 mg 4 times daily) and/or codeine (up to 50 mg 4 times 
daily) or short-acting tramadol (up to 100 mg 4 times daily).  
Patients still having insufficient relief with the rescue medication listed above after the 72-hour 
post-dose pain assessment are allowed to take oral prednisone or prednisolone at a dose up to 
0.5 mg/kg per day for a maximum of 5 days. 
When all patients have conducted the Day 15 visit of the first flare (Visit 4), the database will be 
locked and the main efficacy analysis will be conducted. The main efficacy analysis includes 
primarily the statistical anlysis of all efficacy endpoints for the first flare. A second database lock 
will be conducted when all patients have completed the study. 
4.2 
Selection of study population 
This study is designed to evaluate the efficacy and safety of anakinra in the treatment of gouty 
arthritis flares in adult male and female patients for whom NSAIDs and colchicine are either 
contraindicated or not appropriate due to anticipated changes in patient status, not tolerated or do 
not provide an adequate response. To ensure a reliable diagnosis of gouty arthritis, patients to be 
included in the study must meet the ACR/EULAR 2015 gout classification criteria (Error! 
Reference source not found.).  
A history of  ≥1 self-reported flare of gouty arthritis during the previous 12 months is required 
for inclusion in the study to ensure that the patients have an active gouty arthritis.  
To ensure that a significant number of subsequent flares are treated in the study, the extension 
period will continue for all patients until 52 weeks after randomization of the last randomized 


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patient in the study or a maximum of 104 weeks after randomization of the individual patient in 
the study.  
To be included, patients must have a patient-reported current ongoing flare of gouty arthritis 
characterized by baseline pain intensity in the index joint of ≥50 on a 0 to 100 VAS, as well as 
currently tender (≥1 on a 0-4-point Likert scale) and swollen (≥1 on a 0-4-point Likert scale). 
The onset of the current ongoing flare should be within 4 days prior to randomization. 
Further, if the patient is on urate-lowering therapy, a stable dose and regimen for at least 2 weeks 
prior to randomization and expectance to remain on a stable dose and regimen for ≥2 weeks after 
administration of the first dose of study treatment is required. 
Complete details of the patient inclusion and exclusion criteria are provided in CSP Section 7.3.1 
and CSP Section 7.3.2. 
Patients with data collection failure for primary endpoint are defined as patients who are 
randomized in the clinical study but have no values collected for patient-assessed pain intensity 
from baseline to 72 hours for the first flare. These patients will however continue in the study 
and be included in the ITT and safety populations. For each primary endpoint collection failures, 
one extra patient can be randomized in the study. Maximum 10 extra patients can be randomized 
under this protocol. 
 
4.3 
Method of treatment assignment and randomization 
Up to totally 169 patients can be randomized in the study. Initially 159 patients will be 
randomized, 53 to triamcinolone and 106 to anakinra (53 to 100 mg and 53 to 200 mg). As 
described in Section 7, up to a maximum of 10 extra patients can be randomized. Patients will be 
randomized to treatment with anakinra 100 mg, anakinra 200 mg or triamcinolone 40 mg in a 
1:1:1 ratio. The randomization will be stratified by ULT use (yes/no) and BMI (30.0 or 30.0 
kg/m2) at inclusion. 
For subsequent flares during the extension period, patients will continue to receive the same 
treatment with anakinra 100 mg, anakinra 200 mg or triamcinolone 40 mg.  
An IWRS will be used for the randomization. Biostatistics at Perceptive will generate the 
randomization scheme for the IWRS, which will link sequential patient randomization numbers 
to treatment codes.  
The randomization numbers will be generated in blocks. Within each block, equal numbers of 
patients will be allocated to each treatment group. The block size will not be revealed to any 
personnel involved in the study except the lead statistician at PRA and the study statistician at 
Sobi before breaking of the blind.  
The first part of the study, i.e. treatment and follow-up of the patients’ first flare, is double-blind. 
Treatment assignment will be blinded for the patients, the investigators and any personnel 
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Until all patients have completed the Day 15 visit of the first flare (Visit 4), the randomization 
scheme will only be disclosed to selected CRO personnel to ensure correct packaging of the IMP 
and correct set-up of the IWRS. The disclosure of the randomization scheme and any individual 
patient’s treatment assignment will be protected by the SOPs of the CRO. 
When all patients have completed the Day 15 visit of the first flare, a first database lock will be 
performed and the main efficacy analysis will be conducted (see Section 6.1). An independent 
unblinded programmer at the CRO will create unblinded SDTMs to be sent to Sponsor. Blinding 
will be maintained for patients, investigators, site staff, CRO and applicable vendors throughout 
the extension phase to prevent any bias in data handling. The Sponsor will take no part in the 
operational conduct of the study after the first database lock. Details of this process will be 
outlined in the “Process guideline for data integrity protection after database lock 1”. 
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. Unblinding should be documented according to instructions in the 
IWRS manual. The study monitor and sponsor must as soon as possible be informed about the 
code break. 
5 
Changes from protocol affecting the statistical analysis 
According to the protocol, AEs and SAEs will be classified as occurring during ADA presence 
when the starting date for the AE is within the time period after the latest negative assessment 
until next negative assessment with a positive assessment of ADA in between. Instead AEs and 
SAEs will be presented by ADA positive and ADA negative patients for the whole study period. 
  
The relationship between ADA and efficacy and the relationship between ADA and IL-
Ra/anakinra concentrations over time will also be explored which was not described in the 
protocol. 
6 
Sequence of planned analysis 
6.1 
Main efficacy analysis 
No interim analysis of efficacy data is planned. However, two database locks are planned. The 
first database lock will be performed when all patients have conducted the Day 15 visit (Visit 4) 
of the first flare in the study and the main efficacy analysis will be conducted. The main efficacy 
analysis includes primarily all efficacy endpoints for the first flare.  
All collected data for the first flare, i.e. at a minimum data up to and including the Day 15 visit 
and at a maximum data up to 12 weeks, will be analyzed. Allocation to analysis populations and 
all efficacy analyses including data up to Day 15 will be considered as final.  


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Prior to the first database lock all tasks and criteria defined in the data management plan must be 
completed and documented. After the database lock the blind will be broken and results will be 
generated. The SAP will be finalized and signed prior to the first database lock and subsequently 
the breaking of the blinding. The database lock will be approved by relevant study personnel. 
After the data transfer for the main efficacy analysis has occurred, the database will be unlocked 
to continue with data entry activities for Visit E, Visit 5 and follow-up by phone that had not 
taken place at the cut-off date for the first database lock and for subsequent flares. However, no 
changes to the data up to Day 15 should be performed except that ongoing AEs at Day 15 for the 
first flare might need to be updated.  
6.2 
Final analysis 
The final analysis will include efficacy analyses from subsequent flares and safety and 
exploratory analyses from all flares. It will be performed when all patients have completed the 
study. The database will be locked a second time following the same procedure as described in 
Section 6.1. 
If updates to the SAP are needed after the first database lock, all changes will be described and 
the updated SAP will be finalized, locked and signed prior to final database lock. Any changes to 
the planned analyses will also be described in the CSR. 
6.3 
Reporting 
The CSR for the study will be written after the final database lock and include data and results 
from both the first and subsequent flares. The results generated for the main efficacy analysis, 
i.e. all tables, figures and listings that only includes data up to and including the Day 15 visit, 
will remain unchanged. 
Any post-hoc analyses included in the CSR, which were not identified in the SAP, will be clearly 
identified as such in the relevant Section of the CSR. 
7 
Sample size determination 
Up to totally 169 patients can be randomized in the study. Initially 159 patients will be 
randomized, 53 to triamcinolone and 106 to anakinra (53 to 100 mg and 53 to 200 mg). As 
described in section 4.2, up to a maximum of 10 extra patients can be randomized.  
The sample size calculation is based on the change in pain intensity on a VAS 0 to 100 mm from 
baseline to the average over 24 to 72 hours. A sample size of 106 patients randomized to 
anakinra and 53 patients randomized to triamcinolone is required to ensure a power of 80 % to 
reject the null hypothesis of no difference between anakinra and triamcinolone assuming a true 
difference of 12 mm on VAS mean change and a SD of 25 mm when using a 2-sided test with a 
significance level of 5 %. 


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8 
Analysis populations  
Sections 8.1, 8.2 and 8.3 presents the analysis sets used in the statistical analyses. 
8.1 
Intention-to-treat (ITT) 
The ITT population is the primary analysis population for the primary and secondary efficacy 
endpoints, comprising all randomized patients grouped according to randomized treatment and 
stratum. Presentations of efficacy endpoints for subsequent flares will also be based on the ITT 
population. 
8.2 
Per-protocol population (PP) 
The PP population will comprise all ITT patients who have no major protocol violations 
potentially affecting the primary efficacy endpoint. The patients will be grouped according to 
actual treatment received during the first gouty arthritis flare. Patients assigned to an incorrect 
strata will be grouped according to actual baseline BMI and ULT information. Patient 
assignment to the PP population will be performed prior to breaking the blind. The PP 
population will only be used for analyses of efficacy endpoints for the first flare. 
The following criteria are classed as major protocol deviations/violations and will exclude 
patients from the PP population: 
• 
Incorrectly included: 
o Not fulfilling the ACR/EULAR 2015 Gout Classification Criteria. 
o Not fulfilling baseline pain intensity in the index joint of ≥50 on a 0 to 100 VAS 
or missing baseline pain intensity assessment.  
o The onset of the current ongoing flare is more than 4 days prior to first IMP 
injection (days from onset to first IMP injection will be calculated in full days 
allowing patients with time from onset to randomization <5 days to be included in 
the PP population).  
• 
Missing VAS pain intensity assessments at all of the following timepoints: 24, 48 and 72 
hours.  
• 
More than one incorrect intake of rescue medication, i.e. type or outside permitted time 
window at any of the following timepoints: 24, 48 or 72 hours (see Section 18.1). 
• 
Missing more than one daily IMP injection occasion during the first 3 days of treatment. 
• 
Administration during the first three days of IMP that have had a significant temperature 
excursion.  
8.3 
Safety population 
The safety population will comprise all patients who received at least one dose of  IMP and the 
patients will be grouped according to actual baseline BMI and ULT information during the first 
gouty arthritis flare. 


