Research Protocol ATTACG: Anakinra versus Treatment as usual in the Treatment of ACute Gout Version 5: 9 February 2016 Research Protocol NL52526.044.15 / ATTACG Project Information Study title: Anakinra versus treatment as usual in the treatment of acute gout Short title: ATTACG Dutch title: Anakinra versus standaardbehandeling bij acute jicht Protocol ID: NL52526.044.15 EudraCT number: 2015-000696-27 Version: 5 Date: 9 February 2016 Coordinating investigator: C.A. (Carly) Janssen MSc Principal investigator: Prof. dr. M.A.F.J. (Mart) van de Laar Multicenter research (investigator per site): 1. Medisch Spectrum Twente, Enschede ( Principal site): M.A.F.J. van de Laar & H.E. Vonkeman 2. Rijnstate, Velp: M. Janssen 3. VieCuri Medical Centre, Venlo: T. Jansen 4. Medisch Center Leeuwarden, Leeuwarden: R. Bos 5. Ziekenhuisgroep Twente, Almelo/Hengelo: H. Baan 6. Röpcke-Zweers Ziekenhuis, Hardenberg: C. Lebrun Sponsor (in Dutch verrichter/opdrachtgever): Prof. dr. M.A.F.J (Mart) van de Laar (University of Twente, UT) Subsidizing parties: ZonMw, Sobi Independent physician: Dr. W.M. Smit (Department of Internal Medicine, Medisch Spectrum Twente, Enschede) Pharmacy: Slotervaart Hospital Department of Pharmacy & Pharmacology Louwesweg 6 1066 EC Amsterdam, the Netherlands 2 Research Protocol NL52526.044.15 / ATTACG Table of Contents 1. INTRODUCTION AND RATIONALE............................................................................................................. 9 2. STUDY AIMS ........................................................................................................................................... 10 PRIMARY OBJECTIVE ............................................................................................................................................... 10 SECONDARY OBJECTIVES .......................................................................................................................................... 10 3. STUDY DESIGN ....................................................................................................................................... 11 DURATION AND DESIGN .......................................................................................................................................... 11 MULTI-CENTER RESEARCH ....................................................................................................................................... 11 COORDINATING PHARMACY ..................................................................................................................................... 11 4. STUDY POPULATION .............................................................................................................................. 12 POPULATION......................................................................................................................................................... 12 INCLUSION CRITERIA ............................................................................................................................................... 12 EXCLUSION CRITERIA............................................................................................................................................... 12 5. TREATMENT OF SUBJECTS ...................................................................................................................... 14 INVESTIGATIONAL TREATMENT.................................................................................................................................. 14 COMPARATOR TREATMENT ...................................................................................................................................... 14 NON-ACTIVE PLACEBOS ........................................................................................................................................... 14 URATE LOWERING THERAPY (ULT) ............................................................................................................................ 14 RESCUE MEDICATION ............................................................................................................................................. 14 REFRACTORY GOUT ATTACK ..................................................................................................................................... 15 6. INVESTIGATIONAL TREATMENT ............................................................................................................. 16 NAME AND DESCRIPTIVE.......................................................................................................................................... 16 SUMMARY OF FINDINGS FROM PRE-CLINICAL STUDIES ................................................................................................... 16 SUMMARY OF FINDINGS FROM CLINICAL STUDIES.......................................................................................................... 16 SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS ........................................................................................... 17 DESCRIPTION AND JUSTIFICATION OF ROUTE OF ADMINISTRATION AND DOSAGE ................................................................. 17 PREPARATION AND LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCT......................................................................... 17 DRUG ACCOUNTABILITY........................................................................................................................................... 17 7. NON-INVESTIGATIONAL TREATMENT .................................................................................................... 19 NAME AND DESCRIPTION OF AVAILABLE SOC TREATMENTS ............................................................................................. 19 Colchicine...................................................................................................................................................... 19 NSAID, naproxen........................................................................................................................................... 19 Systemic corticosteroid, prednisolon ............................................................................................................ 19 URATE LOWERING THERAPY .................................................................................................................................... 19 NON-ACTIVE SOC PLACEBOS .................................................................................................................................... 19 DOSAGE AND METHOD OF ADMINISTRATION ............................................................................................................... 19 PREPARATION AND LABELLING OF NON-INVESTIGATIONAL MEDICINAL PRODUCT ................................................................. 20 DRUG ACCOUNTABILITY........................................................................................................................................... 20 8. METHODS .............................................................................................................................................. 21 STUDY ENDPOINTS ................................................................................................................................................. 21 Primary endpoint .......................................................................................................................................... 21 Secondary endpoints of 3 month randomized controlled trial ..................................................................... 21 4 Research Protocol NL52526.044.15 / ATTACG Secondary endpoints of 9 month open label study extension ...................................................................... 21 DATA COLLECTION ................................................................................................................................................. 21 DATA COLLECTION TOOLS ........................................................................................................................................ 23 Patient numbering ........................................................................................................................................ 23 Baseline characteristics ................................................................................................................................ 23 Uric acid and CRP measurement .................................................................................................................. 23 Patient flare diary ......................................................................................................................................... 23 Patient reported outcomes (PROs) ............................................................................................................... 23 Side effects , AE and SAE .............................................................................................................................. 24 Direct and indirect costs ............................................................................................................................... 25 Study drop-out or completion....................................................................................................................... 25 DISTRIBUTION OF MEDICINES TO PARTICIPATING CENTERS .............................................................................................. 25 RANDOMIZATION, BLINDING AND TREATMENT ALLOCATION............................................................................................ 25 WITHDRAWAL OF INDIVIDUAL SUBJECTS FROM THE STUDY ............................................................................................. 26 REPLACEMENT OF INDIVIDUAL SUBJECTS AFTER WITHDRAWAL FROM THE STUDY ................................................................. 26 FOLLOW-UP OF SUBJECTS WITHDRAWN FROM STUDY .................................................................................................... 26 FOLLOW-UP OF SUBJECTS WITHDRAWN FROM TREATMENT ............................................................................................ 26 PREMATURE TERMINATION OF THE STUDY................................................................................................................... 26 9. SAFETY REPORTING................................................................................................................................ 27 SECTION 10 WMO EVENT ...................................................................................................................................... 27 SAFETY MONITORING.............................................................................................................................................. 27 AE REPORTING ...................................................................................................................................................... 27 SAE REPORTING .................................................................................................................................................... 28 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS REPORTING ................................................................................. 28 FOLLOW-UP OF AE AND SAE ................................................................................................................................... 29 ANNUAL SAFETY REPORT ......................................................................................................................................... 29 DATA SAFETY MONITORING BOARD .......................................................................................................................... 29 10. DATA ANALYSES ................................................................................................................................ 30 POPULATIONS ....................................................................................................................................................... 30 PRIMARY EFFICACY ANALYSES ................................................................................................................................... 30 MISSING DATA ...................................................................................................................................................... 31 SECONDARY ANALYSES ............................................................................................................................................ 31 SAFETY ANALYSES .................................................................................................................................................. 31 COST EFFECTIVENESS ANALYSES ................................................................................................................................ 32 SAMPLE SIZE CONSIDERATIONS ................................................................................................................................. 32 11. ETHICAL CONSIDERATIONS ................................................................................................................ 33 REGULATORY AND ETHICAL COMPLIANCE .................................................................................................................... 33 RECRUITMENT AND INFORMED CONSENT PROCEDURES .................................................................................................. 33 COMPENSATION FOR INJURY .................................................................................................................................... 33 12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .......................................................... 34 HANDLING DATA AND DOCUMENTS ........................................................................................................................... 34 MONITORING AND QUALITY ASSURANCE..................................................................................................................... 34 PROTOCOL ADHERENCE AND AMENDMENTS ................................................................................................................ 34 ANNUAL PROGRESS REPORT ..................................................................................................................................... 35 END OF STUDY REPORT............................................................................................................................................ 35 5 Research Protocol NL52526.044.15 / ATTACG PUBLIC DISCLOSURE AND PUBLICATION POLICY ............................................................................................................. 35 13. STRUCTURED RISK ANALYSIS ............................................................................................................. 36 POTENTIAL RISKS AND CONCERNS RELATED TO THIS STUDY.............................................................................................. 36 Summary anakinra and gout studies ............................................................................................................ 36 Risks and concerns related to anakinra ........................................................................................................ 36 Other risks and concerns .............................................................................................................................. 37 REDUCING AND MANAGING THE POTENTIAL RISKS AND CONCERNS ................................................................................... 37 14. REFERENCE LIST ................................................................................................................................. 39 15. APPENDICES ...................................................................................................................................... 43 I. II. III. IV. CRF INFORMATION ....................................................................................................................................... 43 PATIENT FLARE DIARY ..................................................................................................................................... 43 PROS QUESTIONNAIRES ................................................................................................................................. 43 DSMB CHARTER .......................................................................................................................................... 