Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.

BACKGROUND: Interleukin-1 has been implicated as a mediator of recurrent pericarditis. The efficacy and safety of rilonacept, an interleukin-1α and interleukin-1ß cytokine trap, were studied previously in a phase 2 trial involving patients with recurrent pericarditis. METHODS: We conducted a phase 3 multicenter, double-blind, event-driven, randomized-withdrawal trial of rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. The primary efficacy end point, assessed with a Cox proportional-hazards model, was the time to the first pericarditis recurrence. Safety was also assessed. RESULTS: A total of 86 patients with pericarditis pain and an elevated CRP level were enrolled in the run-in period. During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. A total of 61 patients underwent randomization. During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks (95% confidence interval [CI], 4.0 to 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 to 0.18; P<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections. CONCLUSIONS: Among patients with recurrent pericarditis, rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo. (Funded by Kiniksa Pharmaceuticals; RHAPSODY ClinicalTrials.gov number, NCT03737110.).

24-hour urine oxalate and risk of chronic kidney disease.

BACKGROUND: To assess whether 24-hr urine oxalate (UOx) excretion is a risk factor for incident chronic kidney disease (CKD). METHODS: This longitudinal observational US-based study included 426,896 individuals age ≥ 18 years with no CKD at baseline and with at least one UOx and at least 6 months of baseline and 6 months of follow-up data. Of these, 11,239 (2.6%) had an underlying malabsorptive condition. Incident CKD, defined by relevant ICD codes, was identified from a multi-source data cloud containing individual-level healthcare claims and electronic medical records data. The association between categories of UOx and incident CKD was modeled using logistic regression adjusting for age, sex, race, BMI, baseline urine calcium, urine citrate, urine volume, tobacco use, hypertension, diabetes, malabsorption, and cardiovascular disease. RESULTS: Mean follow-up time was 38.9 months (SD 21.7). Compared with individuals with UOx <20 mg/24-hr, the odds of developing incident CKD increased for UOx 20-29 mg/24-hr (multivariate-adjusted (MV) OR: 1.14, 95% CI: 1.07, 1.21) through 80+ mg/24-hr (MVOR: 1.35 [1.21, 1.50] and was statistically significant for each UOx category. A similar pattern was seen in the subgroup with a malabsorptive condition though the magnitudes of association were larger, with the odds of developing incident CKD increased for UOx 20-29 mg/24-hr (MVOR: 1.50 [1.03, 2.20] through 80+ mg/24-hr (MVOR: 2.34 [1.50, 3.63] as compared with UOx <20 mg/24-hr. CONCLUSIONS: The risk of incident CKD increases with increasing 24-hr urine oxalate excretion. Future studies should examine whether reducing urine oxalate diminishes the risk of developing CKD.

Dose selection for glycopyrrolate/eFlow® phase III clinical studies: results from GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer) phase II dose-finding studies.

