Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Phase I/II study of cetuximab in combination with cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

PURPOSE: This was an open, randomized, multicenter, phase I/II study to investigate the safety and tolerability of cetuximab in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Treatment comprised cetuximab (initial dose 400 mg/m2 with subsequent weekly doses of 250 mg/m2) in combination with 3-week cycles of either cisplatin (100 mg/m2) or carboplatin (area under the curve, 5), each in combination with a 5-day infusion of fluorouracil (FU) at escalating doses of 600, 800, and 1,000 mg/m2/d. The study was divided into two phases: A, the first two cycles (6 weeks) focusing on the safety and tolerability of combination therapy; and B, the remaining time for those benefiting from therapy until disease progression or intolerable toxicity. RESULTS: Fifty-three patients were enrolled onto the study. The incidence of dose-limiting toxicities in phase A was acceptable. The most common grade 3/4 adverse events in both groups were leucopenia (38%), asthenia (25%), vomiting (14%), and thrombocytopenia (15%), which are consistent with the known safety profiles of cetuximab, cisplatin/carboplatin, and FU. The overall response rate among patients was 36%, with no clear trend toward an increased efficacy at the highest dose of FU, and no impact of the concomitant chemotherapy regimens on cetuximab pharmacokinetics. CONCLUSION: The combination of cetuximab, cisplatin/carboplatin, and FU was reasonably well tolerated and active in recurrent/metastatic SCCHN, and merits additional investigation. An FU dose of 1,000 mg/m2/d in combination with cisplatin or carboplatin can be recommended for additional studies.Clinical Trial, Phase IClinical Trial, Phase IIJournal ArticleMulticenter StudyRandomized Controlled Trialinfo:eu-repo/semantics/publishe

EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer.

International audiencePURPOSE: To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin. PATIENTS AND METHODS: This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor-expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m(2) day 1 followed by 250 mg/m(2) weekly) plus irinotecan (350 mg/m(2) every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL). RESULTS: Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776;