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Patients randomized to triamcinolone that incorrectly receive at least one dose of anakinra during 
the first flare will be included in the anakinra group, 100 mg or 200 mg depending on the highest 
dose received. 
Patients randomized to anakinra (100 mg or 200 mg) that incorrectly only receive triamcinolone 
and no anakinra during the first flare will be included in the triamcinolone group. 
The safety population will be used for analyses of safety endpoints and serum concentrations for 
the whole study period.  
The assignment to the safety population will remain the same for all flares even if a patient did 
change a treatment in a subsequent flare. Changes in treatment for each subsequent flare will be 
presented in separate tables, i.e. if the actual treatment for the subsequent flare is not the same as 
the first flare. 
9 
General considerations for statistical analysis 
All statistical tests will be 2-sided and performed using a 5 % significance level, if not stated 
otherwise. Results will be presented as the point estimate for each treatment group, the estimated 
difference between groups, the associated 95 %, 2-sided confidence interval and p-value. 
P-values from statistical analyses will be presented to 3 decimal places with values below 0.001 
displayed as <.001 and 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 stated. Minimum and maximum will be presented to the same 
number of decimal places as the raw data and mean, SD, standard error of the mean 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 9.1 or later (SAS Institute 
Inc, Cary, North Carolina, United States).  
9.1 
Handling of missing data and outliers 
Patients should continue in the study even if study treatment is withdrawn and every effort 
should be made to complete the assessments according to the protocol. The evaluation of patient-
assessed pain using VAS and Likert scales have repeated assessment time points and repeated 
measures models will be used to handle missing data, i.e. no imputation is needed. To evaluate 
the robustness of this model for the primary endpoint, sensitivity analyses including multiple 
imputation methods will be performed (see Section 14.1.2). For the secondary time-to-event 
analyses, patients who do not have an event at the time for analysis will be censored at the last 


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time point with recorded information. For other secondary endpoints the analyses will be based 
on observed data.  
In case of missing or incomplete dates or times, no imputations will be made in the listings of 
data. Rules on how to handle partially or completely missing dates or times in calculations are 
described in Section 18. 
9.2 
Multicenter studies 
No effects of centers will be evaluated in this study.  
9.3 
Multiple comparisons and multiplicity 
No adjustment for multiplicity will be performed. 
10 
Patient disposition 
All patient disposition data will be presented by triamcinolone, the combined anakinra group, 
anakinra 100 mg/day, anakinra 200 mg/day and overall.  
The number and percentage of patients who were randomized, initiated treatment, completed and 
discontinued study together with the reasons for discontinuations will be presented both for each 
treated flare and for the full study. If a patient prematurely discontinue the study during a flare, 
all prior flares are completed (i.e. only the last flare may be prematurely discontinued). If the 
discontinuation is after the Day 15 visit, the flare is considered completed (i.e. all flares may be 
completed even if the patient has prematurely discontinued the study). Otherwise, the patient has 
prematurely discontinued the flare with the reason for discontinuation the same as the reason for 
prematurely discontinuation of the study. 
The number of weeks in the study and the number of treated flares experienced by the patients 
during the study will be presented by descriptive statistics for the ITT and safety population. 
Further, the number and percentage of patients experiencing 1 treated flare, 2 treated flares, 3 
treated flares, etc. will also be presented for the ITT and safety population.  
The total number and percentage of patients who completed treatment and discontinued 
treatment together with reason for discontinuation will be tabulated for each flare and overall for 
the safety population. 
The number and percentage of patients in each strata will be presented for the ITT, PP and safety 
populations. Stratification data will be received from the IWRS system and actual strata will be 
derived using CRF data. 
The distribution of patients at each site will be tabulated for the ITT population, sorted by 
descending number of patients.  


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A table displaying the number and percentage of patients with each type of major protocol 
deviations that lead to exclusion from the PP population will be presented. Percentages will be 
based on the ITT population. 
The number and percentage of patients in the ITT population, the PP population and the safety 
population will be presented. 
11 
Demographics and baseline characteristics 
11.1 
Demographics 
The demographic data, including age, sex, race, and ethnicity will be presented by descriptive 
statistics for the ITT, PP and safety populations (see Section 18.1).  
11.2 
Baseline characteristics 
Baseline characteristics of gouty arthritis, such as age at diagnosis, disease duration, and number 
of gouty arthritis flares during the past 12 months will be presented for the ITT, PP, and safety 
populations (see Sections 18.1 18.4, and 18.5). 
The number of patients who completed patient/caregiver IMP injection training and patient diary 
training will be presented for the ITT population. 
The reasons NSAIDs and colchicine are inappropriate will be presented for the ITT, PP and 
safety populations. 
Body height, body weight, BMI, waist circumference, body temperature, systolic and diastolic 
blood pressure, and pulse (see Section 18.3) will be presented  using descriptive statistics for the 
ITT, PP, and safety populations. For subsequent flares, body weight, BMI, body temperature, 
systolic and diastolic blood pressure, and pulse will be presented. 
Each of the ACR EULAR Gout Classification Criteria at baseline will be presented for the ITT, 
PP, and safety populations.  
Medical examination of current flare (Time of pain onset prior to IMP injection, the number and 
distribution of joints involved and the index joint) will be presented for each flare for the ITT, 
PP, and safety populations. 
11.3 
Medical and surgical history and concurrent illnesses 
All medical and surgical history data will be coded using the MedDRA Version 19.1 and the 
same version will be used throughout the study. 
Medical and surgical history at baseline will be presented by SOC and PT for the ITT, PP, and 
safety populations. Medical and surgical history reported after randomization will be presented 
separately (see Section 18.6). 


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Detailed information on the presence of the following selected comorbidities will be presented in 
a separate table for the ITT, PP, and safety populations: eGFR category, current or previous 
symptoms of heart failure, diabetes mellitus, hypertension, obesity, cardiovascular disease, 
hyperlipidemia, cerebrovascular disease and osteoporosis (see Sections Error! Reference 
source not found., 18.8, 18.9, 18.10 and 18.11). 
Data from physical examination will be presented as “normal” or “abnormal” at Day 1 and Day 
15 for each flare for the ITT, PP, and safety populations. Any persisting abnormalities should be 
stated each time the examination is performed in medical history and new abnormalities should 
be recorded as AEs. 
Baseline ECG will be presented for each flare. 
 
12 
Prior and concomitant medication 
All prior and concomitant medication will be coded using the latest version of World Health 
Organization drug dictionary (WHODD B2 DEC_2016 DDE [Enhanced]) and the same version 
will be used throughout the study.  
The preferred term grouped by ATC level 4 will be used for presentation and sorted in 
descending order of frequency in total (all treatment groups together) at the top in the table. 
Prior medication, concomitant medication at randomization and onset of new concomitant 
medication after randomization during the study will be presented separately for the ITT, PP and 
the safety populations (see Section 18.12). 
ULT use, initiated after randomization in addition to the study drug will be presented per flare 
for patients in stratum ULT use=no for the ITT, PP and the safety populations (see Section 
18.14). 
13 
Study drug compliance 
Study drug compliance, calculated as percentage, i.e. actual number of syringes administered 
divided by number of syringes dispensed times 100 will be presented for each flare and overall 
by descriptive statistics (see Section 18.15). 


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14 
Efficacy analyses 
14.1 
Primary efficacy endpoint 
The primary efficacy endpoint will be analyzed using the ITT population (primary population for 
evaluation) and will be based on observed data i.e. no missing data imputation for the primary 
analysis. 
The primary endpoint is the change in patient-assessed pain intensity from baseline to 24 to 
72 hours (average of the assessments performed at 24, 48 and 72 hours) for the patients’ first 
flare (see Section 18.16 for time windows for pain intensity assessments). 
Patients will score their pain intensity in the joint most affected at baseline (i.e., the index joint) 
on a 0 to 100 VAS, ranging from no pain (0) to unbearable pain (100) (see Section 18.17).  
The comparison of primary interest is between anakinra (100 mg and 200 mg combined) and 
triamcinolone, and the null and alternative hypotheses with regard to this are defined as: 
H0: μ anakinra = μ triamcinolone  
HA: μ anakinra ≠ μ triamcinolone  
The primary endpoint will be estimated using a MMRM analysis with the measurements on the 
individual time points as responses (baseline, 6, 12, 18, 24, 48 and 72 hours), and with treatment 
(anakinra 100 mg, anakinra 200 mg and triamcinolone), ULT use (yes/no), BMI (<30.0 and 
≥30.0 kg/m2), visit and treatment-visit-interaction as fixed effects and center as random effect. 
The model is expressed as: 
yij = timej + treatk + time×treatjk + ULTl + BMIm + centern + εij 
where 
yij is the response for patient i on visit j 
timej is the visit effect (baseline, 6, 12, 18, 24, 48 and 72 hours), j=1,…, 7 
treatk is the treatment effect, k=1, 2, 3 
ULTl is the ULT strata effect (yes, no), l=1, 2 
BMIm is the BMI strata effect (<30.0, ≥30.0), m=1, 2 
centern ̴ N(0,σc2) and εij ̴ N(0,σ2) 
The analysis will be based on a restricted maximum likelihood (REML) approach. The following 
order of covariance matrices will be used until convergence is met: 
i. 
Unstructured 
ii. 
Heterogeneous Toeplitz 
iii. 
Heterogeneous first order autoregressive 
iv. 
Homogeneous Toeplitz 
v. 
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vi. 
Heterogeneous compound symmetry 
vii. 
Homogeneous compound symmetry  
Kenward-Roger approximation will be used to estimate denominator degrees of freedom and 
adjust standard errors. 
The estimated mean change from baseline to 24 to 72 hours for each treatment group (anakinra 
and triamcinolone), the estimated difference between the groups and the associated 
95 % confidence interval and p-value based on this model will be presented.  
The assumptions of normality and homogeneity of variance will be assessed by inspection of 
normal probability plots and residual plots. 
The estimated mean change from baseline to 24 to 72 hours and the associated 95 % confidence 
interval for anakinra (combined and each dose group) and triamcinolone will also be presented 
graphically. 
14.1.1 
Subgroup analyses 
In order to examine the consistency of the treatment effect, the MMRM model used for the 
primary analysis will also be used within the following subgroups, using the ITT population: 
• 
ULT usage (yes/no).  
• 
BMI (<30.0 and ≥30.0 kg/m2). 
• 
Age (<65 years and ≥65 years). 
• 
Sex (male, female). 
• 
Race (White and Other). 
• 
Renal function (eGFR category ≥90, ≥60 - <90, ≥30 - <60). 
• 
Usage of rescue medication up to 72 hours during for the first flare (yes/no). 
For each subgroup, the estimated change in pain intensity in each treatment group (anakinra and 
triamcinolone), the estimated difference in change in pain intensity between treatments and the 
corresponding 95 % confidence intervals will be obtained from the model. P-values will not be 
presented. Further, the change in pain intensity will also be evaluated for the 2 anakinra doses for 
each subgroup. 
The estimated difference in change in pain intensity between anakinra and triamcinolone and the 
corresponding 95 % confidence intervals will also be presented graphically in a forest plot. 
To avoid too small subgroups in the analysis regarding race, American Indian or Alaska Native, 
Asian, Black or African American, Native Hawaiian or Other Pacific Islander will be grouped 
together with Other. 
14.1.2 
Sensitivity analysis of the primary endpoint 
To assess the robustness of the primary analysis results and conclusions on the treatment effect 
under varying assumptions, sensitivity analyses presented in Sections 14.1.2.1, 14.1.2.2 and 
14.1.2.3 will be performed.  


