Investigating the use of finerenone in children with chronic kidney disease and proteinuria: design of the FIONA and open-label extension studies.

INTRODUCTION: Proteinuria is a modifiable risk factor for chronic kidney disease (CKD) progression in children. Finerenone, a selective, non-steroidal, mineralocorticoid receptor antagonist (MRA) has been approved to treat adults with CKD associated with type 2 diabetes mellitus (T2DM) following results from the phase III clinical trials FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049). In a pre-specified pooled analysis of both studies (N = 13,026), finerenone was shown to have an acceptable safety profile and was efficacious in decreasing the risk of adverse kidney and cardiovascular outcomes and of proteinuria. OBJECTIVE: FIONA and the associated open-label extension (OLE) study aim to demonstrate that combining finerenone with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) is safe, well-tolerated, and effective in sustainably reducing urinary protein excretion in children with CKD and proteinuria. DESIGN: FIONA (NCT05196035; Eudra-CT: 2021-002071-19) is a randomized (2:1), double-blind, placebo-controlled, multicenter, phase III study of 6 months' duration in approximately 219 pediatric patients. Patients must have a clinical diagnosis of CKD (an eGFR ≥ 30 mL/min/1.73 m2 if ≥ 1 to < 18 years or a serum creatinine level ≤ 0.40 mg/dL for infants 6 months to < 1 year) with significant proteinuria despite ACEi or ARB usage. The primary objective is to demonstrate that finerenone, added to an ACEi or ARB, is superior to placebo in reducing urinary protein excretion. FIONA OLE (NCT05457283; Eudra-CT: 2021-002905-89) is a single-arm, open-label study, enrolling participants who have completed FIONA. The primary objective of FIONA OLE is to provide long-term safety data. FIONA has two primary endpoints: urinary protein-to-creatinine ratio (UPCR) reduction of ≥ 30% from baseline to day 180 and percent change in UPCR from baseline to day 180. A sample size of 198 participants (aged 2 to < 18 years) in FIONA will provide at least 80% power to reject the null hypothesis of either of the two primary endpoints. CONCLUSION: FIONA is evaluating the use of finerenone in children with CKD and proteinuria. Should safety, tolerability, and efficacy be demonstrated, finerenone could become a useful additional therapeutic agent in managing proteinuria and improving kidney outcomes in children with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05196035. Registered on 19 January 2022.

Evaluating Kidney Function Decline in Children with Chronic Kidney Disease Using a Multi-Institutional Electronic Health Record Database.

BACKGROUND: The objectives of this study were to use electronic health record data from a US national multicenter pediatric network to identify a large cohort of children with CKD, evaluate CKD progression, and examine clinical risk factors for kidney function decline. METHODS: This retrospective cohort study identified children seen between January 1, 2009, to February 28, 2022. Data were from six pediatric health systems in PEDSnet. We identified children aged 18 months to 18 years who met criteria for CKD: two eGFR values <90 and ≥15 ml/min per 1.73 m2 separated by ≥90 days without an intervening value ≥90. CKD progression was defined as a composite outcome: eGFR <15 ml/min per 1.73 m2, ≥50% eGFR decline, long-term dialysis, or kidney transplant. Subcohorts were defined based on CKD etiology: glomerular, nonglomerular, or malignancy. We assessed the association of hypertension (≥2 visits with hypertension diagnosis code) and proteinuria (≥1 urinalysis with ≥1+ protein) within 2 years of cohort entrance on the composite outcome. RESULTS: Among 7,148,875 children, we identified 11,240 (15.7 per 10,000) with CKD (median age 11 years, 50% female). The median follow-up was 5.1 (interquartile range 2.8-8.3) years, the median initial eGFR was 75.3 (interquartile range 61-83) ml/min per 1.73 m2, 37% had proteinuria, and 35% had hypertension. The following were associated with CKD progression: lower eGFR category (adjusted hazard ratio [aHR] 1.44 [95% confidence interval (95% CI), 1.23 to 1.69], aHR 2.38 [95% CI, 2.02 to 2.79], aHR 5.75 [95% CI, 5.05 to 6.55] for eGFR 45-59 ml/min per 1.73 m2, 30-44 ml/min per 1.73 m2, 15-29 ml/min per 1.73 m2 at cohort entrance, respectively, when compared with eGFR 60-89 ml/min per 1.73 m2), glomerular disease (aHR 2.01 [95% CI, 1.78 to 2.28]), malignancy (aHR 1.79 [95% CI, 1.52 to 2.11]), proteinuria (aHR 2.23 [95% CI, 1.89 to 2.62]), hypertension (aHR 1.49 [95% CI, 1.22 to 1.82]), proteinuria and hypertension together (aHR 3.98 [95% CI, 3.40 to 4.68]), count of complex chronic comorbidities (aHR 1.07 [95% CI, 1.05 to 1.10] per additional comorbid body system), male sex (aHR 1.16 [95% CI, 1.05 to 1.28]), and younger age at cohort entrance (aHR 0.95 [95% CI, 0.94 to 0.96] per year older). CONCLUSIONS: In large-scale real-world data for children with CKD, disease etiology, albuminuria, hypertension, age, male sex, lower eGFR, and greater medical complexity at start of follow-up were associated with more rapid decline in kidney function.

