A Proof-of-Concept Study of AC-201 to Prevent Gout Flares

Study Overview
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Brief Summary
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Initiation of ULT for gout increases the occurrence of acute gouty arthritis flares due to mobilization of urate from tissue deposits. IL-1β plays a key role in mediating the inflammatory response in gouty arthritis. The efficacy of IL-1β blockade in the prophylaxis of gouty flares during initiation of ULT has been validated in multiple trials of IL-1β inhibitor therapies. Therefore, it is believed that IL-1β is a relevant therapeutic target for gout flares. AC-201 is an IL-1β modulator indicated for the treatment of osteoarthritis with good safety record and very few contraindications to the co-morbidities commonly among gout patients. AC-201 has also been demonstrated to have uric acid-lowering effects in clinical trials. The favorable product profile of AC-201 overall provides a strong rationale for investigating its clinical utility as prophylaxis against flares when initiating ULT.

Detailed Description
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Clinical trials have demonstrated that anti-IL-1 agents (IL-1Ra, IL-1 Trap, and anti-IL-1β monoclonal antibody) can reduce the frequency of gout flares during the initial period of treatment with urate-lowering therapy and prevent of gout flares in gout patients with frequent flares. AC-201 is an oral IL-1 modulator but with a mechanism distinct from that of existing anti-IL-1 agents. The active metabolite of AC-201 has been shown in vitro and in vivo to inhibit the production and activity of IL-1, down-regulate IL-1 receptors, and increase IL1-Ra. Molecular research further suggests that these effects are mediated upstream via inhibition of MAPK signaling pathways and binding of NF-κB and AP-1 transcription factors that encode for a range of pro-inflammatory factors, including IL-1β, TNF-α, IL-6, IL-8, iNOS, and MMPs, which have been implicated in gout flares. AC-201 has also been demonstrated to have uric acid-lowering effects in clinical trials. The favorable product profile of AC-201 overall provides a strong rationale for investigating its clinical utility as prophylaxis against flares when initiating ULT.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Trial Of AC-201 In Subjects With Gout Initiating Urate-Lowering Therapy

Conditions
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Gout Flares

Intervention / Treatment
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* Drug: Placebo
* Drug: AC-201
* Drug: Febuxostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female age 20 to 80 years, inclusive Meets at least 6 of the 12 American College of Rheumatology preliminary criteria (1977) for the classification of acute arthritis of primary gout, OR have proven tophus or documented monosodium urate (MSU) crystals in the joint fluid Serum uric acid ≥7.5 mg/dL at screening Experienced ≥2 gouty arthritis flares within one year prior to screening Exclusion Criteria: Occurrence of a gouty arthritis flare ongoing at screening or during the screening period through baseline Use of allopurinol, febuxostat, benzbromarone, probenecid, or sulfinpyrazone within 4 weeks prior to screening Use of colchicine, glucocorticoids, NSAIDs, or COX-2 inhibitors within 1 week prior to screening Other (non-gout) chronic arthritis, acute inflammatory arthritis, autoimmune diseases with arthritis, or any condition requiring chronic daily use of pain medication History of allergy to any components of study medication, including diacerein Allergy, contraindication, or intolerance to febuxostat Contraindication or allergy to NSAIDs Severe renal impairment Any prior use of biologic anti-inflammatory therapy, such as IL-1 modulators, tumor necrosis factor inhibitors, IL-6 inhibitors, or T-cell costimulation modulator

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo plus Febuxostat | Drug: Placebo<br>* Placebo Capsule BID for 16 Weeks<br>* Other names: PBO;Drug: Febuxostat<br>* Febuxostat 80 mg QD for 16 Weeks<br>* Other names: ULT;|
| Experimental: AC-201<br>AC-201 plus Febuxostat | Drug: AC-201<br>* AC-201 50mg Capsule BID for 16 Weeks<br>Drug: Febuxostat<br>* Febuxostat 80 mg QD for 16 Weeks<br>* Other names: ULT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Gout Flares Per Subject |  | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prophylaxis of Acute Gout Flares, Urate-Lowering Therapy, Hyperuricemia, Gouty arthritis