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14.1.2.1 
Sensitivity to subject population 
The primary efficacy endpoint will be analyzed using an analysis identical to the primary 
analysis described in Section 14.1, but for the PP population. 
14.1.2.2 
Sensitivity to missing data handling 
The primary efficacy analysis MMRM approach assumes that the underlying missing data 
mechanism is MAR. When the assumption of missing data being MAR is valid, the treatment 
effect estimated from the MMRM analysis is unbiased. However, this assumption may not hold 
in all circumstances and the possibility that the missingness mechanism is missing not at random 
(MNAR) should be explored (EMA 2010, National Research Council 2010, Little et al 2002, 
O’Kelly et al 2014). A sensitivity analysis will be performed to assess the robustness of results 
from the primary analysis to potential deviations from the MAR assumptions. 
In this sensitivity analysis a distinction is made between intermittent missing values and 
monotone missing values. Intermittent missing values for a variable Y means that some values 
may be missing, say Yj is missing, while there are values observed for the same patient at a later 
time point, i.e. Yk is observed for some time point k > j. Patients with intermittent missing values 
are said to have a non-monotone missing data pattern. Monotone missing values are missing 
values where Yj being missing implies that all Yk, k > j, are missing for that patient. A patient 
with only monotone missing values (and no intermittent missing values) is said to have a 
monotone missing data pattern. 
In the sensitivity analysis, intermittent missing data are assumed to be MAR, while monotone 
missing values are assumed to be MNAR in the anakinra treatment groups. The analysis assumes 
that the missing outcomes on the different treatment arms vary independently, and includes 
scenarios where monotone missing values in the anakinra treatment arms have worse outcomes 
than monotone missing values in the triamcinolone treatment arm. Missing data in the 
triamcinolone group will be assumed to be MAR (intermittent as well as monotone missing 
values).  
The tipping point analysis involves multiple imputation methodology, where each of the imputed 
datasets is analysed based on the same statistical model used for the primary analysis, i.e. a 
MMRM analysis of pain intensity VAS at time points baseline, 6, 12, 18, 24, 48 and 72 hours 
based on the ITT population.  
 
Exploration of missing data patterns 
SAS PROC MI sorts the data into patterns based on whether the variables are missing or 
observed at each time point, and provides a default output dataset of missing data patterns. Mean 
pain intensity at each time point will be presented for each missing data pattern by treatment 
group. 
14.1.2.3 
Tipping point analysis  
The sensitivity analysis will be based on a tipping point approach to assess how severe the 
departures from the MAR assumption must be in order to overturn a statistical significant result 


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to a non significant result for the primary analysis. This is done by evaluating several 
assumptions for the missing data mechanism until the tipping point is reached, i.e. where the 
study’s conclusion changes. The deviation from the MAR assumption is reflected in the shift 
parameter. If the shift parameter at the tipping point is plausible the conclusions of the primary 
analysis under the MAR assumption is questionable. 
For monotone missing data, the initial shift value will be zero, which represents MAR. The shift 
will remain at zero for the triamcinolone treatment group. For the anakinra treatment groups, the 
shift will be increased, and the process repeated until the study’s conclusion changes, i.e. 
treatment effect is no longer significant.  
The following steps show the process for the tipping point analysis: 
1. Missing VAS values will be imputed based on the Markov-Chain Monte Carlo 
(MCMC) method (assuming MAR).  
In this step, 500 complete datasets will be generated.  
2. For subjects with monotone missing data in the anakinra treatment arms, monotone 
missing values will be imputed based on a MNAR model by adding a delta value to 
the MAR imputed value. Delta adjustment will be based on a scaled delta-adjustment 
approach in which the delta value added at each time point is defined as a percentage 
of the mean pain VAS at that time point.  For the the triamcinolone group monotone 
missing values, imputed based on the MAR assumption in the first step, will not be 
adjusted. 
In this step, the 500 datasets with complete data generated in step 1 will be updated. 
3. The MMRM model used in the primary analysis will be fitted to the 500  imputed 
datasets generated in step 2. As in the primary efficacy analysis, the VAS scores from 
time points baseline, 6, 12, 18, 24, 48 and 72 hours will be included as response. 
Specification of the model and the contrast of primary interest will match the primary 
efficacy analysis. From each analysis of an imputation dataset, adjusted estimates of 
means, mean treatment differences and p-values will be obtained. 
4. The results from the MMRM analyses of the 500 imputed datasets will be combined 
to obtain an overall estimate of the contrast of primary interest, i.e. the mean 
difference between the anakinra groups and the triamcinolone group in change from 
baseline to 24-72 hours in pain VAS score, as well as the p-value obtained after 
accounting for the uncertainty introduced by the missing data. 
5. Steps 2 to 4 will be repeated by gradually increasing the values for the scaled delta 
adjustment until the scaled delta value is found that gives a p-value exceeding 0.05 
(2-sided) or greater.  
In the first step of the delta-adjustment, missing values are imputed based on a MCMC method 
assuming MAR. The MCMC sampling will be performed as implemented in PROC MI in SAS. 
The MCMC method will include a single chain with a burn-in of 1000, a thinning of 100 and 
non-informative priors for all parameters. 


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Treatment group and strata (ULT usage and BMI) are included in the variable list in the MCMC 
step. In this implementation, numeric dummy variables are created and included in the variable 
list together with the VAS pain intensity variables for time points 0, 6, 12, 18, 24, 48 and 72 
hours. Because these dummy variables are observed for all patients, they are not imputed in the 
MCMC step, but contribute to the imputation model to allow for the mean pain intensity at 
different time points to depend on treatment and strata, while assuming the covariance structure 
across treatment and strata. This corresponds to the assumptions made in the analysis model used 
for the primary analysis. 
In the second step, monotone missing values in the anakinra treatment arms are delta-adjusted 
where a delta value is added to the MAR imputed value. This approach corresponds to the third 
approach for pattern imputation with delta adjustment described in Ratitch et al. (2013). 
The delta is defined in terms of percentage of the mean value at a given time point. Because the 
mean VAS pain intensity changes with time, the delta added to the MAR-imputed missing values 
will be different for different time points. Imputed values will be truncated at 100, since this is 
the maximum value possible for a VAS pain intensity measure. No rounding of values is 
performed in the imputation step. 
In the third step, the complete datasets are analysed based on the same analysis model used for 
the primary analysis. In the fourth step, results across the different imputed datasets are 
combined based on the methodology of Rubin (1976) as implemented in PROC MIANALYZE. 
Five hundred (500) imputations will be performed by using a random seed generated from the 
system clock in SAS. In the search for the tipping point, increasing values for the scaled delta 
will be investigated in steps of 5% of the time-specific mean pain intensity VAS. 
In the fifth step, when potentially a tipping point has been found, LS Mean estimates and 
treatment differences with 95 % confidence intervals and p-value will be presented in a table for 
the choice of delta-adjustment that tip over the conlusions. 
Since the tipping point analysis aims to find out how much of a change is required to “tip” the 
result from statistically significant to not statistically significant, it will not be performed for any 
comparison that is not statistically significant at the onset.  
14.2 
Secondary endpoints supporting the primary objective 
The secondary endpoints supporting the primary objective will be analyzed using both the ITT 
population and the PP population. 
14.2.1 
Patient-assessed pain intensity in the index joint on a Visual analogue 
scale (VAS)  
To further evaluate the effect of anakinra, the change from baseline in pain intensity on VAS at 
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Pain intensity on VAS will be evaluated using a mixed model repeated measures analysis similar 
to the primary analysis with the measurements on the individual time points as responses 
(baseline, 6, 12, 18, 24, 36, 48 and 72 hours and Days 5, 6, 7 and 8), and with treatment 
(anakinra 100 mg, anakinra 200 mg and triamcinolone), ULT use (yes/no), BMI (<30.0 and 
≥30.0 kg/m2), visit and treatment-visit-interaction as fixed effects and center as random effect. 
For each time point, the estimated mean change from baseline for each treatment group (anakinra 
and triamcinolone), the estimated difference between the groups and the associated 95 % 
confidence interval and p-value based on this model will be presented.  
The same order of covariance matrices as for the primary endpoint will be used, until 
convergence is met. 
Graphs will be used to visualize the mean pain intensity on VAS estimated from the repeated 
measures model at each time point for each dose group of anakinra and triamcinolone and also 
by subgroups of BMI and ULT usage.  
The observed patient-assessed pain intensity and change from baseline (VAS) in index joint at 
each time point will also be presented by descriptive statistics. 
In addition, the percent change in observed pain intensity at 24, 48 and 72 hours will be 
visualized by graphically presenting the distribution of percent improvement. For each category 
of percent improvement (x-axis), the percentage of patients who improved (y-axis) will be 
plotted. Increments of 10 % will be used for the improvement (≥10 %, ≥20 %, ≥30 %, etc). 
 
