Gout Flares
Conditions
Keywords
Prophylaxis of Acute Gout Flares, Urate-Lowering Therapy, Hyperuricemia, Gouty arthritis
Brief summary
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
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.
Interventions
DRUGPlacebo
Placebo Capsule BID for 16 Weeks
DRUGAC-201
AC-201 50mg Capsule BID for 16 Weeks
DRUGFebuxostat
Febuxostat 80 mg QD for 16 Weeks
Sponsors
TWi Biotechnology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Gout Flares Per Subject | 16 weeks |
Countries
Taiwan
Participant flow
Recruitment details
Overall, 82 patients from 8 clinical centers participated in the study between 28 January 2013 to 04 September 2013.
Pre-assignment details
Participants were assessed at an initial screening visit within 2 weeks before the baseline visit.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Capsule BID Placebo Capsule BID for 16 Weeks | 41 |
| AC-201 50mg Capsule BID AC-201 50mg Capsule BID for 16 Weeks | 41 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Placebo Capsule BID | AC-201 50mg Capsule BID | Total |
|---|---|---|---|
| Age, Continuous | 43.6 years STANDARD_DEVIATION 11.8 | 43.7 years STANDARD_DEVIATION 12.6 | 43.6 years STANDARD_DEVIATION 12.1 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 41 Participants | 41 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 41 | 10 / 41 |
| serious Total, serious adverse events | 1 / 41 | 0 / 41 |
Outcome results
Primary
Number of Gout Flares Per Subject
Time frame: 16 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Number of Gout Flares Per Subject | 3.02 flares |
| AC-201 | Number of Gout Flares Per Subject | 2.45 flares |
p-value: 0.135695% CI: [0.62, 1.07]Possion regression