A Study to Evaluate Efficacy and Safety of Anakinra in the Treatment of Acute Gouty Arthritis

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

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

Official Title
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A Randomized, Double-blind, Active-control, Multicenter, Efficacy and Safety Study of 2 Dose Levels of Subcutaneous Anakinra Compared to Intramuscular Triamcinolone in the Treatment of Acute Gouty Arthritis, Followed by an Extension Period of up to 2 Years

Conditions
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Acute Gouty Arthritis

Intervention / Treatment
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* Drug: Anakinra 100 mg
* Drug: Triamcinolone Acetonide 40 mg
* Drug: Placebo to Anakinra 100 mg
* Drug: Placebo to Triamcinolone Acetonide 40 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed consent Patient meeting the American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) 2015 gout classification criteria History of ≥1 self-reported flares of gouty arthritis within 12 months Current ongoing flare of gouty arthritis characterized by pain intensity Currently tender and swollen joint Onset of current flare within 4 days Intolerant, unresponsive, contraindicated or not appropriate for treatment with NSAIDs and colchicine (both treatment options) If on urate-lowering therapy, on a stable dose and regimen Women of childbearing potential willing to use adequate contraception Inclusion criteria for treatment of subsequent flare(s) Current flare of gouty arthritis characterized by pain intensity Currently tender and swollen joint Women of childbearing potential willing to use adequate contraception Exclusion Criteria: Use of specified pain relief medications or biologics (including glucocorticoids, narcotics, paracetamol/acetaminophen, NSAIDs, colchicine, IL-blockers and tumor necrosis factor inhibitors) within specified periods prior to randomization Contraindication to triamcinolone Polyarticular gouty arthritis involving more than 4 joints Rheumatoid arthritis, evidence/suspicion of infectious/septic arthritis, or other acute inflammatory arthritis History of malignancy within the past 5 years. Exceptions are basal cell skin cancer, carcinoma-in-situ of the cervix or low-risk prostate cancer after curative therapy. Known hypersensitivity to Escherichia coli-derived proteins, Kineret® (anakinra), Kenalog® (triamcinolone acetonide) or any components of the products. Known presence or suspicion of active or recurrent bacterial, fungal or viral infections, including tuberculosis, or HIV infection or hepatitis B or C infection Presence of severe renal function impairment chronic kidney disease (CKD) stages 4 and 5 Presence of neutropenia Uncontrolled clinically significant hematologic, pulmonary, endocrine, metabolic, gastrointestinal, central nervous system or hepatic disease History of myocardial infarction, unstable angina, cerebrovascular events, or coronary artery bypass grafting, New York Heart Association (NYHA) class III or IV heart failure within the previous 3 months Patients who have undergone major surgery within 2 weeks, or have an unhealed operation wound/s Presence of any medical or psychological condition or laboratory result that in the opinion of the investigator might create risk to the patients or to the study. Earlier or current treatment with anakinra Pregnant or lactating women History of >12 flares overall in the 6 months prior to randomization Exclusion criteria for treatment of subsequent flare(s): Known presence or suspicion of active or recurrent bacterial, fungal or viral infections, including tuberculosis, or HIV infection or hepatitis B or C infection. Presence of severe renal function impairment CKD stages 4 and 5 Presence of neutropenia History of myocardial infarction, unstable angina, cerebrovascular events, or coronary artery bypass grafting, NYHA class III or IV heart failure within the previous 3 months Patients who have undergone major surgery within 2 weeks or have an unhealed operation wound/s. Pregnant or lactating women. Presence of any condition or laboratory result that in the opinion of the investigator makes the patient not appropriate for treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anakinra 100 mg<br>1 subcutaneous injection of Anakinra 100 mg once daily for 5 days, 1 subcutaneous injection of Placebo to Anakinra 100 mg once daily for 5 days and 1 single intramuscular injection of Placebo to Triamcinolone Acetonide 40 mg | Drug: Anakinra 100 mg<br>* 100 mg/0.67 mL solution in single-use prefilled syringes for subcutaneous injection<br>* Other names: Kineret;Drug: Placebo to Anakinra 100 mg<br>* sterile solution for injection (0.67 mL) in a single-use prefilled syringe identical to the anakinra syringe<br>* Other names: Placebo Kineret;Drug: Placebo to Triamcinolone Acetonide 40 mg<br>* 1 mL intramuscular injectable suspension with identical appearance as the Triamcinolone Acetonide suspension<br>* Other names: Placebo Kenalog;|