BACKGROUND: Long-acting muscarinic antagonists (LAMAs) are recommended for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrrolate/eFlow® is an investigational drug-device combination of the LAMA glycopyrrolate administered by an eFlow® Closed System (eFlow® CS) nebulizer. The GOLDEN 2 (NCT01706536) and GOLDEN 6 (NCT02038829) Phase II, multicenter studies were conducted to inform dose selection for the GOLDEN Phase III clinical trials. Bronchodilator responses and safety assessments supported dose selection. METHODS: Subjects with moderate-to-severe COPD were randomized into 28-day parallel-group (GOLDEN 2) or 7-day crossover (GOLDEN 6) studies and received placebo, glycopyrrolate (3, 6.25, 12.5, 25, 50 or 100 µg twice daily [BID]) or aclidinium bromide 400 µg BID. The primary endpoint of both studies was change from baseline in trough forced expiratory volume in 1 s (FEV1). Safety assessments included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events, and discontinuation due to TEAE. Lung function data collected in both studies were pooled. RESULTS: The combined GOLDEN 2 (n = 282) and GOLDEN 6 (n = 96) studies included 378 subjects. On Days 7 and 28 there were dose-ordered, statistically significant and clinically important lung function improvements in glycopyrrolate treatment groups. Specifically, on Day 7, glycopyrrolate produced >0.100 L placebo-adjusted changes from baseline in trough FEV1 (12.5 µg BID: 0.122 L; 25 µg BID: 0.123 L; 50 µg BID: 0.137 L) and FEV1 AUC0-12 (12.5 µg BID: 0.145 L; 25 µg BID: 0.178 L; 50 µg BID: 0.180 L). The improvements in lung function for the glycopyrrolate 25 and 50 µg BID doses were comparable to those with aclidinium bromide 400 µg BID (FEV1: 0.149 L; FEV1 AUC0-12: 0.172 L). Acceptable safety profiles were observed across all groups in both studies. CONCLUSIONS: The efficacy and safety findings supported selection of glycopyrrolate 25 and 50 µg BID doses for the Phase III GOLDEN studies and provided preliminary evidence for the use of nebulized glycopyrrolate as a maintenance therapy for COPD.

Transition to rilonacept monotherapy from oral therapies in patients with recurrent pericarditis.

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.

Interleukin-1 Trap Rilonacept Improved Health-Related Quality of Life and Sleep in Patients With Recurrent Pericarditis: Results From the Phase 3 Clinical Trial RHAPSODY.

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 -ß 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.

In Vitro Characterization of the eFlow Closed System Nebulizer with Glycopyrrolate Inhalation Solution.

BACKGROUND: Glycopyrrolate administered by a novel, investigational eFlow® Closed System (CS) nebulizer (eFlow CS) is being evaluated for the maintenance treatment of chronic obstructive pulmonary disease (COPD). The eFlow CS is a hand-held, vibrating membrane nebulizer optimized to deliver 1 mL of glycopyrrolate solution into the lung in <3 minutes. Clinical studies have shown improvements in lung function of subjects treated with nebulized glycopyrrolate. METHODS: The aerosol performance of the eFlow CS nebulizer was characterized by delivered dose, aerodynamic droplet size distribution and nebulization time. Simulated use nebulizer performance over 60 days was assessed by volume median diameter (VMD), nebulized amount, and nebulization time. Nebulization outputs were assayed to ensure adequate delivery of glycopyrrolate with an acceptable impurity profile. Aerosol condensates were analyzed for glycopyrrolate concentration and impurities by ultra-high-performance liquid chromatography and compared with non-nebulized samples. RESULTS: The mean mass median aerodynamic diameter, geometric standard deviation, and fine particle fraction were 3.7 µm, 1.7, and 72%, respectively, and independent of formulation strength (25 and 50 µg/mL). Delivered dose was 88% of the nominal dose for both formulation strengths. The mean delivered dose, assessed by breathing simulation, was 56.8% for 25 µg/mL and 62.6% for 50 µg/mL. Nebulization times were 1-2.5 minutes with no apparent increasing trend with use over a 60-day period. The nebulized amount showed no significant changes, whereas the VMD showed a slight, but not pharmaceutically relevant, increase (0.1-0.2 µm) after 60-day simulated use. Glycopyrrolate concentration and impurity levels of nebulized samples were statistically similar to those of non-nebulized samples. CONCLUSION: The eFlow CS generates glycopyrrolate aerosols with high delivered dose, short treatment time, and small droplet size with narrow size distribution suitable for central and peripheral airway deposition. The unit dose vial mitigates medication misuse and ensures dose uniformity. Results support the use of glycopyrrolate/eFlow CS for the treatment of COPD.

Long-term safety of glycopyrrolate/eFlow® CS in moderate-to-very-severe COPD: Results from the Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer (GOLDEN) 5 randomized study.