43 6 Research Protocol NL52526.044.15 / ATTACG List of abbreviations MSU Monosodium urate NSAIDs Non-steroidal anti-inflammatory drugs SoC Standard of Care ULT Urate lowering therapy IL Interleukin TNF Tumor necrosis factor NI Non-inferiority NVR Dutch Society for Rheumatology (in Dutch: Nederlandse Vereniging voor Reumatologie) SPC Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-tekst) IB Investigator’s Brochure METC Medical Ethical Testing Committee (in Dutch: Medisch Ethische Toetsingscommissie) RA Rheumatoid arthritis SC Subcutaneous CRP C-reactive protein AE Adverse Event SAE Serious Adverse Event HR-QOL Health related quality of life QOL Quality of life EDC Electronic data capture CRF Case report form PROs Patient Reported Outcomes NRS Numeric rating scale HAQ-DI Health Assessment Questionnaire Disability Index SF-36 Short form-36 WPAI 18 Work productivity and activity impairment questionnaire Sobi Swedish Orphan Biovitrum Ltd IMPD Investigational Medicinal Product Dossier DSMB Data Safety Monitoring Board SUSAR Suspected Unexpected Serious Adverse Reaction ITT Intent-to-treat PP Per-protocol CI Confidence interval QALDs Quality adjusted life days ICUR Incremental cost-utility ratio WMO Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch Wetenschappeljik Onderzoek) Dutch Personal Data Protection Act (in Dutch: de Wet bescherming persoonsgegevens) Wbp 7 Research Protocol NL52526.044.15 / ATTACG Summary Background: Gout is a common form of inflammatory arthropathy, with hyperuricemia being the predominant risk factor. The close relationship between gout and hyperuricemia has led to treatment strategies wherein both the acute gout flare and hyperuricemia are targeted simultaneously. Currently available treatment options for gout flares (colchicine, corticosteroids and non-steroidal antiinflammatory drugs; referred to as standard of care (SoC)) are frequently contra-indicated or poorly tolerated by gout patients due to presence of significant multi-morbidity. Anakinra (Kineret) is an IL1 receptor antagonist presently indicated for the treatment of rheumatoid arthritis (RA) and CryopyrinAssociated Periodic Syndromes. At present, anakinra has been studied in a handful of case series and small open label studies for its clinical efficacy and safety in acute gout. Objective: To demonstrate non-inferiority (NI) of anakinra compared with the SoC in the treatment of acute gout flares. Also, to compare the safety and cost per quality-adjusted life day between anakinra and SoC and to compare the 3 and 12 months clinical outcome of patients initially treated with anakinra versus SoC and starting ULT. Study design: A 3 month multi-center randomized, double (dummy)-blinded, placebo controlled NI trial, followed by a 9 month open label follow-up study. Study population: 200 patients with an acute gout flare. Intervention: Patients will be randomized to 5 consecutive days of daily a 100mg injection of anakinra + SoC pill placebo or SoC treatment + 5 consecutive days of anakinra injection placebo. SoC treatment dosage and duration is according to standard procedures. Both arms will receive urate lowering therapy according to standard procedures. Main study endpoints: The main study endpoint is the change in patient-reported pain in the index joint from baseline to the average of pain values at 24, 48 and 72 hours after initiating treatment. Secondary endpoints include (in-) direct costs, quality of life (QOL), physical functioning, treatment side effects, changes in joint swelling & tenderness, C-reactive protein (CRP), uric acid level, patient perceived treatment response and number of recurrent flares. Burden, risks and benefits: Patients will have to visit the treating rheumatologist at day 1, 7 and at month 3 during the study period. At 6 time points over the course of the study patients will have to fill in a survey questionnaire. During the first 7 days after starting the study (or by onset of a new gout attack), patients will additionally be required to fill in a survey on patient reported outcomes, medication intake and experienced side effects. Main risks associated with using anakinra are the possible physical discomfort of subcutaneous (SC) treatment injections, headache, local (skin) injection site reaction, serious (respiratory or skin) reactions, neutropenia or/and allergic reactions. Relapse of a gout flare might occur sooner in patients receiving anakinra or prednisolone compared to patients receiving prophylactics. The potential risks and concerns associated with this study are managed due to strict inclusion and exclusion criteria and the establishment of a Data Safety Monitoring Board (DSMB) and through active safety monitoring. Any remaining risks are considered acceptable since the risks are not considered severe or life threatening. 8 Research Protocol NL52526.044.15 / ATTACG 1. Introduction and Rationale Gout is a common form of inflammatory arthropathy most frequently seen in men and in women primarily after menopause (1-3). Studies in various geographic locations have shown the prevalence of gout to be increasing over time, which is frequently attributed to the increasing longevity of the population and the accumulation of gout risk factors in older age (1, 4-9). Individuals with gout often present with multiple comorbid conditions, including metabolic syndrome (including hypertension, diabetes mellitus and obesity), cardiovascular disease and kidney disease (3, 4, 10). Hyperuricemia is the predominant risk factor for gout and possibly also for many of its most common comorbidities (1). When left untreated, elevated serum uric acid levels can lead to precipitation of monosodium urate (MSU) crystals in and around the joints, initiating and stimulating a local inflammatory response. Although many individuals with chronic hyperuricemia remain asymptomatic, the risk for gout is greater than when serum uric acid levels are kept within the clinical desired range (0.30 - 0.35 mmol/L). The clinical manifestation of an acute gout flare is recognized for causing excruciating pain. It can have its onset in any joint in the body, however, primarily the lower joints in the legs are affected. The close relationship between gout and hyperuricemia has led to treatment strategies wherein both the acute gout flare and hyperuricemia are targeted simultaneously (11-13). Three standard options are available to treat pain and inflammation associated with acute gout, including colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids1. In the Netherlands, allopurinol, febuxostat and benzbromaron are currently available for the treatment of hyperuricemia by normalizing uric acid levels in the body, also referred to as urate lowering therapy (ULT). Reduction of serum uric acid levels following initiation of ULT may induce acute gout flares. To prevent the onset of these flares, NSAIDS and colchicine are, additionally, recommended as prophylactics agents when initiating ULT (14-18). Although gout is a well understood rheumatic disease, currently available treatment options are frequently contra-indicated or poorly tolerated by gout patients, which frequently presents in the presence of significant multi-morbidity. Since the discovery of the inflammasome, the crucial role of interleukin (IL) - 1 in initiating and maintaining gouty inflammation has become well recognized (3, 19). Precipitated MSU crystals at inflamed joint sites get phagocytized by macrophages or monocytes, leading to intracellular activation of the NALP3 inflammasome. This system subsequently activates caspase-1, promoting the maturation of Pro-IL-1β and extracellular excretion of pro-inflammatory IL-1β (19, 20). Secreted IL-1β then binds to the IL-1 receptor on local endothelial cells and macrophages, signaling them to produce further proinflammatory cytokines and chemokines, including tumor necrosis factor (TNF)-α, IL-6, and neutrophil chemo attractants (21). These amplify the inflammatory response, attracting other inflammatory cells, including neutrophils, into the area. For complex gout patients presenting with multiple comorbidities, IL-1 antagonists may be of great significance. In 2013, the European Medicines Agency approved the medicinal product canakinumab, a fully human monoclonal anti-human IL-1β antibody, for the treatment of acute gout flares. Due to very high costs per treatment, this agent is reimbursed only for patients with frequent gout flares (>2 per year) who cannot tolerate any of the three standard treatments, to a maximum of 2.5 Million euros per year in the Netherlands. 1 Throughout the entire protocol these standard treatment options, colchicine, NSAIDs and corticosteroids, will be referred to as standard of care (SoC) 9 Research Protocol NL52526.044.15 / ATTACG Anakinra (Kineret) is a DNA recombinant IL-1 receptor antagonist currently registered for the treatment of rheumatoid arthritis and Cryopyrin-Associated Periodic Syndromes. It acts by competitively inhibiting the binding of IL-1α and IL-1β to IL-1 type I receptors, causing the biological activity of these interleukins to be neutralized. The clinical efficacy and safety of anakinra in acute gout have been investigated and reported on in a few case series or small open label studies (22-36). Although these studies provide a proof of concept for the plausibility and clinical importance of anakinra as a treatment option for acute gout, no large scale clinical trial has yet been performed. The primary goal of the proposed study is to demonstrate the non-inferiority (NI) of anakinra versus treatment as usual in patients with acute gout. Secondary goals are to compare the cost-effectiveness of anakinra to treatment as usual, to evaluate the safety of anakinra and to compare the 3 and 12 months clinical outcome of gout patients initially treated with anakinra or treatment as usual starting ULT. 2. Study Aims Primary objective To demonstrate the NI of anakinra compared with the SoC in the treatment of acute gout flares. Secondary objectives To compare the cost per quality-adjusted life day between anakinra and SoC. To evaluate the safety of anakinra in the treatment of acute gout flares. To compare the 3 and 12 months clinical outcome of patients initially treated with anakinra versus SoC and starting ULT. 10 Research Protocol NL52526.044.15 / ATTACG 3. Study Design Duration and design The total study duration is 12 months. The initial 3 month study is a multi-center randomized, double (dummy)-blinded, placebo controlled NI trial, followed by a 9 month open label extension study. 200 patients with crystal proven acute gout will be randomly allocated in the ratio 1:1 to either 1) 5 consecutive days of 100 mg daily anakinra injection and SoC pill placebo or 2) one of the SoC treatment options and 5 consecutive days of 100 mg anakinra injection placebo. SoC treatment allocation, dosage and duration are in line with the national guidelines for gout setup by the Dutch Society of Rheumatology (Dutch: Nederlandse Vereniging voor Reumatologie, NVR) (16). In line with these guidelines, when tolerable, patients will be appointed SoC treatment with colchicine or NSAID which will then be continued prophylactically for 90 days when initiating ULT. Patients in both arms will also receive ULT according to recommendations as stated in the national guidelines for gout by the NVR (16). Multi-center research Subjects will be included into the study by rheumatologists working in different medical centers in the Netherlands. Between 4-8 centers will participate in this study. General practitioners in the region of the participating medical centers will be informed and asked to refer patients with suspected gout to the closest study center. Coordinating pharmacy The following pharmacy will function as pharmacy for the production, labelling and distribution of study medicines in this study: Slotervaart Hospital Department of Pharmacy & Pharmacology Louwesweg 6 1066 EC Amsterdam, the Netherlands 11 Research Protocol NL52526.044.15 / ATTACG 4. Study Population Population The study population will include both male and female patients with an acute gout flare. Inclusion criteria In order to be eligible to participate in this study, a subject must meet all of the following criteria: At least 18 years of age Signed written informed consent Identification of intracellular MSU crystals in primary joint through aspiration of joint Exclusion criteria A potential subject who meets any of the following criteria will be excluded from participation in this study in case of: Absolute contra-indication for all available types of ULT (allopurinol, febuxostat and benzbromaron) Contra-indications allopurinol: Hypersensitivity to the active substance or to any of the excipients (see for the excipients the official SPC for the brand given). Contra-indications febuxostat: Hypersensitivity to the active substance or to any of the excipients (see for the excipients the official SPC for the brand given). Contra-indications benzbromaron: Hypersensitivity to the active substance or to any of the excipients (see for the excipients the official SPC for the brand given). Patients with known liver disease. Concomitant use of hepatotoxic drugs, particularly antituberculosis agents. Hepatic porphyia. Severe renal impairment (clearance < 30 ml/min.). Patients with secretion of urate higher than 700 mg/24 hours (= 4.2 mmol/24 hour). Urolithiasis. Acute gout flare Absolute contra-indication for anakinra Contra-indications anakinra: Hypersensitivity to the active substance or to any of the excipients (citric acid anhydrous, sodium chloride, disodium edetate dihydrate, polysorbate 80, sodium hydroxide, water for injections) or to E. coli derived proteins. Kineret must not be used in patients with severe renal impairment (creatinine clearance rate < 30 ml/minute). Kineret treatment must not be initiated in patients with neutropenia (absolute neutrophil count <1.5 x 109 /l). Presence of liver disease that according to the treating physician precludes participation in the study Absolute contra-indication for all three of the possible SoC treatments (colchicine, naproxen, prednisolon) Contra-indications colchicine: Hypersensitivity to the active substance or to any of the excipients (microcrystalline cellulose (E460), lactose, sodium carboxy starch, magnesium stearate (E470b)). Women of childbearing age, unless effective contraceptive measures are taken. Colchicine should not be used in patients with severe renal impairment or severe hepatic impairment. Contra-indications naproxen: Hypersensitivity to the active substance or to any of the excipients (potato starch, lactose, hydroxypropyl cellulose (200 CP), magnesium stearate, colloidal anhydrous silicon dioxide). Naproxen is contra-indicated in patients who have 12 Research Protocol NL52526.044.15 / ATTACG previously shown allergic reactions (e.g. asthma, rhinitis or urticaria) in response to acetylsalicylic acid or other prostaglandin-synthesis inhibitors. Severe anaphylactoid reactions have been reported in these patients. In principle, naproxen must not be administered to patients with gastrointestinal ulcerations, congestive gastritis or atrophic gastritis, gastrointestinal bleeding or other bleeding such as cerebrovascular bleeding. Severe renal impairment. Contra-indications prednisolon: Hypersensitivity to the active substance or to any of the excipients (lactose, magnesium stearate (E470b), silicon dioxide (E551), potato starch, pregelatinized potato starch, sodium (potato) starch glycolate, magnesium stearate (E572), erythrosine (E127)). Gastric and duodenal ulcers. Acute infectious processes, particularly viral infections and systemic fungal infections. Tropical worm infections. Administration after vaccination with a live attenuated virus. Ocular herpes simplex. Known history of allergy or sensitivity to latex Current use of any ULT (ULT therapies are allopurinol, febuxostat and benzbromaron) Concurrent use of other IL-1 agents (to this category belong: canakinumab and rilonacept) Patient reports no to mild gout related pain Pregnancy or lactation Women who are planning on becoming pregnant within the study period (12 months) Patients with active or recurrent bacterial, fungal or viral infection Patients using TNF inhibitors (to this category belong: Certolizumab, Golimumab, Adalimumab, Etanercept, Infliximab) Patient has insufficient knowledge of the Dutch language for completing questionnaires independently 13 Research Protocol NL52526.044.15 / ATTACG 5. Treatment of subjects Investigational treatment Patients allocated to the investigational treatment group will receive Kineret (active substance anakinra). For specific information regarding the product characteristics, safety, therapeutic indications, dosage and duration, etcetera, please see Chapter 6: Investigational treatment of this protocol. Comparator treatment Subjects allocated to the active comparator group will receive colchicine, naproxen (NSAIDS) or prednisolon (systemic corticosteroids). These treatments are standard medicinal products currently registered for treating acute gouty arthritis. Per specific case, the treating rheumatologist will decide on the SoC treatment the patient may receive, according to their medical history, contraindications, intolerances, etcetera. This is in line with the guidelines for gout treatment as setup by the NVR (16). All the participating centers will receive medication for all three of the SoC treatments, making the rheumatologists free to choose the best tolerable SoC treatment for the patient. For specific information (e.g. dosage and duration) on the standard treatments, please see Chapter 7: Noninvestigational treatment of this research protocol. Non-active placebos To ensure blinding, patients will receive non-active placebos. Subjects in the investigational anakinra treatment group will receive a non-active placebo resembling the SoC treatments. Subjects in the comparator group will receive a non-active anakinra injection placebo (NaCl 0.9%, 0.67 ml) resembling the anakinra treatment injection. For details on the blinding of study medication see Chapter 8: Methods, section Randomization, Blinding and treatment allocation of this research protocol. Urate lowering therapy (ULT) All subjects included in either treatment arm will start ULT at baseline. ULT is part of standard prophylaxis in the treatment of recurrent acute gout flares according to the NVR treatment guidelines for gout (16). When tolerable, Patients will be appointed ULT with allopurinol When allopurinol cannot be tolerated, alternatively benzbromaron or febuxostat will be appointed. Please see Chapter 7: Noninvestigational treatment of this research protocol for further details. Rescue Medication No rescue medication will be prescribed during the first 7 days after starting the study (baseline – day 7). Patients may use over the counter medicines as NSAIDs and acetaminophen during this time. Patients will be asked to report the use of any over the counter medicines, as well as other medication in the patient flare diary. During the rest of the study period, patients can use over the counter medication and will be asked to rapport the use in the flare diary during the occurrence of refractory gout attacks. 14 Research Protocol NL52526.044.15 / ATTACG Refractory gout attack Patients will return to their treating rheumatologist 7 days after starting the study medication for their initial acute gout flare. In case of an ongoing or new gout flare between day 7 until the end of the study, the treating rheumatologist will decide on the gout treatment to give the patient. Treatment options will be according to standard clinical care. Anakinra treatment will not be available as treatment option for refractory gout attacks. Patients will be instructed to contact their treating rheumatologist in case a new gout flare arises during the study period. The treating rheumatologist can, together with the sponsor, decide if breaking the treatment randomization code is needed in order to provide the best optimal care for the patient. 