Lumacaftor/ivacaftor in people with cystic fibrosis with an A455E-CFTR mutation

BACKGROUND: Previous in vitro organoid data showed A455E-CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E-CFTR mutation. METHODS: Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8-week washout period between. Primary endpoint was absolute change in ppFEV1 from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ-R respiratory domain score. Correlations between organoid-based measurements and clinical endpoints were investigated. RESULTS: Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV1 from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, -2.5 to 2.7; P = 0.928) between LUM/IVA (within-group mean change, 2.7) and placebo (within-group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of -7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ-R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid-based assay demonstrated a concentration-dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV1 and SwCl outcomes showed correlation coefficients of 0.49 and -0.11, respectively. CONCLUSIONS: In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E-CFTR mutation. The primary endpoint (ppFEV1) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331)

A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema

BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internetbased survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9 -point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The fi rst round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of fi ve key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of fi ve key outcomes. Crown Copyright (c) 2024 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). (J Allergy Clin Immunol Pract 2024;12:1614-21

Poverty and Racial Disparities in Kidney Disease: The REGARDS Study

There are pronounced disparities among black compared to white Americans for risk of end-stage renal disease. This study examines whether similar relationships exist between poverty and racial disparities in chronic kidney disease (CKD) prevalence

Physical and Psychological Burden of Chronic Kidney Disease among Older Adults

INTRODUCTION: The purpose of the study is to determine if functional status and quality of life (QoL) vary with glomerular filtration rate (GFR) among older adults. METHODS: We studied adults aged 45 years and older participating in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study. Data included demographic and health information, serum creatinine and hemoglobin, the 4-item Center for Epidemiologic Studies Depression Scale (CES-D-4), the 4-item Cohen's Perceived Stress Scale (PSS-4), reported health status and inactivity and the Medical Outcomes Study Short Form-12 (SF-12) QoL scores. RESULTS: CKD (GFR <60 ml/min/1.73 m(2)) was present in 11.6% of the subjects. As GFR declined, the SF-12 physical component score, adjusted for other participant attributes, declined from 38.9 to 35.9 (p = 0.0001). After adjustment for other risk factors, poorer personal health scores (p < 0.0001) and decreased physical activity (p < 0.0001) were reported as GFR declined. In contrast, after adjusting for other participant characteristics, depression scores and stress scores and the mental component score of the SF-12 were not associated with kidney function. CONCLUSION: Older individuals with CKD in the US population experience an increased prevalence of impaired QoL that cannot be fully explained by other individual characteristics

Sebetralstat: A Rapidly Acting Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema

Sebetralstat is a novel, potent, and selective oral plasma kallikrein inhibitor drug candidate in clinical development for the on-demand treatment of hereditary angioedema (HAE). Upon binding, sebetralstat induces a conformational change in the active site of plasma kallikrein, which contributes to its high potency (Ki 3 nM) and selectivity (>1500 fold) against other serine proteases. Its physiochemical properties promote both rapid dissolution in the stomach and rapid absorption in the upper intestine that contribute to its fast and efficient absorption. A single oral administration of sebetralstat rapidly provides near-complete inhibition of plasma kallikrein and blockade of high-molecular-weight kininogen cleavage as early as 15 min, which drives its clinical efficacy. In a phase 2 clinical trial, sebetralstat significantly reduced the time to beginning of symptom relief (p < 0.0001) with median times of 1.6 h (95% CI: 1.5–3.0) with sebetralstat versus 9.0 h (4.0–17.2) with placebo. KONFIDENT (NCT05259917) is a phase 3 clinical trial assessing the on-demand use of sebetralstat for HAE. If successful, this trial could support the approval of sebetralstat as the first noninvasive, on-demand treatment option to rapidly halt HAE attacks and provide fast symptom relief

Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study):a randomised controlled trial