14.2.2 
Patient-assessed pain intensity in the index joint on a 5-point Likert 
scale 
To further evaluate the effect of anakinra, the change from baseline in pain intensity on the 
Likert scale at 6, 12, 18, 24, 36, 48, 72 hours and at Days 5, 6, 7 and 8 for the first flare will be 
evaluated (see Section 18.18). 
Pain intensity on the Likert scale will be evaluated using a mixed model repeated measures 
analysis similar to the primary analysis with the measurements on the individual time points as 
responses (baseline, 6, 12, 18, 24, 36, 48 and 72 hours and Days 5, 6, 7 and 8), and with 
treatment (anakinra 100 mg, anakinra 200 mg and triamcinolone), ULT use (yes/no), BMI (<30.0 
and ≥30.0 kg/m2), visit and treatment-visit-interaction as fixed effects. For each time point, the 
estimated mean change from baseline for each treatment group (anakinra and triamcinolone), the 
estimated difference between the groups and the associated 95 % confidence interval and p-value 
based on this model will be presented. 
The same order of covariance matrices as for the primary endpoint will be used, until 
convergence is met. 
Graphs will be used to visualize the mean pain intensity on the Likert scale estimated from the 
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The observed patient-assessed pain intensity and change from baseline (Likert) as well as 
observed patient-assessed pain intensity categories (Likert) in index joint at each time point will 
also be presented by descriptive statistics. 
14.3 
Secondary efficacy endpoints 
The secondary efficacy endpoints for the 1st flare will be analyzed using both the ITT population 
and the PP population. 
14.3.1.1 
Pain intensity for anakinra dose groups, 100 and 200 mg 
The primary endpoint, change in patient-assessed pain intensity as measured by VAS from 
baseline to 24 to 72 hour for the first flare, will be evaluated for the 2 different anakinra doses 
(100 mg and 200 mg) in comparison to triamcinolone.  
The effect of the 2 different anakinra doses will be evaluated using the same mixed model 
repeated measures model analysis as for the primary endpoint. The estimated mean change from 
baseline to 24 to 72 hours for each of the 2 anakinra doses (100 mg and 200 mg) and 
triamcinolone, the estimated differences anakinra 100 mg – triamcinolone and anakinra 200 mg 
– triamcinolone and the associated 95 % confidence intervals and p-values from the model will 
be presented. 
The estimated mean change from baseline for the secondary endpoints (VAS and Likert pain 
intensity at each timepoint) supporting the primary endpoint for each of the 2 anakinra doses 
(100 mg and 200 mg) and triamcinolone, the estimated differences anakinra 100 mg – 
triamcinolone and anakinra 200 mg – triamcinolone and the associated 95 % confidence intervals 
and p-values from the model will also be presented. 
14.3.1.2 
Onset of effect 
Onset of effect is defined as at least 20 % reduction from baseline pain intensity on VAS, and the 
time to onset of effect for the first flare will be analyzed using a stratified log-rank test, with 
ULT use (yes, no) and BMI (<30.0, ≥30.0 kg/m2) as stratification factors (see Section 18.19). 
Based on this model, the estimated hazard ratio (anakinra versus triamcinolone), 95 % 
confidence interval and p-value will be presented. Further, the hazard ratios for the comparisons 
of the 2 different anakinra dose groups versus triamcinolone will also be estimated, with 
corresponding 95 % confidence intervals and p-values. 
The hazard ratio and its confidence interval will be estimated based on Peto’s method: 
HR = exp(U/V) 
95 % CI for HR = (exp{U/V – 1.96/ √V}, exp{U/V + 1.96/ √V}) 
Where U =  ∑ (d1i-e1i) is the log-rank test statistic (with d1i and e1i the observed and expected 
events in group 1) and √V the SD of the log-rank test statistic as produced in the PROC 
LIFETEST output. This approach will be adapted for a stratified approach by using the U and V 
statistics obtained directly from the LIFETEST having added a STRATA term for each of the 


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stratification variables. Patients with only baseline values and patients with no values will be 
censored at baseline, i.e. will not be included in the analysis.   
Time to onset of effect will also be presented graphically for the two dose groups of anakinra and 
triamcinolone. 
In addition, the number and proportion of patients with onset of effect in the different treatment 
groups up to 6, 12, 24, 48 and 72 hours will be presented. The percentages will be based on the 
number of patients in the ITT population. 
The number and percentage of patients with and without onset of effect within 24 hours versus 
the number and percentage of patients with and without response within 72 hours will also be 
tabulated. 
14.3.1.3 
Response 
Response is defined as at least 50 % reduction from baseline pain intensity on VAS, and the time 
to response for the first flare will be analyzed using a stratified log-rank test, with ULT use (yes, 
no) and BMI (<30.0, ≥30.0 kg/m2) as stratification factors (see Section 18.20). Based on this 
model, the estimated hazard ratio (anakinra versus triamcinolone), 95 % confidence interval and 
p-value will be presented. Further, the hazard ratios for the comparisons of the 2 different 
anakinra dose groups versus triamcinolone will also be estimated, with corresponding 95 % 
confidence intervals and p-values. 
The hazard ratio and its confidence interval will be estimated based on Peto’s method (see 
Section 14.3.1.2). Patients with only baseline values and patients with no values will be censored 
at baseline, i.e. will not be included in the analysis.   
Time to response will also be presented graphically for the two dose groups of anakinra and 
triamcinolone. 
In addition, the number and proportion of responders in the different treatment groups at 24, 48 
and 72 hours, Day 8 and Day 15 will be presented. The percentages will be based on the number 
of patients in the ITT population. 
The number and percentage of patients with and without response within 72 hours versus the 
number and percentage of patients with and without onset within 24 hours will also be tabulated. 
14.3.1.4 
Resolution of pain 
Resolution of pain is defined as <10 mm in patient-assessed pain intensity on VAS, and the time 
to resolution for the first flare will be analyzed using a stratified log-rank test, with ULT use 
(yes, no) and BMI (<30.0, ≥30.0 kg/m2) as stratification factors (see Section 18.21). Based on 
this model, the estimated hazard ratio (anakinra versus triamcinolone), 95 % confidence interval 
and p-value will be presented. Further, the hazard ratios for the comparisons of the 2 different 
anakinra dose groups versus triamcinolone will also be estimated, with corresponding 95 % 
confidence intervals and p-values. 


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The hazard ratio and its confidence interval will be estimated based on Peto’s method (see 
Section 14.3.1.2). Patients with only baseline values and patients with no values will be censored 
at baseline, i.e. will not be included in the analysis.   
Time to resolution of pain will also be presented graphically for the two dose groups of anakinra 
and triamcinolone. 
In addition, the number and proportion of patients with resolution of pain in the different 
treatment groups at 72 hours, Day 8 and Day 15 will be presented. The percentages will be based 
on the number of patients in the ITT population. 
14.3.1.5 
Rescue medication 
Time to first intake of rescue medication during the first flare will be analyzed using a stratified 
log-rank test, with ULT use (yes, no) and BMI (<30.0, ≥30.0 kg/m2) as stratification factors (see 
Section 18.22). Based on this model, the estimated hazard ratio (anakinra vs. triamcinolone), 
95 % confidence interval and p-value will be presented. Further, the hazard ratios for the 
comparisons of the 2 different anakinra dose groups versus triamcinolone will also be estimated, 
with corresponding 95 % confidence intervals and p-values. 
The hazard ratio and its confidence interval will be estimated based on Peto’s method (see 
Section 14.3.1.2). Patients with only baseline values and patients with no values will be censored 
at baseline, i.e. will not be included in the analysis.   
Time to first intake of rescue medication will also be presented graphically for the two dose 
groups of anakinra and triamcinolone. 
In addition, the proportion and number of patients who took rescue medication from the first 
IMP administration up to 12 hours, >12 to 24 hours, >24 to 48 hours, >48 to 72 hours, >72 hours 
to Day 8, and >Day 8 to Day 15 in the different treatment groups will be presented. The 
proportion and number of patients with 0, 1, 2, 3 or more than 3 occasions with rescue 
medications as well as descriptive statistics for number of occasions will be presented in the 
same time intervals. Multiple occurences of rescue medication within 15 minutes will only count 
as one occurence. 
The type of rescue medication taken will also be summarized in the same time intervals per flare. 
14.3.1.6 
Patient´s assessment of global response to treatment 
Patient’s assessment of global response to treatment at 72 hours, Day 8 and Day 15 for the first 
flare will be evaluated using an analysis of variance including factors for treatment (anakinra 100 
mg, anakinra 200 mg and triamcinolone), ULT use (yes, no) and BMI (<30.0, ≥30.0 kg/m2). The 
estimated mean global response to treatment for each treatment group (anakinra and 
triamcinolone), the estimated difference between the groups and the associated 95 % confidence 
interval and p-value from the model will be presented. Further, the estimated mean global 
response for each of the 2 anakinra doses (100 mg and 200 mg), the difference of the 2 different 
anakinra dose groups versus triamcinolone will also be estimated, with corresponding 95 % 
confidence intervals and p-values. 


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The observed patient-assessed global response categories at each time point will also be 
presented by descriptive statistics. 
The cumulative proportion of patients that reach good patient’s assessed global response to 
treatment (where good response is defined as good, very good or excellent) over time will be 
illustrated graphically. 
 