BACKGROUND: The use of long-acting bronchodilators is an essential component of the management of chronic obstructive pulmonary disease (COPD). The GOLDEN 5 Phase III, randomized, active-controlled, open-label study was conducted to evaluate the long-term safety and tolerability of a nebulized glycopyrrolate formulation (SUN-101) delivered via the investigational eFlow® Closed System (eFlow® CS) nebulizer in subjects with moderate-to-very-severe COPD. METHODS: Subjects were randomized in a 4:3 ratio to nebulized glycopyrrolate 50 µg twice daily (BID) or tiotropium 18 µg once daily (OD) and treated for 48 weeks. Subjects represented the general COPD population with real-world characteristics including severe disease, presence of comorbidities, and receiving background COPD therapy. Primary endpoints were the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs. Secondary endpoints included the number of subjects with major adverse cardiovascular events (MACE); change from baseline in trough forced expiratory volume in 1 s (FEV1), and assessment of patient-reported outcomes. RESULTS: 1086 subjects received at least one dose of study drug. The overall incidence of TEAEs was comparable for subjects treated with glycopyrrolate (69.4%) or tiotropium (67.0%). Serious TEAEs occurred at similar rates in both treatment groups (glycopyrrolate, 12.3%; tiotropium, 10.5%). The most frequent TEAEs were COPD exacerbation/worsening and cough. Discontinuation due to TEAEs was higher in the glycopyrrolate group (10.0%) than the tiotropium group (2.8%) and related, in part, to the open-label study design, prior use of long-acting muscarinic antagonists and aerosol-airway interactions. Fewer subjects in the glycopyrrolate group experienced MACE (glycopyrrolate, n = 3 [0.5%]; tiotropium, n = 8 [1.7%]). Nebulized glycopyrrolate treatment resulted in improvements in trough FEV1 that were maintained over 48 weeks. Patient-reported health outcomes showed improvements, supporting the increases in trough FEV1. CONCLUSIONS: Treatment with nebulized glycopyrrolate was well tolerated over 48 weeks with the most common adverse events being COPD worsening and cough. The overall and cardiac safety and tolerability profile and improvements in pulmonary function and patient-reported health outcomes support the use of nebulized glycopyrrolate as a maintenance treatment for moderate-to-very-severe COPD. CLINICAL TRIAL REGISTRATION NUMBER: NCT02276222.

Efficacy and safety of glycopyrrolate/eFlow® CS (nebulized glycopyrrolate) in moderate-to-very-severe COPD: Results from the glycopyrrolate for obstructive lung disease via electronic nebulizer (GOLDEN) 3 and 4 randomized controlled trials.