| Experimental: Anakinra 200 mg<br>2 subcutaneous injections of Anakinra 100 mg (2 syringes) once daily for 5 days and 1 single intramuscular injection of Placebo to Triamcinolone Acetonide 40 mg | Drug: Anakinra 100 mg<br>* 100 mg/0.67 mL solution in single-use prefilled syringes for subcutaneous injection<br>* Other names: Kineret;Drug: Placebo to Triamcinolone Acetonide 40 mg<br>* 1 mL intramuscular injectable suspension with identical appearance as the Triamcinolone Acetonide suspension<br>* Other names: Placebo Kenalog;|
| Active Comparator: Triamcinolone 40 mg<br>2 subcutaneous injections of Placebo to Anakinra 100 mg once daily for 5 days and 1 single intramuscular injection of Triamcinolone Acetonide 40 mg | Drug: Triamcinolone Acetonide 40 mg<br>* 1 mL intramuscular injection of a 40 mg/mL injectable suspension<br>* Other names: Triamcinolone;Drug: Placebo to Anakinra 100 mg<br>* sterile solution for injection (0.67 mL) in a single-use prefilled syringe identical to the anakinra syringe<br>* Other names: Placebo Kineret;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Patient-assessed Pain Intensity in the Index Joint From Baseline to 24-72 Hours for the First Gout Flare Treated in the Study as Measured by VAS | Patients will score their pain intensity in the joint most affected at baseline (index joint) on a 0-100 mm visual analogue scale (VAS), ranging from no pain (0) to unbearable pain (100). Average of the assessments performed at 24, 48 and 72 hours. | At baseline (pre-dose) and at 24, 48 and 72 hours for the first gout flare treated in the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Patient-assessed Pain Intensity in the Index Joint From Baseline at Time Points From 6 Hours to 8 Days for the First Gout Flare Treated in the Study as Measured by 5-point Likert Scale | Patients will score their pain intensity in the joint most affected at baseline (index joint) on a 5-point Likert scale (0-4 point scale: none, mild, moderate, severe, extreme) at time points baseline (pre-dose) and at 6, 12, 18, 24, 36, 48 and 72 hours and Day 5, 6, 7 and 8. | At baseline (pre-dose) and at 6, 12, 18, 24, 36, 48 and 72 hours and Day 5, 6, 7 and 8 for the first gout flare treated in the study | 
| Median Time to Onset of Effect | Onset of effect defined as 20% change from baseline pain intensity in the index joint on a visual analogue scale (VAS) | From baseline (predose) up to Day15 of the first flare treated in the study | 
| Median Time to Response | Response defined as 50% change from baseline pain intensity on a visual analogue scale (VAS) | From baseline (predose) up to Day15 of the first flare treated in the study | 
| Median Time to Resolution of Pain | Resolution of pain defined as <10 mm on VAS, a continuous 0 to 100 mm visual analogue scale, ranging from no pain (0) to unbearable pain (100), in the index joint | From baseline (predose) up to Day15 of the first flare | 
| Median Time to First Intake of Rescue Medication From First Investigational Drug Administration | Time to first intake of rescue medication for acute gout, measured in hours from first investigational drug administration | From Day 1 to Day 15 for the first flare treated | 
| Physician's Assessment of Global Response to Treatment | 5-point Likert scale (0- to 4-point scale: none, mild, moderate, severe, extreme) where higher score mean worse outcome | At 72 hours, Day 8 and Day 15 for the first flare treated in the study | 
| Physician's Assessment of Clinical Signs in Index Joint: Tenderness | 4-point Likert scale (0=no pain, 1= mild/patient states there is pain when touched, 2= moderate/patient states there is pain and Winces, 3=severe/patient states there is pain, winces and withdraws | at 72 hours, Day 8 and Day 15 for the first flare treated in the study | 
| Physician's Assessment of Clinical Signs in Index Joint: Swelling | 4-point Likert scale (0=no swelling, 1= mild swelling, 2=moderate swelling, 3=severe swelling or bulging beyond joint margins) | at 72 hours, Day 8 and Day 15 for the first flare treated in the study | 
| Physician's Assessment of Clinical Signs in Index Joint: Erythema | Physicians assessment of clinical signs with 2 outcomes: Absent=no erythema, present=erythema | at 72 hours, Day 8 and Day 15 for the first flare treated in the study | 
| Patient´s Assessment of Global Response to Treatment (5-point Likert Scale) | 5-point Likert scale (0- to 4-point scale: 0=excellent, 1=very good, 2=good, 3=fair, 4=poor response to treatment) where lower rate indicates better response to treatment | at 72 hours, Day 8 and Day 15 for the first flare treated in the study | 