14.3.1.7 
Physician’s assessment of global response to treatment 
Physician’s assessment of global response to treatment at 72 hours, Day 8 and Day 15 for the 
first flare will be evaluated using an analysis of variance model including factors for treatment 
(anakinra 100 mg, anakinra 200 mg and triamcinolone), ULT use (yes, no) and BMI (<30.0, 
≥30.0 kg/m2). The estimated mean global response to treatment for each treatment group 
(anakinra and triamcinolone), the estimated difference between the groups and the associated 
95 % confidence interval and p-value from the model will be presented. Further, the difference 
of the 2 different anakinra dose groups versus triamcinolone will also be estimated, with 
corresponding 95 % confidence intervals and p-values. 
The observed physician-assessed global response categories at each time point will also be 
presented by descriptive statistics. 
The cumulative proportion of patients that reach good physician’s assessed global response to 
treatment (where good response is defined as good, very good or excellent) over time will be 
illustrated graphically. 
14.3.1.8 
Physician’s assessment of clinical signs 
The investigator will assess the tenderness, swelling and presence of erythema in the index joint.  
Physician’s assessment of tenderness at 72 hours, Day 8 and Day 15 for the first flare will be 
evaluated using an analysis of covariance model including factors for treatment (anakinra 100 
mg, anakinra 200 mg and triamcinolone), ULT use (yes, no) and BMI (<30.0, ≥30.0 kg/m2), and 
baseline tenderness as covariate. The estimated mean tenderness for each treatment group 
(anakinra and triamcinolone), the estimated difference between the groups and the associated 
95 % confidence interval and p-value from the model will be presented. Further, the estimated 
mean tenderness for each of the 2 anakinra doses (100 mg and 200 mg), the difference of the 2 
different anakinra dose groups versus triamcinolone will also be estimated, with corresponding 
95 % confidence intervals and p-values. The observed physician-assessed clinical signs 
categories at each time point will also be presented by descriptive statistics. 
Physician’s assessment of swelling at 72 hours, Day 8 and Day 15 for the first flare will be 
evaluated using an analysis of covariance model including factors for treatment (anakinra 100 
mg, anakinra 200 mg and triamcinolone), ULT use (yes, no) and BMI (<30.0, ≥30.0 kg/m2), and 
baseline swelling as covariate. The estimated mean swelling for each treatment group (anakinra 
and triamcinolone), the estimated difference between the groups and the associated 95 % 
confidence interval and p-value from the model will be presented. Further, the estimated mean 
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anakinra dose groups versus triamcinolone will also be estimated, with corresponding 95 % 
confidence intervals and p-values. The observed physician-assessed swelling categories at each 
time point will also be presented by descriptive statistics. 
The presence of erythema at 72 hours, Day 8 and Day 15 for the first flare will be analyzed using 
a logistic regression model with treatment, ULT use (yes, no) and BMI (<30.0, ≥30.0 kg/m2) as 
explanatory variables. The proportion of patients with presence of erythema in each treatment 
group, the estimated odds ratio of anakinra to triamcinolone, the corresponding 95 % confidence 
interval and the p-value from the model will be presented. Further, the odds ratios for the 
comparisons of the 2 different anakinra dose groups versus triamcinolone will also be estimated, 
with corresponding 95 % confidence intervals and p-values. The observed physician-assessed 
presence of erythema at each time point will also be presented by descriptive statistics. 
14.3.1.9 
Inflammatory biomarkers 
The change from baseline in CRP (using the central laboratory value) at 72 hours, Day 8 and 
Day 15 will be evaluated using an analysis of covariance model including factors for treatment, 
ULT use (yes, no) and BMI (<30.0, ≥30.0 kg/m2), and baseline CRP as covariate. The estimated 
mean change in CRP for each treatment group (anakinra and triamcinolone), the estimated 
difference between the groups and the associated 95 % confidence interval and p-value from the 
model will be presented. Further, the estimated mean change in CRP for each of the 2 anakinra 
doses (100 mg and 200 mg), the estimated differences anakinra 100 mg – triamcinolone and 
anakinra 200 mg – triamcinolone, and the associated 95 % confidence intervals and p-values 
from the model will be presented. The observed CRP values at each time point will also be 
presented by descriptive statistics.  
The change from baseline in SAA at 72 hours, Day 8 and Day 15 will be evaluated using an 
analysis of covariance model including factors for treatment, ULT use (yes, no) and BMI (<30.0,  
≥30.0 kg/m2), and baseline SAA as covariate. The estimated mean change in SAA for each 
treatment group (anakinra and triamcinolone), the estimated difference between the groups and 
the associated 95 % confidence interval and p-value from the model will be presented. Further, 
the estimated mean change in SAA for each of the 2 anakinra doses (100 mg and 200 mg), the 
estimated differences anakinra 100 mg – triamcinolone and anakinra 200 mg – triamcinolone, 
and the associated 95 % confidence intervals and p-values from the model will be presented. 
The observed SAA values at each time point will also be presented by descriptive statistics. 
The evaluation of CRP and SAA at Week 12 will be presented by descriptive statistics. 
14.3.1.10 
Subsequent flares 
The evaluation of efficacy at subsequent flares will be presented by the combined anakinra 
group, the 2 different anakinra doses (100 mg and 200 mg) and triamcinolone, and by flare, i.e. 
patient’s 2nd flare, 3rd flare, etc. for the ITT population. 
Change in patient-assessed pain intensity in the index joint as measured by VAS score from 
baseline to 24 to 72 hours (average of the assessments performed at 24, 48 and 72 hours) will be 
estimated using the same mixed model repeated measures analysis as for the primary endpoint. 


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The estimated mean change from baseline to 24 to 72 hours for each treatment group (anakinra 
and triamcinolone), the estimated difference between the groups and the associated 95 % 
confidence interval will be presented for each flare. Graphs will be used to visualize pain 
intensity (VAS) at each time point for anakinra (combined and each dose group) and 
triamcinolone estimated from the repeated measures model for each flare. In addition, graphs for 
each treatment group will be used to visualize pain intensity (VAS) over time for all flares in the 
same graph. 
Patient-assessed pain intensity on VAS will be summarized by descriptive statistics for each time 
point, i.e. baseline, 6, 12, 18, 24, 36, 48, and 72 hours and Days 5, 6, 7 and 8, as well as the 
change from baseline at these time points. The presentations will be repeated for patients 2nd 
flare, 3rd flare, etc. 
Patient-assessed pain intensity on Likert will be summarized by descriptive statistics for each 
time point, i.e. baseline, 6, 12, 18, 24, 36, 48, 72 hours and Days 5, 6, 7 and 8 as well as the 
change from baseline at these time points. The presentations will be repeated for patients 2nd 
flare, 3rd flare etc. 
Further, the mean pain intensity on both VAS and Likert over time will be visualized 
graphically. For each treatment group, the mean pain intensity over time will be displayed for 
each flare.  
The number and proportion of responders in the treatment groups at 24, 48 and 72 hours, Day 8 
and Day 15 will be summarized by descriptive statistics. The percentage will be based on the 
number of patients in the ITT population that experienced the specific number of flares. 
The number and proportion of patients with onset of effect in the different treatment groups at 6, 
12, 24, 48 and 72 hours will be summarized by descriptive statistics. The percentage will be 
based on the number of patients in the ITT population that experienced the specific number of 
flares. 
The number and proportion of patients with resolution of pain in the treatment groups at 72 
hours, Day 8 and Day 15 will be summarized by descriptive statistics. The percentage will be 
based on the number of patients in the ITT population that experienced the specific number of 
flares.  
The number and proportion of patients that took rescue medication from the first IMP 
administration at Visit 1 up to and including the Day 15 visit in the treatment groups will be 
summarized by descriptive statistics. The proportion and number of occasions of rescue 
medication events and the type of rescue medication will also be presented.  
Patient’s assessment of global response to treatment at 72 hours, Day 8 and Day 15 will be 
summarized by descriptive statistics. 
Physician’s assessment of global response to treatment at 72 hours, Day 8 and Day 15 will be 
summarized by descriptive statistics. 
Physician’s assessment of clinical signs (tenderness, swelling and presence erythema) at 72 
hours, Day 8 and Day 15 will be summarized by descriptive statistics. 


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The change from baseline in CRP and SAA at 72 hours, Day 8 and Day 15 will be summarized 
by descriptive statistics. 
15 
Serum concentrations of Interleukin 1 receptor antagonist 
(IL-1Ra)/anakinra 
The serum concentration of endogenous IL-1Ra/anakinra at baseline, Day 8, Day 15, Day 28 and 
Week 12 for the first flare and subsequent flare will be presented by descriptive statistics. 
16 
Safety analyses 
The safety population is based on actual treatment during first flare and there is a risk that 
patients´ treatment at new flares differs from the first flare. Therefore the number of patients and 
the actual treatment for each of the subsequent flare will be tabulated versus the number of 
patients in the treatment groups assigned for the safety population. 
16.1 
Drug exposure 
Treatment exposure, calculated as total amount anakinra/triamcinolone given per flare in mg will 
be presented for each flare and for the whole study by descriptive statistics (see Section 18.23). 
16.2 
Adverse events 
All analyses of AEs will be based on the safety population. No hypothesis testing will be 
performed. AEs will be coded using MedDRA Version 19.1. Percentages will be based on the 
number of patients in the safety population for the specific treatment group. 
Since a subsequent flare can occur before the AE reporting period for the current flare has ended, 
the actual length of the AE reporting period can differ between patients. The actual length of the 
AE and the SAE reporting period will be presented by descriptive statistics for each flare and for 
the whole study. 
A TEAE is defined as an AE with a start date/time after the first administration of IMP and not 
after the last day of the AE reporting period for each flare. AEs with unknown start date/time 
will be assumed to be treatment emergent unless the end date/time is known to be before the first 
administration of IMP. Pre-treatment AEs will be identified as AEs with a start date/time before 
the first administration of IMP (see Section 18.24). 
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 drug withdrawn and any TEAE leading to study withdrawal 
will be summarized.  


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The number and percentage of patients with at least one TEAE will be summarized in frequency 
tables by SOC and PT. This table will be repeated by BMI (<30.0, ≥30.0 kg/m2), sex, age (<65,  
≥65 years), race, and by ethnic origin for each flare and overall. 
The number and percentage of patients with at least one TEAE will be summarized in frequency 
tables separately by day of onset: Day 1 to 5, Day 6 to 15 and after Day 15 by SOC and PT for 
each flare and overall. 
The number and percentage of patients with at least one TEAE will be summarized in frequency 
tables by PT in descending order of frequency in the combined anakinra group for each flare and 
overall. 
The number and percentage of patients with at least one TEAE will be summarized in frequency 
tables by PT, classified by maximum severity, in descending order of frequency in the combined 
anakinra group for each flare and overall.  
The number and percentage of patients with at least one TEAE will be summarized in frequency 
tables by PT, classified by relationship in descending order of frequency in the combined 
anakinra group for each flare and overall.  
The number and percentage of patients with non-serious TEAE will be presented by SOC and PT 
in descending order of frequency in the combined anakinra group for each flare and overall. 
16.2.1 
Serious adverse events 
The number and percentage of patients with serious TEAE will be presented by SOC and PT in 
descending order of frequency in the anakinra group for each flare and overall. The narratives 
will be presented in listings. 
The number and percentage of patients with at least one pre-treatment SAE will be summarized 
in frequency tables by SOC and PT. 
The number and percentage of patients with at least one SAE will be summarized in frequency 
tables separately by day of onset: Day 1 to Day 28 and after Day 28 for each flare and overall. 
16.2.2 
Adverse events leading to withdrawal 
The number and percentage of patients with TEAEs leading to study withdrawal will be 
presented by SOC and PT, in descending order of frequency in the anakinra group for each flare 
and overall. 
The number and percentage of patients with TEAEs leading to drug withdrawal will be presented 
by SOC and PT, in descending order of frequency in the anakinra group for each flare and 
overall. 
 


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16.2.3 
Deaths and other serious adverse events 
A summary of deaths and other serious adverse events will be presented in listings.  
The narratives of deaths and other serious adverse events will also be presented in listings. 
16.3 
Laboratory data 
The presentations will be based on the results from the central laboratory safety data. 
The laboratory safety data will be presented as actual values at baseline, 72 hours, Day 8 and 
Day 15 and changes from baseline at 72 hours, Day 8 and Day 15 for each flare by descriptive 
statistics. 
The number and percentage of patients with low, normal, or high laboratory values at baseline 
versus 72 hours, Day 8 and Day 15 for the first flare will be presented using shift tables. For 
subsequent flares the number and percentage of patients with low, normal, or high laboratory 
values at baseline for the flare of interest versus Day 15 will be presented using shift tables.  
The values at 72 hours, Day 8 and Day 15 versus baseline for the flare of interest for each 
laboratory parameter for each flare will be presented in a scatterplot. Side by side plots for 
anakinra (different symbols for 100 mg and 200 mg) and triamcinolone will be performed. 
Treatment emergent abnormal laboratory values will be listed. Values that are normal or high at 
baseline for each flare and shift to low at the corresponding visit, or that are normal or low at 
baseline and shift to high at the corresponding visit. 
16.4 
Vital signs 
Vital signs (blood pressure, pulse rate and body temperature) will be presented as actual values 
at baseline, 72 hours, Day 8 and Day 15 for each flare by descriptive statistics. 
Treatment emergent abnormal vital signs will be listed. Values that are normal or high at 
baseline for each flare and shift to low at the corresponding visit, or that are normal or low at 
baseline and shift to high at the corresponding visit will be listed. See Section 18.25 for 
definition of low, normal and high. 
16.5 
Electrocardiogram  
ECG results at baseline will be summarized for each flare by descriptive statistics. 
16.6 
Anti-drug antibodies  
See Section 18.25 for definitions regarding immunogenicity.  


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16.6.1 
Presence of anti-drug antibodies 
The number and proportion of patients with presence of ADA (treatment induced, treatment 
boosted or treatment unaffected), NAb and cross-reactivity at baseline, Day 8, Day 15, Day 28 
and Week 12 will be summarized for each flare. 
For patients with presence of ADA, the ADA titers at baseline, Day 8, Day 15, Day 28 and Week 
12 will be summarized by descriptive statistics for each flare. Depending on how the results are 
reported, ADA titers might be categorized as eg. low (<50), medium (>50 and <500) or high 
(>500). 
The cumulative number and proportion of ADA positive and ADA negative subjects will also be 
summarized by flare over the study. 
The number and proportion of  transient ADA positive patients, persistent ADA positive patients 
and off-treatment persistent ADA positive patients will be summarized for the whole study, 
The number of patients with occurrence of transient and persistent ADA during the study will be 
presented graphically. 
16.6.2 
Anti-drug antibodies versus safety 
AEs and SAEs will be presented by ADA positive and ADA negative patients for the whole 
study period by SOC and PT. ADA positive patients will then be further categorized in: 
1. Transient ADA positive patients. 
2. Persistent ADA positive patients. 
SAEs will be listed together with the ADA titer for the positive ADA sample taken closest 
before and after the start of the event. 
16.6.3 
Anti-drug antibodies versus efficacy 
The mean pain intensity on VAS at each timepoint up to Day 8 will be presented by ADA 
presence and by NAb presence by descriptive statistics and in graphs as applicable. The 
presentations will be repeated for each subsequent flare. ADA presence will be defined as being 
ADA positive at least once at Day 1 or Day 8; no ADA presence will be defined as being 
negative at both Day 1 and Day 8. Undetermined ADA presence is defined as both assessments 
are missing or if one assessment is negative and the other is missing. 
For subsequent flares, the ADA titer at Day 1 will be plotted against VAS at 72 hours. 
For baseline, Day 8 and Day 15, CRP and SAA will be presented by ADA presence and by NAb 
presence. The presentations will be repeated for each subsequent flare. ADA presence will be 
defined as being ADA positive at least once at Day 1, Day 8 or Day 15; no ADA presence will 
be defined as being negative at both Day 1, Day 8 and Day 15. Undetermined ADA presence is 
defined as all assessments are missing or if 1 or 2 assessments are negative and the other 
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For subsequent flares the ADA titer will be plotted against CRP and SAA at Day 1, Day 8 and 
Day 15. 
16.6.4 
Anti-drug antibodies versus serum concentration of IL-1Ra/anakinra  
If ADA are present, the relationship between ADA and ADA titer and IL-Ra/anakinra 
concentrations over time will be explored, as applicable.  Similarly the relation between presence 
of NAb and IL-Ra/anakinra concentrations over time will be explored. 
17 
Exploratory endpoints 
17.1 
Short Form (36) Health Survey (SF-36) 
Based on the SF-36 questionnaire, the patient’s score for each of the individual 8 domains as 
well as the PCS and the MCS will be calculated (see Section 18.27).  
The change from baseline in SF-36 physical functioning domain score at Day 8 for the first flare 
will be evaluated using an analysis of covariance model including factors for treatment, ULT use 
(yes, no) and BMI (<30.0, ≥30.0 kg/m2), and baseline SF-36 physical functioning score as 
covariate. The estimated mean change in SF-36 physical functioning domain score for each 
treatment group (anakinra and triamcinolone), the estimated difference between the groups and 
the associated 95 % confidence interval and p-value from the model will be presented. 
The patient’s score and the change from baseline for the 8 domains as well as the PCS and the 
MCS at Day 8 and Day 15 will be presented by descriptive statistics. 
For subsequent flares, the 8 domains from SF-36 as well as the PCS and the MCS at Day 8 and 
Day 15 will be presented by descriptive statistics. 
17.2 
EuroQol 5 dimensions 5 levels (EQ-5D-5L) 
The actual values and the changes from baseline in the 5 domains in EQ-5D, the EQ-5D-VAS 
and the EQ-5D Index at baseline, Day 8 and Day 15 for first and subsequent flares will be 
presented by descriptive statistics (see Section 18.28).  
The EQ-5D Index value will also be presented by resolution of pain until Day 8 for the first flare. 
In addition the distribution of categories in each EQ-5D domain will be presented at baseline and 
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17.3 
Work productivity and activity impairment:specific health 
problems (WPAI:SHP) 
Based on the WPAI:SHP the following scores will be calculated for Day 8 and Day 15; percent 
and actual work time missed due to gout, percent impairment while working due to gout, percent 
overall work impairment due to gout, percent activity impairment due to gout and in addition 
total work time will be calculated (see Section 18.29). 
The WPAI:SHP scores at Day 8 and Day 15 for the first flare and subsequent flares will be 
presented by descriptive statistics. 
17.4 
Health care resource utilization  
The number of days with hospitalization and the number of unscheduled outpatient visits 
(Specialist, Nurse practitioner and GP/Family Physician) from Day 1 to Day 15 for the first flare 
and subsequent flares will be presented by descriptive statistics (see Section 18.30). 
17.5 
Exploratory inflammatory biomarkers 
The actual values at all timepoints and change from baseline in exploratory inflammatory 
biomarkers in serum (IL-6, IL-8, calprotectin, MPO and neopterin) at 72 hours, Day 15 and 
Week 12 (in case of no subsequent flare prior to the Week 12 time point) for the first flare and 
subsequent flares will be presented by descriptive statistics. 
18 
Derived and computed variables 
18.1 
Unpermitted rescue medication 
Unpermitted rescue medication that leads to exclusion from PP population is defined as more 
than one incorrect intake, i.e. either type or outside time window (multiple incorrect intakes 
within 15 minutes is counted as one):  
 Unpermitted type 
o Types other than paracetamol/acetaminophen and/or codein or tramadol or rescue 
medications classified as non-medicinal products (e.g. ice/cold pack, vinegar) and 
taken between treatment start and 72 hours.  
o Glucocorticoids (from general concomitant medication and rescue medication) 
taken between treatment start and 72 hours).  
o All unresolved OTHER <72 hours.  


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 Outside time window 
o All rescue (from rescue medication) taken prior to the 24 hours VAS pain 
assessment. If 24 hours VAS pain is missing, taken within 24 hours since 
treatment start.  
o All rescue (from rescue medication) taken within 6 hours prior to the 48 hours 
VAS pain assessment. If 48 hours VAS pain is missing, taken within 42 to 48 
hours since treatment start.  
o All rescue (from rescue medication) taken within 6 hours prior to the 72 hours 
VAS pain assessment. If 72 hours VAS pain is missing, taken within 66 to 72 
hours since treatment start.  
o All rescue (from rescue medication) with a missing timestamp (date and time) 
that can be related to a flare. 
18.2 
Age 
Age will be calculated in full years without decimals, derived through the formula: 
int((input(compress(RFSTDTC, ‘-‘), best.) - input(compress(BRTHDTC, ‘-‘), best.))/10000). 
The method automatically corrects for leap days but is only correct for values without decimals. 
18.3 
Body mass index (BMI) 
BMI will be calculated as: 
BMI = weight (kg)/(height (m)*height (m)) 
18.4 
Age at diagnosis of gouty arthritis 
Age at diagnosis of gouty arthritis will be calculated in full years without decimals, derived 
through the formula: int((input(compress(MHSTDTC (where MHTERM = GOUTY 
ARTHRITIS) , ‘-‘), best.) - input(compress(BRTHDTC, ‘-‘), best.))/10000). 
Since the date of diagnosis of gouty arthritis is only collected as month and year, the day will be 
imputed as the 15th, i.e. YYYY-MM-15, in the calculation. If the month is missing, it will be 
imputed as June, i.e. YYYY-06-15. 
18.5 
Disease duration 
The disease duration (calculated in full years) is defined as: 
 If the date of diagnosis is given only as a year: year of randomization - year of diagnosis. 
 If the date of diagnosis is given as a year and a month: INT((YYYYMMrandomization - 
YYYYMMdiagnosis)/100). 