Background Despite treatment with renin angiotensin aldosterone system (RAAS) inhibitors, patients with diabetes have increased risk of progressive renal failure that correlates with albuminuria. We aimed to assess whether paricalcitol could be used to reduce albuminuria in patients with diabetic nephropathy. Methods In this multinational, placebo-controlled, double-blind trial, we enrolled patients with type 2 diabetes and albuminuria who were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were assigned (1:1:1) by computer-generated randomisation sequence to receive 24 weeks' treatment with placebo, 1 mu g/day paricalcitol, or 2 mu g/day paricalcitol. The primary endpoint was the percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups versus the placebo group. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00421733. Findings Between February, 2007, and October, 2008, 281 patients were enrolled and assigned to receive placebo (n=93), 1 mu g paricalcitol (n=93), or 2 mu g paricalcitol (n=95); 88 patients on placebo, 92 on 1 mu g paricalcitol, and 92 on 2 mu g paricalcitol received at least one dose of study drug, and had UACR data at baseline and at least one timepoint during treatment, and so were included in the primary analysis. Change in UACR was: -3% (from 61 to 60 mg/mmol; 95% Cl -16 to 13) in the placebo group; -16% (from 62 to 51 mg/mmol; -24 to -9) in the combined paricalcitol groups, with a between-group difference versus placebo of -15% (95% CI -28 to 1; p=0.071); -14% (from 63 to 54 mg/mmol; -24 to -1) in the 1 mu g paricalcitol group, with a between-group difference versus placebo of -11% (95% CI -27 to 8; p=0.23); and -20% (from 61 to 49 mg/mmol; -30 to -8) in the 2 mu g paricalcitol group, with a between-group difference versus placebo of -18% (95% CI -32 to 0; p=0.053). Patients on 2 mu g paricalcitol showed an early, sustained reduction in UACR, ranging from -18% to -28% (p=0.014 vs placebo). Incidence of hypercalcaemia, adverse events, and serious adverse events was similar between groups receiving paricalcitol versus placebo. Interpretation Addition of 2 mu g/day paricalcitol to RAAS inhibition safely lowers residual albuminuria in patients with diabetic nephropathy, and could be a novel approach to lower residual renal risk in diabetes

Evaluation of patient‐reported outcome measures for on‐demand treatment of hereditary angioedema attacks and design of KONFIDENT, a phase 3 trial of sebetralstat

Abstract Background Hereditary angioedema (HAE) with C1‐inhibitor deficiency (HAE‐C1‐INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational oral plasma kallikrein inhibitor, demonstrated promising efficacy for on‐demand treatment of HAE‐C1‐INH in a phase 2 trial. We describe the multipronged approach informing the design of KONFIDENT, a phase 3 randomized, placebo‐controlled, three‐way crossover trial evaluating the efficacy and safety of sebetralstat in patients aged ≥12 years with HAE‐C1‐INH. Methods To determine an optimal endpoint to measure the beginning of symptom relief in KONFIDENT, we engaged patients with HAE on clinical outcome measures and subsequently conducted analyses of phase 2 outcomes. Sample size was determined via a simulation‐based approach using phase 2 data. Results Patient interviews revealed a strong preference (71%) for the Patient Global Impression of Change (PGI‐C) over other measures and indicated a rating of “A Little Better” as a clinically meaningful milestone. In phase 2, a rating of “A Little Better” demonstrated agreement with attack severity improvement and resolution on the Patient Global Impression of Severity and had better sensitivity than “Better.” Simulations indicated that 84 patients completing treatment would ensure at least 90% power for assessing the primary endpoint of time to beginning of symptom relief defined as a PGI‐C rating of at least “A Little Better” for two time points in a row. Conclusions Patient feedback and phase 2 data support PGI‐C as the primary outcome measure in the phase 3 KONFIDENT trial evaluating sebetralstat, which has the potential to be the first oral on‐demand treatment for HAE‐C1‐INH attacks

Bardoxolone methyl and kidney function in CKD with type 2 diabetes.

BACKGROUND: Chronic kidney disease (CKD) associated with type 2 diabetes is the leading cause of kidney failure, with both inflammation and oxidative stress contributing to disease progression. Bardoxolone methyl, an oral antioxidant inflammation modulator, has shown efficacy in patients with CKD and type 2 diabetes in short-term studies, but longer-term effects and dose response have not been determined. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned 227 adults with CKD (defined as an estimated glomerular filtration rate [GFR] of 20 to 45 ml per minute per 1.73 m(2) of body-surface area) in a 1:1:1:1 ratio to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily. The primary outcome was the change from baseline in the estimated GFR with bardoxolone methyl, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks. RESULTS: Patients receiving bardoxolone methyl had significant increases in the mean (±SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m(2) of 8.2±1.5 ml in the 25-mg group, 11.4±1.5 ml in the 75-mg group, and 10.4±1.5 ml in the 150-mg group; P CONCLUSIONS: Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD. (Funded by Reata Pharmaceuticals; BEAM ClinicalTrials.gov number, NCT00811889.)