Clinical, methodology, and patient/carer expert advice in pediatric drug development by conect4children.

Many medicines are used "off-label" in children outside the terms of the license. Feasible pediatric clinical trials are a challenge to design. Conect4children (c4c) is an Innovative Medicines Initiative project to set up a pan-European pediatric clinical trial network aiming to facilitate the development of new medicines for children. To optimize pediatric trial development by promoting innovative trial design, c4c set up a European multidisciplinary advice service, including the voice of young patients and families, tailored to industry and academia. A network of experts was established to provide multidisciplinary advice to trial sponsors. Experts were selected to join clinical and innovative methodology expert groups. A patient and public involvement (PPI) database, to include the expert opinion of patients and parents/carers was formed. A stepwise process was developed: (1) sponsors contact c4c, (2) scoping interview takes place, (3) ad hoc advice group formed, (5) advice meeting held, and (6) advice report provided. Feedback on the process was collected. Twenty-four clinical and innovative methodology expert groups (>400 experts) and a PPI database of 135 registrants were established. As of September 30, 2022, 36 advice requests were received, with 25 requests completed. Clinical and methodology experts and PPI representatives participated in several advice requests. Sponsors appreciated the advice quality and the multidisciplinary experts from different countries, including experts not known before. Experts and PPI participants were generally satisfied with the process. The c4c project has shown successful proof of concept for a service that presents a new framework to plan innovative and feasible pediatric trials.

Pulmonary arterial hypertension in the USA: an epidemiological study in a large insured pediatric population.

Pulmonary arterial hypertension (PAH) is rare in children and few data are available in a pediatric general population. This study aims to calculate the annual incidence and prevalence of PAH and to describe these children in a large US population of patients aged under 18 years. Using the US MarketScan claims database we identified 695 children with PAH in 2010-2013. We calculated annual incidence rates and prevalence overall, by age and PAH type (idiopathic and non-idiopathic) using Byar's method. We also described characteristics, co-morbidities, treatment patterns, and diagnostic procedures for these children. In 2010-2013, the annual incidence rates of PAH per 1,000,000 children-years was in the range of 4.8-8.1; 0.5-0.9 for idiopathic PAH and 4.3-7.3 for non-idiopathic PAH. The annual prevalence of PAH was in the range of 25.7-32.6 per 1,000,000 children; 4.4-6.0 for idiopathic PAH and 21.3-27.0 for non-idiopathic PAH. Incidence rates and prevalence were highest in children under age 2 years. Around 36% of affected children were born prematurely. Most (75%) had some type of congenital heart defect and 13% had Down's syndrome. Most patients received PAH monotherapy (83%), while 13% received dual therapy. Phosphodiesterase type 5 inhibitors were the most commonly used treatments. Around 92% had at least one echocardiogram and 37% a right heart catheterization. PAH is very rare in children especially in the absence of etiological factors such as congenital heart defects. A large proportion of diagnoses in children seem to be based on echocardiography rather than right heart catheterization.

Prospective, randomised trial of the time dependent antiplatelet effects of 500 mg and 250 mg acetylsalicylic acid i. v. and 300 mg p. o. in ACS (ACUTE).