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18.6 
Start of medical and surgical history 
If the start date is missing, the medical and surgery history will be reported as started after 
randomization (first IMP injection). 
18.7 
eGFR category 
The definition of eGFR categories is presented in Table 1. 
Table 1 
eGFR categories 
eGFR categories (mL/min/1.73 m2) 
≥90 
60 to 89 
30 to 59 
15 to 29 
<15 
Abbreviations: GFR, Glomerular filtration rate. 
The eGFR will be calculated according to the MDRD (Modification of Diet in Renal Disease) 
formula: 
eGFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American). 
Where Scr is serum creatinine in µmol/L. 
18.8 
Obesity 
Obesity is defined as a BMI ≥30. 
18.9 
Cardiovascular disease 
Cardiovascular disease is defined as a history of angina pectoris or myocardial infarction. 
18.10 
Hyperlipidemia 
Hyperlipidemia is defined as Cholesterol >240 mg/dL or taking stable cholesterol-lowering 
treatments defined as ATC codes: C10, increased low-density lipoprotein levels (>160 mg/dL) , 
hypertriglyceridaemia (triglycerides >150 mg/dL), or decreased high-density lipoprotein levels 
(<40 mg/dL in male or <50 mg/dL in female). 


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18.11 
Cerebrovascular disease 
Cerebrovascular disease is defined as previous ischemic or hemorrhagic stroke, previous TIA, 
carotid or vertebral stenosis/occlusion. 
18.12 
Start of prior and concomitant medication 
If the start or end date of medication is (partly) missing so that categorization in time periods of 
medication cannot be done, the question regarding if medication was taken prior to the study will 
be used for the categorization. 
18.13 
Glucocorticoid use 
Glucocorticoid use is defined as ATC codes: H02A, H02B or M01BA. 
18.14 
ULT use 
ULT use during the study  is defined as ATC codes: M04AA, M04AB or M04AX. 
18.15 
Study drug compliance 
The first IMP injections will be given at site (one i.m. and 2 s.c. injections) at Visit 1 and drugs 
for 2 days (24 and 48 hours) will be dispensed. At Visit 2 (72 hours) the 2 s.c. injections will be 
given at site and drug will be dispensed for one additional day (Day 5). The number of syringes 
given at site, the number of days for which IMP was dispensed (2 syringes per day) and number 
of syringes returned will be recorded in the CRF. The number of syringes used at home will be 
recorded in the eDiary at 24 and 48 hours and at Day 5.  
Drug compliance will be calculated as: 
([Number of syringes dispensed – number of syringes returned]/ number of syringes 
dispensed)*100 
Number of syringes dispensed will be calculated as: 
Total number of syringes supposed to be given at site at Visit 1 (3 syringes) and Visit 2 
(2 syringes) + total number of syringes dispensed at Visit 1 and Visit 2 
Number of syringes returned will be calculated as: 
Number of unused syringes at site at Visit 1 and Visit 2 + total number of unused 
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18.16 
Time windows for pain intensity assessments (Visual analogue 
scale – VAS-  and Likert)  
The time windows presented in Table 2 are used for collecting pain assessments in the eDiary at 
the nominal times for baseline, 6, 12, 18, 24, 36, 48, 72 hours and Days 5, 6, 7,8, 9, 10, 11, 12, 
13, 14 and 15. Time for first IMP injection is time=0. For assessments where the nominal time 
would fall during the patients sleep, pain intensity was collected prior to sleep and at awakening. 
These assessments will be assigned to the nominal time if they fall within its below time-
window. 
Table 2 
Time windows for pain intensity assessments (VAS and Likert) 
 
Time window 
Nominal time 
Start time (h) 
End time (h) 
Baseline 
 
≤0 
6 h 
>0 
≤9 
12 h 
>9 
≤15 
18 h 
>15 
≤21 
24 h 
>21 
≤30 
36 h 
>30 
≤42 
48 h 
>42 
≤60 
72 h 
>60 
≤84 
Day 5 
>84 
≤108 
Each following day until Day 15 but day 15 
does not have an end. 
+24 
+24 
Abbreviations: h, hours; VAS, Visual analogue scale. 
If IMP is not taken the following rules will be used: 
 For the first flare, for patients not receiving treatment the baseline VAS pain 
measurement from their date of randomization will be used as the baseline assessment. 
 For subsequent flares, if a patient doesn’t receive treatment, the flare will not be 
accounted for. 
 
If multiple assessments fall within the same windows the following rules will be used: 
 If multiple assessments fall into the same time window, the one closest to the nominal 
time will be used. 
 If multiple assessments in the same time window are equidistant to the nominal time, the 
latest will be used. 
 If multiple assessments have the exact timestamp, an average will be used. 


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18.17 
Pain intensity on Visual analogue scale (VAS) 
The patients will score their current pain intensity in the joint most affected (i.e., the index joint) 
on a continuous 0 to 100 VAS, ranging from no pain (0) to unbearable pain (100). The original 
100 mm scale has been transferred into ePRO format and proportionally scaled down to 5 cm in 
length. The conceptual equivalency of the pen-and-paper and the ePRO format has been tested 
and is described in a Cognitive Debriefing and Usability Testing of Pain Scales for Gouty 
Arthritis Report.  
For each flare, the pain intensity will be assessed in the index joint and recorded in the patient 
diary prior to the first IMP administration. Subsequent pain assessment will be recorded in the 
patient diary at 6, 12, 18, 24, 36, 48, and 72 hours and Days 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 
15. At 24, 48, and 72 hours and Day 5, the assessments will take place just before IMP 
administration. If the time point for a specific assessment occurs during sleep, pain intensity will 
be recorded just before and after sleep, and the assessment closest to the scheduled time point 
will be used in the analysis (see Section 18.16). 
For each time point (6, 12, 18, 24, 36, 48, and 72 hours and Days 5, 6, 7 and 8), the change from 
baseline in pain intensity on VAS is defined as: 
 
VAS pain intensity at specific time point – VAS pain intensity at baseline 
18.18 
Pain intensity on Likert 
In addition to the VAS scale, the patients will score their current pain intensity in the index joint 
on a 5-point Likert scale (0 to 4 point scale: “none”, “mild”, “moderate”, “severe”, “extreme”).  
For each flare, the pain intensity will be assessed in the index joint and recorded in the patient 
diary prior to the first IMP administration. Subsequent pain assessment will be recorded in the 
patient diary at 6, 12, 18, 24, 36, 48, and 72 hours and Days 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 
15. At 24, 48, and 72 hours and Day 5 the assessments will take place before IMP 
administration. If the time point for a specific assessment occurs during sleep, pain intensity will 
be recorded just before and after sleep, and the assessment closest to the scheduled time point 
will be used in the analysis. 
For each time point (6, 12, 18, 24, 36, 48, and 72 hours and Days 5, 6, 7 and 8), the change from 
baseline in pain intensity on Likert is defined as: 
 
Likert pain intensity at specific time point – Likert pain intensity at baseline 
18.19 
Onset of effect 
Onset of effect is defined as ≥20 % change from baseline pain intensity on VAS, and time to 
onset of effect is defined as the first time point after first IMP injection when this is observed 
using all measurements at all actual timepoints. The percentage of change from baseline in pain 
intensity on VAS is defined as: 


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(VAS pain intensity at specific time point – VAS pain intensity at baseline) / (VAS pain 
intensity at baseline) 
18.20 
Response 
Response is defined as ≥50 % change from baseline pain intensity on VAS, and time to response 
is defined as the first time point after first IMP injection when this is observed using all 
measurements at all actual timepoints. The percentage of change from baseline in pain intensity 
on VAS is defined as: 
 
(VAS pain intensity at specific time point – VAS pain intensity at baseline) / (VAS pain 
intensity at baseline) 
18.21 
Resolution of pain 
Resolution of pain is defined as <10 in pain intensity on VAS, and time to resolution of pain is 
defined as the first time point after first IMP injection when this is observed using all 
measurements at all actual timepoints.  
18.22 
Time to rescue medication 
Intake of rescue medication is recorded by the patient using the eDiary: 
101 = Acetaminophen  
102 = Paracetamol  
103 = Acetaminophen/Codeine  
104 = Paracetamol/Codeine  
105 = Codeine  
106 = Tramadol  
(107 = Ice/cold-pack will not be counted as rescue in the time to rescue calculation)  
108 = Other (non medicinal products will not be counted as rescue) 
If other is selected the type will be recorded in the Rescue Medication in the eCRF. Patients still 
having insufficient relief with the rescue medication listed above after the 72 hour assessment 
are allowed to take glucocorticoids which can  be recorded in the Rescue Medication form or 
Concomitant Medication form in the eCRF. If a patient has taken glucocorticoids, but has no 
earlier intake of rescue medication from the list, the glucocorticoid intake will be counted as 
rescue. 
The date and time when the first rescue medication is taken in either system will be used in the 
calculation of time to intake of rescue medication, defined as (in hours): 
Date/time of intake of first rescue medication – date/time of intake of first IMP 
In case of incomplete or missing date and/or time for either occasion, the following rules will be 
applied: 


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• 
If the minute is missing, the time will be set to the full hour before, i.e. HH:00. If this 
imputation gives a time point that is prior to the first dose of IMP, the time will be set to 
the same time point as the first IMP injection. 
• 
If both the hour and minutes are missing, the time will be set to 00:00. 
• 
In the event of missing date, timing of rescue medication cannot be assessed and this 
recording will not be included in the analysis. 
• 
For glucocorticoids captured as concomitant medication where only date and no timing 
information is available time is set to 00:00  
 
18.23 
Drug exposure 
Drug exposure will be calculated as the total amount IMP (mg) given for each flare and for the 
total study.  
For each flare, the patient should receive 11 syringes. At Visit 1 (Day 1), 1 injection of 
triamcinolone or placebo and 2 injections of anakinra and/or placebo will be given on site and 4 
syringes of anakinra and/or placebo will be dispensed for 2 days of treatment at home at 24 and 
48 hours. At Visit 2 (Day 4), 2 injections of anakinra and/or placebo will be given on site and 2 
syringes of anakinra and/or placebo will be dispensed for 1 day of treatment at home at Day 5. 
At Visit 2 (Day 4) and Visit 3 (Day 8), unused syringes will be returned. 
For patients randomized to anakinra 100 mg, one syringe will contain 100 mg anakinra and one 
syringe will contain placebo. 
For each day, the number of used syringes will be recorded (in the CRF if on site and in the 
eDiary if at home). For anakinra, the pair of syringes are numbered 1 and 2 and is randomly 
linked to anakinra or placebo. If only a single syringe is used, its number is recorded. 
The number of dispensed syringes for use at home and the number of returned unused syringes 
are recorded in the CRF dispense log. 
Anakinra: 
 Total amount given for one flare will be calculated as number of syringes containing 
Anakinra used*100 mg. 
 If a treatment at home is not recorded in the diary but no corresponding unused syringes 
are returned, it is assumed that the syringes were used (If the number of syringes injected 
as recorded in the eDiary is less than unused syringes returned recorded in CRF dispense 
log, the number of syringes used for the flare will be updated to match the dispense log.) 
 If a patient, randomized to anakinra 100 mg, has only used a single syringe the number of 
the syringe will be taken into account, i.e. dependent on if the number is linked to 
anakinra or placebo, 100 mg or 0 mg will be used in the exposure calculation. If there is 
no information which syringe was used, it is assumed to be anakinra 100 mg. 