15 Research Protocol NL52526.044.15 / ATTACG 6. Investigational treatment For a detailed description of the investigational product characteristics, therapeutic indications, dosages, pharmaceutical properties, side effects, etcetera, please see the Summary of Product Characteristics (SPC) and Investigator’s Brochure (IB) submitted as part of the dossier for the Medical Ethical Testing Committee (in Dutch: Medisch Ethische Toetsingscommissie, METC). A short summary of general information regarding anakinra and studies with anakinra for gout is given below. Name and descriptive Kineret contains the active substance anakinra. It is a recombinant, nonglycosylated form of the human IL-1 receptor antagonist (r-metHuIL-1ra). Besides the inclusion of a single methionine residue at its amino terminus, it is identical to the naturally present human IL-1 receptor antagonist. Anakinra is produced by means of recombinant DNA technology in Escherichia coli cells. Currently, Kineret is registered for treating adults with signs and symptoms of rheumatoid arthritis (RA) and for cryopyrinassociated periodic syndromes. Summary of findings from pre-clinical studies Pre-clinical information regarding anakinra is listed in the SPC. One animal study has been done with anakinra and gout by So et al. 2007 (34). The effectiveness of IL-1 inhibition in relieving inflammatory manifestations associated with gout was studied in in-vivo MSU crystal-induced inflammation BALB/c mice. The mice were given anakinra injections, anti-IL-1R1 monoclonal antibodies or anti-TNF monoclonal antibodies and the level of neutrophil recruitment was determined. Both anakinra and the anti-IL-1R1 monoclonal antibody showed comparable inhibitory effects on neutrophil recruitment. The results were statistically significant compared to a positive MSU control. Summary of findings from clinical studies In total, the clinical effectiveness of anakinra in gout has been documented in 15 case reports and/or series and 1 small open-label study (updated 20 March 2015) (22-37). The patients included in these studies were all complex gouty arthritis patients with severe comorbidities and/or intolerance to conventional therapies. Treatment with anakinra was, therefore, used as an alternative agent. In the 15 case reports and/or series, anakinra demonstrated to rapidly and effectively alleviate the pain associated with gout in the majority of the patients. Dosage regimes differed between patients, with some taking 100 mg anakinra daily for three consecutive days, whilst others took anakinra daily or every other day for up to six months. In this population, observed side effects included one injection site reaction, neutropenia in another patient, one case of leukopenia, seven infectious complications and twice the occurrence of a H1N1 Influenza infection after initiating anakinra therapy. One critically ill case developed an infectious complication (herpes zoster) one day after completing a 6-day anakinra treatment, possibly related to the anakinra treatment. One patient developed a postoperative wound infection, whereby the site was possibly already infected before anakinra treatment was initiated. Four patients could not discontinue anakinra treatment without getting an acute flare within several days after stopping. One open-label clinical trial has been documented, including 10 patients taking 100 mg subcutaneous (SC) anakinra for 3 consecutive days (34). Patients responded rapidly to anakinra, with the most rapid onset observed within 24 hours. The subjective symptoms of gout were greatly relieved 48 hours after the first injection in all patients. No side effects were observed during the study period, 16 Research Protocol NL52526.044.15 / ATTACG and there were no infectious complications. Only one patient had a minor flare at one month followup. For anakinra in gout, no randomized-controlled clinical trials have been reported. In general, the documented studies show the possible efficacy of anakinra for the treatment and rapid relief of acute gout flares in severe and complex comorbid gout patients, not able to take or tolerate conventional therapies. Summary of known and potential risks and benefits The potential risks associated with using anakinra for the treatment of acute gouty arthritis are: Physical discomfort of SC treatment injection Local (skin) injection site reaction (pain, inflammation, erythema, or ecchymoses) Serious infections (respiratory and skin infections, Influenza infections) Allergic reaction and anaphylaxis (angioedema, urticarial and pruritus) to anakinra or other constituents, including latex Decreased neutrophil count, leading to neutropenia Drug interaction between ULT and anakinra Elevated levels of liver enzymes Gastrointestinal disturbances related to liver disorders (yellow skin and eyes, nausea, loss of appetite, dark-colored urine, light-colored stools) Headaches The potential benefits associated with the use of anakinra for the treatment of acute gout arthritis are alleviation of inflammation, pain and disease burden. Description and justification of route of administration and Dosage Active and placebo Kineret will be administered by SC injection once daily. Each syringe contains 100mg anakinra or non-active anakinra (NaCL 0.9%, 0.67 ml) placebo. The route of administration will be identical to current standard procedures applied for RA patients. To prevent and avoid discomfort at the site of injection, it is recommended to change the injection site location regularly. Current recommendations as listed in the SPC for the method of administration for anakinra, will also be applicable and followed in this study. Preparation and labelling of investigational medicinal product Finished products of anakinra and anakinra placebo injections will be delivered by Swedish Orphan Biovitrum AB (Sobi) to the coordinating pharmacy before the start of the study. The coordinating pharmacy is responsible for preparing and re-labeling these medicinal products. During preparation and labeling of anakinra and anakinra placebos, the coordinating pharmacy will comply with the GMP guidelines. Drug accountability The allocation of anakinra and anakinra placebo to the local pharmacy of each participating sites will be done under strict supervision of the central coordinating pharmacy and the proper environmental settings. The study medication will be delivered to, accepted by and stored at the local pharmacy of each participating site. The nurse/treating rheumatologist is responsible for retrieving these packages 17 Research Protocol NL52526.044.15 / ATTACG and handing these over to the patient or the patient can retrieve the medication package and return to the treating rheumatologist/nurse who will further guide the patient. If during the trial any of the products are not fit for use or are not being used, these will be retoured to the central coordinating pharmacy and replaced if needed and possible. The treating rheumatologist/nurse should together with the local pharmacy ensure proper sending of the unusable medication to the coordinating pharmacy in case of retouring products. 18 Research Protocol NL52526.044.15 / ATTACG 7. Non-investigational treatment Name and description of available SoC treatments Colchicine Colchicine is indicated for treating acute gouty arthritis in patients who cannot tolerate, or who have contra-indications for, NSAIDs. It is also used as a prophylaxis for gout flares when initiating ULT in patients who cannot tolerate, or who have contra-indications for, NSAIDs. NSAID, naproxen Therapeutic indications for naproxen include many inflammatory musculoskeletal diseases, including gouty arthritis. Naproxen is a prostaglandin synthetase inhibitor and belongs to the group of NSAIDs, which are used to control pain and inflammation. Systemic corticosteroid, prednisolon Prednisolon is used to treat rheumatic conditions and other bodily disorders. Prednisolon is a corticosteroid which primarily acts as a glucocorticosteroid. The therapeutic effect of glucocorticosteroids is mostly through two mechanisms; an anti-inflammatory or immunosuppressive (anti-allergic) mechanism. Urate Lowering Therapy Different ULT treatments are available; allopurinol, febuxostat and benzbromaron. All are aimed at lowering the urate/uric acid levels in the blood serum, however, the mechanism of action differs between the three. Allopurinol and febuxostat work by inhibiting the action of the enzyme xanthine oxidase, which plays a role by the conversion from hypoxanthine into uric acid. Benzbromaron acts as a uricosuric agent, which causes the excretion of uric acid in the urine to be increased. Non-active SoC placebos Oral SoC placebo medication will be provided in capsules, identical in size, shape color and appearance to the active SoC treatment. For details about the blinding of study medication, see Chapter 8: Methods, section Randomization, Blinding and treatment allocation. Dosage and method of administration For all SoC treatments and placebos and ULT treatments, the dosage, duration and method of administration will be in line with the Gout Guidelines of the NVR and standard care procedures (16). For colchicine (placebo) this is 3 daily dosages of 0.5 mg for 90 days, for naproxen (placebo) twice a day 500 mg for 90 days and for prednisolone (placebo) 35 mg daily dosage for 5 days. Colchicine and naproxen will be continued for 90 days as these are given as prophylaxes when initiating ULT. Patients receiving naproxen will be prescribed antacids in line with the standard procedure when receiving NSAID for longer periods of time. For ULT treatment the first choice will be allopurinol 100 mg daily for 1 week followed by 300 mg. Alternatively benzbromaron or febuxostat will be used. Dosage will be adjusted according to treating to target of urate serum concentration below 0.30 mmol/L. ULT will be initiated at baseline. 19 Research Protocol NL52526.044.15 / ATTACG Preparation and labelling of non-investigational medicinal product The central coordinating pharmacy will ensure the proper number of SoC treatments and placebos will be acquired before the start of the study. During the preparation and labeling of SoC treatment and SoC placebos the coordinating pharmacy will comply with the GMP guidelines. Drug accountability The allocation of SoC and SoC placebo to the local pharmacy of each participating sites will be done under strict supervision of the central coordinating pharmacy and the proper environmental settings. The study medication will be delivered to, accepted by and stored at the local pharmacy of each participating site. The nurse/treating rheumatologist is responsible for retrieving these packages and handing these over to the patient or the patient can retrieve the medication package and return to the treating rheumatologist/nurse who will further guide the patient. If during the trial any of the products are not fit for use or are not being used, these will be retoured to the central coordinating pharmacy and replaced if needed and possible. The treating rheumatologist/nurse should together with the local pharmacy ensure proper sending of the unusable medication to the coordinating pharmacy in case of retouring products. 20 Research Protocol NL52526.044.15 / ATTACG 8. Methods Study endpoints Primary endpoint Change in patient-reported pain in the index joint from baseline to the average of pain values at 24, 48 and 72 hours Secondary endpoints of 3 month randomized controlled trial Time to 50% reduction in pain in the primary affected joint Time to remission of pain Time to first reoccurrence of flare number of new flares Decrease of primary joint swelling according to patient across day 2-5 Decrease of primary joint tenderness according to patient across day 2-5 Decrease in C-reactive protein (CRP) levels after 7 days of treatment Decrease of serum uric acid concentration after 3 months Treatment response according to patient across day 2 -7 % dropout due to adverse events (AE) % dropout due to serious adverse events (SAE) physical function Health related quality of life (HR-QOL) Experienced side effects Direct and indirect costs Secondary endpoints of 9 month open label study extension Time to first reoccurrence of flare number of new flares % patients starting with canakinumab treatment % patients with serum uric acid concentration ≤ 0.36 mmol/l Physical function HR-QOL Experienced side effects Direct and indirect costs Data collection All data will be collected using an electronic case report form (CRF). The electronic data capture (EDC) system used is ROMA2, currently also being used for different clinical trials within the field of rheumatology. Within ROMA2 a study specific template will be developed. All data will be collected and entered by the participating sites directly into the EDC system. The sites will be fully trained for using the EDC system. The data which is to be collected from the patients directly (e.g. questionnaires) will also be collected using the EDC system. The data will be saved in a secure database. 21 Research Protocol NL52526.044.15 / ATTACG Patient data collection and follow-up will take place at baseline, days 2-7, month 3 and thereafter at month 6, 9 and 12. In case of recurrence of gout flares, patients are asked to contact the treating rheumatologist and to keep a flare diary for 7 consecutive days. Treating rheumatologists are asked to document any side effects, AE and SAE in the CRF. Decisions regarding treatment of recurrent flares are at the discretion of the attending physician and the patient. See schedule below for follow-up moments: Table 1. Patient follow-up scheme. Baseline (day 1) Eligibility criteria (e.g. aspiration of joint fluid) Informed consent Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Month 3 followup (month 6, 9) Study end (month 12) X X Demographics X Patient medical status X Serum uric acid X X X X* X* CRP level X X X X* X* Flare diary X Physical functioning X X X X X HR-QOL X X X X X Work productivity & health care volumes X X X X X X X AE and SAE Onset new flare X X X X X X X X Study dropout/ X** completion * Laboratory results that become available during the routine clinical care during the course of the study will be collected. **Patients lost during follow-up will be recorded in the CRF 22 Research Protocol NL52526.044.15 / ATTACG Data collection tools Patient numbering Each patient is identified by a unique 5 character patient identification number, assigned by the EDC system. The first two numbers will index the center number at which the patient is included and the final three numbers index the patient’s order of inclusion at the study site. Baseline characteristics At baseline, demographic characteristics including sex, age, weight, length, blood pressure will be collected. A patient medical status including gout status, comorbidities and other medication usage will also be obtained at baseline and updated throughout the study. Whether the patient entered the study through primary or secondary health care will also be noted. See Appendix I for the specific CRF information gathered by the treating rheumatologist. Uric acid and CRP measurement At baseline, serum uric acid and CRP level will be determined. During the course of the study, CRP and serum uric acid levels will be recorded according to the data collection scheme in Table 1. Whenever laboratory results on CRP levels and serum uric acid levels become available during routine/regular clinical care, these results will also be collected during the course of this study. Patient flare diary A digital (or if needed pen and paper) flare diary will be filled in at home during the occurrence of acute gout flares for 7 consecutive days upon flare onset. The following will be recorded daily: pain intensity, swelling, tenderness, treatment response, global assessment of overall wellbeing, study medication intake, other medication intake and experienced side effects. The side effects will be reported to the treating rheumatologist, who will register these effects along with potential AE and SAE. Study medication intake will be noted for determining the compliance of patients to the study medication. See Appendix II for the patient flare diary. Patient reported outcomes (PROs) PROs will be measured using standardized instruments available, at baseline and during follow-up according to the data collection scheme in Table 1. PROs are made available to the patients on the computer and if needed a paper and pencil version will be available as well. The patient reported domains measured are pain intensity, amount of swelling, tenderness of joint, treatment response, physical functioning, health related quality of life, work productivity. See for all PROs questionnaires and flare diary Appendix III and II. Below a specific explanation of the specific tool used to measure each specific PRO: Pain intensity: Pain intensity at the primary joint during treatment follow-up time will be assessed using a 5-point Likert scale (1 = none; 2 = mild; 3 = moderate; 4 = severe; 5 = extreme) and a 100mm visual analog scale (0 = no pain, 100 = worst imaginable pain). Also a numeric rating scale (NRS) will be used to measure pain intensity (0 = no pain at all until 10 = worst imaginable pain). 23 Research Protocol NL52526.044.15 / ATTACG Swelling: The amount of swelling of the primary joint will be measured using a 5-point Likert scale (1 = none; 2 = mild; 3 = moderate; 4 = severe; 5 = extreme). Tenderness: The tenderness of the primary joint will be determined using 5-point Likert scale (1 = none; 2 = mild; 3 = moderate; 4 = severe; 5 = extreme). Treatment response: Treatment response according to the patient will be assessed using a 9point Likert scale (1=fully disappeared; 2=very much improved; 3=much improved; 4=slightly improved; 5=no changes; 6=slightly worse; 7=much worse; 8=very much worse; 9=not applicable). Global assessment of overall wellbeing: The global assessment of overall wellbeing will be assessed using a 10 point NRS (0 = worst imaginable health until 10 = best imaginable wellbeing). Physical functioning: Disability will be assessed using the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) (38). HAQ-DI assesses disability using 20 questions regarding dressing and grooming, arising, eating, walking, hygiene, reach, grip and activities. Individual item scores can be adjusted for the use of aids or help from others in completing the activities referred to in the item. Category scores represent the highest individual item score in each category and an overall disability score is obtained by averaging the category scores. Higher scores indicated more disability. HR-QOL: HR-QOL will be assessed using the medical outcomes survey short form 36 (SF-36) (39). The SF-36 assesses the 8 HR-QOL domains of: bodily pain, physical role function, physical function, general health, emotional role function, vitality, and social function. For each domain a summary score is obtained ranging from 0-100, with higher scores representing better health. Work productivity and health care volumes: Work productivity will be assessed using the Work Productivity and Activity Impairment Questionnaire (WPAI) (40). The WPAI includes questions about employment: time lost from work, reduced productivity at work and reduced productivity while engaged in regular activities in the previous week. Patients will also be asked to report the volume of hospital related care using a standardized questionnaire. Side effects , AE and SAE Side effects, AEs and SAEs will be obtained during follow-up according to the data collection scheme in Table 1. Patients are asked to report any side effects experienced in the daily flare diary and subsequently report this to their treating rheumatologist at follow-up moments. At each visit rheumatologists will be requested to state whether or not patients experience specific side effects potentially related to IL-1 suppression including: serious infections, malignancy, opportunistic infections, drug induced liver injury, major adverse cardiovascular events, severe injection site reactions, AEs related to immunogenicity/allergincity, worsening uric acid levels, disorders of lipoprotein metabolism, worsening kidney function, potential vaccine interactions and pregnancy. All AE – including SAE irrespective of causality and safety endpoints (where relevant) – will be collected and recorded in the CRF, irrespective of causal association. If an AE or SAE occurs in between followup moments this should be reported to the treating rheumatologist and be reported in the CRF. Patients can report side effects through the online web portal. For details regarding the safety monitoring during this study, see Chapter 9: Safety reporting, section Safety monitoring of this protocol. 24 Research Protocol NL52526.044.15 / ATTACG Direct and indirect costs The direct and indirect costs will be calculated from the work productivity and health care volumes questionnaire filled in by the patient. Volumes of hospital related care, i.e. consultations with the rheumatologist and the rheumatology nurse, hospital admissions, as well as medication use (exact dose of gout medication and administration period) will be prospectively registered in the electronic CRF. Direct costs will be calculated by multiplying volumes of care by their respective costs. The standard cost prices from the 2016Dutch Guideline for Cost Analyses will be used for hospital related care. Cost prices for medication will be retrieved from the 2016 Dutch national tariff list provided by the Dutch Board of Health Insurances. Study drop-out or completion Information about patients that decide to stop with the study prematurely will be documented in the CRF. In the CRF will be noted when a patient has completed the study. Distribution of medicines to participating centers The distribution of the study medication to each of the participating sites will be done in 2 shifts. The first shift will consist out of small batches and aims to determine the speed of inclusion at each participating site. Depending on these findings, the study medication will be allocated a second time. The central coordinating pharmacy is responsible for proper distribution of the study medication to each site, including the proper environmental settings (e.g. temperature). The study medication will be delivered to and accepted by the local pharmacy of each participating site. The study medication will be stored at the local pharmacy of the participating site. Randomization, blinding and treatment allocation Patients will be asked to participate in this study, be given additional information and asked informed consent by their treating rheumatologist. At times, a research nurse can give additional information or ask for patient informed consent when asked to do so by the rheumatologist. When patients have signed the written informed consent, the treating rheumatologist will give the patient a prescription wherein states which one of the three SoC treatments the patient can be given. As the packages are stored at the local pharmacy, the patient self or the nurse/treating rheumatologist can retrieve these packages and hand it over to the patient. Depending on the tolerable SoC treatment, patients will be appointed randomly to either the anakinra treatment or the patients’ tolerable SoC treatment. The randomization is based on a previous computer-generated randomization list (anakinra or SoC) per SoC treatment. No stratification will be carried out. When the patient has received the medication package he/she will be instructed by the nurse on how to properly inject themselves with the syringe as well as other baseline characteristics will be gathered. The research nurse will register the new patient in the EDC, which will assign the patient an automated unique 5 character patient identification number. See Chapter 8: Methods, section Patient numbering for details regarding this number. The treatment packages will also each be identified by a number, which will be linked to the patient identification number in the EDC. Each treatment package will contain either anakinra injections along with the tolerable SoC placebo medication, or anakinra placebo injections with the tolerable active SoC treatment. Oral SoC medication and placebos will be provided in capsules, identical in size, shape color and appearance. For details on SoC treatments and placebos see the Investigational Medicinal Product 25 Research Protocol NL52526.044.15 / ATTACG Dossier (IMPD) submitted as part of the dossier for the METC. Anakinra and anakinra placebo are a solution for injection, available in pre-filled syringes ready for SC use. Treating rheumatologists/nurses do not have access to the randomization (treatment) code except in case of a SAE and/or SUSAR. In this case, the code may be broken only in circumstances when knowledge of the study medication is essential for treating the patient. In case of a SAE or SUSARs, the local responsible investigator will contact the sponsor directly (see Chapter 9: Safety Reporting, section SAE reporting). The sponsor and local head investigator will together decide if the code needs to be broken. If needed, the sponsor may contact the Data Safety Monitoring Board (DSMB) for further advice regarding the specific matter. Withdrawal of individual subjects from the study Subjects are free to quit the study at any time for any reason if they wish to do so without any further consequences to their medical treatment. The treating rheumatologist and/or study investigator can decide to withdraw a subject from the study for urgent medical reasons or because of serious protocol violation. Replacement of individual subjects after withdrawal from the study If subjects are withdrawn from the study, no replacement of the subject will occur. In the total sample size calculation a dropout rate of 10-13% was included. Follow-up of subjects withdrawn from study The data retrieved from subjects who were withdrawn from the study will be used for data analyses. Follow-up of subjects withdrawn from treatment Patients who will be withdrawn form treatment due to intolerable side effects or due to lack of efficacy, will be instructed by their physician to continue to fill in questionnaires until the end of the study. Premature termination of the study The sponsor and/or DSMB may decide to prematurely end the study when feels the health of the subjects are put at jeopardy. For details on the DSMB see Chapter 9: DSMB of this protocol. 26 Research Protocol NL52526.044.15 / ATTACG 9. Safety reporting Section 10 WMO event In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and the reviewing accredited METC if anything occurs, on the basis of which it appears that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The study will be suspended pending further review by the accredited METC, except insofar as suspension would jeopardise the subjects’ health. The investigator will take care that all subjects are kept informed. Safety monitoring Patients will be informed to contact their treating rheumatologist when severe side effects (e.g. infections) occur and asked to report side effects during the entire study period directly to their treating rheumatologist and by reporting this through the web portal and/or in the flare diary during gout attacks. All AE/SAE will be collected and recorded in the electronic CRF and database, irrespective of causal association. All AE/SAE directly observed or reported by the patient or caregiver to the treating rheumatologist or other site personnel, from the time of prescribing anakinra or SoC and entering this study, should be evaluated by the site and assessed for seriousness and relatedness to anakinra or SoC, as defined below in the section ‘AE reporting’. AE reporting An AE is the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting anakinra or SoC even if the event is not considered to be related to anakinra or SoC. Medical conditions/diseases present before starting anakinra or SoC are only considered AEs if they worsen after starting anakinra or SoC. Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or symptoms, are considered clinically significant, or require therapy. All AE reported spontaneously by the subject or observed by the investigator or the staff are to be recorded regardless of whether considered related to anakinra or SoC. In addition, all reports of the following special scenarios are considered an AE irrespective if a clinical event has occurred: Drug-drug or drug-food interaction Drug exposure during pregnancy Lack of effectiveness Overdose Drug abuse and misuse Drug maladministration or accidental exposure Dispensing errors / medication errors Off-label use Withdrawal or rebound symptoms All AEs recorded on the adverse event CRF in the EDC system should include the following information: The severity grade Relationship to medicinal product being studied Duration (start and end date, if applicable) 27 Research Protocol NL52526.044.15 / ATTACG Whether it constitutes a SAE (if so, follow rules for SAE reporting) Whether the AE is treated SAE reporting A SAE is any untoward medical occurrence or effect that: Results in death; Is life threatening (at the time of the event); Requires hospitalisation or prolongation of existing inpatients’ hospitalisation; Results in persistent or significant disability or incapacity; Is a congenital anomaly or birth defect; Any other important medical event that may not result in death, be life threatening, or require hospitalization, may be considered a serious adverse event when, based upon appropriate medical judgement, the event may jeopardize the subject or may require an intervention to prevent one of the outcomes listed above. Information about all SAEs (and SUSAR, see below) is collected and recorded on the adverse event CRF in the EDC system and should include information as mentioned in the previous subsection AE Reporting. In case a (S)AE arises (or SUSAR, see below) occurs within the first 30 days after start of the study, the responsible investigator at that participating site should report this to the sponsor directly (within 24 hours; email: m.vandelaar@mst.nl / tel: 053 – 487 2450). The sponsor will report the SAEs (or SUSAR) through the web portal ToetsingOnline to the accredited METC that approved the protocol, within 15 days after the sponsor has first knowledge of the SAE. SAEs (or SUSARs) that result in death or are life threatening should be reported expedited. The expedited reporting will occur not later than 7 days after the responsible investigator has first knowledge of the adverse event. This is for a preliminary report with another 8 days for completion of the full report. After the first 30 days after starting the study, the occurrence of any (S)AE and/or SUSAR will not need to be reported (expeditely) as mentioned above, but will need to be summarized in a line listing which will be made available to the accrediting METC periodically. Documented SAEs (and SUSARs) as a result of anakinra injection during the duration of the trial, independent of causality, will be reported to Sobi within 24 hours of first awareness. This can be done by sending an email to the Sobi Drug Safety Department (drugsafety@sobi.com). The sponsor and investigator shall assist Sobi in obtaining follow-up information for any reported serious adverse events. Suspected unexpected serious adverse reactions reporting Adverse reactions are all untoward and unintended responses to an investigational product related to any dose administered. Unexpected serious adverse reactions are Suspected unexpected serious adverse reactions (SUSARs) if the following three conditions are met: 1. the event must be serious; 28 Research Protocol NL52526.044.15 / ATTACG 2. there must be a certain degree of probability that the event is a harmful and an undesirable reaction to the medicinal product under investigation, regardless of the administered dose; 3. the adverse reaction must be unexpected, that is to say, the nature and severity of the adverse reaction are not in agreement with the product information as recorded in: SPC for an authorised medicinal product; Investigator’s Brochure for an unauthorised medicinal product. When, within the first 30 days after start of the study, the head investigator at a participating centre has first knowledge of any (S)AE, independent of whether it might be a SUSAR, he/she will report this immediately to the sponsor (within 24 hours; email: m.vandelaar@mst.nl / tel: 053 – 487 2450). The sponsor will decide, depending on the assessment of the head investigator, if the (S)AE is a SUSAR. The recording of SUSARS in the CRF and reporting of SUSARs to Sobi and the METC will be done by the sponsor and follow the same procedure as for the reporting of SAE (see previous section: SAE reporting). The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as notification to the competent authority. The reporting of SUSARs occurring 30 days after start of the study, will be reported in a line listing made available to the accrediting METC periodically. Follow-up of AE and SAE All AEs will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist. AEs,SAEs and SUSARs need to be reported in the CRF system till end of study within the Netherlands, as defined in the protocol. Annual safety report In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout the clinical trial, a safety report to the accredited METC and competent authority. The annual safety report will be combined with the annual progress report. This safety report consists of: 1. A list of all suspected (unexpected or expected) serious adverse reactions, along with an aggregated summary table of all reported serious adverse reactions, ordered by organ system, per study; 2. A report concerning the safety of the subjects, consisting of a complete safety analysis and an evaluation of the balance between the efficacy and the harmfulness of the medicine under investigation. Data Safety Monitoring Board To perform ongoing safety surveillance of the study participants, an independent DSMB will be established before the first participant starts the study. For further details regarding the DSMB, see the DSMB charter in Appendix IV. 29 Research Protocol NL52526.044.15 / ATTACG 10. Data analyses Populations Primary efficacy analyses will be performed for both the intention-to-treat (ITT) and per-protocol (PP) populations. The ITT population will consist of all randomized subjects who have been administered at least one dose of study medication. The PP population will exclude all subjects in the ITT population who meet any of the following criteria: • • Have taken any interfering concomitant medications during the first three days of the study. Have missing data for one or more assessments of the primary outcome. Primary efficacy analyses The primary outcome of this study is the difference between treatment arms in change in patientreported pain on a 5-point Likert scale in the index joint from baseline to the average of the patientreported pain values at 24, 48 and 72 hours (referred to hereafter as Δpain). In accordance with FDA, EMA and consort guidelines, the NI-margin for this study was established after carefully considering the maximum clinically tolerable loss of efficacy of anakinra compared with SoC and by estimating a putative placebo effect from historical results of clinical studies in acute gout employing the 5-point Likert pain scale as the primary outcome (41-44). Previous NI studies in gout with the 5-point Likert scale have employed a difference of 0.5 points in favor of the active comparator as a NI margin based on clinical reasoning only (i.e. the maximum clinically tolerable loss of efficacy) (44-46). A review of studies identified in a systematic search of the PubMed database revealed that all but one of the previous clinical studies in acute gout compared different NSAIDs (44-46). No difference in efficacy was found between treatment arms in any of the