| Change From Baseline in the Inflammatory Biomarker C Reactive Protein | This endpoint represents the change from baseline, mg/dL, of the inflammatory biomarker C reactive protein | baseline (predose) and at 72 hours, Day 8 and Day 15 for the first flare treated in the study | 
| Change From Baseline in the Inflammatory Biomarker Serum Amyloid A | This endpoint represents the change from baseline, mg/L, of the inflammatory biomarker Serum amyloid A | baseline (predose) and at 72 hours, Day 8 and Day 15 for the first flare treated in the study | 
| The Percent of Patients With at Least One Adverse Event | All adverse events to be recorded Day 1 - Day 28 for each flare. Serious adverse events (SAE) will be collected from informed consent until week 12 for each flare. Any SAE with suspected causal relationship should be reported irrespective of the time of occurrence. | Through study completion, at 12 weeks after last flare treated during the extension period | 
| The Percent of Patients With at Least One Serious Adverse Event, Including Death | Serious Adverse Events (SAE) will be collected from informed consent until week 12 for each flare. Any SAE with suspected causal relationship should be reported irrespective of the time of occurrence. | Through study completion, at 12 weeks after last flare treated during the extension period | 
| Serum Concentration of Endogenous Interleukin-1 Receptor Antagonist /Anakinra | This endpoint represents the level of of endogenous interleukin-1 receptor antagonist /anakinra | Baseline (predose) and at 72 hours, Day 8, Day 15, Day 28 and Week 12 for the first flare and subsequent flares treated during the extension period | 
| Proportion of Patients With Anti-drug Antibodies (ADA) Against Anakinra | Confirmed ADA positive samples will be analysed for the presence of neutralizing antibodies | Baseline (predose) and at 72 hours, Day 8, Day 15, Day 28 and Week 12 for the first flare and subsequent flares treated treated during the extension period | 
| Proportion of Patients With Neutralizing Antibodies | Confirmed ADA positive samples will be analysed for the presence of neutralizing antibodies | Baseline (predose) and at 72 hours, Day 8, Day 15, Day 28 and Week 12 for the first flare and subsequent flares treated during the extension period | 
| Change From Baseline in Short Form (36) Health Survey, Acute Version 2 (SF-36®) Physical Functioning Domain Score | SF-36® measures the impact of disease on overall quality of life. It consists of 8 individual domains. Score range from 0 to 100, where 0 represents the worst possible health and 100 is perfect health. | at baseline, Day 8 and Day 15 for the first flare treated in the study | 
| Change From Baseline in Health Related Quality of Life EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) | Exploratory objective. The EQ-5D-5L, a self-report questionnaire, is a descriptive system of Health related quality of life (HRQL) states consisting of 5 dimensions (Mobility, Self-care, Usual activities, Pain/Discomfort, Anxiety/Depression), each of which can have 5 responses. The responses record 5 levels of severity (no problems/slight problems/moderate problems/severe problems/extreme problems) within a particular EQ-5D dimension. | at baseline, Day 8 and Day 15 for the first flare treated in the study | 
| Percent Impairment While Working During Last Week Due to Gout During the First Flare and Subsequent Flares | The WPAI yeilds four types of scores of which Work productivity loss is one. SHP is derived from WPAI as follows: The WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity as follows: Questions: Q1 = currently employed Q2 = hours missed due to specified problem Q3 = hours missed other reasons Q4 = hours actually worked Q5 = degree problem affected productivity while working Q6 = degree problem affected regular activities Scores: Multiply scores by 100 to express in percentages. Percent impairment while working due to problem: Q5/10 The answer on Q5 is given on a scale from 0 (PROBLEM had no effect on work) to 10 (PROBLEM completely prevented me from working). Thus the analysis values from which mean and SD have been calculated and reported are the outcomes from Q5 (ranging from 0 to 10) multiplied with 100 and divided by 10. | Recorded up to Day 15 for the first flare and subsequent flares treated during the extension period | 
| Health Care Resource Utilization Due to a Gouty Arthritis Flare | Exploratory objective: number of days with hospitalization and un-scheduled outpatient visits | Recorded up to Day 15 for the first flare and subsequent flares treated during the extension period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gout, Interleukin 1 receptor antagonist, IL-1 receptor antagonist