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Triamcinolone: Total amount for one flare is the same as the exposure at Day 1, and if dose is 
recorded as administered in the CRF the exposure is 40 mg for that flare. 
18.24 
Adverse event start/stop day 
The start day of an AE will be linked to the specific flare, and is defined as: 
Start date of adverse event – Date for 1st IMP injection for latest flare + 1 
where the date for 1st IMP injection for latest flare is based on the latest flare prior to start of the 
specific AE. 
The stop day of an AE is defined as: 
Stop date of the adverse event – Date for the 1st IMP injection for the latest flare + 1 
where the date for the 1st IMP injection for the latest flare is based on the latest flare prior to the 
start of the specific AE. 
For AEs starting within 72 hours after the 1st IMP administration for the latest flare, the start 
hour will also be calculated and is defined as: 
Start date/time hour of adverse event – Date/time hour for 1st IMP injection for latest flare 
In addition for the subsequent flares the start and stop dates will also be calculated from the date 
for the 1st IMP injection for the 1st flare. 
In case of incomplete or missing start date, the following rules will be applied: 
• 
If the day is missing, and the month and year is the same as for the date for 1st IMP 
injection for the latest flare, the start date will be set to the date for 1st IMP injection for 
the specific flare. Otherwise the date will be set to YYYY-MM-01. 
• 
If day and month are missing, and the year is the same as for the date for the 1st IMP 
injection for the first flare, the start date will be set to the date for 1st IMP injection for 
the specific flare. Otherwise the date will be set to YYYY-01-01. 
• 
If day, month and year are missing, the start date will be set to the date for the 1st IMP 
injection for the first flare, i.e. baseline visit. 
In case of incomplete or missing stop date for a resolved AE, the following rules will be applied: 
• 
If the day is missing, the stop date will be set to the last day of the month, i.e. YYYY-
MM-30/31 if this date becomes before the end of study date, otherwise the date will be 
set to end of study date. 
• 
If day and month is missing, the stop day will be set to YYYY-12-31 if this date becomes 
before the end of study date, otherwise the date will be set to end of study date. 
• 
If day, month and year is missing, the AE will be set to ongoing. 


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18.25 
Treatment emergent abnormal vital signs 
Treatment emergent vital signs are defined as: Values that are normal or high at baseline for each 
flare and shift to low at the corresponding visit, or that are normal or low at baseline and shift to 
high at the corresponding visit.  
The normal reference ranges used are: 
• 
Systolic blood pressure (mmHg): 100 to 140 
• 
Diastolic blood pressure (mmHg): 60 to 90 
• 
Pulse rate (beats/min): 50 to 90  
18.26 
Immunogenicity 
The following definitions based on Shankar et.al. (2014) will apply for this study: 
 Treatment induced ADA: de novo development following administration of IMP (i.e., 
formation of ADA any time after the initial IMP administration for the first flare in a 
patient without pre-existing ADA). 
 Treatment boosted ADA: Baseline ADA boosted to higher level following IMP 
administration (i.e., at any time after the initial IMP administration for the first flare the 
ADA titer is greater than the baseline titer by a factor of four). 
 Treatment-unaffected ADA: Baseline ADA that does not change following IMP 
administration. 
 ADA positive patient: A patient with at least one treatment-induced or treatment-boosted 
ADA positive sample at any time during the treatment or follow-up observation period. 
 ADA negative patient: A patient without a treatment induced or treatment-boosted ADA 
positive sample during the treatment or follow-up observation period. 
 Transient ADA positive patient: Patient with at least one treatment induced ADA 
positive sample after baseline and an ADA negative sample at the last sampling time 
point. 
 Persistent ADA positive patient: Patient with treatment induced ADA-positive sample at 
2 or more sequential sampling time points during the treatment including follow-up 
period and an ADA positive sample at the last sampling time point. 
 Off-treatment persistent ADA positive patient: Patient remaining ADA positive after both 
anakinra drug and any transient ADA would be expected to have cleared (16 weeks after 
last dose within a flare). ADA detected after this period should be considered persistent 
off-treatment. 
18.27 
Short Form (36) Health Survey (SF-36) 
The SF-36® Health Survey (acute Version 2) consists of 36 questions that will be scored and 
grouped into 8 health domains as well as one psychometrically-based PCS score and one MCS 
score. The calculations of the health domain scores and the PCS and MCS scores will be done 


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using the QualityMetric Health Outcomes™ Scoring Software 5.0, Version 5.0.6163.22119 
using the 2009 US Norm as well as “Maximum Data Recovery” as missing data estimation 
method. 
The 8 health domains are: 
 
Physical functioning (PF) 
 
Role-physical (RP) 
 
Bodily pain (BP) 
 
General health (GH) 
 
Vitality (VT) 
 
Social functioning (SF) 
 
Role-emotional (RE) 
 
Mental health (MH) 
For each health domain score and PCS and MCS scores, the change from baseline is defined as: 
 Domain score at specific time point – domain score at baseline 
18.28 
EuroQol 5 dimensions 5 levels (EQ-5D-5L) 
5 dimensions: The EQ-5D-5L consists of 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) each of which can take one of 5 responses. The responses 
record 5 levels of severity (no problems/slight problems/moderate problems/severe 
problems/extreme problems) within a particular EQ-5D dimension, coded as 1 to 5. 
For each dimension, the change from baseline is defined as: 
Dimension score at specific time point – dimension score at baseline 
If the score at either of the time points is missing, no change from baseline will be calculated. 
Index value: The descriptive system can be represented as a health state, e.g. health state 21143 
represents a patient who indicates slight problems on the mobility dimension, no problems on the 
self-care and usual activities dimensions, severe pain or discomfort, and moderate problems on 
the anxiety/depression dimension. These health states will be converted to a single index value 
using the existing value sets for the US.  
VAS: The patients will record their self-rated health on a 0 to 100 VAS. The change from 
baseline is defined as: 
VAS at specific time point – VAS at baseline 
If the VAS assessment at either of the time points is missing, no change from baseline will be 
calculated. 


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18.29 
Work productivity and activity impairment:specific health 
problems (WPAI:SHP) 
The WPAI:SHP contains questions related to the patients quantitative assessment of the amount 
of absenteeism, presenteeism and daily activity impairment attributable to gout. The questions in 
the WPAI:SHP records the following: 
• 
Q1 = currently employed 
• 
Q2 = hours missed from work due to specified problem (gout) 
• 
Q3 = hours missed from work due to other reasons 
• 
Q4 = hours actually worked 
• 
Q5 = degree problem affected productivity while working (score 0 to 10) 
• 
Q6 = degree problem affected regular activities (score 0 to 10) 
Based on these questions, the percentage of work time missed due to gout, percentage of 
impairment while working due to gout, percentage of overall work impairment due to gout, 
percentage of activity impairment due to gout and total work time will be derived. Calculations 
will only be performed if the patient has responses to all questions involved in a respective 
formula. If hours worked=0, productivity assessments related to work will not be calculated, 
only the percentage of activity impairment due to problem. 
Currently employed will be set to Yes if Question 1 is answered ‘Yes’, or if Question 1 is 
answered ‘No’ or missing and questions regarding hours missed or worked >0 (Questions 2, 3, 
and 4). 
Percent work time missed due to problem is defined as: 
Question 2 / (Question 2 + Question 4) 
Percent impairment while working due to problem is defined as: 
Question 5 / 10 
Percent overall work impairment due to problem is defined as: 
[Question 2 / (Question 2 + Question 4)] +  
[ (1 - (Question 2 / (Question 2 + Question 4) ) ) x (Question 5 / 10 ) ] 
Percent activity impairment due to problem is defined as:  
Question 6 / 10  
Total work time is defined as: 
Qustion 2 + Question 3 + Question 4 


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18.30 
Health care resource utilization  
At Day 8 and Day 15, patients will be asked about their unscheduled outpatient visits as well as 
days of hospitalization due to the acute gout flare during the last week. The total number of 
outpatient visits for Week 1 and Week 2, respectively, is defined as: 
No. visits to a Specialist + No. visits to a Nurse + No. visits to a Family Physician 
The total number of outpatient visits for a flare is defined as: 
Total No. visits for Week 1 + Total No. visits for Week 2 
The total number of days of hospitalization for a flare is defined as: 
Total No. days of hospitalization for Week 1 + Total No. days of hospitalization for Week 
2 
 
 
 


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19 
References 
Neogi T, et al. 2015 Gout Classification Criteria. An American College of 
Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 
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European Medicines Agency. Guideline on Missing Data in Confirmatory Clinical Trials. July, 
2010. 
Little RJA, Rubin DB. Statistical Analysis with Missing Data. 2nd Edition. New York: John 
Wiley; 2002.  
National Research Council. The Prevention and Treatment of Missing Data in Clinical 
Trials.Panel on Handling Missing Data in Clinical Trials. Committee on National Statistics, 
Division of Behavioral and Social Sciences and Education. Washington, DC: The National 
Academic Press, 2010. 
O’Kelly M, Ratitch B. Clinical trials with missing data: A guide for practitioners. 1st Edition. 
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Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga A, et al. Assessment and 
reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized 
terminology and tactical recommendations. AAPS J. 2014;16(4):658-73. 
http://www.reillyassociates.net/WPAI_General.html 
Ratitch B, O’Kelly M, Tosiello R. (2013). Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models, Pharmaceut. 
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Rubin DB (1976). Inference and missing data. Biometrika. 1976; 63(3):581-92.