studies and mean Δpain ranged from -1.2 to -1.4 (M=-1.4) in these studies. Although no placebo controlled trials had yet been performed, one recent study randomized patients to SC rilonacept 320 mg at baseline plus the NSAID indomethacin 50 mg, oral TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n = 76); or SC rilonacept 320 mg at baseline plus oral placebo (n = 75)(47). No significant difference in Δpain was observed between the rilonacept + indomethacin group and the placebo + indomethacin group. From these results the authors concluded that rilonacept in combination with indomethacin did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare. However, significant between group differences were observed between the rilonacept + placebo group and the rilonacept + indomethacin group (Dif. Δpain = -0.7, 95% CI = -0.4 -1.0). Anakinra will be declared non-inferior to SoC in case it can be demonstrated that the difference between anakinra and SoC does not exceed 0.4 points in favor of SoC on Likert pain. This NI margin corresponds to the lower bound of the 95% CI for the difference between groups (indomethacin + rilonacept vs placebo + rilonacept) observed in the study by Terkeltaub et al. 2013 (47). This NI margin is slightly more stringent than employed in previous NI studies in acute gout and represents a conservative estimate of the effect of anakinra relative to historical placebo, since the assumed 30 Research Protocol NL52526.044.15 / ATTACG placebo effect corresponds to the historically observed effect of placebo plus single injection rilonacept. The hypotheses tested in this study are: H0: ΔpainAnakinra - ΔpainSoC > 0.4 Ha: ΔpainAnakinra - ΔpainSoC ≤ 0.4 The study hypotheses will be tested in an analysis of covariance model (ANCOVA) with treatment group as a fixed factor and baseline pain scores as a covariate. NI of anakinra compared with SoC will be accepted if the upper bound of the 95% CI around the estimated difference in the primary endpoint lies to the left of the NI margin of 0.4, both in the ITT analysis and the PP analysis. Non-compliance may bias ITT analysis towards NI, a sensitivity analysis will be performed where non-compliant patients will be excluded from the ITT analysis (48). For the purpose of this analysis, patients who report to have missed 1 or more dosages of anakinra or SoC during the first three days and/or report having taken any pain-relieving agent during the same period will be considered non-compliant. In case NI of anakinra compared with SoC has been accepted, a superiority analysis will be performed on the ITT population. Superiority of anakinra versus SoC will be concluded in case the upper bound of the 95% CI around ΔpainAnakinra - ΔpainSoC < 0. Missing Data It will be assumed that any missing data will occur at random and missing values will be imputed for the ITT population using multiple imputation by chained equations. The imputation models will be specified to include the individual pain scores observed at days 1-7 and any available variable that has a statistical association with the outcome to be imputed or with missingness, as identified in a logistic regression analysis with missingness as the dependent variable (49). 20 datasets with imputed plausible values will obtained, with 200 iterations between data sets. Rubin’s rules will be employed to obtain pooled parameter estimates and their associated standard errors for all analyses. The results of the analysis of the primary study hypothesis using the pooled results will be compared to the results obtained on the observed data alone. Secondary analyses Secondary efficacy endpoints will be analyzed by specifying a series of linear mixed-effects models with the endpoint as the dependent variable and time, treatment group and their interaction as fixed effects. Continuous variables will be summarized with sample size, mean, standard deviation and range. Frequency counts and percentage of subjects within each category will be provided for categorical data. Safety analyses Safety will be evaluated by tabulations of AE/SAE and will be presented with descriptive statistics at baseline and follow-up visits for each treatment group. 31 Research Protocol NL52526.044.15 / ATTACG Cost effectiveness analyses The primary utility measure of the study is quality adjusted life days (QALDs), and will be calculated from the SF-36 scores (SF-6D). The incremental cost-utility ratio (ICUR) will be calculated by dividing the difference in costs by the difference in the QALDs produced by the two groups. The ICUR is expressed as costs per QALD gained. Sample size considerations A standard deviation of 0.94 will be assumed for Δpain, corresponding to the findings of previous studies (44-47). Furthermore it is assumed that there is no difference in effectiveness between anakinra and SoC. 87 patients per arm need to be included to be 80% sure that a 97.5 % CI for SoC - Anakinra does not contain the NI limit of 0.4. Taking a 10-13% drop out rate into account, 100 patients per arm will be included in the study to ensure sufficient power for the per protocol analyses. 32 Research Protocol NL52526.044.15 / ATTACG 11. Ethical considerations Regulatory and ethical compliance The study will be conducted in accordance with the ethical principles outlined in the Declaration of Helsinki (version 2013) and the Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch Wetenschappeljik Onderzoek, WMO 2006)(50). Recruitment and informed consent procedures Adequate and complete oral and written information about the nature, purpose(s), risk(s) and benefit(s) of the study will be made available to potential subjects by the treating rheumatologist/nurse. The subjects will be informed about the opportunity to ask an independent physician additional questions and are given a maximum of one day for making a decision. This relatively short period of time is necessary, given that most gout attacks spontaneously resolve in 1 to 2 weeks. Eligible patients will only be included in the study after providing written (witnessed, where required by law or regulation), METC approved informed consent. Informed consent must be obtained before conducting any study procedures. The process of obtaining informed consent should be documented in the patient source documents. Treating rheumatologists will be provided with an informed consent form template that complies with the relevant guidelines and regulatory requirements. Compensation for injury Each participating centre has a liability insurance (in Dutch: aansprakelijkheidsverzekering) which is in accordance with article 7, subsection 9 of the WMO for the participants taking part in the study at that centre. The sponsor (linked to Medisch Spectrum Twente, Enschede) has an insurance (in Dutch: proefpersonenverzekering) which is in accordance with the legal requirements in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical Research in Humans 2015). This insurance provides cover for damage to research subjects through injury or death caused by the study. The insurance applies to the damage that becomes apparent during the study or within 4 years after the end of the study. All subjects at the different participating centres are covered by the insurance. 33 Research Protocol NL52526.044.15 / ATTACG 12. Administrative aspects, Monitoring and Publication Handling data and documents Each patient’s data collected for this study will be stored under an assigned unique number. All patient data will be stored in the ROMA database. The ROMA database is a secure environment that adheres to all available international guidelines and fulfills NEN7510 and ISO 27001 regulations. Back-ups of the entire database are made daily. Data protection and privacy regulations will be observed in capturing, forwarding, processing and storing patient data. Patients must be informed accordingly, and will be asked to give their consent on data-handling procedures in accordance with the Dutch Personal Data Protection Act (in Dutch: De Wet bescherming persoonsgegevens, Wbp). The collected data will be kept for 15 years after completion of the study. Data will be kept and stored in ROMA. Data and official documents will also be stored at the University of Twente. Monitoring and quality assurance Monitoring before, during and after completion of the study will take place to ensure the rights and safety of the patients, data integrity and validity of the study results. A DSMB is appointed before the start of the study and the occurrence of any AEs, SAEs and/or SUSARs is reported in the electronic CRF (see Chapter 9: Safety Reporting). The coordinating investigator will contact and visit the participating sites whenever needed during the course of the study. To minimize the onset of problems and to ensure the responsibilities and procedures for data entry are well understood among the study staff, a pre-study initiation visit will be conducted at each of the participating centres. Site monitoring visits will be done whenever needed to sort out possible problems and to ensure data quality. The study specific template within the EDC system ROMA2 will be pre-tested before study initiation. During the course of the study the collected data in the electronic CRF will be checked regularly (once per week) for missing data, entry faults, etc. If problems occur, the coordinating investigator will take the necessary actions to reassure the quality of the data (e.g. visiting site, explanation using EDC system, etc.). After study completion the data will be reviewed and analyses will be done as described in Chapter 10: Data Analyses of this protocol. Protocol adherence and amendments Treating rheumatologists or other involved health care professionals will apply due diligence to avoid protocol violations. The protocol will be amended and updated as needed throughout the course of the study. A substantial amendment is defined as an amendment to the terms of the METC application, or to the protocol or any other supporting documentation, that is likely to affect to a significant degree: the safety or physical or mental integrity of the subjects of the trial; the scientific value of the trial; the conduct or management of the trial; or the quality or safety of any intervention used in the trial. 34 Research Protocol NL52526.044.15 / ATTACG All substantial amendments requires a written protocol amendment that must be notified to and approved by the relevant METC, competent authority and Sobi before implementation. Nonsubstantial amendments, affecting only typing errors and administrative aspects of the study, do not need to be notified to the accredited METC and the competent authority; but the METC must be kept informed of such administrative changes and the sponsor should record and file these changes. Annual progress report The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC once a year. Information will be provided on the date of inclusion of the first subject, numbers of subjects included and numbers of subjects that have completed the trial, serious adverse events/ serious adverse reactions, other problems, and amendments. This report will be combined with the annual safety report. End of study report The sponsor will notify the accredited METC and the competent authority of the end of the study within a period of 90 days. The end of the study is defined as when the last patient has completed the last questionnaires at month 12. In case the study is ended prematurely, the sponsor will notify the accredited METC and the competent authority within 15 days, including the reasons for the premature termination. Within one year after the end of the study, the sponsor will submit a final study report with the results of the study, including any publications/abstracts of the study, to the accredited METC and the competent authority. Public disclosure and publication policy Upon study completion and finalization of the study report, the results of the study may either be submitted for publication and/or posted in a publicly accessible database of results. Publication will follow the International Committee of Medical Journal Editors (ICMJE) guidelines. Analysis and publication has to comply with the conditions described in the contract with Sobi underlying this proposal. 35 Research Protocol NL52526.044.15 / ATTACG 13. Structured Risk Analysis Potential risks and concerns related to this study Summary anakinra and gout studies Anakinra was registered for market use on March 8 2002 for treating RA. The exact mechanism of action is known and can be found in the SPC. Pertaining to gout, anakinra has been tested in both animals and humans. Anakinra showed inhibitory effects on the peritoneal neutrophil recruitment in an in-vivo mouse model (BALB/C mice) of MSU crystal-induced inflammation(34). In total, 16 clinical studies have been documented for acute gout and the usage of anakinra as treatment therapy, of which 11 single case reports, 4 case series and one controlled open label study (22-37). No randomizedcontrolled clinical trials have been reported. The patients included in the documented studies were all complex gouty arthritis patients with severe comorbidities and/or intolerance to conventional therapies. Treatment with anakinra was, therefore, used as an alternative agent. Dosage regime of anakinra differed between studies, however, the dosage 100 mg anakinra was reported in all studies. Frequently used dosage regime was once daily 100 mg anakinra for 3 consecutive days. However, some patients with chronic tophaceous gout used daily treatment for up to a 6 months, without any observed adverse effects. Rapid treatment response to anakinra was observed in the majority of the patients in the reported clinical studies. Observed side effects due to usage of anakinra were an injection site reaction by one patient, neutropenia by another patient, one case of leukopenia, seven infectious complications and twice a H1N1 Influenza infection occurred during anakinra treatment by a patient, although it is not clear whether this was caused by anakinra treatment. One critically ill case developed an infectious complication (herpes zoster) one day after completing a 6-day anakinra treatment, although it is not clear whether this was related to the anakinra treatment. Also, one patient developed a postoperative wound infection, although it is not clear whether the site was already infected before anakinra treatment was initiated. Four patients could not discontinue anakinra treatment without getting an acute flare within 4 days of stopping and one patient had a minor flare at one month follow-up. For specific details regarding these studies, see IB. Risks and concerns related to anakinra The potential risks associated with anakinra for the treatment of acute gouty arthritis are: Physical discomfort of SC treatment injection Local (skin) injection site reaction associated with pain, inflammation, erythema, or ecchymoses Serious infections including respiratory infections and skin infections, Influenza infections Allergic reaction and anaphylaxis (angioedema, urticarial and pruritus) to anakinra or other constituents, including latex Decreased neutrophil count, potentially leading to neutropenia Drug interaction between ULT and anakinra Elevated levels of liver enzymes Gastrointestinal disturbances related to liver disorders (yellow skin and eyes, nausea, loss of appetite, dark-colored urine, light-colored stools) Headaches 36 Research Protocol NL52526.044.15 / ATTACG These risks are defined according to the documented information and side effects in the literature and the concerns as listed in the SPC. For elaborate explanations regarding these side effects see SPC and IB. Other risks and concerns NSAIDs and colchicine are intended as prophylactics for gout flares when initiating ULT. Patients receiving anakinra treatment or prednisolone treatment (when allocated into the SoC group) will not receive colchicine or NSAID prophylactics when initiating ULT. Relapse of a gout flare might occur sooner in this population compared to the other study arm that will receive prophylactics. Reducing and managing the potential risks and concerns To ensure the risks associated with the injection of anakinra remain limited, the inclusion and exclusion criteria of this study are strict. Eligible patients will be excluded from the study if there are contraindications to the use of anakinra or any of its constituents. This will reduce the chance of allergic reactions to anakinra in the study population. Additionally, patients with pre-existing neutropenia or with untreated infections will not be included in the study. Also, pregnant, lactating women and women who are planning on becoming pregnant within the study period (12 months) are not allowed to participate in the study, as the effect of anakinra on unborn or nursed children is unknown. Patients using TNF inhibitors are also excluded from this study, as concurrent use of anakinra with TNF inhibitors has been shown to be associated with the development of severe infections and neutropenia. A DSMB will be established to ensure the safety of the participants. As no information is available on the possible drug reaction between ULT and anakinra, any reported SAE or SUSAR will be evaluated for possible interaction by the DSMB as well as the treating rheumatologist. Moreover, patients experiencing any side effects or other AE will be instructed to immediately contact their treating rheumatologist. The treating rheumatologist will give the patient the needed care and report any SAE and/or SUSARs to the sponsor. The sponsor will report the events in accordance with Chapter 9: Safety Reporting, of this protocol. If needed, the sponsor and/or DSMB will decide to prematurely terminate the study if there is a possibility that the safety of the participants is being put in jeopardy. Anakinra has been used for treating patients with RA since 2002. The long experience with this product in RA patients has resulted in a good description of its safety profile and the possible side effects. Such information has contributed to clearly defining the potential risks associated with using anakinra in the present study. In addition, patients with chronic RA may use anakinra daily for long periods of time (years if needed) to treat the disease. Therefore, it is expected that the risks associated with the 5 day anakinra treatment in this study will be limited and is therefore judged an acceptable treatment duration. Moreover, the applied daily dosage of 100mg anakinra in this study is the same as the recommended dosage for treating RA patients and as used in other documented studies, suggesting the dosage is acceptable. When a new acute gout flare arises after the first study week (baseline – day 7), all patients should contact their treating rheumatologist who will treat the patient with the best available care. The group not receiving prophylactic agents will receive the same optimal care as patients receiving prophylactics. In some cases it might be needed to break the randomization (treatment) code to be 37 Research Protocol NL52526.044.15 / ATTACG able to provide the patient the best care. Patients will be instructed by the research nurse and/or their treating rheumatologist on how to handle in case another flare arises. By applying the above, the concerns associated with not taking prophylactics will remain limited. The risks associated with this study have been evaluated and minimized by setting up strict inclusion and exclusion criteria and by establishing a DSMB. Not all risks could however be eliminated. The remaining risks are acceptable since the risks are not considered to be severe or life threatening. 