BACKGROUND: SUN-101 is a combination of glycopyrrolate delivered through an innovative, electronic nebulizer, intended for the treatment of patients with COPD. The objective of this study was to assess the efficacy and safety of this new drug device combination. METHODS: Replicate Phase III randomized, double-blind, placebo-controlled studies were conducted to evaluate the efficacy and safety of glycopyrrolate solution administered by an investigational eFlow® Closed System (eFlow® CS) nebulizer in subjects with moderate-to-very-severe COPD, including those with continued background use of a long-acting beta2-agonist ± inhaled corticosteroid and/or history of cardiovascular (CV) disease. Subjects were randomized in a 1:1:1 ratio to receive placebo or glycopyrrolate (25 µg or 50 µg twice daily [BID]) for 12 weeks. The primary efficacy endpoint was the change from baseline in trough forced expiratory volume in 1 s (FEV1) at Week 12 compared with placebo. Secondary endpoints included change from baseline in forced vital capacity (FVC) after 12 weeks, change from baseline in health status measured by St George's Respiratory Questionnaire (SGRQ) at 12 weeks/end of study (EOS), and change in rescue medication use, as well as change from baseline in FEV1 area under the curve from 0 to 12 h after 12 weeks in the GOLDEN 3 sub-study. Daytime and night-time symptoms were recorded using an electronic diary. Safety was monitored throughout the study, including major adverse cardiovascular events. RESULTS: A total of 653 subjects were randomized in GOLDEN 3 and 641 in GOLDEN 4. Treatment with glycopyrrolate 25 µg BID and 50 µg BID resulted in statistically significant and clinically important changes from baseline in trough FEV1 compared with placebo at Week 12 (GOLDEN 3: 0.105 L and 0.126 L; p ≤ 0.0001; GOLDEN 4: 0.084 L and 0.082 L; p ≤ 0.0001). Nebulized glycopyrrolate 25 µg BID and 50 µg BID also resulted in improvements in FVC change from baseline versus placebo at Week 12 (GOLDEN 3: 0.149 L and 0.167 L, p < 0.001; GOLDEN 4: 0.130 L and 0.113 L, p < 0.01), and in SGRQ change from baseline score versus placebo at Week 12/EOS (GOLDEN 3: -3.072 [p < 0.05] and -1.848; GOLDEN 4: -3.585 and -3.557, p < 0.01). LS mean change from baseline in EXACT-respiratory symptoms total score at Week 12 for placebo and nebulized glycopyrrolate 25 and 50 µg BID were -0.936, -1.903 and -1.502 for GOLDEN 3 and -0.376, -1.647 and -1.532 for GOLDEN 4. Rescue medication use was unchanged. Nebulized glycopyrrolate was well tolerated at both doses based on the incidence of adverse events and CV events. CONCLUSIONS: The results of these studies demonstrated statistically significant and clinically important improvements in pulmonary function and patient-reported health outcomes, with an acceptable safety profile, support the use of glycopyrrolate/eFlow® CS as a potential maintenance treatment for moderate-to-very-severe COPD.

The safety and immunogenicity of a CETP vaccine in healthy adults.

A cholesterol ester transfer protein (CETP) vaccine (CETi-1) that induces auto-antibodies that specifically bind and inhibit activity of endogenous CETP has been demonstrated in rabbits to significantly increase HDL-C and reduce the development of atherosclerosis. In a Phase I human trial with CETi-1, one patient at the highest dose (250 mg) out of a total of 36 patients who received a single injection developed anti-CETP antibodies. In an extension study of 23 patients, 53% (8/15) who received a second injection of the active vaccine developed anti-CETP antibodies compared with 0% (0/8) in the placebo group. The vaccine was well tolerated and no significant laboratory abnormalities occurred. CETi-1 is a feasible therapy in humans to induce CETP auto-antibodies. Future research will determine if repeat inoculations will induce a sufficient anti-CETP antibody response to inhibit CETP and increase HDL levels.

Successful management of an ABO-mismatched lung allograft using antigen-specific immunoadsorption, complement inhibition, and immunomodulatory therapy.

BACKGROUND: Successful management of an ABO-mismatched lung allograft recipient has not previously been described. METHODS: Because of a clerical error, a 67-year-old blood type B patient with idiopathic pulmonary fibrosis received a left single-lung allograft from a blood type A donor. Cyclophosphamide was added to immunosuppression with anti-thymocyte globulin induction, cyclosporine, mycophenolate mofetil, and prednisone. When increasing anti-A antibody titers were detected, antigen-specific immunoadsorption, anti-CD20 monoclonal antibody, and recombinant soluble complement receptor type 1 (TP10) were administered. RESULTS: Rising anti-A antibody titers were reduced acutely by immunoadsorption, and remained low during long-term follow-up. Humoral injury to the graft was not detected. Acute cellular rejection and multiple complications were successfully managed. Three years after transplantation the patient is clinically well on stable maintenance immunosuppression and prophylactic photochemotherapy. CONCLUSIONS: Modulation of anti-A antibody, preserved graft function, and a favorable patient outcome can be achieved for an ABO-mismatched lung allograft.

One-year safety and efficacy study of arformoterol tartrate in patients with moderate to severe COPD.

BACKGROUND: Arformoterol tartrate (arformoterol, 15 µg bid) is a nebulized long-acting ß2-agonist approved for maintenance treatment of COPD. METHODS: This was a multicenter, double-blind, randomized, placebo-controlled study. Patients (aged ≥ 40 years with baseline FEV1 ≤ 65% predicted, FEV1 > 0.50 L, FEV1/FVC ≤ 70%, and ≥ 15 pack-year smoking history) received arformoterol (n = 420) or placebo (n = 421) for 1 year. The primary assessment was time from randomization to respiratory death or first COPD exacerbation-related hospitalization. RESULTS: Among 841 patients randomized, 103 had ≥ 1 primary event (9.5% vs 15.0%, for arformoterol vs placebo, respectively). Patients who discontinued treatment for any reason (39.3% vs 49.9%, for arformoterol vs placebo, respectively) were followed for up to 1 year postrandomization to assess for primary events. Fewer patients receiving arformoterol than placebo experienced COPD exacerbation-related hospitalizations (9.0% vs 14.3%, respectively). Twelve patients (2.9%) receiving arformoterol and 10 patients (2.4%) receiving placebo died during the study. Risk for first respiratory serious adverse event was 50% lower with arformoterol than placebo (P = .003). Numerically more patients on arformoterol (13; 3.1%) than placebo (10; 2.4%) experienced cardiac serious adverse events; however, time-to-first cardiac serious adverse event was not significantly different. Improvements in trough FEV1 and FVC were greater with arformoterol (least-squares mean change from baseline vs placebo: 0.051 L, P = .030 and 0.075 L, P = .018, respectively). Significant improvements in quality of life (overall St. George's Hospital Respiratory Questionnaire and Clinical COPD Questionnaire) were observed with arformoterol vs placebo (P < .05). CONCLUSIONS: Arformoterol demonstrated an approximately 40% lower risk of respiratory death or COPD exacerbation-related hospitalization over 1 year vs placebo. Arformoterol was well-tolerated and improved lung function vs placebo. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00909779; URL: www.clinicaltrials.gov.

A phase 2 prospective, randomized, double-blind trial comparing the effects of tranexamic acid with ecallantide on blood loss from high-risk cardiac surgery with cardiopulmonary bypass (CONSERV-2 Trial).

OBJECTIVE: Ecallantide is a recombinant peptide in the same class as aprotinin that inhibits plasma kallikrein, a major component of the contact coagulation and inflammatory cascades. Therefore, ecallantide was expected to reduce blood loss associated with cardiac surgery requiring cardiopulmonary bypass. METHODS: This prospective multinational, randomized, double-blind trial enrolled patients undergoing cardiac surgery using cardiopulmonary bypass for procedures associated with a high risk of bleeding. Patients were randomly assigned to ecallantide (n = 109) or tranexamic acid (high dose, n = 24; low dose, n = 85). Efficacy was assessed from the volume of packed red blood cells administered within the first 12 hours after surgery. RESULTS: The study was terminated early after the independent data safety and monitoring board observed a statistically significantly higher 30-day mortality in the ecallantide group (12%) than in the tranexamic acid groups (4%, P = .041). Patients receiving ecallantide received more packed red blood cells within 12 hours of surgery than tranexamic acid-treated patients: median = 900 mL (95% confidence interval, 600-1070) versus 300 mL (95% confidence interval, 0-523) (P < .001). Similar differences were seen at 24 hours and at discharge. Patients treated with the higher tranexamic acid dose received less packed red blood cells, 0 mL (95% confidence interval, 280-600), than the group treated with the lower dose, 400 mL (95% confidence interval, 0-400) (P = .008). No deaths occurred in the higher dose tranexamic acid group. CONCLUSIONS: Ecallantide was less effective at reducing perioperative blood loss than tranexamic acid. High-dose tranexamic acid was more effective than the low dose in reducing blood loss.