Wheeler, Alistair

Objective Polypharmacy management of recurrent pericarditis (RP) often involves long-term therapies, often with negative effects. Slow tapering of oral therapies is often required to avoid recurrence. A post hoc analysis of the phase III trial Rilonacept inHibition of interleukin-1 Alpha and beta for recurrent Pericarditis: a pivotal Symptomatology and Outcomes Study (RHAPSODY) evaluated investigator approaches to transitioning to IL-1 blockade monotherapy with rilonacept, which was hypothesised to allow accelerated withdrawal of common multidrug pericarditis regimens. Methods RHAPSODY was a multicentre (Australia, Israel, Italy, USA), double-blind, placebo-controlled, randomised-withdrawal trial in adults and adolescents with RP. Investigators initiated rilonacept at the labelled dose level and discontinued oral pericarditis therapies during the 12-week run-in; randomised patients received study drug as monotherapy. Time to rilonacept monotherapy was quantified in patients receiving multidrug regimens at baseline who achieved rilonacept monotherapy during run-in. Results In 86 enrolled patients, mean time to rilonacept monotherapy was 7.9 weeks, with no recurrences. Of these, 64% (n=55) entered on multidrug regimens: non-steroidal anti-inflammatory drugs (NSAIDs) plus colchicine (44% (24/55)), colchicine plus glucocorticoids (24% (13/55)), or NSAIDs, colchicine, plus glucocorticoids (33% (18/55)). Investigators transitioned patients receiving colchicine and glucocorticoids at baseline to rilonacept monotherapy without recurrence regardless of taper approach: sequential (n=14; median, 7.7 weeks) or concurrent (n=17; median, 8.0 weeks). Median time to rilonacept monotherapy was similar regardless of glucocorticoid dose and duration: ≤15 mg/day (n=21): 7.3 weeks; >15 mg/day (n=18): 8.0 weeks; long-term (≥28 days): 7.6 weeks. Conclusions Rapid discontinuation of oral RP therapies while transitioning to rilonacept monotherapy was feasible without triggering pericarditis recurrence. Trial registration number NCT03737110.

Background Recurrent pericarditis is characterized by painful flares and inflammation, which negatively impact health‐related quality of life. RHAPSODY (rilonacept inhibition of interleukin‐1 alpha and beta for recurrent pericarditis: a pivotal symptomatology and outcomes study) evaluated the efficacy and safety of rilonacept (IL‐1α and ‐β cytokine trap) in recurrent pericarditis. A secondary analysis of these data evaluated the patient‐reported outcome questionnaire score change during the trial. Methods and Results Participants completed 5 patient‐reported outcome (PRO) questionnaires assessing pericarditis pain, health‐related quality of life, general health status, sleep impact, and overall symptom severity. PRO score changes during the treatment run‐in period (12 weeks) and the blinded randomized withdrawal period (up to 24 weeks) were evaluated using descriptive statistics and mixed model repeated measures analyses. Participants with PRO data from the run‐in period (n=84) and the randomized withdrawal period (n=61; 30 rilonacept, 31 placebo) were included in analyses. Run‐in baseline PRO scores indicated that pericarditis symptoms during pericarditis recurrence impacted health‐related quality of life. All PRO scores significantly improved ( P <0.001) on rilonacept treatment during the run‐in period. For the randomized withdrawal period, PRO scores were maintained for participants receiving rilonacept. For those receiving placebo and who experienced a recurrence, PRO scores deteriorated at the time of recurrence and then improved following rilonacept bailout. At randomized withdrawal Week 24/End of Study, scores of participants who received bailout rilonacept were similar to those of participants who had continued rilonacept. Conclusions These results demonstrate the burden of pericarditis recurrences and the improved physical and emotional health of patients with recurrent pericarditis while on rilonacept treatment. These findings extend prior rilonacept efficacy results, demonstrating improvements in patient‐reported health‐related quality of life, sleep, pain, and global symptom severity while on treatment. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03737110.

Background: Post-episode tapering of Standard of Care (SoC) medication in patients with recurrent pericarditis (RP) varies considerably. Gradual tapering of corticosteroids (CS) is recommended in ESC guidelines (decreasing by 1-2.5 mg/day every 2-6 weeks over 1-2 years) to prevent recurrence. We describe successful faster tapering of SoC treatment onto rilonacept monotherapy during RHAPSODY, a Phase 3, placebo-controlled, randomized-withdrawal (RW) trial in RP. Methods: Patients with acute symptomatic RP despite stable doses of NSAIDs, colchicine, and/or CS in any combination enrolled in a 12-week run-in period in which weekly rilonacept was initiated. After 1-week of stabilization, tapering of CS began at a rate dependent on baseline dose, to be completed by Week 10 for randomization at Week 12 when clinical response was confirmed by reduced pain and normalized CRP levels. Colchicine tapering/discontinuation was initiated no earlier than Week 4. This analysis evaluates time to rilonacept monotherapy in subgroups receiving different combinations of background therapies. Results: 79 of 86 patients were receiving pharmacotherapy at run-in baseline. Median (95% CI) time to monotherapy (n=79) was 7.9 (7.0-8.1) weeks. Of the patients receiving CS at baseline (41/86 [48%]), 39 (95%) tapered to rilonacept monotherapy, and median time to monotherapy was 7.9 (7.1-8.1) weeks. Of the patients receiving colchicine at baseline (65/86 [76%]), 61 (94%) patients achieved rilonacept monotherapy, and median time to monotherapy was 8.0 (7.1-8.3) weeks. Patients receiving only one SoC therapy achieved rilonacept monotherapy faster (6.1 [0.4-8.1] weeks) than those receiving 2 (8.0 [6.7-9.9] weeks) or 3 (7.7 [7.0-8.3] weeks) therapies. All patients who did not achieve monotherapy had withdrawn from the study for reasons unrelated to pericarditis. Conclusion: All patients randomized in the RHAPSODY trial discontinued SoC and transitioned to rilonacept monotherapy (median time 7.9 weeks) without a recurrent pericarditis episode during run-in. With rilonacept, time to successful discontinuation of SoC, including high dose CS, was substantially more rapid than current treatment practices. RHAPSODY data helped support FDA approval of the first therapy for RP.