38 Research Protocol NL52526.044.15 / ATTACG 14. Reference List 1. Doherty M. New insights into the epidemiology of gout. Rheumatology (Oxford). 2009;48 Suppl 2:ii2-ii8. 2. Annemans L, Spaepen E, Gaskin M, Bonnemaire M, Malier V, Gilbert T, et al. Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000-2005. Ann Rheum Dis. 2008;67(7):960-6. 3. Richette P, Bardin T. Gout. Lancet. 2010;375(9711):318-28. 4. Roddy E, Doherty M. Epidemiology of gout. Arthritis Res Ther. 2010;12(6):223. 5. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63(10):3136-41. 6. B L, T W, Hn Z, Ww Y, Hp Y, Cx L, et al. The prevalence of hyperuricemia in China: a metaanalysis. BMC Public Health. 2011;11(832):1471-2458. 7. Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann R. Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol. 2004;31(8):1582-7. 8. Miao Z, Li C, Chen Y, Zhao S, Wang Y, Wang Z, et al. Dietary and lifestyle changes associated with high prevalence of hyperuricemia and gout in the Shandong coastal cities of Eastern China. J Rheumatol. 2008;35(9):1859-64. 9. Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther. 2006;8(1):12. 10. Keenan RT, O'Brien WR, Lee KH, Crittenden DB, Fisher MC, Goldfarb DS, et al. Prevalence of Contraindications and Prescription of Pharmacologic Therapies for Gout. The American Journal of Medicine. 2011;124(2):155-63. 11. Tausche AK, Jansen TL, Schroder HE, Bornstein SR, Aringer M, Muller-Ladner U. Gout--current diagnosis and treatment. Dtsch Arztebl Int. 2009;106(34-35):549-55. 12. Terkeltaub R. Gout. Novel therapies for treatment of gout and hyperuricemia. Arthritis Res Ther. 2009;11(4):23. 13. Burns CM, Wortmann RL. Latest evidence on gout management: what the clinician needs to know. Ther Adv Chronic Dis. 2012;3(6):271-86. 14. Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 2004;31(12):2429-32. 15. Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64(10):1447-61. 39 Research Protocol NL52526.044.15 / ATTACG 16. Richtlijn Jicht. Utrecht (NL): Nederlandse Vereniging voor Reumatologie, 2013. 17. Wortmann RL, Macdonald PA, Hunt B, Jackson RL. Effect of prophylaxis on gout flares after the initiation of urate-lowering therapy: analysis of data from three phase III trials. Clinical therapeutics. 2010;32(14):2386-97. 18. Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65(10):1312-24. 19. Pope RM, Tschopp J. The role of interleukin-1 and the inflammasome in gout: implications for therapy. Arthritis Rheum. 2007;56(10):3183-8. 20. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237-41. 21. Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R. Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum. 2005;52(9):2936-46. 22. Bartov JB, Ali Y. Successful use of the interleukin 1 antagonist, anakinra, in a patient with gout, chronic kidney disease, and aplastic anemia. J Clin Rheumatol. 2013;19(8):454-6. 23. Chen K, Fields T, Mancuso CA, Bass AR, Vasanth L. Anakinra's efficacy is variable in refractory gout: report of ten cases. Semin Arthritis Rheum. 2010;40(3):210-4. 24. Direz G, Noel N, Guyot C, Toupance O, Salmon JH, Eschard JP. Efficacy but side effects of anakinra therapy for chronic refractory gout in a renal transplant recipient with preterminal chronic renal failure. Joint Bone Spine. 2012;79(6):631. 25. Donmez S, Pamuk ON. Chronic tophaceous gout. J Rheumatol. 2014;41(3):554-5. 26. Funck-Brentano T, Salliot C, Leboime A, Zafrani L, Servais A, Larousserie F, et al. First observation of the efficacy of IL-1ra to treat tophaceous gout of the lumbar spine. Rheumatology (Oxford). 2011;50(3):622-4. 27. Ghosh P, Cho M, Rawat G, Simkin PA, Gardner GC. Treatment of acute gouty arthritis in complex hospitalized patients with anakinra. Arthritis Care Res (Hoboken). 2013;65(8):1381-4. 28. Gratton SB, Scalapino KJ, Fye KH. Case of anakinra as a steroid-sparing agent for gout inflammation. Arthritis Rheum. 2009;61(9):1268-70. 29. McGonagle D, Tan AL, Shankaranarayana S, Madden J, Emery P, McDermott MF. Management of treatment resistant inflammation of acute on chronic tophaceous gout with anakinra. Ann Rheum Dis. 2007;66(12):1683-4. 30. Nocturne G, Ora J, Ea HK, Liote F. Influenza A H1N1 and anakinra exposure in a patient with gout. Joint Bone Spine. 2010;77(4):369-70. 40 Research Protocol NL52526.044.15 / ATTACG 31. O'Brien KL, Pereira SE, Wagner J, Shadman M, Hendrie P, Nelson K, et al. Transfusionassociated graft-versus-host disease in a liver transplant recipient: an unusual presentation and review of the literature. Transfusion. 2013;53(1):174-80. 32. Ottaviani S, Molto A, Ea HK, Neveu S, Gill G, Brunier L, et al. Efficacy of anakinra in gouty arthritis: a retrospective study of 40 cases. Arthritis Res Ther. 2013;15(5):R123. 33. Singh D, Huston KK. IL-1 inhibition with anakinra in a patient with refractory gout. J Clin Rheumatol. 2009;15(7):366. 34. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9(2):R28. 35. Tran AP, Edelman J. Interleukin-1 inhibition by anakinra in refractory chronic tophaceous gout. Int J Rheum Dis. 2011;14(3):e33-7. 36. Vitale A, Cantarini L, Rigante D, Bardelli M, Galeazzi M. Anakinra treatment in patients with gout and type 2 diabetes. Clin Rheumatol. 2014. 37. Thueringer JT, Doll NK, Gertner E. Anakinra for the treatment of acute severe gout in critically ill patients. Seminars in Arthritis and Rheumatism 2015;[In Press, Corrected Proof]. 38. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980;23(2):137-45. 39. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Medical care. 1992;30(6):473-83. 40. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. PharmacoEconomics. 1993;4(5):353-65. 41. Committee for medicinal products for human use. Guideline on the choice of the noninferiority margin. London: European Medicines Agency (EMEA); 2005. 42. Guidance for Industry: Non-Inferiority Clinical Trials In: Services USDoHaH, editor. Rockville, Maryland, USA: Food and Drug Administration; 2010. 43. Piaggio G, Elbourne DR, Pocock SJ, Evans SW, Altman DG, f CG. Reporting of noninferiority and equivalence randomized trials: Extension of the CONSORT 2010 statement. JAMA. 2012;308(24):2594-604. 44. Willburger RE, Mysler E, Derbot J, Jung T, Thurston H, Kreiss A, et al. Lumiracoxib 400 mg once daily is comparable to indomethacin 50 mg three times daily for the treatment of acute flares of gout. Rheumatology. 2007;46(7):1126-32. 45. Schumacher Jr HR, Boice JA, Daikh DI, Mukhopadhyay S, Malmstrom K, Ng J, et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis. Bmj. 2002;324(7352):1488-92. 46. Rubin BR, Burton R, Navarra S, Antigua J, Londoño J, Pryhuber KG, et al. Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg 41 Research Protocol NL52526.044.15 / ATTACG three times daily in acute gout: A randomized controlled trial. Arthritis & Rheumatism. 2004;50(2):598-606. 47. Terkeltaub RA, Schumacher HR, Carter JD, Baraf HS, Evans RR, Wang J, et al. Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator. Arthritis Res Ther. 2013;15(1):R25. 48. Matilde Sanchez M, Chen X. Choosing the analysis population in non-inferiority studies: per protocol or intent-to-treat. Statistics in medicine. 2006;25(7):1169-81. 49. Sterne JA, White IR, Carlin JB, Spratt M, Royston P, Kenward MG, et al. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. Bmj. 2009;338:b2393. 50. World medical association declaration of helsinki: Ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-4. 42 Research Protocol NL52526.044.15 / ATTACG 15. Appendices I. CRF Information II. Patient flare diary III. PROs questionnaires IV. DSMB Charter 43 ATTACG studie CRF - TOELATINGSCRITERIA (Pagina 1/2) Datum (dd mm jjjj) Patiëntcode/ medicatiecode: - - Centrum (kies 1): MST VieCuri MC ZGT MCL Rijnstate Ropcke-Zweers Ziekenhuis Initialen behandelaar Locatie centrum: INCLUSIECRITERIA 1. Poliklinische patiënt met microscopisch kristalbewezen gedocumenteerde jicht Ja Nee 2. Op moment van inclusie is de patiënt 18 jaar of ouder Ja Nee 3. Patiënt heeft de patiënteninformatie ondertekend Ja Nee Ja Nee Ja Nee Ja Nee EXCLUSIECRITERIA 1. Patiënt heeft een absolute contra-indicatie voor alle beschikbare urinezuur verlagende therapie (allopurinol, febuxostat, benzbromaron) Contra-indicaties allopurinol: Overgevoeligheid voor de werkzame stof (allopurinol) of voor één van de hulpstoffen (zie hiervoor de officiële productinformatie) Contra-indicaties febuxostat: Overgevoeligheid voor de werkzame stof (febuxostat) of voor één van de hulpstoffen (zie hiervoor de officiële productinformatie). Contra-indicaties benzbromaron: Overgevoeligheid voor het werkzaam bestanddeel (benzbromaron) of voor één van de hulpstoffen (zie hiervoor de officiële productinformatie). Patiënten met bekende leverziekte. Gelijktijdig gebruik van hepatotoxische geneesmiddelen, in het bijzonder anti-tuberculose agentia. Hepatische porfyrie. Ernstige nierinsufficiëntie (klaring < 30 ml/min). Patiënten met hyperuraturie hoger dan 700 mg/24 uur (= 4,2 mmol/24 uur). Urolithiasis. Acute jichtaanval. 2. Patiënt heeft een absolute contra-indicatie voor anakinra Contra-indicaties anakinra: Overgevoeligheid voor de werkzame stof (anakinra) of voor één van de hulpstoffen (citroenzuur watervrij, natriumchloride, dinatriumedetaat-dihydraat, polysorbaat 80, natriumhydroxide, water voor injectie), of voor eiwitten geproduceerd met behulp van E. coli. Anakinra (Kineret) mag niet worden gebruikt bij patiënten met ernstige nierfunctiestoornissen (CLcr < 30 ml/minuut). Er mag geen Kineret-behandeling worden begonnen bij patiënten met neutropenie (Absolute Neutrophil Count <1,5 x 109/l). 3. Aanwezigheid van leveraandoeningen die volgens de behandelende arts deelname aan de studie onmogelijk maken Versie 3 - 09/02/2016 ATTACG studie CRF - TOELATINGSCRITERIA (Pagina 2/2) 4. Patiënt heeft een absolute contra-indicatie voor alle 3 standaard jichtaanvalmiddelen; colchicine, naproxen en prednisolon Ja Nee Contra-indicaties colchicine: Overgevoeligheid voor de werkzame stof (colchicine) of voor één van de hulpstoffen (microkrystallijne cellulose (E460), magnesiumstearaat (E470b), lactose, natriumcarboxyzetmeel). Vrouwen in de vruchtbare leeftijd, tenzij doeltreffende anticonceptie-maatregelen worden genomen. Patiënten met ernstige nierfunctiestoornissen. Patiënten met ernstige leverfunctiestoornissen. Contra-indicaties naproxen: Overgevoeligheid voor naproxen of voor één van de hulpstoffen (aardappelzetmeel, lactose, hydroxypropylcellulose (200 CP), magnesiumstearaat, watervrij colloïdaal siliciumdioxide). Naproxen mag ook niet toegediend worden aan patiënten, die na toediening van acetylsalicylzuur of andere prostaglandinesynthetaseremmende middelen een allergische reactie vertoond hebben, zoals astma, rhinitis of urticaria. Ernstige anafylactoïde reacties zijn bij deze patiënten gerapporteerd. Naproxen mag in principe niet toegediend worden aan patiënten met ulceraties van het maagdarmkanaal, gastritis congestiva of gastritis atrophica, maagdarmbloedingen of andere bloedingen zoals cerebrovasculaire bloedingen. Ernstige nierinsufficiëntie Contra-indicaties prednisolon: Overgevoeligheid voor prednisolon of één van de andere bestanddelen van de tabletten (lactose, magnesiumstearaat (E470b), siliciumdioxide (E551), aardappelzetmeel, voorverstijfseld aardappelzetmeel, natrium (aardappel)zetmeelglycollaat. Ulcus ventriculi en ulcus duodeni. Acute infectieuze processen, met name virusinfecties en systemische schimmelinfecties. Tropische worminfecties. Toediening na vaccinatie met levend verzwakt virus. Herpes simplex oculi. 5. De patiënt heeft een verleden van latex sensitiviteit of allergie Ja Nee 6. Actueel gebruik van urinezuur verlagende therapie (UVT) Ja Nee 7. Patiënt gebruikt andere interleukine-1 therapieën Ja Nee Ja Nee Ja Nee 10. Patiënt is een vrouw die binnen de studie periode zwanger denkt te raken (12 maanden) Ja Nee 11. Patiënt heeft een actieve of terugkerende bacteriële, schimmel of virale infectie Ja Nee 12. Patiënt gebruikt TNF-remmers Ja Nee Ja Nee Ja Nee Tot UVT behoren allopurinol, febuxostat en benzbromaron. Tot andere interleukine-1 therapieën behoren canakinumab en rilonacept. 8. Patiënt rapporteert geen tot milde jicht gerelateerde pijn 9. Patiënt is zwanger of geeft borstvoeding Tot TNF-remmers behoren: Certolizumab, Golimumab, adalimumab, etanercept, infliximab 13. Patiënt beschikt over onvoldoende beheersing van de Nederlandse taal om zelfstandig vragenlijsten in te vullen Is de patiënt toelaatbaar tot de studie volgens de bovengenoemde criteria? (Een patiënt is alleen toelaatbaar als aan alle inclusie criteria voldaan is en niet aan het exclusiecriteria) Versie 3 - 09/02/2016 ATTACG studie CRF - PATIËNTKARAKTERISTIEKEN Eerstelijnszorg (via de huisarts, spoedeisende hulp) Patiënt is binnengekomen via: Tweedelijnszorg (via de polikliniek reumatologie) Biometrische kenmerken 1. Geslacht Man Vrouw 2. Leeftijd (jaren) Geschat? 3. Lengte (cm) Ja Nee 4. Gewicht (kg) Ja Nee 5. Diastolische bloeddruk (mm/Hg) 6. Systolische bloeddruk (mm/Hg) 7. Hartslag (per minuut) Versie 3 - 09/02/2016 ATTACG studie CRF - JICHT STATUS Jicht status (1/4) Diagnosedatum 1. Jicht diagnose datum - (dd-mm-jjjj) - Dit is de datum waarop voor het eerst jicht werd gediagnosticeerd bij de patiënt. Dit kan zijn door de huisarts, reumatoloog of iemand anders. 2. Jicht type Monoarticulair Oligoarticulair Polyarticulair Bij monoarticulaire jicht is 1 gewricht aangedaan door jicht. Bij Oligoarticulaire jicht zijn er meer dan 1, maar minder dan 5 gewrichten aangedaan. Bij polyarticulaire jicht zijn er meer dan 5 gewrichten aangedaan. 3. Topheuze jicht Ja Nee 4. Beloop Intermitterend Chronisch 5. Aantal jichtaanvallen. (Noteer het aantal jichtaanvallen sinds het vorige bezoek. Noteer bij het eerste bezoek het aantal aanvallen over de afgelopen 12 maanden) Versie 3 - 09/02/2016 ATTACG studie CRF - JICHT STATUS Jicht status (2/4) 6. Voldoet de patiënt aan het volgende: Ten minste 1 episode van zwelling, pijn of gevoeligheid in een perifeer gewricht of bursa (nu en/of ooit in het verleden) Ja (ga door naar vraag 7) Nee (je hoeft verder niets in te vullen voor jicht status, ga door naar sectie comborbiditeiten) 7. Voldoet de patiënt aan het volgende: Aanwezigheid van urinezuurkristallen in een symptomatisch gewricht of bursa (i.e. in gewrichtsvloeistof) of tophus Ja (je hoeft verder niets in te vullen voor jicht status, ga door naar sectie comborbiditeiten) Nee (ga door naar vraag 8) 8. Patroon van gewricht/bursa betrokkenheid tijdens symptomatische episode(n) nu en/of ooit in het verleden (1 antwoord mogelijk): Symptomatische episoden zijn periodes van symptomen inclusief alle soorten zwelling, pijn, gevoeligheid in een perifeer gewricht of bursa. Gewricht(en) of bursa(e) anders dan de enkel, middenvoet of MTP1 (of de betrokkenheid van deze alleen als onderdeel van een polyarticulair voorval) Enkel OF middenvoet (als onderdeel van een monoarticulaire of oligoarticulaire episode zonder de betrokkenheid van MTP1) MTP1 (als onderdeel van een monoarticulaire of oligoarticulaire episode) 9. Kenmerken van symptomatische episode(n) (nu en/of ooit in het verleden) (1 antwoord mogelijk): i. Erytheem rondom het aangetaste gewricht (patiënt-gerapporteerd of door de arts waargenomen) ii. Aanraking of druk uitoefenen op het aangetaste gewricht wordt niet verdragen iii. Grote moeite met lopen of het onvermogen om aangetaste gewricht te gebruiken Geen kenmerken 1 kenmerk 2 kenmerken 3 kenmerken Versie 3 - 09/02/2016 ATTACG studie CRF - JICHT STATUS Jicht status (3/4) 10. Tijdsverloop van episode(n) nu en/of ooit in het verleden: Bij aanwezigheid (ooit) van 2 of meer is er sprake van een typische episode, ongeacht anti-inflammatoire behandeling: i. Tijd tot maximaal bereikte pijn <24 uur ii. Resolutie van symptomen is minder of gelijk dan 14 dagen iii. Volledige resolutie (tot baseline niveau) tussen symptomatische episoden Geen typerende episode(n) 1 Typische episode Terugkerende typerende episode(n) 11. Klinisch bewijs van tophi: Druipende of krijt - achtige subcutane knobbel onder transparante huid, vaak met bovenliggende vasculariteit, gelegen in typische locaties: gewrichten, oren, bursitis olecrani, vingertoppen, pezen (bijv. Achilles). Afwezig Aanwezig 12. Urinezuurspiegel: Gemeten middels de uricase methode. Idealiter gemeten op een tijdstip wanneer er door de patiënt geen urinezuurverlagende therapie werd ingenomen en 4 weken na de start van de episode bij de patiënt (i.e., tijdens interkritische periode); als praktisch uitvoerbaar, opnieuw testen onder dergelijke condities. De hoogste waarde, onafhankelijk van wanneer gemeten, dient te worden gescoord. <4 mg/dL (<0.24 mmol/L) 4 - <6 mg/dL (0.24 - <0.36 mmol/L) 6 - <8 mg/dL (0.36 - <0.48 mmol/L) 8 - <10 mg/dL (0.48 - <0.60 mmol/L) groter of gelijk aan 10 mg/dL (groter of gelijk aan 0.6 mmol/L) 13. Analyse gewrichtsvloeistof van een symptomatisch (nu en/of ooit in het verleden) gewricht of bursa: Dient beoordeeld te worden door een getrainde waarnemer. Niet gedaan Urinezuurkristallen negatief Versie 3 - 09/02/2016 ATTACG studie CRF - JICHT STATUS Jicht status (4/4) 14. Beeldvormend onderzoek van uraatafzetting in symptomatisch (nu en/of ooit in het verleden) gewricht of bursa: Echografisch bewijs van dubbel contour sign (zie uitleg *) of DECT vertoont uraatafzetting (zie uitleg **). Niet gedaan Afwezig Aanwezig (geldt voor beide technieken) * Hyperechoische onregelmatige versterkingen die onafhankelijk zijn van de insonatie hoek van de ultrasoon geluid bundel (noot: valspositief "dubbel contour sign"(artefact) zou kunnen verschijnen aan het hyaline kraakbeen oppervlak maar dienen te verdwijnen met een verandering van de insonatie hoek van de sonde). ** Aanwezigheid van kleurgecodeerd uraat bij de articulaire of peri-articulaire plaatsen. Afbeeldingen zijn verkregen door het gebruik van een dual energy computer tomografie (DECT) scanner, met data verworven bij 80 en 140kV en geanalyseerd met jicht-specifieke software met een twee materiaal decompositie algoritme dat uraat kleur codeerd. Een positieve scan is gedefinieerd als de aanwezigheid van kleurgecodeerd uraat by articulaire of peri-articulaire plaatsen. Nagelbed, submillimeter, huid, 'motion', 'beam hardening' en vasculaire artefacten dienen niet te worden geïnterpreteerd als bewijs voor DECT uraatafzetting. 15. Beeldvormend onderzoek van jicht-gerelateerde gewrichtsschade: Conventionele radiografie van de handen en/of voeten toont ten minste één erosie (zie uitleg ***) Niet gedaan Afwezig Aanwezig *** Erosie wordt gedefinieerd als een corticale breuk met een sclerotische marge en overhangende rand; exclusief DIP gewrichten en zeemeeuw uiterlijk. Versie 3 - 09/02/2016 ATTACG studie CRF - COMORBIDITEITEN COMORBIDITEITEN Cardiovasculaire ziekte Ja Nee Hyperlipidemie Ja Nee Hypertensie Ja Nee Lymfoproliferatieve maligniteit Ja Nee Metabolisch syndroom syndroom Nierinsufficientie Ja Nee Ja Nee Obesitas Ja Nee Overige malignitieit Ja Nee Overige comorbiditeiten Ja Nee Indien ja, welke comorbiditeiten? Versie 3 - 09/02/2016 ATTACG studie CRF - LABORATORIUM Serum urine zuur (mmol/l) CRP (mg/l) Versie 3 - 09/02/2016 , , ATTACG studie CRF - JICHTMEDICATIE Jichtmedicatie Noteer hier ALLE medicatie die voor JICHT gestart is op moment van inclusie of gestart is tijdens de studie op recept van de reumatoloog, zowel ontstekingsremmende als urinezuur verlagende therapieën. Voor codes zie onderaan de pagina. Laat het veld stopdatum leeg indien de medicatie voortgezet wordt. Naam Dosering Eenheden Frequentie , per Startdatum - Route Stopdatum - - - Reden van stoppen Niet effectief Hersteld Last van Bijwerkingen Indien last van Bijwerkingen, wat waren de bijwerkingen? Naam Dosering Eenheden Route per , Startdatum - Frequentie Stopdatum - - Reden van stoppen Hersteld Niet effectief Last van Bijwerkingen Indien last van Bijwerkingen, wat waren de bijwerkingen? Codes route 1. Intra-articluair 2. Intramusculair 3. Intraveneus 4. Intranasaal Versie 3 - 09/02/2016 5. Oraal 6. Rectaal 7. Subcutaan 8. Overig - ATTACG studie CRF - OVERIGE MEDICATIE Overige medicatie (Noteer hier alle medicatie die op dit moment voor aandoeningen anders dan jicht gebruikt worden of die in de afgelopen 12 maanden zijn gebruikt) Naam Dosering Eenheden , Frequentie Route per Startdatum Stopdatum (indien van toepassing) - - - - Reden van stoppen: Hersteld Niet effectief Last van bijwerkingen Indien last van bijwerkingen, wat waren de bijwerkingen? Naam Dosering Eenheden Route per , Startdatum - Frequentie Stopdatum - - Reden van stoppen: Hersteld Niet effectief - Last van bijwerkingen Indien last van bijwerkingen, wat waren de bijwerkingen? Codes route 1. Intra-articluair 2. Intramusculair 3. Intraveneus 4. Intranasaal 5. Oraal 6. Rectaal 7. Subcutaan 8. Overig 59360 Versie 3 - 09/02/2016 ATTACG studie CRF - BIJWERKINGEN Infectieziekte Ja Nee Leveraandoeningen na starten medicatie Ja Nee Ja Nee Ja Nee Verslechtering nierfunctie Ja Nee Tumor lysis Ja Nee Zwanger Ja Nee Overig Ja Nee Hart en vaataandoeningen Verslechtering van serum urinezuur Indien ja, welke? Versie 3 - 09/02/2016 ATTACG studie CRF - ADVERSE EVENTS 1. Omschrijving van de bijwerking 2. Begindatum bijwerking (dd-mm-jjjj) - 3. Stopdatum bijwerking (dd-mm-jjjj) - - - 4. Hoe is het met deze bijwerking afgelopen bij de patiënt? Hersteld Hersteld met restverschijnselen Herstellende Overleden Onbekend 5. Is deze bijwerking behandeld? Nee Onbekend Ja 6. Relatie tot studie medicatie? Verdacht Samengaand Interactie Geen / n.v.t. Anders 7. Zijn er naast de studie medicatie mogelijk andere oorzaken of omstandigheden die de bijwerking kunnen hebben veroorzaakt of verergerd? Nee Onbekend Ja 8. Heeft de bijwerking geleid tot een van de volgende situaties? Overlijden Levensbedreigende situatie Ziekenhuisopname Blijvende arbeidsongeschiktheid Aangeboren afwijking Overige ernstige afwijkingen 9. Welke actie is er ondernomen? Geen Dosering verhoogd Bijvend gestaakt Dosering onveranderd Tijdelijk gestaakt Onbekend Dosering verlaagd Anders / n.v.t. Versie 3 - 09/02/2016 ATTACG studie CRF - STUDIE UITVAL 1. Datum laatste dosis studie medicatie - - 2. Datum studie uitval - - 3. Belangrijkste reden voor uitval (Serious) Adverse events SUSAR Besluit van patiënt Besluit behandelaar Patiënt overleden Overige reden, namelijk: 4. Specificeer de reden voor uitval hieronder nader Versie 3 - 09/02/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 1 (Pagina 1 van 3) Patiëntcode./ medicatiecode 1. Wat is de datum waarop deze jichtaanval begon? (dd-mm-jjjj) - - 2. Wat is de datum vandaag? (dd-mm-jjjj) - - 3. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) 1 geen pijn 2 milde pijn 3 4 5 matige pijn veel pijn extreme pijn 4. Hoe gevoelig voor aanraking zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gevoelig licht gevoelig redelijk gevoelig heel gevoelig extreem gevoelig 5. Hoe gezwollen zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 niet gezwollen 2 enigszins gezwollen 3 4 5 redelijk gezwollen heel gezwollen extreem gezwollen 6. Wat vindt u van het beloop van uw klachten sinds het begin van deze jichtaanval? (1 vakje volledig inkleuren) 1 2 geheel zeer veel verdwenen verbeterd 3 4 veel verbeterd enigszins verbeterd 5 6 7 8 9 niet iets veel zeer veel niet van veranderd verslechterd verslechterd verslechterd toepassing 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 1 (Pagina 2 van 3) 7. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) Helemaal geen pijn 0 1 2 3 4 5 6 7 8 9 10 Ondraaglijke pijn 8. Als u denkt aan alle manieren waarop uw jicht u vandaag beïnvloedt, hoe gaat het dan met u? (1 vakje volledig inkleuren) Zeer slecht Zeer goed 0 1 2 3 4 5 6 7 8 9 10 9. Heeft u last van bijwerkingen? Zo ja, noteer hieronder de bijwerkingen die u vandaag ervaart: (1 letter per vakje) 10. Heeft u vandaag uw studiemedicatie ingenomen? (1 vakje volledig inkleuren) Nee Ja, alle medicijnen zoals voorgeschreven Ja, maar gedeeltelijk/niet alles zoals voorgeschreven 11. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? Wilt u dit aangeven door een verticaal streepje ( I ) te zetten op onderstaande lijn? helemaal geen pijn ondraaglijke pijn 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 1 (Pagina 3 van 3) 12. Heeft u de afgelopen 24 uur naast uw onderzoeksmedicatie, nog andere medicijnen ingenomen om uw jichtaanval te bestrijden? Zo ja, noteer hieronder de medicatie die u heeft ingenomen. Hieronder valt ook paracetamol en ibuprofen gebruik: (1 letter per vakje). Medicijn 1 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 2 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 3 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 2 (Pagina 1 van 3) Patiëntcode./ medicatiecode 1. Wat is de datum vandaag? (dd-mm-jjjj) - - 2. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) 1 2 3 4 5 geen pijn milde pijn matige pijn veel pijn extreme pijn 3. Hoe gevoelig voor aanraking zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gevoelig licht gevoelig redelijk gevoelig heel gevoelig extreem gevoelig 4. Hoe gezwollen zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gezwollen enigszins gezwollen redelijk gezwollen heel gezwollen extreem gezwollen 5. Wat vindt u van het beloop van uw klachten sinds het begin van deze jichtaanval? (1 vakje volledig inkleuren) 1 2 geheel zeer veel verdwenen verbeterd 3 4 veel verbeterd enigszins verbeterd 5 6 7 8 9 niet iets veel zeer veel niet van veranderd verslechterd verslechterd verslechterd toepassing 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 2 (Pagina 2 van 3) 6. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) Helemaal geen pijn 0 1 2 3 4 5 6 7 8 9 10 Ondraaglijke pijn 7. Als u denkt aan alle manieren waarop uw jicht u vandaag beïnvloedt, hoe gaat het dan met u? (1 vakje volledig inkleuren) Zeer slecht Zeer goed 0 1 2 3 4 5 6 7 8 9 10 8. Heeft u last van bijwerkingen? Zo ja, noteer hieronder de bijwerkingen die u vandaag ervaart: (1 letter per vakje) 9. Heeft u vandaag uw studiemedicatie ingenomen? (1 vakje volledig inkleuren) Nee Ja, alle medicijnen zoals voorgeschreven Ja, maar gedeeltelijk/niet alles zoals voorgeschreven 10. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? Wilt u dit aangeven door een verticaal streepje ( I ) te zetten op onderstaande lijn? helemaal geen pijn ondraaglijke pijn 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 2 (Pagina 3 van 3) 11. Heeft u de afgelopen 24 uur naast uw onderzoeksmedicatie, nog andere medicijnen ingenomen om uw jichtaanval te bestrijden? Zo ja, noteer hieronder de medicatie die u heeft ingenomen. Hieronder valt ook paracetamol en ibuprofen gebruik: (1 letter per vakje). Medicijn 1 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 2 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 3 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 3 (Pagina 1 van 3) Patiëntcode./ medicatiecode 1. Wat is de datum vandaag? (dd-mm-jjjj) - - 2. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) 1 geen pijn 2 milde pijn 3 4 5 matige pijn veel pijn extreme pijn 3. Hoe gevoelig voor aanraking zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gevoelig licht gevoelig redelijk gevoelig heel gevoelig extreem gevoelig 4. Hoe gezwollen zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gezwollen enigszins gezwollen redelijk gezwollen heel gezwollen extreem gezwollen 5. Wat vindt u van het beloop van uw klachten sinds het begin van deze jichtaanval? (1 vakje volledig inkleuren) 1 2 geheel zeer veel verdwenen verbeterd 3 4 veel verbeterd enigszins verbeterd 5 6 7 8 9 niet iets veel zeer veel niet van veranderd verslechterd verslechterd verslechterd toepassing 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 3 (Pagina 2 van 3) 6. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) Helemaal geen pijn 0 1 2 3 4 5 6 7 8 9 10 Ondraaglijke pijn 7. Als u denkt aan alle manieren waarop uw jicht u vandaag beïnvloedt, hoe gaat het dan met u? (1 vakje volledig inkleuren) Zeer slecht Zeer goed 0 1 2 3 4 5 6 7 8 9 10 8. Heeft u last van bijwerkingen? Zo ja, noteer hieronder de bijwerkingen die u vandaag ervaart: (1 letter per vakje) 9. Heeft u vandaag uw studiemedicatie ingenomen? (1 vakje volledig inkleuren) Nee Ja, alle medicijnen zoals voorgeschreven Ja, maar gedeeltelijk/niet alles zoals voorgeschreven 10. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? Wilt u dit aangeven door een verticaal streepje ( I ) te zetten op onderstaande lijn? helemaal geen pijn ondraaglijke pijn 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 3 (Pagina 3 van 3) 11. Heeft u de afgelopen 24 uur naast uw onderzoeksmedicatie, nog andere medicijnen ingenomen om uw jichtaanval te bestrijden? Zo ja, noteer hieronder de medicatie die u heeft ingenomen. Hieronder valt ook paracetamol en ibuprofen gebruik: (1 letter per vakje). Medicijn 1 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 2 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 3 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 4 (Pagina 1 van 3) Patiëntcode./ medicatiecode 1. Wat is de datum vandaag? (dd-mm-jjjj) - - 2. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) 1 2 3 4 5 geen pijn milde pijn matige pijn veel pijn extreme pijn 3. Hoe gevoelig voor aanraking zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gevoelig licht gevoelig redelijk gevoelig heel gevoelig extreem gevoelig 4. Hoe gezwollen zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gezwollen enigszins gezwollen redelijk gezwollen heel gezwollen extreem gezwollen 5. Wat vindt u van het beloop van uw klachten sinds het begin van deze jichtaanval? (1 vakje volledig inkleuren) 1 2 geheel zeer veel verdwenen verbeterd 3 4 veel verbeterd enigszins verbeterd 5 6 7 8 9 niet iets veel zeer veel niet van veranderd verslechterd verslechterd verslechterd toepassing 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 4 (Pagina 2 van 3) 6. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) Helemaal geen pijn 0 1 2 3 4 5 6 7 8 9 10 Ondraaglijke pijn 7. Als u denkt aan alle manieren waarop uw jicht u vandaag beïnvloedt, hoe gaat het dan met u? (1 vakje volledig inkleuren) Zeer slecht Zeer goed 0 1 2 3 4 5 6 7 8 9 10 8. Heeft u last van bijwerkingen? Zo ja, noteer hieronder de bijwerkingen die u vandaag ervaart: (1 letter per vakje) 9. Heeft u vandaag uw studiemedicatie ingenomen? (1 vakje volledig inkleuren) Nee Ja, alle medicijnen zoals voorgeschreven Ja, maar gedeeltelijk/niet alles zoals voorgeschreven 10. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? Wilt u dit aangeven door een verticaal streepje ( I ) te zetten op onderstaande lijn? helemaal geen pijn ondraaglijke pijn 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 4 (Pagina 3 van 3) 11. Heeft u de afgelopen 24 uur naast uw onderzoeksmedicatie, nog andere medicijnen ingenomen om uw jichtaanval te bestrijden? Zo ja, noteer hieronder de medicatie die u heeft ingenomen. Hieronder valt ook paracetamol en ibuprofen gebruik: (1 letter per vakje). Medicijn 1 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 2 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 3 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 5 (Pagina 1 van 3) Patiëntcode./ medicatiecode 1. Wat is de datum vandaag? (dd-mm-jjjj) - - 2. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) 1 geen pijn 2 3 milde pijn matige pijn 4 5 veel pijn extreme pijn 3. Hoe gevoelig voor aanraking zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gevoelig licht gevoelig redeijk gevoelig heel gevoelig extreem gevoelig 4. Hoe gezwollen zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gezwollen enigszins gezwollen redelijk gezwollen heel gezwollen extreem gezwollen 5. Wat vindt u van het beloop van uw klachten sinds het begin van deze jichtaanval? (1 vakje volledig inkleuren) 1 2 geheel zeer veel verdwenen verbeterd 3 4 veel verbeterd enigszins verbeterd 5 6 7 8 9 niet iets veel zeer veel niet van veranderd verslechterd verslechterd verslechterd toepassing 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 5 (Pagina 2 van 3) 6. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) Helemaal geen pijn 0 1 2 3 4 5 6 7 8 9 10 Ondraaglijke pijn 7. Als u denkt aan alle manieren waarop uw jicht u vandaag beïnvloedt, hoe gaat het dan met u? (1 vakje volledig inkleuren) Zeer slecht Zeer goed 0 1 2 3 4 5 6 7 8 9 10 8. Heeft u last van bijwerkingen? Zo ja, noteer hieronder de bijwerkingen die u vandaag ervaart: (1 letter per vakje) 9. Heeft u vandaag uw studiemedicatie ingenomen? (1 vakje volledig inkleuren) Nee Ja, alle medicijnen zoals voorgeschreven Ja, maar gedeeltelijk/niet alles zoals voorgeschreven 10. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? Wilt u dit aangeven door een verticaal streepje ( I ) te zetten op onderstaande lijn? helemaal geen pijn ondraaglijke pijn 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 5 (Pagina 3 van 3) 11. Heeft u de afgelopen 24 uur naast uw onderzoeksmedicatie, nog andere medicijnen ingenomen om uw jichtaanval te bestrijden? Zo ja, noteer hieronder de medicatie die u heeft ingenomen. Hieronder valt ook paracetamol en ibuprofen gebruik: (1 letter per vakje). Medicijn 1 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 2 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 3 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 6 (Pagina 1 van 3) Patiëntcode./ medicatiecode 1. Wat is de datum vandaag? (dd-mm-jjjj) - - 2. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) 1 2 3 4 5 geen pijn milde pijn matige pijn veel pijn extreme pijn 3. Hoe gevoelig voor aanraking zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gevoelig licht gevoelig redelijk gevoelig heel gevoelig extreem gevoelig 4. Hoe gezwollen zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gezwollen enigszins gezwollen redelijk gezwollen heel gezwollen extreem gezwollen 5. Wat vindt u van het beloop van uw klachten sinds het begin van deze jichtaanval? (1 vakje volledig inkleuren) 1 2 geheel zeer veel verdwenen verbeterd 3 4 veel verbeterd enigszins verbeterd 5 6 7 8 9 niet iets veel zeer veel niet van veranderd verslechterd verslechterd verslechterd toepassing 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 6 (Pagina 2 van 3) 6. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) Helemaal geen pijn 0 1 2 3 4 5 6 7 8 9 10 Ondraaglijke pijn 7. Als u denkt aan alle manieren waarop uw jicht u vandaag beïnvloedt, hoe gaat het dan met u? Zeer slecht Zeer goed 0 1 2 3 4 5 6 7 8 9 10 8. Heeft u last van bijwerkingen? Zo ja, noteer hieronder de bijwerkingen die u vandaag ervaart: (1 letter per vakje) 9. Heeft u vandaag uw studiemedicatie ingenomen? (1 vakje volledig inkleuren) Nee Ja, alle medicijnen zoals voorgeschreven Ja, maar gedeeltelijk/niet alles zoals voorgeschreven 10. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? Wilt u dit aangeven door een verticaal streepje ( I ) te zetten op onderstaande lijn? helemaal geen pijn ondraaglijke pijn 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 6 (Pagina 3 van 3) 11. Heeft u de afgelopen 24 uur naast uw onderzoeksmedicatie, nog andere medicijnen ingenomen om uw jichtaanval te bestrijden? Zo ja, noteer hieronder de medicatie die u heeft ingenomen. Hieronder valt ook paracetamol en ibuprofen gebruik: (1 letter per vakje). Medicijn 1 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 2 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 3 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 7 (Pagina 1 van 3) Patiëntcode./ medicatiecode 1. Wat is de datum vandaag? (dd-mm-jjjj) - - 2. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) 1 2 geen pijn milde pijn 3 4 5 matige pijn veel pijn extreme pijn 3. Hoe gevoelig voor aanraking zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gevoelig licht gevoelig redelijk gevoelig heel gevoelig extreem gevoelig 4. Hoe gezwollen zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag? (1 vakje volledig inkleuren) 1 2 3 4 5 niet gezwollen enigszins gezwollen redelijk gezwollen heel gezwollen extreem gezwollen 5. Wat vindt u van het beloop van uw klachten sinds het begin van deze jichtaanval? (1 vakje volledig inkleuren) 1 2 geheel zeer veel verdwenen verbeterd 3 4 veel verbeterd enigszins verbeterd 5 6 7 8 9 niet iets veel zeer veel niet van veranderd verslechterd verslechterd verslechterd toepassing 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 7 (Pagina 2 van 3) 6. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren) Helemaal geen pijn 0 1 2 3 4 5 6 7 8 9 10 Ondraaglijke pijn 7. Als u denkt aan alle manieren waarop uw jicht u vandaag beïnvloedt, hoe gaat het dan met u? (1 vakje volledig inkleuren) Zeer slecht Zeer goed 0 1 2 3 4 5 6 7 8 9 10 8. Heeft u last van bijwerkingen? Zo ja, noteer hieronder de bijwerkingen die u vandaag ervaart: (1 letter per vakje) 9. Heeft u vandaag uw studiemedicatie ingenomen? (1 vakje volledig inkleuren) Nee Ja, alle medicijnen zoals voorgeschreven Ja, maar gedeeltelijk/niet alles zoals voorgeschreven 10. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? Wilt u dit aangeven door een verticaal streepje ( I ) te zetten op onderstaande lijn? helemaal geen pijn ondraaglijke pijn 52901 Versie 3 - 27/01/2016 ATTACG studie JICHTAANVAL DAGBOEK - DAG 7 (Pagina 3 van 3) 11. Heeft u de afgelopen 24 uur naast uw onderzoeksmedicatie, nog andere medicijnen ingenomen om uw jichtaanval te bestrijden? Zo ja, noteer hieronder de medicatie die u heeft ingenomen. Hieronder valt ook paracetamol en ibuprofen gebruik: (1 letter per vakje). Medicijn 1 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 2 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram Medicijn 3 Naam medicijn volgens de verpakking Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn? Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is) , Microgram Milligram 52901 Versie 3 - 27/01/2016 ATTACG studie VRAGENLIJST VOOR PATIËNTEN - FYSIEK FUNCTIONEREN 1/2 De volgende vragen gaan over de invloed van uw ziekte op het functioneren in het dagelijks leven. Kruis het antwoord aan dat het best beschrijft wat u meestal kon doen in de AFGELOPEN WEEK. zonder enige moeite met enige moeite met veel moeite onmogelijk uit te voeren AANKLEDING EN VERZORGING - Kunt u zichzelf aankleden, inclusief veters strikken en knopen dichtmaken? - Kunt u uw haren wassen? OPSTAAN - Kunt u opstaan vanuit een rechte stoel? - Kunt u in en uit bed komen? ETEN - Kunt u vlees snijden? - Kunt u een vol kopje of glas naar de mond brengen? - Kunt u een nieuw pak melk openen? LOPEN - Kunt u buitenshuis op een vlakke grond wandelen? - Kunt u vijf traptreden oplopen? Kruis aan welke HULPMIDDELEN u normaal gebruikt voor de bovenstaande activiteiten: Wandelstok Rollator / looprekje Krukken Rolstoel Hulpmiddelen, gebruikt bij het aankleden (knoophaak, ritssluiting-trekker, lange-steel schoenlepel, etc.) Speciale of aangepaste hulpmiddelen bij eten of drinken Speciale of aangepaste stoel Overig, namelijk: Kruis elke categorie aan waarvoor u normaal HULP VAN ANDEREN nodig heeft: Aankleden / verzorging Eten Opstaan Lopen 9373 Versie 3 - 27/01/2016 ATTACG studie VRAGENLIJST VOOR PATIËNTEN - FYSIEK FUNCTIONEREN 2/2 Kruis het antwoord aan dat het best beschrijft wat u meestal kon doen IN DE AFGELOPEN WEEK. zonder enige moeite met enige moeite met veel moeite onmogelijk uit te voeren HYGIËNE - Kunt u zelf uw lichaam wassen en afdrogen? - Kunt u in en uit bad komen? - Kunt u op en van het toilet? komen? REIKEN - Kunt u een 2,5 kg wegend voorwerp, zoals een pak suiker, bereiken en omlaaghalen van net boven uw hoofd? - Kunt u voorover buigen om kleren van de vloer op te rapen? GRIJPKRACHT - Kunt u auto-portieren openen? - Kunt u deksels van potten, die al eens geopend zijn, losdraaien? - Kunt u een kraan open- en dichtdraaien? ACTIVITEITEN - Kunt u boodschappen doen en winkelen? - Kunt u in en uit een auto komen? - Kunt u klusssen doen, zoals stofzuigen of tuinieren? Kruis aan welke HULPMIDDELEN u normaal gebruikt voor de bovenstaande activiteiten: Verhoogd toilet Lange-steel hulpmiddelen om iets te bereiken Zitje in de badkuip Lange-steel hulpmiddelen in de badkamer Potdeksel-opener Overig, namelijk: Badkuip-muurstang Kruis elke categorie aan waarvoor u normaal HULP VAN ANDEREN nodig heeft: Wassen en toiletbezoek Voorwerpen pakken en openen Naar voorwerpen reiken Boodschappen doen en klussen 9373 Versie 3 - 27/01/2016 ATTACG studie VRAGENLIJST VOOR PATIËNTEN - GEZONDHEIDSSTATUS 1/4 Deze vragenlijst gaat over uw standpunten t.a.v. uw gezondheid. Wilt u elke vraag beantwoorden door het juiste hokje aan te kruisen. Wanneer u twijfelt over het antwoord op een vraag, probeer dan het antwoord te geven dat het meest van toepassing is. 1. Hoe zou u over het algemeen uw gezondheid noemen? uitstekend zeer goed goed matig slecht 2. Hoe beoordeelt u nu uw gezondheid over het algemeen, vergeleken met een jaar geleden? veel beter nu dan een jaar geleden wat beter nu dan een jaar geleden ongeveer hetzelfde nu als een jaar geleden wat slechter nu dan een jaar geleden veel slechter nu dan een jaar geleden 3. De volgende vragen gaan over bezigheden die u misschien doet op een doorsnee dag. Wordt u door uw gezondheid op dit moment beperkt bij deze bezigheden? Zo ja, in welke mate? ja, ernstig beperkt ja, een beetje beperkt nee, helemaal niet beperkt a. Forse inspanning, zoals hardlopen, tillen van zware voorwerpen, een veeleisende sport beoefenen b. Matige inspanning, zoals een tafel verplaatsen, stofzuigen, zwemmen of fietsen c. Boodschappen tillen of dragen d. Een paar trappen oplopen e. Eén trap oplopen f. Bukken, knielen of hurken g. Meer dan een kilometer lopen h. Een paar honderd meter lopen i. Ongeveer honderd meter lopen j. Uzelf wassen of aankleden 9373 SF-36v2™ Health Survey 1992,2003 Health Assessment Lab, Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. SF-36® is a registered trademark of Medical Outcomes Trust. (SF-36v2 Standard, Netherlands (Dutch)) ATTACG studie VRAGENLIJST VOOR PATIËNTEN - GEZONDHEIDSSTATUS 2/4 4. Hoe vaak heeft u in de afgelopen 4 weken, één van de volgende problemen bij uw werk of andere dagelijkse bezigheden gehad, ten gevolge van uw lichamelijke gezondheid? altijd meestal soms zelden nooit a. U besteedde minder tijd aan werk of andere bezigheden b. U heeft minder bereikt dan u zou willen c. U was beperkt in het soort werk of andere bezigheden d. U had moeite om uw werk of andere bezigheden uit te voeren (het kostte u bijvoorbeeld extra inspanning) 5. Hoe vaak heeft u in de afgelopen 4 weken, één van de volgende problemen ondervonden bij uw werk of andere dagelijkse bezigheden, ten gevolge van emotionele problemen (zoals depressieve of angstige gevoelens)? altijd meestal soms zelden nooit a. U besteedde minder tijd aan werk of andere bezigheden b. U heeft minder bereikt dan u zou willen c. U deed uw werk of andere bezigheden niet zo zorgvuldig als gewoonlijk 6. In hoeverre hebben uw lichamelijke gezondheid of emotionele problemen u gedurende de afgelopen 4 weken gehinderd in uw normale omgang met familie, vrienden of buren, of bij activiteiten in groepsverband? helemaal niet enigszins nogal veel heel erg veel 9373 SF-36v2™ Health Survey 1992,2003 Health Assessment Lab, Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. SF-36® is a registered trademark of Medical Outcomes Trust. (SF-36v2 Standard, Netherlands (Dutch)) ATTACG studie VRAGENLIJST VOOR PATIËNTEN - GEZONDHEIDSSTATUS 3/4 7. Hoeveel lichamelijke pijn heeft u de afgelopen 4 weken gehad? geen heel licht licht nogal ernstig heel ernstig 8. In welke mate bent u de afgelopen 4 weken door pijn gehinderd in uw normale werk (zowel werk buitenshuis als huishoudelijk werk)? helemaal niet enigszins nogal veel heel erg veel 9. Deze vragen gaan over hoe u zich voelt en hoe het met u ging in de afgelopen 4 weken. Wilt u alstublieft bij elke vraag het antwoord geven dat het best benadert hoe u zich voelde? Hoe vaak gedurende de afgelopen 4 weken... altijd meestal soms zelden nooit a. Voelde u zich levenslustig? b. Was u erg zenuwachtig? c. Zat u zo in de put dat niets u kon opvrolijken? d. Voelde u zich rustig en tevreden? e. Had u veel energie? f. Voelde u zich somber en neerslachtig? g. Voelde u zich uitgeput? h. Voelde u zich gelukkig? i. Voelde u zich moe? 9373 SF-36v2™ Health Survey 1992,2003 Health Assessment Lab, Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. SF-36® is a registered trademark of Medical Outcomes Trust. (SF-36v2 Standard, Netherlands (Dutch)) ATTACG studie VRAGENLIJST VOOR PATIËNTEN - GEZONDHEIDSSTATUS 4/4 10. Hoe vaak hebben uw lichamelijke gezondheid of emotionele problemen u gedurende de afgelopen 4 weken gehinderd bij uw sociale activiteiten (zoals vrienden of familie bezoeken, etc.)? altijd meestal soms zelden nooit 11. Hoe JUIST of ONJUIST is elk van de volgende uitspraken voor u? volkomen juist grotendeels juist weet ik niet groten- volkomen deels onjuist onjuist a. Ik lijk wat gemakkelijker ziek te worden dan andere mensen b. Ik ben even gezond als andere mensen die ik ken c. Ik verwacht dat mijn gezondheid achteruit zal gaan d. Mijn gezondheid is uitstekend 9373 SF-36v2™ Health Survey 1992,2003 Health Assessment Lab, Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. SF-36® is a registered trademark of Medical Outcomes Trust. (SF-36v2 Standard, Netherlands (Dutch)) ATTACG studie VRAGENLIJST VOOR PATIËNTEN - ZORGGEBRUIK (1/2) 1. Heeft u een bezoek gebracht aan een van onderstaande gezondheidsmedewerkers SINDS UW VORIGE BEZOEK BIJ DE REUMATOLOOG? Zo ja, geef aan hoe vaak u geweest bent. Reumatoloog Maagdarmlever arts Psychiater Verpleegkundig consulent / onderzoeksverpleegkundige Nefroloog Fysiotherapeut Physician assistant / verpleegkundige specialist Neuroloog Ergotherapeut Huisarts Oncoloog Oefentherapeut Anestesioloog Oogarts Hydrotherapeut Bedrijfsarts Orthopeed Podotherapeut Cardioloog Orthop. schoenmaker Chirurg Revalidatie arts Dermatoloog Kaakchirurg Gynaecoloog Uroloog Hematoloog Vaatchirurg Internist Maatschappelijk werker Plastisch chirurg Psycholoog KNO arts Psychotherapeut Longarts 9373 Versie 2 - 30/06/2015 ATTACG studie VRAGENLIJST VOOR PATIËNTEN - ZORGGEBRUIK (2/2) 2. Heeft u sinds uw vorige bezoek bij de reumatoloog professionele hulp gekregen in verband met persoonlijke verzorging of verpleging? Zo ja, hoeveel uur gemiddeld per week? 3. Heeft u sinds uw vorige bezoek bij de reumatoloog gebruik gemaakt van betaalde huishoudelijke hulp, bijvoorbeeld alfa hulp? Zo ja hoeveel uur gemiddeld per week? 4. Heeft u sinds uw vorige bezoek bij de reumatoloog hulp gekregen van uw partner, familie of vrienden in verband met persoonlijke verzorging of het huishouden als gevolg van jicht? Zo ja hoeveel uur gemiddeld per week? 5. Wat is uw arbeidssituatie (meerdere antwoorden mogelijk) Betaald werk VUT/pensioen WAO/WIA Vrijwilligerswerk Geen van bovenstaande 6. Heeft u een van onderstaande behandelingen ondergaan sinds uw vorige bezoek bij de reumatoloog? Zo ja, geef het aantal aan Maken van een röntgen foto Het maken van een MRI Maken van een echo Het maken van een CT-scan 7. Bent u sinds uw vorige bezoek bij de reumatoloog in een van onderstaande zorginstellingen opgenomen geweest? Zo ja, geef de duur van de opname dan in dagen. Het is niet nodig om dagopnames voor de toediening van medicatie te noteren Academisch ziekenhuis Dagen Intensive care academisch ziekenhuis Dagen Algemeen ziekenhuis Dagen Intensive care algemeen ziekenhuis Dagen Revalidatiecentrum Dagen Verpleeghuis Dagen 9373 Versie 2 - 30/06/2015 ATTACG studie VRAGENLIJST VOOR PATIËNTEN - WERK PRODUCTIVITEIT (1/1) 1. Hebt u op dit moment een baan (werkt u tegen betaling)? Indien nee, kies nee en ga verder naar vraag 6 Ja Nee 2. Hoeveel uur was u tijdens de afgelopen zeven dagen afwezig van uw werk in verband met uw jicht? Reken hierbij de uren die u gemist hebt op dagen waarop u ziek was, later op het werk kwam, vroeger wegging enz. Reken hier de tijd die u gemist hebt omdat u aan deze studie meedoet niet bij uur 3. Hoeveel uur bent u tijdens de afgelopen 7 dagen afwezig geweest van uw werk vanwege een andere reden, zoals vakantie, feestdagen, tijd die u vrij hebt genomen om aan deze studie deel te nemen? uur 4. Hoeveel uur hebt u in de afgelopen 7 dagen daadwerkelijk gewerkt? (indien 0, ga door naar vraag 6) uur 5. Hoezeer heeft uw jicht in de afgelopen 7 dagen uw productiviteit beïnvloed TERWIJL U AAN HET WERK WAS? (denk aan de dagen waarop u beperkt werd in de hoeveelheid of het soort werk dat u kon doen, minder bereikte dan u gewild had of niet zo zorgvuldig kon werken als gewoonlijk.) Jicht had geen invloed op mijn werk 0 1 2 3 4 5 6 7 8 9 Jicht heeft mij volledig belet mijn werk te doen 10 6. Hoezeer heeft uw jicht tijdens de afgelopen 7 dagen uw vermogen beïnvloed uw normale dagelijkse activiteiten, buiten uw baan, uit te voeren? Met normale bezigheden bedoelen we activiteiten die u gewoonlijk uitvoert zoals werk in en rondom het huis, winkelen, voor de kinderen zorgen, lichaamsbeweging, studeren, enz. Denk aan de momenten waarop u beperkt werd in de hoeveelheid of soort activiteiten die u kon doen of minder bereikte dan u gewild had. Jicht had geen invloed op mijn activiteiten 0 1 2 3 4 5 6 7 8 9 10 Jicht heeft mij volledig belet mijn activiteiten te doen 9373 Versie 2 - 30/06/2015 DSMB Charter “ATTACG: Anakinra versus treatment as usual in the treatment of acute gout” Dossier: NL52526.044.15 / EudraCT number: 2015-000696-27 Introduction This charter is for the Data Safety Monitoring Board (DSMB) which will act in advisory capacity to prof. dr. M.A.F.J. van de Laar, Medisch Spectrum Twente, Ariënsplein 1 7511 JX, Enschede, conducting the ATTACG study funded by ZonMw. The purpose of this document is to describe the roles and responsibilities of the DSMB, describe board processes and describe the method of reporting. DSMB Roles and Responsibilities The DSMB roles and responsibilities are: - To perform ongoing safety surveillance of the study participants To advise prof. dr. M.A.F.J. van de Laar on if breaking the randomization (treatment) code is needed if cases of SAE or SUSARs arise during the trial To report to prof. dr. M.A.F.J. van de Laar on the safety of anakinra during the trial To decide to prematurely stop the study if felt the safety of the patients is being jeopardized The DSMB will discharge itself from its duties when the last participant completes the study. Membership The DSMB will consist of 3 advisory members: 1. Prof. dr. Rene Westhovens, rheumatologist, Universiteit Ziekenhuis Leuven, Belgium. 2. Dr. Mark Reinders, hospital pharmacist, Atrium Medisch Centrum, Heerlen, the Netherlands. 3. Prof. dr. Thomas Bardin, rheumatologist, Hôpital Lariboisière, Paris, France / professor of rheumatology, Université Paris VII. There are no financial, scientific, or other conflict of interest with the study. Before the trial The DSMB will be informed about its duties and the study before the start of the trial by means of this DSMB charter and the final study protocol. If needed, the principal investigator (tel. 053-487 2450 / email: m.vandelaar@mst.nl) or coordinating investigator (tel. 06-2855-4650 email: c.a.janssen@utwente.nl) may be contacted if any aspects of the study and duties of the DSMB are not clear. During the trial The DSMB will review safety data when 50 patients allocated to the anakinra treatment study group have been included in the study. At this point in time the committee will review the safety data on the documented and frequency of side effects and/or AE/SAE among patients using anakinra. The coordinating investigator will provide the necessary data to the DSMB. A recommendation regarding the outcome of this evaluation will be made available to the principal investigator. At any point in time an emergency evaluation of the safety data may be called upon (by DSMB chairman or principal investigator) should safety issues or other unanticipated problems arise. In cases of SAE or SUSARs and the sponsor feels breaking the randomization (treatment) code may need to be broken in order to treat the patient, the sponsor may decide to contact the DSMB for advice regarding this matter. A recommendation to terminate the study may be made by the DSMB at any time. The DSMB should communicate such a recommendation to the principal investigator immediately by telephone and confirmed by email (tel. 053 – 487 2450 / email: m.vandelaar@mst.nl). Reporting A formal report, including an advice and/or recommendation for continuation or modification of the study will be prepared by the DSMB and when finalized be submitted to the principal investigator. The principal investigator is responsible for distributing the DSMB recommendations to all other study investigators. A copy of all the DSMB recommendations will be sent to the authorizing METC. When the principal investigator decides not to implement the recommendations, besides the copy, a clear and convincing reasoning for why the advice has not been followed should be included and sent to the authorizing METC as well. Confidentiality All materials, discussions and proceedings of the DSMB are completely confidential. Members and other participants in the DSMB meetings are expected to maintain confidentiality.