Comparative Pharmacokinetics and Safety Assessment of 1st- and 2nd-Generation Zinpentraxin Alfa Drug Products in Healthy Volunteers: A Randomized Crossover Study.

Zinpentraxin alfa is a recombinant form of the human pentraxin-2 that was studied in idiopathic pulmonary fibrosis (IPF). To improve the purity and yield of the drug material, a 2nd-generation drug product was developed. To characterize and compare the pharmacokinetic (PK) properties of the 1st- and 2nd-generation zinpentraxin alfa, PK studies were conducted in healthy volunteers (HVs). In a phase 1 randomized, double-blind, 2-sequence crossover, sequential 2-stage study (ISRCTN59409907), single intravenous (IV) doses of 1st- and 2nd-generation zinpentraxin alfa at 10 mg/kg were studied with a blinded interim analysis (IA) at the end of stage 1. Bioequivalence (BE) was achieved for the maximum observed plasma concentration (Cmax), but the overall exposure was higher for the 2nd- compared to the 1st-generation zinpentraxin alfa. The study was stopped after stage 1 as the gating criteria were met based on the result of the blinded IA. Safety profiles were similar for the 1st- and 2nd-generation drug products, and antidrug antibody (ADA) was not observed in this study.

Capacity for the management of kidney failure in the International Society of Nephrology Africa region: report from the 2023 ISN Global Kidney Atlas (ISN-GKHA).

The burden of chronic kidney disease and associated risk of kidney failure are increasing in Africa. The management of people with chronic kidney disease is fraught with numerous challenges because of limitations in health systems and infrastructures for care delivery. From the third iteration of the International Society of Nephrology Global Kidney Health Atlas, we describe the status of kidney care in the ISN Africa region using the World Health Organization building blocks for health systems. We identified limited government health spending, which in turn led to increased out-of-pocket costs for people with kidney disease at the point of service delivery. The health care workforce across Africa was suboptimal and further challenged by the exodus of trained health care workers out of the continent. Medical products, technologies, and services for the management of people with nondialysis chronic kidney disease and for kidney replacement therapy were scarce due to limitations in health infrastructure, which was inequitably distributed. There were few kidney registries and advocacy groups championing kidney disease management in Africa compared with the rest of the world. Strategies for ensuring improved kidney care in Africa include focusing on chronic kidney disease prevention and early detection, improving the effectiveness of the available health care workforce (e.g., multidisciplinary teams, task substitution, and telemedicine), augmenting kidney care financing, providing quality, up-to-date health information data, and improving the accessibility, affordability, and delivery of quality treatment (kidney replacement therapy or conservative kidney management) for all people living with kidney failure.

Zinpentraxin Alfa for Idiopathic Pulmonary Fibrosis: The Randomized Phase III STARSCAPE Trial.

Rationale: A phase II trial reported clinical benefit over 28 weeks in patients with idiopathic pulmonary fibrosis (IPF) who received zinpentraxin alfa. Objectives: To investigate the efficacy and safety of zinpentraxin alfa in patients with IPF in a phase III trial. Methods: This 52-week phase III, double-blind, placebo-controlled, pivotal trial was conducted at 275 sites in 29 countries. Patients with IPF were randomized 1:1 to intravenous placebo or zinpentraxin alfa 10 mg/kg every 4 weeks. The primary endpoint was absolute change from baseline to Week 52 in FVC. Secondary endpoints included absolute change from baseline to Week 52 in percent predicted FVC and 6-minute walk distance. Safety was monitored via adverse events. Post hoc analysis of the phase II and phase III data explored changes in FVC and their impact on the efficacy results. Measurements and Main Results: Of 664 randomized patients, 333 were assigned to placebo and 331 to zinpentraxin alfa. Four of the 664 randomized patients were never administered study drug. The trial was terminated early after a prespecified futility analysis that demonstrated no treatment benefit of zinpentraxin alfa over placebo. In the final analysis, absolute change from baseline to Week 52 in FVC was similar between placebo and zinpentraxin alfa (-214.89 ml and -235.72 ml; P = 0.5420); there were no apparent treatment effects on secondary endpoints. Overall, 72.3% and 74.6% of patients receiving placebo and zinpentraxin alfa, respectively, experienced one or more adverse events. Post hoc analysis revealed that extreme FVC decline in two placebo-treated patients resulted in the clinical benefit of zinpentraxin alfa reported by phase II. Conclusions: Zinpentraxin alfa treatment did not benefit patients with IPF over placebo. Learnings from this program may help improve decision making around trials in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT04552899).

Idiopathic pulmonary fibrosis therapy development: a clinical pharmacology perspective.

Drug development for idiopathic pulmonary fibrosis (IPF) has been challenging due to poorly understood disease etiology, unpredictable disease progression, highly heterogeneous patient populations, and a lack of robust pharmacodynamic biomarkers. Moreover, because lung biopsy is invasive and dangerous, making the extent of fibrosis as a direct longitudinal measurement of IPF disease progression unfeasible, most clinical trials studying IPF can only assess progression of fibrosis indirectly through surrogate measures. This review discusses current state-of-art practices, identifies knowledge gaps, and brainstorms development opportunities for preclinical to clinical translation, clinical populations, pharmacodynamic endpoints, and dose optimization strategies. This article highlights clinical pharmacology perspectives in leveraging real-world data as well as modeling and simulation, special population considerations, and patient-centric approaches for designing future studies.

Efficacy, safety, and tolerability of lebrikizumab in adolescent patients with uncontrolled asthma (ACOUSTICS).

Background: Lebrikizumab is a monoclonal antibody that modulates activity of interleukin-13. The Phase 3 ACOUSTICS study assessed lebrikizumab efficacy and safety in adolescents with uncontrolled asthma despite standard-of-care treatment. Methods: Adolescents (aged 12-17 years) with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40%-90% predicted, and stable background therapy were randomised 1:1:1 to receive lebrikizumab 125 or 37.5 mg or placebo subcutaneously once every 4 weeks. Primary efficacy endpoint was asthma exacerbation rate over 52 weeks. Results: Between August 2013 and July 2016, 579 patients were screened and 346 were randomised; 224 (65%) completed the study with 52 weeks of treatment. Lebrikizumab 125 mg (n = 116) reduced the exacerbation rate at 52 weeks versus placebo (n = 117; adjusted rate ratio [RR] 0.49 [95% CI 0.28-0.83]; 51% rate reduction). Lebrikizumab 37.5 mg (n = 113) was less effective at reducing exacerbations (RR 0.60 [95% CI 0.35-1.03]; 40% rate reduction). In patients with blood eosinophil counts ≥300 cells/µl, both lebrikizumab doses reduced exacerbations (125 mg: RR 0.44 [95% CI 0.21-0.89]; 37.5 mg: 0.42 [95% CI 0.19-0.93]). Treatment-emergent adverse events, serious adverse events, and adverse events leading to study discontinuation occurred in 155 (68%), 7 (3%), and 5 (2%) of 229 patients who received lebrikizumab (both 125 and 37.5 mg doses) and in 72 (62%), 4 (3%), and 1 (1%) of 117 who received placebo, respectively. No deaths occurred. Conclusion: Lebrikizumab 125 mg reduced asthma exacerbation rates in adolescents with uncontrolled asthma. However, the study was prematurely terminated (sponsor's decision) potentially limiting interpretation of results. Clinical trial registration: NCT01875003 (www.ClinicalTrials.gov).

Long-term evaluation of the safety and efficacy of recombinant human pentraxin-2 (rhPTX-2) in patients with idiopathic pulmonary fibrosis (IPF): an open-label extension study.

BACKGROUND: Recombinant human pentraxin-2 (rhPTX-2) significantly decreased decline in percent predicted forced vital capacity (FVC) and stabilized 6-min walk distance (6MWD) in patients with idiopathic pulmonary fibrosis (IPF) during the 28-week, placebo-controlled, randomized period of the Phase II PRM-151-202 study. Interim (76-week) data from the open-label extension (OLE) demonstrated sustained safety and efficacy with rhPTX-2 treatment. Here, we present the entire long-term OLE safety and efficacy data to 128 weeks. METHODS: Patients who completed the randomized PRM-151-202 study period were eligible for the OLE, during which all patients received rhPTX-2, having started rhPTX-2 (i.e., crossed from placebo) or continued rhPTX-2 after Week 28. rhPTX-2 was administered in 28-week cycles, with 10 mg/kg intravenous infusions (60 min) on Days 1, 3, and 5 in the first week of each cycle, then one infusion every 4 weeks up to Week 128. The OLE primary objective was to assess the long-term safety and tolerability of rhPTX-2. Other outcomes included FVC, 6MWD, and patient-reported outcomes (descriptive analysis). RESULTS: All 111 patients who completed the randomized period entered the OLE (n = 37 started rhPTX-2; n = 74 continued rhPTX-2); 57 (51.4%) completed to Week 128. The treatment-emergent adverse event (TEAE) profile was consistent with the randomized period, with the majority of TEAEs graded mild or moderate. Serious TEAEs occurred in 47 patients (42.3%), most frequently IPF (n = 11; 9.9%), pneumonia (n = 7; 6.3%), and acute respiratory failure (n = 3; 2.7%). Three patients underwent lung transplantation. Most serious TEAEs (and all 14 fatal events) were considered unrelated to rhPTX-2 treatment. For patients starting vs continuing rhPTX-2, mean (95% confidence interval) changes from baseline to Week 128 were, respectively, - 6.2% (- 7.7; - 4.6) and - 5.7% (- 8.0; - 3.3) for percent predicted FVC and - 36.3 m (- 65.8; - 6.9) and - 28.9 m (- 54.3; - 3.6) for 6MWD; however, conclusions were limited by patient numbers at Week 128. CONCLUSIONS: Long-term treatment (up to 128 weeks) with rhPTX-2 was well tolerated in patients with IPF, with no new safety signals emerging in the OLE. The limited efficacy data over 128 weeks may suggest a trend towards a treatment effect. Trial registration NCT02550873; EudraCT 2014-004782-24.

Evaluation of inpatient postpartum recovery using the Obstetric Quality of Recovery-10 patient-reported outcome measure: a single-center observational study.

BACKGROUND: Few adequately validated patient-reported outcome measures are available, which can assess recovery profiles following childbirth. OBJECTIVE: We aimed to determine whether quantitative recovery (using the Obstetric Quality of Recovery-10 patient-reported outcome measure) was superior following vaginal delivery compared with cesarean delivery and evaluate validity, reliability, and responsiveness of this patient-reported outcome measure in the obstetrical setting in the United States. STUDY DESIGN: Women recruited into this single-center observational cohort study completed the Obstetric Quality of Recovery-10 and EuroQol 5-dimension 3L patient-reported outcome measures within 72 hours of childbirth. We assessed the validity with hypothesis testing and structural validity. In hypothesis testing, the primary outcome was Obstetric Quality of Recovery-10 scores after vaginal vs cesarean delivery. Secondary outcomes were differences in Obstetric Quality of Recovery-10 scores for vaginal delivery following induction of labor vs spontaneous labor and scheduled vs unplanned cesarean delivery, correlation with clinical parameters (American Society of Anesthesiologists classification grade, body mass index, length of hospital stay, estimated blood loss, transfusion requirement, antiemetic use, and neonatal intensive care unit admission), and qualitative ranking of Obstetric Quality of Recovery-10 items for each delivery mode. Structural validity was assessed by determining the correlation of the Obstetric Quality of Recovery-10 scores with the EuroQol 5-dimension 3L and global health visual analog scale scores. Reliability was assessed using Cronbach alpha and inter-item correlation of Obstetric Quality of Recovery-10 items. Responsiveness was assessed by evaluating the change in Obstetric Quality of Recovery-10 scores over the 72-hour postpartum period. RESULTS: Data from 215 women were analyzed. In hypothesis testing, the median (interquartile range) Obstetric Quality of Recovery-10 scores were higher following vaginal delivery than cesarean delivery (86 [77-94] vs 77 [64-86], respectively; P<.001). Multivariate model demonstrated that Obstetric Quality of Recovery-10 scores were significantly lower after cesarean delivery when adjusting for American Society of Anesthesiologists classification grade, age, body mass index, and ethnicity (R=-8.97; P<.001). Obstetric Quality of Recovery-10 scores were similar between induction of labor and spontaneous labor, and scheduled cesarean delivery and unplanned cesarean delivery. Obstetric Quality of Recovery-10 was correlated with length of hospital stay (R=-0.248; P<.001), estimated blood loss (R=-0.3429; P<.001), transfusion requirement (R=-0.140; P=.041), and antiemetic use (R=-0.280; P<.001). The highest ranked Obstetric Quality of Recovery-10 items were ability to hold baby, feeling in control, and ability to look after personal hygiene. The lowest ranked items were pain and shivering. In structural validity, correlation of Obstetric Quality of Recovery-10 score was moderate with the global health visual analog scale (r=0.511) and EuroQol 5-dimension 3L scores (r=-0.509). In reliability, Cronbach alpha was 0.72 and more than 80% of individual items correlated. In responsiveness, Obstetric Quality of Recovery-10 scores did not change significantly over the study period. CONCLUSION: Quantitative inpatient recovery following vaginal delivery is superior to cesarean delivery. The Obstetric Quality of Recovery-10 appears to be a valid and reliable patient-reported outcome measure following these delivery modes. Further studies are needed to determine how to improve recovery domains identified in this study, to evaluate Obstetric Quality of Recovery-10 in different languages and determine whether these domains impact outcomes beyond hospitalization.

Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy.

BACKGROUND: Patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) often continue to experience symptoms despite receiving standard-of-care therapy with H1-antihistamines along with 1 or more add-on therapies. OBJECTIVES: We sought to evaluate the safety and efficacy of 24 weeks of treatment with omalizumab in patients with persistent CIU/CSU despite treatment with H1-antihistamines at up to 4 times the approved dose plus H2-antihistamines, leukotriene receptor antagonists, or both. METHODS: In this phase III study patients were randomized to receive 6 subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo, followed by a 16-week observation period. The primary objective of the study was to evaluate the overall safety of omalizumab compared with placebo. Efficacy (itch severity, hive, and urticaria activity scores) was evaluated at weeks 12 and 24. RESULTS: The overall incidence and severity of adverse events and serious adverse events were similar between omalizumab and placebo recipients; the safety profile was consistent with omalizumab in patients with allergic asthma. At week 12, the mean change from baseline in weekly itch severity score was -8.6 (95% CI, -9.3 to -7.8) in the omalizumab group compared with -4.0 (95% CI, -5.3 to -2.7) in the placebo group (P < .001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24. CONCLUSION: Omalizumab was well tolerated and reduced the signs and symptoms of CIU/CSU in patients who remained symptomatic despite the use of H1-antihistamines (up to 4 times the approved dose) plus H2-antihistamines, leukotriene receptor antagonists, or both.

Cryoablation versus radiofrequency ablation for treatment of atrioventricular nodal reentrant tachycardia: cryoablation with 6-mm-tip catheters is still less effective than radiofrequency ablation.

BACKGROUND: The treatment of choice for atrioventricular nodal reentrant tachycardia (AVNRT) is catheter ablation of the atrioventricular nodal slow pathway. OBJECTIVE: The purpose of this study was to ascertain whether cryoablation (Cryo) with 6-mm-tip catheters is as effective as radiofrequency ablation (RF). METHODS: Patients who had catheter ablation for AVNRT between 2005 and 2008 were identified. The main outcome measure was overall success without the use of an alternative energy source and no recurrence. RESULTS: Two hundred eighty-eight procedures in 272 patients were identified; 184 were female (68%), and the mean age was 53 +/- 14 (17-88) years. There were 123 Cryo and 149 RF procedures. Cryo had a lower overall success rate (83% vs. 93%; P = .02). Mean procedure times were similar in both groups (90 minutes; P = .5). Fluoroscopy time was longer with Cryo: 16 (7-48) versus 14 (5-50) minutes (P = .04). Only one case of atrioventricular block was observed in the RF group (0.7%). Cryo was more expensive than RF ( pounds sterling 3141 vs. pounds sterling 2153). CONCLUSION: Even when delivering multiple lesions with 6-mm-tip catheters, Cryo is less effective than RF. RF is recommended as a first-line treatment, although the only major complication occurred in the RF group.