Tim Jansen, Phil Piscitelli, Cynthia Barrow, Kip Vought, Amy Poshusta, Heather Kapushoc, Andrea Leonard-Segal, Mustafa Noor, Damaris Skouras, Charles Dinarello, Naomi Schlesinger
Affiliation(s):
Viecuri Medisch Centrum, Rheumatology, Venlo, Netherlands
Background: The formation of the NOD-, LRR-, and pyrin-containing 3 (NLRP3) inflammasome plays a critical role in the initiation of the inflammatory reaction induced by the monosodium urate (MSU) crystals in an acute gout flare. Once assembled, the NLRP3 inflammasome converts pro-interleukin-1β into its active form and initiates IL-1β-dependent inflammation. NLRP3 activation, therefore, occurs upstream of IL- 1β, the pivotal cytokine in gouty inflammation and the causative agent mediating the symptoms of acute gout flares, including joint pain due to inflammation. Monoclonal antibodies against IL-1β can decrease inflammatory pain by removal of IL-1 β from circulation and shutting down the IL-1β-mediated inflammatory cascade. However, they must be injected and are associated with immune suppression and increased risk of infection. There remains an unmet need for an orally administered treatment of acute gout to safely reduce IL-1β-mediated inflammatory pain without the risk of immunosuppression. In an initial dose-range finding study, PODAGRA I, we reported preliminary evidence of efficacy and safety in this setting with dapansutrile, an orally administered specific inhibitor of the NLRP3 inflammasome.
Objectives: PODAGRA II study is designed to further evaluate the effects of dapansutrile on reducing acute gout joint pain and IL-1β-dependent inflammation.
Methods: The study (NCT05658575/EudraCT 2019-002717-19) is a multicenter, placebo-controlled, prospective, randomized, double-blind trial conducted in the Netherlands, Spain, France, and the USA. A total of 300 patients with acute symptomatic gout flare are being randomized centrally to receive either dapansutrile (2000 mg loading dose followed by 1000 mg BID) or matching placebo tablets for 7 days (2:1 ratio dapansutrile: placebo). The study is designed to determine the superiority of dapansutrile compared to placebo on the symptoms and signs of an acute gout flare. The primary endpoint is the subject-reported pain intensity score in the target joint (evaluated on a 100-mm visual analogue scale) at 72 hours. Secondary endpoints include patient- and investigator-assessment of response to treatment and the investigator-assessed scores for joint tenderness, swelling, erythema, warmth, and range of motion. A subject-assessed quality-of-life questionnaire will be collected, and biomarkers associated with acute gout inflammation (IL-1 β, IL-6 and CRP) will be evaluated. In order to demonstrate both statistical and clinical significance, approximately 170 and 85 evaluable subjects are needed in the dapansutrile and placebo arms, respectively. This assumes a one-sided significance level of α = 0.025, 85% power (1-β), a standard deviation of 25 points, an expected mean difference (δ=10 points) plus an additional clinical significance of (δ=10 points). To account for dropouts and non-evaluable subjects, up to 200 subjects in the dapansutrile arm, and up to 100 in the placebo arm will be randomized.
Results: The trial has launched and currently enrolling subjects.
Conclusion: PODAGRA II will be the first placebo-controlled, adequately powered, large, multi-center study with dapansutrile, an oral NLRP3-specific inhibitor. As gout is a prototypical disease of NLRP3 activation, this trial will provide important new data on NLRP3 inhibition leading to a reduction in joint pain and associated with an acute gout flare