Little is known about the onset of action after intravenous or oral administration of acetylsalicylic acid (ASA) in patients with acute coronary syndromes (ACS). The aim of the study was to compare intravenous 250 or 500 mg acetylsalicylic acid (ASA) with oral 300 mg in ASA naïve patients with ACS concerning the onset of antiplatelet effects measured by time dependent thromboxane inhibition. A total of 270 patients with ACS < 24 hours were randomised into one of three treatment arms comprising administration of a single dose of ASA as soon as possible after admission. The primary endpoint was platelet inhibition assessed by measurement of arachidonic acid (AA)-induced platelet thromboxane release (TXB2) 5 minutes (min) after study drug administration. Both 250 mg and 500 mg ASA i. v. inhibited TXB2 formation nearly completely (geometric means: from 581.7 and 573.9 ng/ml at baseline to 3.9 and 3.1 ng/ml at 5 min, respectively) compared to 300 mg oral ASA (geometric means: from 652.0 to 223.7 ng/ml) (p-value, ANCOVA: < 0.0001). Similar results were obtained for inhibition of AA-induced platelet aggregation (Multiplate ASPItest; from means 86.41 and 85.72 U to 23.04 and 20.57 U at 5 min, respectively) compared to 300 mg oral ASA from mean 87.18 to 75.56 U (p-value, ANCOVA: <0.0001). The rate of bleedings was low and comparable between the groups. In summary, the administration of a single dose of 250 or 500 mg ASA IV compared to 300 mg orally is associated with a faster and more complete inhibition of thromboxane generation and platelet aggregation. Bleeding complications were comparable between the groups.

Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure.

The burden of heart failure (HF) increases worldwide with an aging population, and there is a high unmet medical need in both, heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). The nitric oxide (NO) pathway is a key regulator in the cardiovascular system and modulates vascular tone and myocardial performance. Disruption of the NO-cyclic guanosine monophosphate (cGMP) signaling axis and impaired cGMP formation by endothelial dysfunction could lead to vasotone dysregulation, vascular and ventricular stiffening, fibrosis, and hypertrophy resulting in a decline of heart as well as kidney function. Therefore, the NO-cGMP pathway is a treatment target in heart failure. Exogenous NO donors such as nitrates have long been used for treatment of cardiovascular diseases but turned out to be limited by increased oxidative stress and tolerance. More recently, novel classes of drugs were discovered which enhance cGMP production by targeting the NO receptor soluble guanylate cyclase (sGC). These compounds, the so-called sGC stimulators and sGC activators, are able to increase the enzymatic activity of sGC to generate cGMP independently of NO and have been developed to target this important signaling cascade in the cardiovascular system.This review will focus on the role of sGC in cardiovascular (CV) physiology and disease and the pharmacological potential of sGC stimulators and sGC activators therein. Preclinical data will be reviewed and summarized, and available clinical data with riociguat and vericiguat, novel direct sGC stimulators, will be presented. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF).

Prevalence of Diabetes and Diabetic Nephropathy in a Large U.S. Commercially Insured Pediatric Population, 2002-2013.

OBJECTIVE: To estimate the prevalence of diabetes and diabetic nephropathy in a large population of U.S. commercially insured patients aged <18 years from 2002 to 2013. RESEARCH DESIGN AND METHODS: Using the U.S. MarketScan Commercial Claims and Encounters Database, we identified 96,171 pediatric patients with diabetes and 3,161 pediatric patients with diabetic nephropathy during 2002-2013. We estimated prevalence of pediatric diabetes overall, by diabetes type, age, and sex, and prevalence of pediatric diabetic nephropathy overall, by age, sex, and diabetes type. RESULTS: The annual prevalence of diabetes in the whole pediatric population increased from 1.86 to 2.82 per 1,000 during 2002-2013: 1.48 to 2.32 per 1,000 for type 1 diabetes and 0.38 to 0.67 per 1,000 for type 2 diabetes in 2002-2006 and then 0.56 to 0.49 per 1,000 thereafter. The annual prevalence of diabetic nephropathy in pediatric patients with diabetes increased from 1.16 to 3.44% for all cases and 0.83 to 2.32% for probable cases only in 2002-2013. Prevalence of diabetes and diabetic nephropathy was highest in patients aged 12 to <18 years. While prevalence of type 1 diabetes was higher in male than in female youth, prevalence of type 2 diabetes and diabetic nephropathy was higher in female than in male youth. There was no difference in prevalence of diabetic nephropathy by diabetes type. CONCLUSIONS: The prevalence of diabetes and diabetic nephropathy increased in the U.S. MarketScan commercially insured pediatric population from 2002 to 2013. The prevalence of diabetes and diabetic nephropathy markedly increased starting at age 12 years.

Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options--a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference.

While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF.